Trial Outcomes & Findings for Imatinib Mesylate With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed or Recurrent Glioma (NCT NCT00021229)

NCT ID: NCT00021229

Last Updated: 2014-07-31

Results Overview

The dose limiting toxicity (DLT) analysis population consists of phase I stratum I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (course 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD. The estimated MTD based on the 23 participants who either had a DLT during course 1 or 2 or completed courses 1 and 2 without DLT is 265 mg/m2/day.

• Recruitment status: TERMINATED
• Study phase: PHASE1/PHASE2
• Target enrollment: 85 participants
• Primary outcome timeframe: Day 1 of Imatinib Mesylate Therapy to Week 8
• Results posted on: 2014-07-31

Participant Flow

Participants from PBTC member institutions were enrolled on the phase I component between 09May2001 and 28MAY2004 (stratum I), 15AUG2003 (stratum IIA), and 15AUG2004 (stratum IIB). The phase II component of the study opened on 28MAY2004 and was terminated on 13APR2005 due to poor accrual.

The intent of the phase I part of the study was to estimate the maximum tolerated dose (MTD) independently in stratum I, in stratum IIA, and in stratum IIB. The estimated MTD from stratum I was the recommended dose for the phase II part. Phase I participants in stratum I who received study drug at the MTD contributed to the phase II objectives.

Participant milestones

Measure	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum I: Radiation + Imatinib Mesylate Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIA: Imatinib Mesylate Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.
Overall Study STARTED	16	36	33
Overall Study Enrolled in Phase I	16	35	33
Overall Study Maximum Tolerated Dose (MTD) Estimation	12	23	20
Overall Study Enrolled in Phase II	0	14	0
Overall Study COMPLETED	0	1	0
Overall Study NOT COMPLETED	16	35	33

Reasons for withdrawal

Measure	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum I: Radiation + Imatinib Mesylate Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIA: Imatinib Mesylate Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.
Overall Study Adverse Event	2	10	5
Overall Study Death	0	0	1
Overall Study Withdrawal by Subject	1	7	7
Overall Study Progressive Disease	12	15	19
Overall Study Protocol Violation	0	1	1
Overall Study Physician Decision	1	0	0
Overall Study Punctate hemmorrhage post RT	0	2	0

Baseline Characteristics

Imatinib Mesylate With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed or Recurrent Glioma

Baseline characteristics by cohort

Measure	Stratum I: Radiation + Imatinib Mesylate n=36 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIA: Imatinib Mesylate n=33 Participants Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Stratum IIB: Imatinib Mesylate n=16 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Total n=85 Participants Total of all reporting groups
Age, Categorical <=18 years	36 Participants n=5 Participants	30 Participants n=7 Participants	15 Participants n=5 Participants	81 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Continuous	8.05 years STANDARD_DEVIATION 4.3 • n=5 Participants	10.9 years STANDARD_DEVIATION 5.4 • n=7 Participants	14.1 years STANDARD_DEVIATION 4.7 • n=5 Participants	10.3 years STANDARD_DEVIATION 5.3 • n=4 Participants
Sex: Female, Male Female	18 Participants n=5 Participants	20 Participants n=7 Participants	9 Participants n=5 Participants	47 Participants n=4 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	13 Participants n=7 Participants	7 Participants n=5 Participants	38 Participants n=4 Participants
Region of Enrollment United States	36 participants n=5 Participants	33 participants n=7 Participants	16 participants n=5 Participants	85 participants n=4 Participants

PRIMARY outcome

Timeframe: Day 1 of Imatinib Mesylate Therapy to Week 8

Population: Per protocol, participants included phase I stratum I participants who developed dose-limiting toxicities during the maximum tolerated dose (MTD) estimation period (courses 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without dose-limiting toxicities.

The dose limiting toxicity (DLT) analysis population consists of phase I stratum I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (course 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD. The estimated MTD based on the 23 participants who either had a DLT during course 1 or 2 or completed courses 1 and 2 without DLT is 265 mg/m2/day.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=23 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Number of Participants in Phase I Stratum I With Dose Limiting Toxicities (DLT) Observed During First 8 Weeks (Courses 1 and 2) of Imatinib Therapy	5 Participants	—	—

PRIMARY outcome

Timeframe: Day 1 of Imatinib Mesylate Therapy to Week 8

Population: Per protocol, participants included phase I stratum II participants who developed dose-limiting toxicities (DLT) during the maximum tolerated dose (MTD) estimation period (courses 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without DLTs.

The dose limiting toxicity (DLT) analysis population consisted of phase I stratum II participants who developed DLT during the maximum tolerated dose (MTD) estimation period (courses 1 and 2) or who completed the MTD estimation period (courses 1 and 2) without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD. The estimated MTD based on the DLT analysis population of 20 in stratum IIA was 465 mg/m2/day. An MTD was not established in stratum IIB as no DLTs were observed at the higher dose levels of 620 and 800 mg/m2/day.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=20 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate n=12 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Number of Participants in Phase I Stratum II With Dose Limiting Toxicities (DLT) Observed During First 8 Weeks (Courses 1 and 2) of Imatinib Therapy	2 Participants	0 Participants	—

PRIMARY outcome

Timeframe: Assessed pre-radiation, before the first dose of imatinib, and then every 8 weeks

Population: Per protocol, 40 participants who received at least one dose of drug were needed for this objective. The analysis population consists of stratum I participants enrolled at the maximum tolerated dose (phase 1) and the participants enrolled to the phase II part. The study was terminated because of poor accrual and the objective was not met.

Progression-free survival is defined as the interval from initiation of treatment to the earliest of disease progression (tumor increase of 25% over baseline tumor measurement; appearance of new lesion(s); or progressive/worsening neurological status) or death for patients who failed, or to the last date of follow up for patients without failure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and two weeks post completion of radiation

Population: The analysis population consists of Stratum I patients enrolled who had both pre and post radiation (RT) volume FLAIR measures. Stratum II participants did not receive RT and thus were not included.

This study attempted to investigate in an exploratory manner the effect of radiation (RT) on changes in various neuroimaging variables in pediatric brainstem gliomas (stratum I). Neuroimaging changes may have some association with outcome (response, survival, etc.). Volume FLAIR is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain. Volume FLAIR was obtained at baseline (pre-radiation) and within two (+/- one) weeks after completion of RT.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=24 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Change From Baseline in Volume FLAIR at Two Weeks After Completion of Radiation	7.62 cubic centimeters Interval -17.95 to 41.32	—	—

SECONDARY outcome

Timeframe: Day 1 of Course 1

Population: The analysis population consists of participants who enrolled at the maximum tolerated dose (MTD) of the phase I component and who submitted day 1 course 1 samples for the PK studies. An MTD was not estimated in stratum IIB. For this stratum, reported are values at the stratum IIA MTD to allow comparison.

Peak concentration (cmax) is a pharmacokinetic measure defined as the highest concentration of a drug measured after the drug is administered. The cmax of imatinib mesylate on day 1 of course 1 is reported. Two milliliter (0.5 ml for children under the age of 5) blood samples were collected immediately prior to imatinib mesylate administration on Day 1 of Course 1 and at the following timepoints following drug administration: 0.5, 1, 1.5, 2, 4, 10 and 12 hours after the morning dose.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=3 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate n=9 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate n=3 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Peak Concentration (Cmax)	1.3 µg/ml Interval 0.7 to 2.1	2.6 µg/ml Interval 1.5 to 5.9	1.3 µg/ml Interval 0.8 to 2.1

SECONDARY outcome

Timeframe: Assessed before radiation therapy, before the first dose of imatinib, then every 8 weeks.

Population: The analysis population consists of the stratum I participants who received imatinib mesylate at or above the maximum tolerated dose. The median survival reported is based on these 20 participants.

Overall Survival (OS) is defined as the interval from initiation of treatment to death or date of last contact for surviving patients.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=20 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Median Overall Survival	324.5 Days 95% Confidence Interval 8.7 • Interval 216.0 to 383.0	—	—

SECONDARY outcome

Timeframe: Pre-treatment

Population: Per protocol, the analysis population consists of participants treated on the phase I component who submitted pre-treatment urine samples for the biomarker study.

This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Basic fibroblast growth factor (bFGF) may play a role in tumor development by helping tumor vessels establish and grow. Urine was collected from participants before treatment to measure the baseline urine bFGF values.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=16 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate n=17 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate n=10 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Pre-treatment Basic Fibroblast Growth Factor Values From Urine	5665 pg/ml Standard Deviation 4006	10322 pg/ml Standard Deviation 14443	5312 pg/ml Standard Deviation 6262

SECONDARY outcome

Timeframe: Pre-treatment

Population: Per protocol, the analysis population consists of participants treated on the phase I component who submitted pre-treatment blood samples for the biomarker study.

This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Basic fibroblast growth factor (bFGF) may play a role in tumor development by helping tumor vessels establish and grow. Blood (plasma) was drawn from participants before treatment to measure the baseline plasma bFGF values.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=19 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate n=16 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate n=10 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Pre-treatment Basic Fibroblast Growth Factor Values From Plasma	8.69 pg/ml Standard Deviation 7.16	32.3 pg/ml Standard Deviation 64.5	11.3 pg/ml Standard Deviation 12.2

SECONDARY outcome

Timeframe: Pre-treatment

Population: Per protocol, the analysis population consists of participants treated on the phase I component who submitted pre-treatment urine samples for the biomarker study.

This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Vascular endothelial growth factor (VEGF) may play a role in tumor development by helping tumor vessels establish and grow. Urine was collected from participants before treatment to measure the baseline urine VEGF values.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=16 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate n=17 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate n=10 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Pre-treatment Vascular Endothelial Growth Factor From Urine	79 pg/ml Standard Deviation 69.9	86.1 pg/ml Standard Deviation 93.9	45.3 pg/ml Standard Deviation 38.0

SECONDARY outcome

Timeframe: Pre-treatment

Population: Per protocol, the analysis population consists of participants treated on the phase I component who submitted pre-treatment blood samples for the biomarker study.

This study attempted to investigate in an exploratory manner the effect of biological markers on tumor growth. Vascular endothelial growth factor (VEGF) may play a role in tumor development by helping tumor vessels establish and grow. Blood (plasma) was drawn from participants before treatment to measure the baseline plasma VEGF values.

Outcome measures

Measure	Stratum I: Radiation + Imatinib Mesylate n=19 Participants Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIB: Imatinib Mesylate n=16 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.	Stratum IIB: Imatinib Mesylate n=10 Participants Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Pre-treatment Vascular Endothelial Growth Factor Values From Plasma	119.9 pg/ml Standard Error 168.5	155.2 pg/ml Standard Error 229.7	78.2 pg/ml Standard Error 59.4

Adverse Events

Stratum I: Radiation + Imatinib Mesylate

Serious events: 13 serious events

Other events: 33 other events

Deaths: 0 deaths

Stratum IIA: Imatinib Mesylate

Serious events: 13 serious events

Other events: 31 other events

Deaths: 0 deaths

Stratum IIB: Imatinib Mesylate

Serious events: 5 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Measure	Stratum I: Radiation + Imatinib Mesylate n=36 participants at risk Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIA: Imatinib Mesylate n=33 participants at risk Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Stratum IIB: Imatinib Mesylate n=16 participants at risk Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Blood and lymphatic system disorders Leukocytes (total WBC)	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Abdominal pain or cramping	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Bicarbonate	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders CNS hemorrhage/bleeding	19.4% 7/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	21.2% 7/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Colitis	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Confusion	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Constipation	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Creatinine	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Dehydration	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Depressed level of consciousness	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Diarrhea without colostomy	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Edema	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Fatigue	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Fever (in the absence of neutropenia)	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Headache	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.8% 3/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Vascular disorders Hematemesis	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Hematuria	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Hemoglobin (Hgb)	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hyperglycemia	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Vascular disorders Hypertension	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Hepatobiliary disorders Hypoalbuminemia	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypocalcemia	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypokalemia	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hyponatremia	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypophosphatemia	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Respiratory, thoracic and mediastinal disorders Hypoxia	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Incontinence	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Infections and infestations Infection without neutropenia	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Inpatient Hospital Days	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Lymphopenia	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Melena/GI bleeding	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Memory loss	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Metabolic/Laboratory- Other	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Musculoskeletal and connective tissue disorders Musculoskeletal - Other	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Nausea	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Neurology - Other	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Neuropathy - Motor	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Neuropathy - cranial	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Neuropathy - sensory	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Neutrophils/granulocytes (ANC/AGC)	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Pain - other	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Skin and subcutaneous tissue disorders Pigmentation changes	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Platelets	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Respiratory, thoracic and mediastinal disorders Pleural effusion (non-malignant)	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Skin and subcutaneous tissue disorders Rash/desquamation	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Renal/Genitourinary - Other	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Seizures	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Speech impairment	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Thrombosis/embolism	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Tremor	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Vomiting	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.

Other adverse events

Measure	Stratum I: Radiation + Imatinib Mesylate n=36 participants at risk Children with newly diagnosed brainstem gliomas received imatinib twice daily at a starting dose of 200 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 8 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Local irradiation (RT) was administered concurrently with imatinib at the initiation of treatment with conventional fractionation at 180 cGy/day fractions, five days per week for six weeks, to a total dose of 5580 cGy. Because of concerns of intratumoral hemorrhage during RT, the protocol was amended (08JAN2003) to enroll patients without evidence of hemorrhage prior to RT and begin imatinib treatment 2 weeks (± 1 week) after completion of RT. Participants enrolled to the phase II part received imatinib at the MTD (from phase I) after RT. Six participants were enrolled on the phase I before the amendment, 29 after the amendment, and 1 on the phase II.	Stratum IIA: Imatinib Mesylate n=33 participants at risk Children with recurrent high-grade gliomas not on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Ten participants were enrolled on the phase I before the amendment and 23 after the amendment.	Stratum IIB: Imatinib Mesylate n=16 participants at risk Children with recurrent high-grade gliomas on enzyme-inducing anticonvulsant drugs (EIACDs) received imatinib twice daily at a starting dose of 350 mg/m2/day. Treatment cycles were 4 weeks (maximum tolerated dose (MTD) estimation period - first 4 weeks) and imatinib was continued for up to 52 weeks in the absence of progression or serious toxicity. Study participants did not receive radiation therapy in this stratum. Because of concerns of intratumoral hemorrhage, the protocol was amended (08JAN2003) to extend the MTD estimation period to 8 weeks (courses 1 and 2). Eight participants were enrolled on the phase I before the amendment and eight after the amendment.
Gastrointestinal disorders Abdominal pain or cramping	22.2% 8/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Investigations Alkaline phosphatase	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Skin and subcutaneous tissue disorders Alopecia	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Anorexia	27.8% 10/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	15.2% 5/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Musculoskeletal and connective tissue disorders Arthralgia (joint pain)	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Ataxia (incoordination)	22.2% 8/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	15.2% 5/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.8% 3/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Bicarbonate	11.1% 4/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Hepatobiliary disorders Bilirubin	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders CNS hemorrhage/bleeding	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Cognitive/disturbance/learning problems	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Eye disorders Conjunctivitis	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Constipation	38.9% 14/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Constitutional symptoms - Other	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.1% 4/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Respiratory, thoracic and mediastinal disorders Cough	11.1% 4/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Investigations Creatinine	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Endocrine disorders Cushingnoid appearance	22.2% 8/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Dehydration	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Depressed level of consciousness	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Skin and subcutaneous tissue disorders Dermatology/skin -Other	11.1% 4/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	15.2% 5/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Diarrhea without colostomy	19.4% 7/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.2% 6/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Dizziness/light-headedness	11.1% 4/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.8% 3/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Dyspepsia/heartburn	16.7% 6/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Dysphagia, esophagitis, odynophagia (painful swallowing)	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Dysuria	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Ear and labyrinth disorders Earache (otalgia)	13.9% 5/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Vascular disorders Edema	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.8% 3/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Respiratory, thoracic and mediastinal disorders Epistaxis	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Ear and labyrinth disorders External auditory canal	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Fatigue	36.1% 13/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	33.3% 11/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	25.0% 4/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Fever (in the absence of neutropenia)	13.9% 5/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Flatulence	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Investigations GGT	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.8% 3/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Gastrointestinal-Other	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Headache	50.0% 18/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	48.5% 16/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	56.2% 9/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Hemoglobin	47.2% 17/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	30.3% 10/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	43.8% 7/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Hepatobiliary disorders Hepatic-Other	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypercholesterolemia	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hyperglycemia	30.6% 11/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	27.3% 9/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	31.2% 5/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hyperkalemia	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.8% 3/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypermagnesemia	16.7% 6/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypernatremia	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Vascular disorders Hypertension	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypertriglyceridemia	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hyperuricemia	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Hepatobiliary disorders Hypoalbuminemia	13.9% 5/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.1% 4/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	37.5% 6/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypocalcemia	27.8% 10/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	21.2% 7/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	31.2% 5/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypoglycemia	13.9% 5/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypokalemia	25.0% 9/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	21.2% 7/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.8% 3/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypomagnesemia	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hyponatremia	27.8% 10/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	50.0% 8/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Hypophosphatemia	44.4% 16/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	30.3% 10/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	37.5% 6/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Incontinence	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Infections and infestations Infection without neutropenia	27.8% 10/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	15.2% 5/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Infections and infestations Infection/Febrile Neutropenia-Other	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Ear and labyrinth disorders Inner ear/hearing	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Psychiatric disorders Insomnia	13.9% 5/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Irritability (<3 years of age)	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Leukocytes	50.0% 18/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	27.3% 9/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	37.5% 6/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Lymphopenia	52.8% 19/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	24.2% 8/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	43.8% 7/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Metabolism and nutrition disorders Metabolic/Laboratory - Other	13.9% 5/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Psychiatric disorders Mood alteration - anxiety, agitation	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Psychiatric disorders Mood alteration - depression	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Musculoskeletal and connective tissue disorders Muscle weakness	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Musculoskeletal and connective tissue disorders Musculoskeletal-Other	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Musculoskeletal and connective tissue disorders Myalgia (muscle pain)	11.1% 4/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Nausea	33.3% 12/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	30.3% 10/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	43.8% 7/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Neurology - other	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Neuropathic pain	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Neuropathy - cranial	19.4% 7/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Neuropathy - motor	25.0% 9/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	27.3% 9/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	37.5% 6/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Neuropathy - sensory	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Neutrophils/granulocytes	41.7% 15/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	24.2% 8/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	25.0% 4/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Nystagmus	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Eye disorders Ocular/Visual - Other	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	9.1% 3/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
General disorders Pain - other	16.7% 6/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.1% 4/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	31.2% 5/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Psychiatric disorders Personality/behavioral	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Platelets	22.2% 8/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	18.2% 6/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	31.2% 5/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Skin and subcutaneous tissue disorders Pruritus	11.1% 4/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Respiratory, thoracic and mediastinal disorders Pulmonary-Other	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Skin and subcutaneous tissue disorders Rash/desquamation	19.4% 7/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	24.2% 8/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	31.2% 5/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Renal/Genitourinary-Other	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Hepatobiliary disorders SGOT (AST)	38.9% 14/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	24.2% 8/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	25.0% 4/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Hepatobiliary disorders SGPT (ALT)	41.7% 15/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	27.3% 9/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	25.0% 4/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Seizure(s)	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.1% 4/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	31.2% 5/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Speech impairment	13.9% 5/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Stomatitis/pharyngitis	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Blood and lymphatic system disorders Transfusions: pRBCs	0.00% 0/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Nervous system disorders Tremor	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Urinary frequency/urgency	2.8% 1/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Renal and urinary disorders Urinary retention	8.3% 3/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	3.0% 1/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Eye disorders Vision - blurred vision	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Eye disorders Vision - double vision	25.0% 9/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.1% 2/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.5% 2/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Gastrointestinal disorders Vomiting	63.9% 23/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	39.4% 13/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	50.0% 8/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Investigations Weight gain	13.9% 5/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	12.1% 4/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Investigations Weight loss	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	6.2% 1/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.
Skin and subcutaneous tissue disorders Rash/Dermatitis	5.6% 2/36 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/33 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.	0.00% 0/16 • Adverse events were assessed weekly during the first four weeks (course 1), every 2 weeks during the next 2 courses (8 weeks total), every 4 weeks for all subsequent courses (up to 13 courses), and through 30 days following the end of treatment. Assessments were made routinely for all patients per the schedule of clinical and laboratory assessments outlined in the protocol.

Additional Information

Pediatric Brain Tumor Consortium (James M. Boyett, Ph.D)

Pediatric Brain Tumor Consortium

Phone: 901-595-4986

Email: james.boyett@stjude.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60