Trial Outcomes & Findings for Study Comparing Inotuzumab Ozogamicin In Combination With Rituximab Versus Defined Investigator's Choice In Follicular Non-Hodgkin's Lymphoma (NHL) (NCT NCT00562965)

Last Updated: 2018-01-09

Results Overview

PFS was defined as the time from randomization to disease progression or death due to any cause, whichever occurred first, censored at the last tumor evaluation date. PFS calculated as (Months) = (first event date minus randomization date plus 1) divided by 30.44.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

29 participants

Primary outcome timeframe

Baseline until disease progression or death or up to 1 year after last dose of study drug

Results posted on

2018-01-09

Participant Flow

Enrollment of participants started on 15 November 2007 and completed on 16 January 2009. The trial was terminated (07 April 2011) due to poor accrual of 29 out of 978 planned participants.

Participant milestones

Participant milestones
Measure	Rituximab + Inotuzumab Ozogamicin Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Overall Study STARTED	15	14
Overall Study Treated	15	13
Overall Study COMPLETED	12	8
Overall Study NOT COMPLETED	3	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Rituximab + Inotuzumab Ozogamicin Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Overall Study Withdrawal by Subject	0	1
Overall Study Death	2	4
Overall Study Lost to Follow-up	1	0
Overall Study Other	0	1

Baseline Characteristics

Study Comparing Inotuzumab Ozogamicin In Combination With Rituximab Versus Defined Investigator's Choice In Follicular Non-Hodgkin's Lymphoma (NHL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab + Inotuzumab Ozogamicin n=15 Participants Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND n=14 Participants Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.	Total n=29 Participants Total of all reporting groups
Age, Continuous	62.3 years STANDARD_DEVIATION 11.4 • n=5 Participants	60.9 years STANDARD_DEVIATION 12.4 • n=7 Participants	61.7 years STANDARD_DEVIATION 11.7 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline until disease progression or death or up to 1 year after last dose of study drug

Population: Intent-to-treat population included all participants who were randomized in to the study.

Outcome measures

Outcome measures
Measure	Rituximab + Inotuzumab Ozogamicin n=15 Participants Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND n=14 Participants Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Progression-Free Survival (PFS)	NA months Interval 22.2 to Median and upper limit of confidence interval was not estimable because majority of participants were censored.	16.4 months Interval 7.9 to 28.4

SECONDARY outcome

Timeframe: Baseline, every 6 to 12 weeks during treatment period, end of treatment (EOT) (42 days after last dose), every 12 weeks during follow-up for up to 1 year after the last dose of study drug

Population: Intent-to-treat population included all participants who were randomized in to the study.

OR was based on assessment of complete response(CR),unconfirmed CR(Cru),partial response(PR) as per International Response Criteria for Non-Hodgkin's Lymphoma.Confirmed response=response persists on repeat imaging at least 4 weeks after initial response.CR=complete disappearance of all detectable clinical/radiographic evidence of disease,lymph nodes regressed to normal size \[at least 1.5 centimeter(cm) or less\],spleen regressed,not palpable on physical examination,bone marrow infiltrate cleared on repeat aspiration/biopsy.PR=at least 50 percent (%) decrease in sum of product diameters of 6 greatest dominant nodes,no increase in other nodes,liver/spleen,no new sites of disease. CRu=residual lymph node greater than 1.5 cm in transverse diameter that has regressed more than 75% in product diameter.Individual nodes previously confluent,regressed more than 75% in product diameters.Indeterminate bone marrow (increased number/size of lymph aggregates without cytologic/architectural atypia).

Outcome measures

Outcome measures
Measure	Rituximab + Inotuzumab Ozogamicin n=15 Participants Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND n=14 Participants Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Percentage of Participants With Objective Response (OR)	93.3 percentage of participants Interval 68.1 to 99.8	64.3 percentage of participants Interval 35.1 to 87.2

SECONDARY outcome

Timeframe: Baseline up to Month 6, 12, 24

Population: Intent-to-treat population included all participants who were randomized in to the study.

Overall survival was defined as the time from randomization to death due to any cause, censoring at the date of last contact or the end of the study. Participants who withdrew or lost to follow-up from study without having death documented were censored at the date of last contact. Kaplan-Meier estimates of the probability of survival at 6, 12 and 24 months was used to estimate the survival function.

Outcome measures

Outcome measures
Measure	Rituximab + Inotuzumab Ozogamicin n=15 Participants Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND n=14 Participants Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Overall Survival Probability at Months 6, 12 and 24 Overall Survival: Baseline up to Month 6	100.0 percent chance of survival Interval 100.0 to 100.0	92.3 percent chance of survival Interval 77.8 to 100.0
Overall Survival Probability at Months 6, 12 and 24 Overall Survival: Baseline up to Month 24	86.7 percent chance of survival Interval 69.5 to 100.0	67.1 percent chance of survival Interval 40.7 to 93.6
Overall Survival Probability at Months 6, 12 and 24 Overall Survival: Baseline up to Month 12	86.7 percent chance of survival Interval 69.5 to 100.0	83.9 percent chance of survival Interval 63.4 to 100.0

SECONDARY outcome

Timeframe: 0, 1, 168 hours on Cycle 1, 2; 0, 1, 2, 168 hours on Cycle 3, 4

Population: Data for this outcome measurement was not collected since pharmacokinetic parameters were not analyzed in this study due to very few number of participants with PK samples.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 42 days post-treatment

Population: Safety population included all participants who received at least 1 dose of a test article. Here 'N' signifies those participants who were evaluable for this outcome measure.

Assessments of QT interval was performed only in rituximab + inotuzumab ozogamicinin group. QT interval corrected using Fridericia's formula (QTcF) and Bazett's formula (QTcB) was analyzed as per common terminology criteria for adverse events (CTCAE) version 3.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening or disabling AE, Grade 5 = death related to AE. Number of participants with change in CTCAE grading at post-baseline time point compared to the baseline were presented. The post-baseline value was defined as the maximum grade after the first dose date on or before the end of treatment.

Outcome measures

Outcome measures
Measure	Rituximab + Inotuzumab Ozogamicin n=9 Participants Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Number of Participants With Clinically Significant Change From Baseline in QT Interval Findings QTcB: BL normal, post-BL Grade 1	2 participants	—
Number of Participants With Clinically Significant Change From Baseline in QT Interval Findings QTcB: BL normal, post-BL normal	4 participants	—
Number of Participants With Clinically Significant Change From Baseline in QT Interval Findings QTcB: BL normal, post-BL Grade 2	3 participants	—
Number of Participants With Clinically Significant Change From Baseline in QT Interval Findings QTcF: BL normal, post-BL normal	6 participants	—
Number of Participants With Clinically Significant Change From Baseline in QT Interval Findings QTcF: BL normal, post-BL Grade 1	3 participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 42 days post-treatment

Population: Safety population included all participants who received at least 1 dose of a test article (either rituximab + inotuzumab ozogamicin or control regimens R-CVP + R-FND).

AE=any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. TEAE=between first dose of study drug and up to 42 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Outcome measures

Outcome measures
Measure	Rituximab + Inotuzumab Ozogamicin n=15 Participants Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND n=13 Participants Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Number of Participants With Grade 3 or 4 Treatment Emergent Adverse Events (TEAEs)	12 participants	13 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 42 days post-treatment, disease follow up (every 12 weeks for a minimum of 1 year and up to 2 years)

Population: Safety population included all participants who received at least 1 dose of a test article (either rituximab + inotuzumab ozogamicin or control regimens R-CVP + R-FND).

Criteria for laboratory test abnormality: Blood Chemistry (alkaline phosphatase \[greater than{\>}5\*upper limit of normal {ULN}, calcium \[less than {\<}1.75 millimole per liter {mmol/L}, creatinine \[\>3\*ULN\], glucose \[\>13.9 mmol/L\], phosphorous \[\<0.6 mmol/L\], potassium \[\<3 mmol/L\], aspartate transaminase \[\>5.0\*ULN\], total bilirubin \[\>3\*ULN\]), Coagulation (international normalized ratio \[\>2\*ULN\]), Hematology (hemoglobin \[\<80 grams/Liter\], lymphocytes \[\<0.5\*10\^9/L\], absolute neutrophil count \[\<1\*10\^9/L\], platelet count \[\<50\*10\^9/L\], WBC \[\<2.0\*10\^9/L\]).

Outcome measures

Outcome measures
Measure	Rituximab + Inotuzumab Ozogamicin n=15 Participants Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND n=13 Participants Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Number of Participants With Clinically Significant Change From Baseline in Laboratory Findings Baseline up to 42 days post-treatment	11 participants	12 participants
Number of Participants With Clinically Significant Change From Baseline in Laboratory Findings Disease follow up	8 participants	7 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 42 days post-treatment, disease follow up (every 12 weeks for a minimum of 1 year and up to 2 years)

Population: Safety population included all participants who received at least 1 dose of a test article (either rituximab + inotuzumab ozogamicin or control regimens R-CVP + R-FND).

Criteria for determining significant change from baseline in vital signs abnormalities: heart rate value of \<40 beats per minute and value \>150 beats per minute, systolic blood pressure (SBP) of \<80 or \>210 millimeter of mercury (mmHg), diastolic blood pressure (DBP) of \<40 or \>130 mmHg, temperature \<32 or \>40 degree centigrade, and body weight\>=10% increase or decrease of body weight in kilogram (kg).

Outcome measures

Outcome measures
Measure	Rituximab + Inotuzumab Ozogamicin n=15 Participants Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND n=13 Participants Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs Disease follow up	3 participants	2 participants
Number of Participants With Clinically Significant Change From Baseline in Vital Signs Baseline up to 42 days post-treatment	0 participants	1 participants

Adverse Events

Rituximab + Inotuzumab Ozogamicin

Serious events: 6 serious events

Other events: 15 other events

Deaths: 0 deaths

Control Regimens R-CVP + R-FND

Serious events: 6 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Measure	Rituximab + Inotuzumab Ozogamicin n=15 participants at risk Participants received intravenous infusion of rituximab 375 milligram per square meter (mg/m\^2) of body surface area (BSA) on Day 1 followed by intravenous infusion of inotuzumab ozogamicin (CMC-544) 1.8 mg/m\^2 of BSA on Day 2 for each cycle up to 8 cycles. Each cycle was of 28 days.	Control Regimens R-CVP + R-FND n=13 participants at risk Participants received either regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA along with intravenous infusion of cyclophosphamide 750 mg/m\^2 of BSA and vincristine 1.4 mg/m\^2 of BSA on Day 1 followed by oral prednisone/prednisolone 40 mg/m\^2 of BSA on Days 1 through 5 for up to 8 cycles (R-CVP); or regimen containing intravenous infusion of rituximab 375 mg/m\^2 of BSA on Day 1 followed by intravenous infusion of novantrone (mitoxantrone) 10 mg/m\^2 of BSA on Day 2, intravenous infusion of fludarabine 25 mg/m\^2 of BSA on Days 2 through 4, and oral dexamethasone 20 mg once daily on Days 1 through 5 for up to 8 cycles (R-FND). Each regimen cycle was of 21 days.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	23.1% 3/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Blood and lymphatic system disorders Leukopenia	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Blood and lymphatic system disorders Neutropenia	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	15.4% 2/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Gastrointestinal disorders Abdominal pain	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
General disorders Asthenia	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
General disorders Chills	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
General disorders Pyrexia	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Hepatobiliary disorders Venoocclusive liver disease	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Infections and infestations Cellulitis	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Infections and infestations Lower respiratory tract infection	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Infections and infestations Pneumonia	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	15.4% 2/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Infections and infestations Pneumonia cryptococcal	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Infections and infestations Sepsis	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Infections and infestations Viral infection	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Investigations Blood creatinine increased	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Investigations Gamma-glutamyltransferase increased	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Investigations Lipase increased	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Respiratory, thoracic and mediastinal disorders Lung infiltration	6.7% 1/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	0.00% 0/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/15 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.	7.7% 1/13 • Baseline up to 42 days post--treatment Same event may appear as both AE and SAE, the presented events are distinct.Event may be serious in 1 subject and nonserious in another,or 1 subject may have experienced both SAE and non-SAE during study.TEAE=from first study drug dose up to 42 days after last dose,were absent before treatment or that worsened relative to pretreatment state.