Trial Outcomes & Findings for Erlotinib and Temsirolimus in Treating Patients With Recurrent Malignant Glioma (NCT NCT00112736)

Last Updated: 2015-06-15

Results Overview

Oral erlotinab at 150mg constant dose, 3 pts will be treated with temsirolimus IV with escalating doses, starting at 50mg. Doses will increase or decrease based on toxicity observed. 3 pts will be treated at each dose level - 3 dose levels were observed: 50mg, 25mg, and 15mg

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

69 participants

Primary outcome timeframe

based on first 4 weeks of treatment - cycle 1

Results posted on

2015-06-15

Participant Flow

Patients were enrolled between 2005 and 2008. Patients were recruited from outpatient medical clinics and referrals.

Participant milestones

Participant milestones
Measure	Phase I (Erlotinib & Temsirolimus) PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (dose escalation). Every 28 days until disease progression or unacceptable toxicity. erlotinib: Given orally temsirolimus: Given IV pharmacological study: Correlative studies	Phase II (Erlotinib & Temsirolimus) Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity. PHASE II (preoperative component): Patients who are surgical candidates may opt to undergo surgical resection of the tumor. Beginning 5-7 days before surgery, these patients receive oral erlotinib once daily until surgery. Patients also receive temsirolimus IV over 30 minutes at the MTD and then undergo surgical resection of the tumor 3-24 hours later. Beginning 2-4 weeks after surgery, patients receive temsirolimus at the MTD and erlotinib as in phase I. therapeutic conventional surgery: Undergo surgical resection laboratory biomarker analysis: Correlative studies
Overall Study STARTED	22	47
Overall Study COMPLETED	21	47
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I (Erlotinib & Temsirolimus) PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (dose escalation). Every 28 days until disease progression or unacceptable toxicity. erlotinib: Given orally temsirolimus: Given IV pharmacological study: Correlative studies	Phase II (Erlotinib & Temsirolimus) Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity. PHASE II (preoperative component): Patients who are surgical candidates may opt to undergo surgical resection of the tumor. Beginning 5-7 days before surgery, these patients receive oral erlotinib once daily until surgery. Patients also receive temsirolimus IV over 30 minutes at the MTD and then undergo surgical resection of the tumor 3-24 hours later. Beginning 2-4 weeks after surgery, patients receive temsirolimus at the MTD and erlotinib as in phase I. therapeutic conventional surgery: Undergo surgical resection laboratory biomarker analysis: Correlative studies
Overall Study 1 pt never had had RX due rapid decline	1	0

Baseline Characteristics

Erlotinib and Temsirolimus in Treating Patients With Recurrent Malignant Glioma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I n=9 n=9 Participants PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (dose escalation). Every 28 days until disease progression or unacceptable toxicity. erlotinib: Given orally temsirolimus: Given IV	Phase II n=16 n=16 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity. Anaplastic Glioma erlotinib: Given orally temsirolimus: Given IV	Phase II n=43 n=43 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity. Glioblastoma erlotinib: Given orally temsirolimus: Given IV	Total n=68 Participants Total of all reporting groups
Age, Continuous	57 years n=5 Participants	47 years n=7 Participants	50 years n=5 Participants	51 years n=4 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants	20 Participants n=4 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	12 Participants n=7 Participants	31 Participants n=5 Participants	48 Participants n=4 Participants
Karnofsky Performance Scale (KPS)	90 units on a scale n=5 Participants	90 units on a scale n=7 Participants	90 units on a scale n=5 Participants	90 units on a scale n=4 Participants
Prior Chemotherapy treatments	2 treatments n=5 Participants	1 treatments n=7 Participants	1 treatments n=5 Participants	1 treatments n=4 Participants
Histology anaplastic glioma	3 participants n=5 Participants	16 participants n=7 Participants	0 participants n=5 Participants	19 participants n=4 Participants
Histology glioblastoma	6 participants n=5 Participants	0 participants n=7 Participants	43 participants n=5 Participants	49 participants n=4 Participants

PRIMARY outcome

Timeframe: based on first 4 weeks of treatment - cycle 1

Population: Per protocol -

Outcome measures

Outcome measures
Measure	Phase I - Dose Escalation n=21 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at (dose escalation or dose de-escalation). Every 28 days until disease progression or unacceptable toxicity. Dose levels: cohort 1 - 50mg - 3pts cohort 2 - 25mg -6pt cohort 3 - 15mg - 12pts	Phase 1 - 25 mg Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (25mg). Every 28 days until disease progression or unacceptable toxicity.	Phase 1 - 15mg PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (15mg). Every 28 days until disease progression or unacceptable toxicity.
Maximum Tolerated Dose (Phase I)	15 mg	—	—

PRIMARY outcome

Timeframe: first 4 weeks of treatment

Dose limiting toxities defined as: grade 3 thrombocytopenia, grade 4 anemia and neutropenia, grade \>/= nonhematologic toxicity, and failure to recover from toxicites to be eligible for retreatment in 2 weeks of the last dose of either drug. Also grade 3 nonhematologic toxicities only if they wre refractory to maxiaml medical therapy. MTD defined as dose at which fewer than one-third of patients experienced a DLT Outcome measure defines number of participants who had a defined dose limiting toxicity.

Outcome measures

Outcome measures
Measure	Phase I - Dose Escalation n=3 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at (dose escalation or dose de-escalation). Every 28 days until disease progression or unacceptable toxicity. Dose levels: cohort 1 - 50mg - 3pts cohort 2 - 25mg -6pt cohort 3 - 15mg - 12pts	Phase 1 - 25 mg n=6 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (25mg). Every 28 days until disease progression or unacceptable toxicity.	Phase 1 - 15mg n=12 Participants PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (15mg). Every 28 days until disease progression or unacceptable toxicity.
Safety/Dose Limiting Toxities Phase I	2 participants	3 participants	3 participants

PRIMARY outcome

Timeframe: at least 8 weeks of treatment

Population: Response was reviewed only in those patients treated at the MTD (15mg temsirolimus)

pt must have at least 8 weeks of treatment to receive MRI scan, scans are every other cycle (every 2 months). Response measured by a bidimensionally measured leison and clearly defined margins by CT or MRI scan. Complete Response (CR): complete disappearance of all measurable and evaluable disease. No new lesions, not on any steroids Partial Response (PR): \>= 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Steriod dose must be no greater than max used in 1st 8wks of therapy Stable: not qualify for CR, PR, or progression. Steriod dose must be no greater than max used in 1st 8wks of therapy Progression (PD): 25% increase in the sum of products of all measurable lesions over smallest sum observed, OR clear worsening or failure to return for evalution due to death or deteriorating condition (unless clearly unrelated to brain cancer).

Outcome measures

Outcome measures
Measure	Phase I - Dose Escalation n=12 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at (dose escalation or dose de-escalation). Every 28 days until disease progression or unacceptable toxicity. Dose levels: cohort 1 - 50mg - 3pts cohort 2 - 25mg -6pt cohort 3 - 15mg - 12pts	Phase 1 - 25 mg Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (25mg). Every 28 days until disease progression or unacceptable toxicity.	Phase 1 - 15mg PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (15mg). Every 28 days until disease progression or unacceptable toxicity.
Efficacy - Response Phase 1 Stable	2 participants	—	—
Efficacy - Response Phase 1 Complete Response	0 participants	—	—
Efficacy - Response Phase 1 Partial response	1 participants	—	—
Efficacy - Response Phase 1 Progressive Disease	9 participants	—	—

PRIMARY outcome

Timeframe: Days 1, 2 of cycle 1, prior to dosing of both drugs, at end of temsirolimus infusion and at 1,2,4,6, and 24 hr after erlotinib administration

Population: per protocol

Tersirolimus Cmax (ng/mL) for cycle 1 is presented in the outcome measure table below for the 3 dose levels blood samples (5ml) was collected in EDTA containing tubes on days 1 and 2 of cycle 1 Collection time points: prior to dosing of both drugs, at end of temsirolimus infusion and at 1,2,4,6, and 24 hr after erlotinib administration

Outcome measures

Outcome measures
Measure	Phase I - Dose Escalation n=11 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at (dose escalation or dose de-escalation). Every 28 days until disease progression or unacceptable toxicity. Dose levels: cohort 1 - 50mg - 3pts cohort 2 - 25mg -6pt cohort 3 - 15mg - 12pts	Phase 1 - 25 mg n=6 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (25mg). Every 28 days until disease progression or unacceptable toxicity.	Phase 1 - 15mg n=3 Participants PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (15mg). Every 28 days until disease progression or unacceptable toxicity.
Pharmacokinetics (Phase I)	460 ng/mL Standard Deviation 219	428 ng/mL Standard Deviation 115	451 ng/mL Standard Deviation 281

PRIMARY outcome

Timeframe: Evaluated at baseline and every other cycle, till Month 6

Population: Primary endpoint PFS6 date of registration; Sample size chosen to discriminate between 15% \& 35% PFS6 rates for GBM patients. With accrual 32 GBM patients, trial would be considered successful if 8 achieved PFS6. This yields 0.92 power to detect a 35% PFS6 rate, with 0.90 probability of rejecting the treatment regimen if the PFS6 rate is only 15%.

Progression (PD): 25% increase in the sum of products of all measurable lesions over smallest sum observed, OR clear worsening or failure to return for evalution due to death or deteriorating condition (unless clearly unrelated to brain cancer). Responses had to be present on 2 consecutive scans and were centrally reviewed.

Outcome measures

Outcome measures
Measure	Phase I - Dose Escalation n=43 Participants Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at (dose escalation or dose de-escalation). Every 28 days until disease progression or unacceptable toxicity. Dose levels: cohort 1 - 50mg - 3pts cohort 2 - 25mg -6pt cohort 3 - 15mg - 12pts	Phase 1 - 25 mg Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (25mg). Every 28 days until disease progression or unacceptable toxicity.	Phase 1 - 15mg PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (15mg). Every 28 days until disease progression or unacceptable toxicity.
Progression-free Survival at 6 Months (Phase II)	6 participants	—	—

Adverse Events

Phase I (Erlotinib & Temsirolimus)

Serious events: 3 serious events

Other events: 21 other events

Deaths: 0 deaths

Phase II (Erlotinib & Erlotinib)

Serious events: 2 serious events

Other events: 37 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase I (Erlotinib & Temsirolimus) n=21 participants at risk PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (dose escalation). Every 28 days until disease progression or unacceptable toxicity. erlotinib: Given orally temsirolimus: Given IV pharmacological study: Correlative studies	Phase II (Erlotinib & Erlotinib) n=59 participants at risk Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity. PHASE II (preoperative component): Patients who are surgical candidates may opt to undergo surgical resection of the tumor. Beginning 5-7 days before surgery, these patients receive oral erlotinib once daily until surgery. Patients also receive temsirolimus IV over 30 minutes at the MTD and then undergo surgical resection of the tumor 3-24 hours later. Beginning 2-4 weeks after surgery, patients receive temsirolimus at the MTD and erlotinib as in phase I. therapeutic conventional surgery: Undergo surgical resection laboratory biomarker analysis: Correlative studies
Cardiac disorders Myocardial infarction	4.8% 1/21 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
General disorders fever	4.8% 1/21 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Musculoskeletal and connective tissue disorders generalized muscle weakness	0.00% 0/21 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Respiratory, thoracic and mediastinal disorders Upper respiratory infection	4.8% 1/21 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Eye disorders retinopathy	0.00% 0/21 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.

Other adverse events

Additional Information

Dr. Patrick Y Wen

Adult Brain Tumor Consortium (ABTC)

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Phase I (Erlotinib & Temsirolimus) n=21 participants at risk PHASE I: Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 (dose escalation). Every 28 days until disease progression or unacceptable toxicity. erlotinib: Given orally temsirolimus: Given IV pharmacological study: Correlative studies	Phase II (Erlotinib & Erlotinib) n=59 participants at risk Oral erlotinib 1 daily days 1-28 (150mg), temsirolimus IV 30 minutes days 1, 8, 15, 22 at MTD phse I. Every 28 days until disease progression or unacceptable toxicity. PHASE II (preoperative component): Patients who are surgical candidates may opt to undergo surgical resection of the tumor. Beginning 5-7 days before surgery, these patients receive oral erlotinib once daily until surgery. Patients also receive temsirolimus IV over 30 minutes at the MTD and then undergo surgical resection of the tumor 3-24 hours later. Beginning 2-4 weeks after surgery, patients receive temsirolimus at the MTD and erlotinib as in phase I. therapeutic conventional surgery: Undergo surgical resection laboratory biomarker analysis: Correlative studies
Investigations White blood Cells	9.5% 2/21 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Investigations Platelets	19.0% 4/21 • Number of events 4 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	3.4% 2/59 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Metabolism and nutrition disorders Anorexia	9.5% 2/21 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Metabolism and nutrition disorders dehydration	14.3% 3/21 • Number of events 3 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Gastrointestinal disorders diarrhea	9.5% 2/21 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
General disorders fatigue	9.5% 2/21 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	3.4% 2/59 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Metabolism and nutrition disorders hypercholesterolemia	4.8% 1/21 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Metabolism and nutrition disorders hypertriglyceridemia	9.5% 2/21 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Metabolism and nutrition disorders hypocalcemia	9.5% 2/21 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Metabolism and nutrition disorders hypophosphatemia	23.8% 5/21 • Number of events 5 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	6.8% 4/59 • Number of events 4 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Cardiac disorders hypotension	9.5% 2/21 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Infections and infestations Mucosal infection	4.8% 1/21 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Investigations Liver Function Test abnormality	14.3% 3/21 • Number of events 3 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Gastrointestinal disorders Mucositis oral	28.6% 6/21 • Number of events 6 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	8.5% 5/59 • Number of events 5 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Gastrointestinal disorders Nausea	4.8% 1/21 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Skin and subcutaneous tissue disorders Pruritus	9.5% 2/21 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Skin and subcutaneous tissue disorders Dry Skin	0.00% 0/21 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Metabolism and nutrition disorders hyperglycemia	0.00% 0/21 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	3.4% 2/59 • Number of events 2 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Skin and subcutaneous tissue disorders Rash	38.1% 8/21 • Number of events 8 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	16.9% 10/59 • Number of events 10 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Gastrointestinal disorders Vomiting	4.8% 1/21 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	0.00% 0/59 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Metabolism and nutrition disorders hypernatremia	0.00% 0/21 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Investigations Lymphocyte count decrease	0.00% 0/21 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	8.5% 5/59 • Number of events 5 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/21 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.	1.7% 1/59 • Number of events 1 • Adverse Events were collected weekly for the first cycle and then at the start of each cycle while on treatment and at time of off study.