Trial Outcomes & Findings for Cabozantinib +/- Trastuzumab In Breast Cancer Patients w/ Brain Metastases (NCT NCT02260531)

Last Updated: 2021-05-20

Results Overview

The central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

36 participants

Primary outcome timeframe

Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.

Results posted on

2021-05-20

Participant Flow

36 patients were enrolled between November 2014 and June 2018

Participant milestones

Participant milestones
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ HER2-positive * Cabozantinib- orally administered daily per treatment cycle * Trastuzumab- IV administered once per cycle * MRI- Baseline, Cycle 2 Day 1, and every 2 cycles * Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1, Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.	Cohort 2 - Cabozantinib for ER+ and/or PR+ Hormone receptor-positive (ER+ and/or PR+) * Cabozantinib- orally administered daily per treatment cycle * MRI- Baseline, Cycle 2 Day 1, and every 2 cycles * Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1, Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- Triple negative (ER-, PR-, HER2-) * Cabozantinib- orally administered daily per treatment cycle * MRI- Baseline, Cycle 2 Day 1, and every 2 cycles * Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1, Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.
Overall Study STARTED	21	7	8
Overall Study COMPLETED	21	7	8
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Cabozantinib +/- Trastuzumab In Breast Cancer Patients w/ Brain Metastases

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 Participants HER2-positive * Cabozantinib- orally administered daily per treatment cycle * Trastuzumab- IV administered once per cycle * MRI- Baseline, Cycle 2 Day 1, and every 2 cycles * Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1, Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops. Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 Participants Hormone receptor-positive (ER+ and/or PR+) * Cabozantinib- orally administered daily per treatment cycle * MRI- Baseline, Cycle 2 Day 1, and every 2 cycles * Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1, Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 Participants Triple negative (ER-, PR-, HER2-) * Cabozantinib- orally administered daily per treatment cycle * MRI- Baseline, Cycle 2 Day 1, and every 2 cycles * Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1, Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.	Total n=36 Participants Total of all reporting groups
Age, Continuous	52 years n=99 Participants	48 years n=107 Participants	48 years n=206 Participants	50 years n=7 Participants
Sex: Female, Male Female	21 Participants n=99 Participants	7 Participants n=107 Participants	8 Participants n=206 Participants	36 Participants n=7 Participants
Sex: Female, Male Male	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race/Ethnicity, Customized Race · White	19 Participants n=99 Participants	5 Participants n=107 Participants	8 Participants n=206 Participants	32 Participants n=7 Participants
Race/Ethnicity, Customized Race · African American	0 Participants n=99 Participants	2 Participants n=107 Participants	0 Participants n=206 Participants	2 Participants n=7 Participants
Race/Ethnicity, Customized Race · More than one race	1 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants
Race/Ethnicity, Customized Race · Other	1 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants
Region of Enrollment United States	21 participants n=99 Participants	7 participants n=107 Participants	8 participants n=206 Participants	36 participants n=7 Participants
Prior anti-HER2 therapy-Trastuzumab	21 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	21 Participants n=7 Participants
Prior anti-HER2 therapy-Lapatinib	10 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	10 Participants n=7 Participants
ECOG performance status 0	13 Participants n=99 Participants	3 Participants n=107 Participants	1 Participants n=206 Participants	17 Participants n=7 Participants
ECOG performance status 1	8 Participants n=99 Participants	4 Participants n=107 Participants	7 Participants n=206 Participants	19 Participants n=7 Participants
Prior Stereotactic radiosurgery Yes	7 Participants n=99 Participants	4 Participants n=107 Participants	1 Participants n=206 Participants	12 Participants n=7 Participants
Prior Stereotactic radiosurgery No	14 Participants n=99 Participants	3 Participants n=107 Participants	7 Participants n=206 Participants	24 Participants n=7 Participants
Prior Whole brain radiation Yes	16 Participants n=99 Participants	5 Participants n=107 Participants	4 Participants n=206 Participants	25 Participants n=7 Participants
Prior Whole brain radiation No	5 Participants n=99 Participants	2 Participants n=107 Participants	4 Participants n=206 Participants	11 Participants n=7 Participants
No Prior CNS radiation	4 Participants n=99 Participants	2 Participants n=107 Participants	4 Participants n=206 Participants	10 Participants n=7 Participants
Surgical resection of CNS metastasis Yes	1 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants	4 Participants n=7 Participants
Surgical resection of CNS metastasis No	20 Participants n=99 Participants	6 Participants n=107 Participants	6 Participants n=206 Participants	32 Participants n=7 Participants
Sites of metastatic disease Lung	9 participants n=99 Participants	2 participants n=107 Participants	3 participants n=206 Participants	14 participants n=7 Participants
Sites of metastatic disease Liver	7 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants	9 participants n=7 Participants
Sites of metastatic disease Bone	10 participants n=99 Participants	5 participants n=107 Participants	1 participants n=206 Participants	16 participants n=7 Participants
Sites of metastatic disease Breast (Ipsilateral or Contralateral) or chest wall	2 participants n=99 Participants	0 participants n=107 Participants	1 participants n=206 Participants	3 participants n=7 Participants
Sites of metastatic disease Lymph nodes	5 participants n=99 Participants	1 participants n=107 Participants	1 participants n=206 Participants	7 participants n=7 Participants
Number of sites of metastases at study entry	2 Sites n=99 Participants	1 Sites n=107 Participants	2 Sites n=206 Participants	2 Sites n=7 Participants

PRIMARY outcome

Timeframe: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.

Outcome measures

Outcome measures
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 Participants HER2-positive * Cabozantinib- orally administered daily per treatment cycle, 60 mg per day * Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 Participants Hormone receptor-positive (ER+ and/or PR+) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 Participants Triple negative (ER-, PR-, HER2-) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
CNS Objective Response Rate (ORR)	5 percentage of participants Interval 0.2 to 24.0	14 percentage of participants Interval 0.4 to 58.0	0 percentage of participants Interval 0.0 to 37.0

SECONDARY outcome

CNS volumetric ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) defined as: CR * Complete resolution of all measurable (≥ 1 cm diameter) and non-measurable brain metastases * No new CNS lesions (new lesion defined as ≥ 6 mm diameter) PR * ≥ 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain metastases compared to baseline * No progression of non-measurable lesions * No new lesions (new lesion defined as ≥ 6 mm) ORR also requires: * Stable or decreasing steroid dose * No new/progressive tumor-related neurologic signs or symptoms

Outcome measures

Outcome measures
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 Participants HER2-positive * Cabozantinib- orally administered daily per treatment cycle, 60 mg per day * Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 Participants Hormone receptor-positive (ER+ and/or PR+) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 Participants Triple negative (ER-, PR-, HER2-) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
CNS Volumetric Objective Response Rate (ORR)	5 percentage of participants Interval 0.2 to 24.0	0 percentage of participants Interval 0.0 to 41.0	0 percentage of participants Interval 0.0 to 37.0

SECONDARY outcome

The non-central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation non-CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Outcome measures

Outcome measures
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 Participants HER2-positive * Cabozantinib- orally administered daily per treatment cycle, 60 mg per day * Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 Participants Hormone receptor-positive (ER+ and/or PR+) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 Participants Triple negative (ER-, PR-, HER2-) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
Non-CNS Objective Response Rate (ORR)	0 percentage of participants Interval 0.0 to 16.0	0 percentage of participants Interval 0.0 to 41.0	0 percentage of participants Interval 0.0 to 37.0

SECONDARY outcome

Timeframe: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.

Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Outcome measures

Outcome measures
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 Participants HER2-positive * Cabozantinib- orally administered daily per treatment cycle, 60 mg per day * Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 Participants Hormone receptor-positive (ER+ and/or PR+) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 Participants Triple negative (ER-, PR-, HER2-) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
Median Progression-Free Survival (PFS)	4.1 Months Interval 2.8 to 6.2	0.8 Months Interval 0.5 to Insufficient number of participants with events	2.4 Months Interval 2.0 to Insufficient number of participants with events

SECONDARY outcome

Timeframe: Evaluate at 12 weeks.

Clinical benefit rate (CBR) was defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 criteria by 12 weeks. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.

Outcome measures

Outcome measures
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 Participants HER2-positive * Cabozantinib- orally administered daily per treatment cycle, 60 mg per day * Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 Participants Hormone receptor-positive (ER+ and/or PR+) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 Participants Triple negative (ER-, PR-, HER2-) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
12-Week Clinical Benefit Rate	43 percentage of participants Interval 24.0 to 63.0	14 percentage of participants Interval 0.4 to 58.0	13 percentage of participants Interval 1.0 to 47.0

SECONDARY outcome

Population: Data was not collected

Site that a patient has his/her first tumor progression (CNS vs Non-CNS)

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months.

OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.

Outcome measures

Outcome measures
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 Participants HER2-positive * Cabozantinib- orally administered daily per treatment cycle, 60 mg per day * Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 Participants Hormone receptor-positive (ER+ and/or PR+) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 Participants Triple negative (ER-, PR-, HER2-) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
Overall Survival (OS)	13.8 Months Interval 8.2 to Insufficient number of participants with events	NA Months Insufficient number of participants with events	5.1 Months Interval 2.1 to Insufficient number of participants with events

SECONDARY outcome

Timeframe: Participants should be re-evaluated for response every 6 weeks. Patients with stable or responsive disease after completion of 6 cycles may have the frequency of scans reduced to once every 3 cycles, and in long-term follow-up every 6 months until death.

All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.

Outcome measures

Outcome measures
Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 Participants HER2-positive * Cabozantinib- orally administered daily per treatment cycle, 60 mg per day * Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 Participants Hormone receptor-positive (ER+ and/or PR+) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 Participants Triple negative (ER-, PR-, HER2-) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
Incidence of Grade 4 Treatment-Related Toxicity	4 participants Interval 1.05 to 8.82	0 participants Interval 0.0 to 2.87	0 participants Interval 0.0 to 2.96

Adverse Events

Cohort 1 - Cabozantinib, Trastuzumab for HER2+

Serious events: 6 serious events

Other events: 21 other events

Deaths: 11 deaths

Cohort 2 - Cabozantinib for ER+ and/or PR+

Serious events: 4 serious events

Other events: 7 other events

Deaths: 3 deaths

Cohort 3 - Cabozantinib for ER-, PR-, HER2-

Serious events: 6 serious events

Other events: 8 other events

Deaths: 8 deaths

Serious adverse events

Other adverse events

Additional Information

Sara Tolaney, MD, MPH

Dana-Farber Cancer Institute

Phone: 617-632-3800

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Cohort 1 - Cabozantinib, Trastuzumab for HER2+ n=21 participants at risk HER2-positive * Cabozantinib- orally administered daily per treatment cycle, 60 mg per day * Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 2 - Cabozantinib for ER+ and/or PR+ n=7 participants at risk Hormone receptor-positive (ER+ and/or PR+) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.	Cohort 3 - Cabozantinib for ER-, PR-, HER2- n=8 participants at risk Triple negative (ER-, PR-, HER2-) \- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
Hepatobiliary disorders Portal vein thrombosis	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	14.3% 1/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Investigations Ejection fraction decreased	4.8% 1/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Gastrointestinal disorders Diarrhea	4.8% 1/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Gastrointestinal disorders Dyspepsia	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	14.3% 1/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Gastrointestinal disorders Mucositis oral	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	14.3% 1/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Gastrointestinal disorders Nausea	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Gastrointestinal disorders Vomiting	4.8% 1/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
General disorders Fatigue	4.8% 1/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	14.3% 1/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Investigations Alanine aminotransferase increased	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	14.3% 1/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Investigations Aspartate aminotransferase increased	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	28.6% 2/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Investigations Lipase increased	14.3% 3/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Investigations Platelet count decreased	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Investigations Serum amylase increased	4.8% 1/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Metabolism and nutrition disorders Hyponatremia	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	0.00% 0/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Vascular disorders Hypertension	4.8% 1/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	0.00% 0/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)
Vascular disorders Thromboembolic event	4.8% 1/21 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	14.3% 1/7 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)	12.5% 1/8 • Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)