Trial Outcomes & Findings for A Study of Avastin (Bevacizumab) in Combination With Fotemustine in Patients With Metastatic Melanoma (NCT NCT01069627)

Last Updated: 2018-12-06

Results Overview

The percentage of participants with an objective response, defined as achieving CR or PR, as evaluated by the Response Evaluation Criteria In Solid Tumors (RECIST) criteria. CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target), PR: at least a 30 percent (%) decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

20 participants

Primary outcome timeframe

Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Results posted on

2018-12-06

Participant Flow

Participant milestones

Participant milestones
Measure	Bevacizumab + Fotemustine Cycle 1 (3-week cycle): Participants received bevacizumab 15 milligrams/kilogram (mg/kg) intravenously (IV) on Day 1 and fotemustine 100 mg per square meter (mg/m\^2) IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Overall Study STARTED	20
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	20

Reasons for withdrawal

Reasons for withdrawal
Measure	Bevacizumab + Fotemustine Cycle 1 (3-week cycle): Participants received bevacizumab 15 milligrams/kilogram (mg/kg) intravenously (IV) on Day 1 and fotemustine 100 mg per square meter (mg/m\^2) IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Overall Study Disease progression	7
Overall Study Adverse Event	12
Overall Study Protocol Violation	1

Baseline Characteristics

A Study of Avastin (Bevacizumab) in Combination With Fotemustine in Patients With Metastatic Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab + Fotemustine n=20 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Age, Continuous	51 years STANDARD_DEVIATION 15 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: Intent-to-Treat (ITT) Population: all participants who signed the informed consent form and were assigned a study patient number; data for 1 participant were not assessable as the participant was discontinued from the study due to a protocol violation.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=20 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Percentage of Participants With Complete Response (CR) or Partial Response (PR)	15 percentage of participants Interval 3.0 to 38.0

PRIMARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; data for 1 participant were not assessable as the participant was discontinued from the study due to a protocol violation.

The percentage of participants with an objective response of CR, PR, or SD, as evaluated by RECIST criteria. CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target), PR: at least a 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for pregressive disease (PD). The clinical benefit was finally assessed by computing absolute frequencies and percentages participants with best overall tumor response equal to CR, PR, or SD.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=20 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Percentage of Participants With Clinical Benefit of CR, PR, or Stable Disease (SD)	65 percentage of participants Interval 41.0 to 85.0

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; data for 1 participant were not assessable as the participant was discontinued from the study due to a protocol violation.

TTP was defined as the time in days from the date of first study treatment until the date of tumor progression or death. Failure events were defined as occurrence of death or progression of disease. Data for participants who were alive without tumor progression at the end of the study were censured at the end of the observation period.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=19 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Time to Progression (TTP) - Percentage of Participants With an Event	73.68 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; data for 1 participant were not assessable as the participant was discontinued from the study due to a protocol violation.

TTP was defined as the time in days from the of first study treatment until the date of tumor progression or death. Failure events were defined as occurrence of death or progression of disease. Data for participants who were alive without tumor progression at the end of the study were censored at the end of the observation period. Median TTP was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=19 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
TTP - Time to Event	249.00 days Interval 122.0 to 726.0

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; only participants with a best overall response of CR were included in the analysis.

Evaluated only for participants whose best overall response was CR. The start date was the date of first documented CR and the end date was defined as the date of first documented progression of disease, or death. Participants who did not experience progression of disease were censored at last tumor assessment date or at maximum follow-up.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=1 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Duration of CR - Percentage of Participants With an Event	0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; only participants with a CR were included in the analysis

The start date was the date of first documented CR and the end date was defined as the date of first documented progression of disease, or death. Participants who did not experience progression of disease were censored at last tumor assessment date or at maximum follow-up. Median duration of CR was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=1 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Duration of CR - Time to Event	NA days Complete response was achieved by a single participant who reached confirmed CR during the study period. This participant did not have worsening of his status during the observation period, no failures were observed relative to this endpoint.

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; only participants with a best overall response of CR or PR were included in the analysis.

The start date was the date of first documented CR or PR and the end date was defined as the date of first documented progression of disease, or death. Participants who did not experience progression of disease were censored at last tumor assessment date or at maximum follow-up.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=3 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Duration of Overall Response of CR or PR - Percentage of Participants With an Event	66.67 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; only participants with a best overall response of CR or PR were included in the analysis.

The start date was the date of first documented CR or PR and the end date was defined as the date of first documented progression of disease. Participants who did not experience progression of disease were censored at last tumor assessment date or at maximum follow-up. Median duration of CR or PR was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=3 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Duration of Overall Response of CR or PR - Time to Event	324.00 days Interval 155.0 to Number of data points is too small to support the calculation of an upper limit for the 95% confidence interval.

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; only participants with a best overall response of CR, PR, or SD were included in the anlaysis.

Stable disease was defined as achieving CR, PR, or SD. The start date was the date of first documented CR, PR, or SD and the end date was defined as the date of first documented progression of disease, or death. Participants who did not experience progression of disease were censored at last tumor assessment date or at maximum follow-up.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=12 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Duration of Stable Disease - Percentage of Participants With an Event	58.33 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; only participants with a best overall response of CR, PR, or SD were included in the analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=12 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Duration of Stable Disease - Time to Event	619.00 days Interval 249.0 to Number of data points is too small to support the calculation of an upper limit for the 95% confidence interval.

SECONDARY outcome

Timeframe: Baseline, every 3 weeks to end-of-treatment, every 3 months during follow-up, to death or end-of-study (maximum of 36 months)

Population: ITT population

OS was defined as the time from the starting day of the therapy up to death or the last date the participant was known to be alive.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=20 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Overall Survival (OS) - Percentage of Participants With an Event	60 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 3 weeks to end-of-treatment, every 3 months during follow-up, to death or end-of-study (maximum of 36 months)

Population: ITT population

The time from the starting day of the therapy up to death or the last date the participant was known to be alive. Median OS was estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=20 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
OS - Time to Event	615.00 days Interval 298.0 to 796.0

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT Population; data for 1 participant were not assessable as the participant was discontinued from the study due to a protocol violation.

The time from date of start of treatment to the earliest among date of progression, date of death due to any cause, or date of discontinuation due to reason other than 'Protocol Violation' or 'Administrative Problem'. For the participants who did not experience treatment failure, TTF was censored at last adequate tumour assessment.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=19 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Time to Treatment Failure (TTF) - Percentage of Participants With an Event	100 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; data for 1 participant were not assessable as the participant was discontinued from the study due to a protocol violation.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=19 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
TTF - Time to Event	126.00 days Interval 43.0 to 158.0

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT Population; data for 1 participant were not assessable as the participant was discontinued from the study due to a protocol violation.

The time between date of start of treatment until first documented CR. This analysis included all responders. Participants who did not achieve a confirmed CR were censored at last adequate tumour assessment date or at maximum follow-up.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=19 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Time to CR - Percentage of Participants With an Event	5.26 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT population; only participants with a CR were included in the analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=1 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Time to CR - Time To Event	76.00 days Standard Deviation NA Number of data points is too small to support the calculation of the standard deviation.

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT Population; data for 1 participant were not assessable as the participant was discontinued from the study due to a protocol violation.

The time between date of start of treatment until first documented response of CR or PR. This analysis included all responders. Participants who did not achieve a confirmed CR or PR were censored at last adequate tumour assessment date or at maximum follow-up.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=19 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Time to Overall Response of CR or PR - Percentage of Participants With an Event	15.79 percentage of participants

SECONDARY outcome

Timeframe: Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Population: ITT Population; only participants with a response of CR or PR were included in the analysis.

Outcome measures

Outcome measures
Measure	Bevacizumab + Fotemustine n=3 Participants Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Time to Overall Response of CR or PR - Time to Event	116.50 days Standard Deviation 7.58

Adverse Events

Bevacizumab + Fotemustine

Serious events: 4 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Bevacizumab + Fotemustine n=20 participants at risk Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Blood and lymphatic system disorders Thrombocytopenia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Reproductive system and breast disorders Metrorrhagia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.

Other adverse events

Other adverse events
Measure	Bevacizumab + Fotemustine n=20 participants at risk Cycle 1 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 and fotemustine 100 mg/m\^2 IV on Days 1, 8, and 15 followed by 1 week off. Cycle 1 was not repeated. Cycle 2 (3-week cycle): Participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. Cycle 2 was not repeated. Cycles 3-8 (3-week cycles): Participants received bevacizumab 15 mg/kg IV and fotemustine 100 mg/m\^2 IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks for 4 to 6 cycles. Cycles 9 and beyond (3-week cycles): If the previous 6 to 8 cycles were tolerated with no disease progression, then participants received bevacizumab 15 mg/kg IV on Day 1 followed by 2 weeks off. This cycle was repeated every 3 weeks until disease progression or unacceptable toxicity.
Blood and lymphatic system disorders Anaemia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Blood and lymphatic system disorders Febrile neutropenia	10.0% 2/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Blood and lymphatic system disorders Leukopenia	15.0% 3/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Blood and lymphatic system disorders Lymphadenopathy	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Blood and lymphatic system disorders Neutropenia	65.0% 13/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Blood and lymphatic system disorders Thrombocytopenia	70.0% 14/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Eye disorders Cataract	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Abdominal pain	10.0% 2/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Abdominal pain upper	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Constipation	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Diarrhoea	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Dyspepsia	10.0% 2/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Dysphagia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Gastric dilatation	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Nausea	15.0% 3/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Oesophageal achalasia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Rectal haemorrhage	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Salivary gland mass	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Vomiting	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
General disorders Asthenia	50.0% 10/20 • From date of first administration of study drug to 28 days after last administration of study drug.
General disorders Mucosal inflammation	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
General disorders Oedema	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
General disorders Oedema peripheral	10.0% 2/20 • From date of first administration of study drug to 28 days after last administration of study drug.
General disorders Pyrexia	15.0% 3/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Immune system disorders Hypersensitivity	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Infections and infestations Cystitis	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Infections and infestations Influenza	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Infections and infestations Lymphangitis	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Infections and infestations Nasopharyngitis	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Infections and infestations Urinary tract infection	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Injury, poisoning and procedural complications Thermal burn	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Investigations Alanine aminotransferase	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Investigations Aspartate aminotransferase	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Investigations Haematocrit decreased	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Investigations Red blood cell count decreased	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Metabolism and nutrition disorders Anorexia	15.0% 3/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Metabolism and nutrition disorders Hyperuricaemia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Metabolism and nutrition disorders Hypokalaemia	10.0% 2/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Musculoskeletal and connective tissue disorders Back pain	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	10.0% 2/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Musculoskeletal and connective tissue disorders Vertebral column mass	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Nervous system disorders Dizziness	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Nervous system disorders Headache	10.0% 2/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Psychiatric disorders Depression	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Psychiatric disorders Insomnia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Renal and urinary disorders Haematuria	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Reproductive system and breast disorders Metrorrhagia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Cough	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Dysphonia	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	20.0% 4/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Skin and subcutaneous tissue disorders Skin disorder	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Vascular disorders Hypertension	40.0% 8/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Vascular disorders Hypotension	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Vascular disorders Thrombosis	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Gingival bleeding	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Haemorrhoids	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.
Gastrointestinal disorders Mouth haemorrhage	5.0% 1/20 • From date of first administration of study drug to 28 days after last administration of study drug.

Additional Information

Medical Communications

Hoffmann-LaRoche

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Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request the Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
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Restriction type: OTHER