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

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01069627
• Collaborator: (none)
• Enrollment: 20
• Locations: 4
• Arm: 1
• Actual Duration (Months): 31
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will investigate the efficacy and safety of bevacizumab + fotemustine in patients with stage IV melanoma, previously untreated with chemo- or immunotherapy for metastatic disease. Patients will receive Avastin (15mg/kg intravenously[IV]) on Day 1 of every 3 week cycle, in combination with fotemustine (100mg/m² IV) on Days 1, 8 and 15, followed by 4 weeks rest, followed by 100mg/m² IV every 3 weeks for 4-6 cycles. The anticipated time on study treatment is until disease progression, and the target sample size is <100 individuals.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: bevacizumab [Avastin]; Drug: fotemustine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Study to Assess the Anti-tumor Activity of Avastin in Combination With Fotemustine as First-line Therapy in Patients With Metastatic Melanoma
• Actual Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: bevacizumab [Avastin]; 15 mg/kg intravenously on day 1 of every 3 week cycle; Drug: fotemustine; 100 mg/m² intravenously on Days 1, 8, and 15, followed by 4 weeks of rest, then every 21 days up to 4 to 6 cycles

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

2. Percentage of Participants With Clinical Benefit of CR, PR, or Stable Disease (SD) [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

Secondary Outcome Measures

1. Time to Progression (TTP) - Percentage of Participants With an Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

2. TTP - Time to Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

3. Duration of CR - Percentage of Participants With an Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

4. Duration of CR - Time to Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

5. Duration of Overall Response of CR or PR - Percentage of Participants With an Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

6. Duration of Overall Response of CR or PR - Time to Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

7. Duration of Stable Disease - Percentage of Participants With an Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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.

8. Duration of Stable Disease - Time to Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

   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. Median duration of CR, PR, or SD was estimated using the Kaplan-Meier method.

9. Overall Survival (OS) - Percentage of Participants With an Event [Baseline, every 3 weeks to end-of-treatment, every 3 months during follow-up, to death or end-of-study (maximum of 36 months)]

   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.

10. OS - Time to Event [Baseline, every 3 weeks to end-of-treatment, every 3 months during follow-up, to death or end-of-study (maximum of 36 months)]

    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.

11. Time to Treatment Failure (TTF) - Percentage of Participants With an Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

    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.

12. TTF - Time to Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

    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. Median TTF was estimated using the Kaplan-Meier method.

13. Time to CR - Percentage of Participants With an Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

    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.

14. Time to CR - Time To Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

    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. Mean time to CR was estimated using the Kaplan-Meier method.

15. Time to Overall Response of CR or PR - Percentage of Participants With an Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

    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.

16. Time to Overall Response of CR or PR - Time to Event [Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months]

    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 tumor assessment date or at maximum follow-up. Mean time to CR or PR was estimated using the Kaplan-Meier method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• cutaneous malignant melanoma;

• advanced, inoperable stage IV melanoma;

• measurable and/or evaluable sites of metastases.

Exclusion Criteria:

• prior chemotherapy and/or IFN/IL2 based immunotherapy for metastatic disease;

• prior malignancies within past 5 years, with the exception of cured non-melanoma skin cancer, or in situ cancer of cervix;

• clinically significant cardiovascular disease;

• ongoing treatment with aspirin (>325mg/day) or other medications known to predispose to gastrointestinal ulceration.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Firenze		Italy	50100
2		Genova		Italy	16132
3		Milano		Italy	20133
4		Torino		Italy	10126

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Chair: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01069627
• Other Study ID Numbers: ML19309
• First Posted: Feb 17, 2010
• Last Update Posted: Dec 6, 2018
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Melanoma; Bevacizumab; Fotemustine

Study Results

Participant Flow

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Period Title: Overall Study
STARTED	20
COMPLETED	0
NOT COMPLETED	20

Baseline Characteristics

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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 Participants	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51 (15)
Sex: Female, Male (Count of Participants)
Female	8 40%
Male	12 60%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Complete Response (CR) or Partial Response (PR)
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	20
Number (95% Confidence Interval) [percentage of participants]	15 75%

2. Secondary Outcome

Title	Time to Progression (TTP) - Percentage of Participants With an Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	19
Number [percentage of participants]	73.68 368.4%

3. Secondary Outcome

Title	TTP - Time to Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	19
Median (95% Confidence Interval) [days]	249.00

4. Secondary Outcome

Title	Duration of CR - Percentage of Participants With an Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	1
Number [percentage of participants]	0 0%

5. Secondary Outcome

Title	Duration of CR - Time to Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	1
Median (95% Confidence Interval) [days]	NA

6. Secondary Outcome

Title	Duration of Overall Response of CR or PR - Percentage of Participants With an Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	3
Number [percentage of participants]	66.67 333.4%

7. Primary Outcome

Title	Percentage of Participants With Clinical Benefit of CR, PR, or Stable Disease (SD)
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	20
Number (95% Confidence Interval) [percentage of participants]	65 325%

8. Secondary Outcome

Title	Duration of Overall Response of CR or PR - Time to Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	3
Median (95% Confidence Interval) [days]	324.00

9. Secondary Outcome

Title	Duration of Stable Disease - Percentage of Participants With an Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	12
Number [percentage of participants]	58.33 291.7%

10. Secondary Outcome

Title	Duration of Stable Disease - Time to Event
Description	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. Median duration of CR, PR, or SD was estimated using the Kaplan-Meier method.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	12
Median (95% Confidence Interval) [days]	619.00

11. Secondary Outcome

Title	Overall Survival (OS) - Percentage of Participants With an Event
Description	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.
Time Frame	Baseline, every 3 weeks to end-of-treatment, every 3 months during follow-up, to death or end-of-study (maximum of 36 months)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	20
Number [percentage of participants]	60 300%

12. Secondary Outcome

Title	OS - Time to Event
Description	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.
Time Frame	Baseline, every 3 weeks to end-of-treatment, every 3 months during follow-up, to death or end-of-study (maximum of 36 months)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	20
Median (95% Confidence Interval) [days]	615.00

13. Secondary Outcome

Title	Time to Treatment Failure (TTF) - Percentage of Participants With an Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	19
Number [percentage of participants]	100 500%

14. Secondary Outcome

Title	TTF - Time to Event
Description	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. Median TTF was estimated using the Kaplan-Meier method.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	19
Median (95% Confidence Interval) [days]	126.00

15. Secondary Outcome

Title	Time to CR - Percentage of Participants With an Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	19
Number [percentage of participants]	5.26 26.3%

16. Secondary Outcome

Title	Time to CR - Time To Event
Description	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. Mean time to CR was estimated using the Kaplan-Meier method.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	1
Mean (Standard Deviation) [days]	76.00 (NA)

17. Secondary Outcome

Title	Time to Overall Response of CR or PR - Percentage of Participants With an Event
Description	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.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	19
Number [percentage of participants]	15.79 79%

18. Secondary Outcome

Title	Time to Overall Response of CR or PR - Time to Event
Description	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 tumor assessment date or at maximum follow-up. Mean time to CR or PR was estimated using the Kaplan-Meier method.
Time Frame	Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
Measure Participants	3
Mean (Standard Deviation) [days]	116.50 (7.58)

Adverse Events

Time Frame	From date of first administration of study drug to 28 days after last administration of study drug.
Arm/Group Title	Bevacizumab + Fotemustine
Arm/Group Description	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.
All Cause Mortality
	Bevacizumab + Fotemustine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab + Fotemustine
	Affected / at Risk (%)	# Events
Total	4/20 (20%)
Blood and lymphatic system disorders
Thrombocytopenia	1/20 (5%)
Reproductive system and breast disorders
Metrorrhagia	1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/20 (5%)
Pleural effusion	1/20 (5%)
Pulmonary embolism	1/20 (5%)
Other (Not Including Serious) Adverse Events
	Bevacizumab + Fotemustine
	Affected / at Risk (%)	# Events
Total	18/20 (90%)
Blood and lymphatic system disorders
Anaemia	1/20 (5%)
Febrile neutropenia	2/20 (10%)
Leukopenia	3/20 (15%)
Lymphadenopathy	1/20 (5%)
Neutropenia	13/20 (65%)
Thrombocytopenia	14/20 (70%)
Eye disorders
Cataract	1/20 (5%)
Gastrointestinal disorders
Abdominal pain	2/20 (10%)
Abdominal pain upper	1/20 (5%)
Constipation	1/20 (5%)
Diarrhoea	1/20 (5%)
Dyspepsia	2/20 (10%)
Dysphagia	1/20 (5%)
Gastric dilatation	1/20 (5%)
Nausea	3/20 (15%)
Oesophageal achalasia	1/20 (5%)
Rectal haemorrhage	1/20 (5%)
Salivary gland mass	1/20 (5%)
Vomiting	1/20 (5%)
Gingival bleeding	1/20 (5%)
Haemorrhoids	1/20 (5%)
Mouth haemorrhage	1/20 (5%)
General disorders
Asthenia	10/20 (50%)
Mucosal inflammation	1/20 (5%)
Oedema	1/20 (5%)
Oedema peripheral	2/20 (10%)
Pyrexia	3/20 (15%)
Immune system disorders
Hypersensitivity	1/20 (5%)
Infections and infestations
Cystitis	1/20 (5%)
Influenza	1/20 (5%)
Lymphangitis	1/20 (5%)
Nasopharyngitis	1/20 (5%)
Urinary tract infection	1/20 (5%)
Injury, poisoning and procedural complications
Thermal burn	1/20 (5%)
Investigations
Alanine aminotransferase	1/20 (5%)
Aspartate aminotransferase	1/20 (5%)
Haematocrit decreased	1/20 (5%)
Red blood cell count decreased	1/20 (5%)
Metabolism and nutrition disorders
Anorexia	3/20 (15%)
Hyperuricaemia	1/20 (5%)
Hypokalaemia	2/20 (10%)
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)
Musculoskeletal chest pain	1/20 (5%)
Musculoskeletal pain	1/20 (5%)
Pain in extremity	2/20 (10%)
Vertebral column mass	1/20 (5%)
Nervous system disorders
Dizziness	1/20 (5%)
Headache	2/20 (10%)
Psychiatric disorders
Depression	1/20 (5%)
Insomnia	1/20 (5%)
Renal and urinary disorders
Haematuria	1/20 (5%)
Reproductive system and breast disorders
Metrorrhagia	1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	1/20 (5%)
Dysphonia	1/20 (5%)
Dyspnoea	1/20 (5%)
Epistaxis	4/20 (20%)
Oropharyngeal pain	1/20 (5%)
Pleural effusion	1/20 (5%)
Pulmonary embolism	1/20 (5%)
Skin and subcutaneous tissue disorders
Skin disorder	1/20 (5%)
Vascular disorders
Hypertension	8/20 (40%)
Hypotension	1/20 (5%)
Thrombosis	1/20 (5%)

Limitations/Caveats

Nonserious adverse events presented in this record include all adverse events reported during the study, not just nonserious events.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.