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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: bevacizumab [Avastin]
* Drug: fotemustine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: bevacizumab [Avastin]<br>* 15 mg/kg intravenously on day 1 of every 3 week cycle<br>Drug: fotemustine<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) - Percentage of Participants With an Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| TTP - Time to Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Duration of CR - Percentage of Participants With an Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Duration of CR - Time to Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Duration of Overall Response of CR or PR - Percentage of Participants With an Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Duration of Overall Response of CR or PR - Time to Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Duration of Stable Disease - Percentage of Participants With an Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Duration of Stable Disease - Time to Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Overall Survival (OS) - Percentage of Participants With an Event | 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. | 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 - Time to Event | 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. | Baseline, every 3 weeks to end-of-treatment, every 3 months during follow-up, to death or end-of-study (maximum of 36 months) | 
| Time to Treatment Failure (TTF) - Percentage of Participants With an Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| TTF - Time to Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Time to CR - Percentage of Participants With an Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Time to CR - Time To Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Time to Overall Response of CR or PR - Percentage of Participants With an Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months | 
| Time to Overall Response of CR or PR - Time to Event | 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. | Baseline, every 9 weeks during study treatment, and every 3 months during follow-up, up to 36 months |