Malignant Melanoma
Conditions
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.
Interventions
DRUGbevacizumab [Avastin]
15 mg/kg intravenously on day 1 of every 3 week cycle
DRUGfotemustine
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
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + Fotemustine 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. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | Disease progression | 7 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Bevacizumab + Fotemustine |
|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 15 |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 20 |
| serious Total, serious adverse events | 4 / 20 |
Outcome results
Primary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Percentage of Participants With Clinical Benefit of CR, PR, or Stable Disease (SD) | 65 percentage of participants |
Primary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Percentage of Participants With Complete Response (CR) or Partial Response (PR) | 15 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Duration of CR - Percentage of Participants With an Event | 0 percentage of participants |
Secondary
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.
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Fotemustine | Duration of CR - Time to Event | NA days |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Duration of Overall Response of CR or PR - Percentage of Participants With an Event | 66.67 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Fotemustine | Duration of Overall Response of CR or PR - Time to Event | 324.00 days |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Duration of Stable Disease - Percentage of Participants With an Event | 58.33 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Fotemustine | Duration of Stable Disease - Time to Event | 619.00 days |
Secondary
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.
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)
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Fotemustine | OS - Time to Event | 615.00 days |
Secondary
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.
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)
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Overall Survival (OS) - Percentage of Participants With an Event | 60 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Time to CR - Percentage of Participants With an Event | 5.26 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bevacizumab + Fotemustine | Time to CR - Time To Event | 76.00 days |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Time to Overall Response of CR or PR - Percentage of Participants With an Event | 15.79 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab + Fotemustine | Time to Overall Response of CR or PR - Time to Event | 116.50 days | Standard Deviation 7.58 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Time to Progression (TTP) - Percentage of Participants With an Event | 73.68 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Fotemustine | Time to Treatment Failure (TTF) - Percentage of Participants With an Event | 100 percentage of participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Fotemustine | TTF - Time to Event | 126.00 days |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Fotemustine | TTP - Time to Event | 249.00 days |