Melanoma
Conditions
Keywords
Avastin, BEAM, Metastatic melanoma
Brief summary
This Phase II, multicenter, randomized, double-blind, placebo-controlled trial was designed to estimate the efficacy and characterize the safety of bevacizumab when combined with carboplatin + paclitaxel chemotherapy compared with carboplatin + paclitaxel chemotherapy alone in patients with previously untreated metastatic melanoma.
Interventions
DRUGbevacizumab
15 mg/kg by intravenous (IV) infusion on the first day of each 3-week cycle (dose was based on patient's weight at screening and remained the same throughout study)
DRUGcarboplatin
Dose based on patients' creatinine clearance (Calvert formula) and administered by intravenous (IV) infusion on the first day of each 3-week cycle, for a maximum of 10 cycles
DRUGpaclitaxel
175 mg/m\^2 by IV infusion on the first day of each 3-week cycle (dose was based on patient's weight and could be adjusted for weight change)
DRUGplacebo
Administered by IV infusion on the first day of each 3-week cycle
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed Informed Consent Form * Age ≥ 18 years * Metastatic melanoma (Stage IV) * Histologically confirmed malignant melanoma with measurable or non-measurable disease * Ability and willingness to comply with study and follow-up procedures
Exclusion criteria
* Prior treatment for Stage IV disease with chemotherapy or biologic therapy such as interferon and interleukin-2 * Complete surgical resection or irradiation of all identifiable sites of disease at randomization * Radiation therapy within 14 days prior to Day 1 * Prior therapy with bevacizumab, sorafenib, sunitinib, or other vascular endothelial growth factor (VEGF) pathway-targeted therapy * Melanoma of ocular origin * Known central nervous system (CNS) disease/brain metastases (history of brain disease or active disease) * Life expectancy of \< 12 weeks * Current, recent, or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study * Inadequate organ function * History of other malignancies within 5 years of Day 1, except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications * Inadequately controlled hypertension * History of hypertensive crisis or hypertensive encephalopathy * New York Heart Association (NYHA) Class II or greater CHF * History of myocardial infarction or unstable angina within 6 months prior to Day 1 * History of stroke or transient ischemic attack within 6 months prior to Day 1 * Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis within 6 months prior to Day 1 * History of hemoptysis within 1 month prior to Day 1 * Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study * Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1 * History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 * Serious, non-healing wound, active ulcer, or untreated bone fracture * Known hypersensitivity to any component of bevacizumab * Pregnancy (positive pregnancy test) or lactation * Current, ongoing treatment with full-dose warfarin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From randomization up to102 weeks. As of the clinical cut-off date (April 2009), the maximum time on treatment was 88 weeks, median time was 12.4 weeks for the Placebo arm and 16.1 weeks for the bevacizumab arm. | Progression-free survival (PFS) was defined as the time from randomization to documented disease progression (at least a 20% increase in the sum of the longest diameter of target lesions or the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions) or death on study (death from any cause occurring no later than 30 days after last dose of any study treatment), whichever occurred first, as determined by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST). Median PFS was estimated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Objective Response | Up to 102 weeks | Objective response was assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and was inclusive of complete and partial response determined on two consecutive investigator assessments conducted ≥ 4 weeks apart. |
| Percentage of Participants With an Objective Response | Up to 102 weeks | Objective response was defined as a complete or partial response according to RECIST criteria as assessed by the investigator on two consecutive assessments conducted at least 4 weeks apart. The 95% Confidence Interval (CI) was calculated using the normal approximation to the binomial distribution. |
| Duration of Objective Response | Up to 102 weeks | Duration of objective response was defined as the time from the initial objective response to documented disease progression or death, whichever occurred first, assessed by the investigator using RECIST. Progressive disease was defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started, or the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Duration of response was estimated using the Kaplan-Meier method. |
| Overall Survival (OS) | Up to 102 weeks | Overall survival was defined as the time from randomization to death from any cause. Median OS was estimated using the Kaplan-Meier method. For patients without documentation of death, overall survival will be censored at the time of the last known contact. |
| Twenty-Four Week Landmark Stable Disease | 24 weeks | As assessed by the investigator using RECIST and defined as the absence of disease progression for 24 weeks from the time of randomization. The percentage of patients who did not experience disease progression or death at 24 weeks following randomization was estimated using Kaplan-Meier methodology. If no tumor assessments were performed after the baseline visit, the patient will be censored at the date of randomization plus 1 day. |
| Number of Participants With Select Adverse Events | Participants were monitored for AEs from initiation of treatment to 30 days after treatment termination. | Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v3.0. Select adverse events included arterial thromboembolic events (any grade), bleeding other than pulmonary or central nervous system (CNS) bleeding (Grade \>= 3), CNS bleeding (any grade), febrile neutropenia (any grade), hypertension (Grade \>= 3), neutropenia (Grade \>= 3), pulmonary bleeding (any grade) and wound dehiscence (Grade \>= 3). \*All serious adverse events are listed in the Adverse Event Reporting section. |
| Six-month Landmark Survival Rate | 6 months | Six-month Landmark Survival Rate was defined as the percentage of participants surviving at 6 months following randomization. Overall Survival was estimated using the Kaplan-Meier method. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carboplatin+Paclitaxel+Placebo Administered by intravenous (IV) infusion every 3 weeks until disease progression, unacceptable toxicity, or for a maximum of 102 weeks, whichever occurred first. Carboplatin administration was stopped after completion of 10 treatment cycles, while paclitaxel continued to be administered with placebo. | 71 |
| Carboplatin+Paclitaxel+Bevacizumab Administered by IV infusion every 3 weeks until disease progression, unacceptable toxicity, or for a maximum of 102 weeks, whichever occurred first. Carboplatin administration was stopped after completion of 10 treatment cycles, while paclitaxel continued to be administered with bevacizumab. | 143 |
| Total | 214 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 13 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Lack of Efficacy | 50 | 100 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 4 | 8 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Carboplatin+Paclitaxel+Placebo | Carboplatin+Paclitaxel+Bevacizumab | Total |
|---|---|---|---|
| Age, Continuous | 58.7 years STANDARD_DEVIATION 12.6 | 59.1 years STANDARD_DEVIATION 11.3 | 58.9 years STANDARD_DEVIATION 11.7 |
| Age, Customized <= 65 years | 46 participants | 104 participants | 150 participants |
| Age, Customized > 65 years | 25 participants | 39 participants | 64 participants |
| Sex: Female, Male Female | 21 Participants | 45 Participants | 66 Participants |
| Sex: Female, Male Male | 50 Participants | 98 Participants | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 69 / 69 | 141 / 143 |
| serious Total, serious adverse events | 20 / 69 | 40 / 143 |
Outcome results
Primary
Progression-free Survival
Progression-free survival (PFS) was defined as the time from randomization to documented disease progression (at least a 20% increase in the sum of the longest diameter of target lesions or the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions) or death on study (death from any cause occurring no later than 30 days after last dose of any study treatment), whichever occurred first, as determined by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST). Median PFS was estimated using the Kaplan-Meier method.
Time frame: From randomization up to102 weeks. As of the clinical cut-off date (April 2009), the maximum time on treatment was 88 weeks, median time was 12.4 weeks for the Placebo arm and 16.1 weeks for the bevacizumab arm.
Population: Intent-to-treat (randomized) population. For patients without documentation of disease progression or death on study, PFS was censored at the time of the last tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin+Paclitaxel+Placebo | Progression-free Survival | 4.2 months |
| Carboplatin+Paclitaxel+Bevacizumab | Progression-free Survival | 5.6 months |
Secondary
Duration of Objective Response
Duration of objective response was defined as the time from the initial objective response to documented disease progression or death, whichever occurred first, assessed by the investigator using RECIST. Progressive disease was defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started, or the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Duration of response was estimated using the Kaplan-Meier method.
Time frame: Up to 102 weeks
Population: Intent-to-treat (randomized) population. Only patients with measurable disease who achieved a response (either partial or complete) were included in the analysis of duration of response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin+Paclitaxel+Placebo | Duration of Objective Response | 7.7 months |
| Carboplatin+Paclitaxel+Bevacizumab | Duration of Objective Response | 6.9 months |
Secondary
Number of Participants With Objective Response
Objective response was assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and was inclusive of complete and partial response determined on two consecutive investigator assessments conducted ≥ 4 weeks apart.
Time frame: Up to 102 weeks
Population: Intent-to-treat (randomized) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Objective Response | 11 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Objective Response | 36 participants |
Secondary
Number of Participants With Select Adverse Events
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v3.0. Select adverse events included arterial thromboembolic events (any grade), bleeding other than pulmonary or central nervous system (CNS) bleeding (Grade \>= 3), CNS bleeding (any grade), febrile neutropenia (any grade), hypertension (Grade \>= 3), neutropenia (Grade \>= 3), pulmonary bleeding (any grade) and wound dehiscence (Grade \>= 3). \*All serious adverse events are listed in the Adverse Event Reporting section.
Time frame: Participants were monitored for AEs from initiation of treatment to 30 days after treatment termination.
Population: The Safety-evaluable population consisted of all patients who received at least one full or partial dose of any component of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Select Adverse Events | Arterial thromboembolic events (any grade) | 1 participants |
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Select Adverse Events | Bleeding other than pulmonary or CNS (Grade >=3) | 4 participants |
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Select Adverse Events | Febrile neutropenia (any grade) | 1 participants |
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Select Adverse Events | Hypertension (Grade >= 3) | 0 participants |
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Select Adverse Events | Neutropenia (Grade >= 3) | 13 participants |
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Select Adverse Events | Pulmonary bleeding (any grade) | 1 participants |
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Select Adverse Events | Wound dehiscence (Grade >= 3) | 0 participants |
| Carboplatin+Paclitaxel+Placebo | Number of Participants With Select Adverse Events | CNS bleeding (any grade) | 0 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Select Adverse Events | Hypertension (Grade >= 3) | 5 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Select Adverse Events | Arterial thromboembolic events (any grade) | 4 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Select Adverse Events | Pulmonary bleeding (any grade) | 2 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Select Adverse Events | Bleeding other than pulmonary or CNS (Grade >=3) | 0 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Select Adverse Events | CNS bleeding (any grade) | 1 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Select Adverse Events | Neutropenia (Grade >= 3) | 34 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Select Adverse Events | Febrile neutropenia (any grade) | 7 participants |
| Carboplatin+Paclitaxel+Bevacizumab | Number of Participants With Select Adverse Events | Wound dehiscence (Grade >= 3) | 2 participants |
Secondary
Overall Survival (OS)
Overall survival was defined as the time from randomization to death from any cause. Median OS was estimated using the Kaplan-Meier method. For patients without documentation of death, overall survival will be censored at the time of the last known contact.
Time frame: Up to 102 weeks
Population: Intent-to-treat (randomized) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin+Paclitaxel+Placebo | Overall Survival (OS) | 8.6 months |
| Carboplatin+Paclitaxel+Bevacizumab | Overall Survival (OS) | 12.3 months |
Secondary
Percentage of Participants With an Objective Response
Objective response was defined as a complete or partial response according to RECIST criteria as assessed by the investigator on two consecutive assessments conducted at least 4 weeks apart. The 95% Confidence Interval (CI) was calculated using the normal approximation to the binomial distribution.
Time frame: Up to 102 weeks
Population: Randomized Patients with Measurable Disease at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin+Paclitaxel+Placebo | Percentage of Participants With an Objective Response | 16.4 percentage of participants |
| Carboplatin+Paclitaxel+Bevacizumab | Percentage of Participants With an Objective Response | 25.5 percentage of participants |
Secondary
Six-month Landmark Survival Rate
Six-month Landmark Survival Rate was defined as the percentage of participants surviving at 6 months following randomization. Overall Survival was estimated using the Kaplan-Meier method.
Time frame: 6 months
Population: Intent-to-treat (randomized) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin+Paclitaxel+Placebo | Six-month Landmark Survival Rate | 74.6 percentage of participants |
| Carboplatin+Paclitaxel+Bevacizumab | Six-month Landmark Survival Rate | 78.2 percentage of participants |
p-value: 0.572495% CI: [-8.7, 15.7]z-test
Secondary
Twenty-Four Week Landmark Stable Disease
As assessed by the investigator using RECIST and defined as the absence of disease progression for 24 weeks from the time of randomization. The percentage of patients who did not experience disease progression or death at 24 weeks following randomization was estimated using Kaplan-Meier methodology. If no tumor assessments were performed after the baseline visit, the patient will be censored at the date of randomization plus 1 day.
Time frame: 24 weeks
Population: Intent-to-treat (randomized) patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin+Paclitaxel+Placebo | Twenty-Four Week Landmark Stable Disease | 38.0 percentage of participants |
| Carboplatin+Paclitaxel+Bevacizumab | Twenty-Four Week Landmark Stable Disease | 50.2 percentage of participants |
p-value: 0.098295% CI: [-2.3, 26.6]z-test