A Study of Bevacizumab With Carboplatin and Paclitaxel Chemotherapy for the First-Line Treatment of Patients With Metastatic Melanoma

Study Overview
=================
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.

Official Title
-----------------
A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Carboplatin and Paclitaxel Chemotherapy for the First-Line Treatment of Patients With Metastatic Melanoma

Conditions
-----------------
Melanoma

Intervention / Treatment
-----------------
* Drug: bevacizumab
* Drug: carboplatin
* Drug: paclitaxel
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Carboplatin+Paclitaxel+Placebo<br> | Drug: carboplatin<br>* 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<br>Drug: paclitaxel<br>* 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)<br>Drug: placebo<br>* Administered by IV infusion on the first day of each 3-week cycle<br>|
| Experimental: Carboplatin+Paclitaxel+Bevacizumab<br> | Drug: bevacizumab<br>* 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)<br>Drug: carboplatin<br>* 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<br>Drug: paclitaxel<br>* 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)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 102 weeks | 
| 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. | Up to 102 weeks | 
| 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. | Up to 102 weeks | 
| 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. | Up to 102 weeks | 
| 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. | 6 months | 
| 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. | 24 weeks | 
| 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. | Participants were monitored for AEs from initiation of treatment to 30 days after treatment termination. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Avastin, BEAM, Metastatic melanoma