A Treatment Combination for Patients With Unresectable Stage III or Stage IV Melanoma

Study Overview
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Brief Summary
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The objectives of this study are to compare the anti-tumor activity as measured by Progression Free Survival (PFS) and tolerability of Sorafenib in combination with Paclitaxel and Carboplatin versus Paclitaxel and Carboplatin in combination with placebo in subjects with unresectable Stage III or Stage IV melanoma who progressed after receiving only one prior therapy containing Dacarbazine (DTIC) or Temozolomide (TMZ).

Official Title
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Phase III Randomized, Placebo Controlled Study of Sorafenib in Repeated Cycles of 21 Days in Combination With Paclitaxel/Carboplatin Chemotherapy in Subjects With Unresectable Stage III or Stage IV Melanoma.

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Sorafenib (Nexavar, BAY43-9006)
* Drug: Carboplatin/Paclitaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who have a life expectancy of at least 12 weeks Subjects with histologically or cytologically confirmed unresectable (Stage III) or metastatic (Stage IV) melanoma Subjects must have progressed after receiving at least one cycle of DTIC or TMZ containing regimen Subjects who have an ECOG PS of 0 or 1 Measurable disease defined as at least one lesion that can be accurately and serially measured per the modified RECIST criteria Exclusion Criteria: Primary ocular or mucosal melanoma Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta [Noninvasive papillary carcinoma], Tis [Carcinoma in situ: flat tumor]& T1 [Tumor invades subepithelial connective tissue]) or any cancer curatively treated < 5 years prior to study entry History of cardiac disease Known history of human immunodeficiency virus (HIV) infection

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib (Nexavar, BAY43-9006)<br>Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period. | Drug: Sorafenib (Nexavar, BAY43-9006)<br>* Sorafenib, 400 mg po (per os), 2 tablets (200 mg each) bid Study Days 2-19<br>Drug: Carboplatin/Paclitaxel<br>* Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1<br>|
| Active Comparator: Carboplatin/Paclitaxel (C/P)<br>Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period. | Drug: Carboplatin/Paclitaxel<br>* Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1<br>Drug: Placebo<br>* Placebo, 2 tablets bid Study Days 2-19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was calculated as the time (days) from date of randomization to date of first observed DP (per modified Response Evaluation Criteria In Solid Tumors [RECIST] or clinical judgment, whichever was earlier: CR, PR, stable disease, progressive disease) or death due to any cause, if death occurred before progression was documented. The actual date of tumor assessments was used for this calculation. PFS for subjects without progression or death was censored at the last date of tumor evaluation. PFS for subjects who had no tumor assessments after baseline and did not die was censored at 1 day. | Time from randomization to documented tumor progression or death (median time of 124 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) was calculated as the number of days from date of randomization to death date. Subjects who had not died at the time of analysis were censored at their last contact date. | Time from randomization to death (median time of 294 days) | 
| Time to Progression (TTP) | TTP was calculated as the time (days) from date of randomization to date of first observed disease progression (DP) (per modified RECIST or clinical judgment, whichever was earlier: CR, PR, stable disease, progressive disease). The actual dates of tumor assessments were used for this calculation. TTP for subjects without disease progression at the time of analysis, including subjects with death prior to progression, was censored at the last date of tumor evaluation. TTP for subjects who had no tumor assessments after baseline was censored at 1 day. | Time from randomization to documented tumor progression (median time of 126 days) | 
| Duration of Response (DOR) | Duration of response was defined as the time from the first documented objective response of Partial Response (PR: At least a 30% decrease in the sum of the longest diameter [SLD] of target lesions, taking as reference the baseline SLD or better) or Complete Response (CR: Disappearance of all target lesions), whichever was noted earlier, to disease progression or death (if death occurred before progression was documented). Duration of response for subjects who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. | Time from initial response to documented tumor progression or death (median time of 197 days) | 
| Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | Change in ECOG PS is defined as an improvement (increase) or worsening (decrease) of at least one grade from the baseline ECOG score (from 0 [fully active] to 5 [dead]). Change in ECOG PS was recorded at the visit at which best confirmed response (BCR) using the modified RECIST (PR, CR, stable disease or Progressive Disease (PD)) was first noted (the change was 7% for both Sorafenib and Placebo). The BCR is the BCR recorded from the start of the treatment until DP/recurrence (taking as reference for DP, the smallest measurements recorded since treatment started). | baseline and at visit when best response was noted (maximum treatment duration of 68.3 weeks) |