A Phase II, Multi-Center, Open-Label, Uncontrolled Study to Evaluate the Efficacy and Safety of Sorafenib Given Daily in Combination With Repeated 21-Day Cycles of Dacarbazine (DTIC) Chemotherapy in Subjects With Advanced Metastatic Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to see whether a new type of anti-cancer drug, known as BAY 43-9006, can be given safely and with good effect in combination with dacarbazine (DTIC). DTIC is the current standard chemotherapy drug given for melanoma that has spread through the body. Although this drug can be effective on its own and is generally well tolerated, not all patients will benefit, so there is a need to test new drugs and drug combinations for treating melanoma.

Detailed Description
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Issues on Safety outcomes are addressed in the Adverse Event section.

Official Title
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A Phase II, Multi-center, Open-label, Uncontrolled Study to Evaluate the Efficacy and Safety of BAY 43-9006 Given Daily in Combination With Repeated 21-Day Cycles of Dacarbazine (DTIC) Chemotherapy in Subjects With Advanced Metastatic Melanoma.

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Sorafenib (Nexavar, BAY43-9006) + Dacarbazine (DTIC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with advanced, metastatic, histologically confirmed melanoma, for whom treatment with dacarbazine is considered medically acceptable Age >= 18 years Subject has measurable and evaluable disease defined as at least one metastatic lesion that can be accurately and serially measured by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan as per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Cutaneous lesions measuring at least 20mm in longest diameter can be considered measurable (and therefore target lesions) via color photography including a ruler Subject has biopsiable disease at baseline and is willing to provide biopsy samples, or does not have biopsiable disease at baseline Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Exclusion Criteria: Primary ocular or mucosal melanoma (cutaneous vulval melanoma is permitted) 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, Tis & T1] or any cancer curatively treated > 3 years prior to study entry (Active coronary artery disease or ischemia (myocardial infarction more than 6 months prior to study entry is allowed) Uncontrolled hypertension (> grade 2 National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0) Active, clinically serious infections (> grade 2 NCI-CTCAE version 3.0) Subjects with seizure disorder requiring medication are excluded History of or suspected Human Immunodeficiency Virus (HIV) infection, or chronic hepatitis B or C Symptomatic metastatic brain or meningeal tumors unless the subject is > 6 months from definitive therapy, has a negative imaging study within 4 weeks prior to study entry and is clinically stable with respect to the tumor at the time of study entry. Also the subject must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies) Pregnant or breast-feeding subjects

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib + Dacarbazine<br>Dacarbazine 1000 mg/m^2 on day one of repeated 21 day cycles, in combination with daily continuous oral sorafenib (Nexavar, BAY 43-9006), 400 mg twice a day (bid) | Drug: Sorafenib (Nexavar, BAY43-9006) + Dacarbazine (DTIC)<br>* Dacarbazine 1000 mg/m^2 on day one of repeated 21 day cycles, in combination with daily continuous oral sorafenib (Nexavar, BAY 43-9006), 400 mg twice a day (bid)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Best Response | Best Overall Response (BOR): Best tumor response achieved during or within 30 days after active therapy confirmed according to the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR): The disappearance of all target and non-target lesions. Partial response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. SD was defined as steady state of disease, PD was defined as an increase of at least 20% increase in the sum of the LD of target lesions or appearance of new lesions. | during or within 30 days after active therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free Survival (PFS) was the time from the first dose of combination therapy to disease progression (radiological or clinical, whichever is earlier) or death (if death occurs before progression is documented). PFS for subjects without tumor progression or death at the time of analysis were censored at the date of last tumor evaluation. | from start of treatment until progression or death before progression (median 259 days) | 
| Percentage of Subjects With Progression-free Survival at Specific Time-points | Progression-free Survival (PFS) was the time from the first dose of combination therapy to disease progression (radiological or clinical, whichever is earlier) or death (if death occurs before progression is documented). PFS for subjects without tumor progression or death at the time of analysis were censored at the date of last tumor evaluation. | from start of treatment until progression or death before progression after 3, 6 and 12 months | 
| Overall Survival | Overall Survival was the number of days from the date that combination treatment started until the date of death. | from start of treatment until death (median 259 days) | 
| Duration of Response | Duration of Response was assessed in subjects who showed a Partial Response (PR) or Complete Response (CR). It was defined as the time from the first documented objective response to Progressive Disease (PD), or death if before documented progression. Duration of response for subjects who have not progressed or died at the time of analysis was censored at the date of last tumor assessment. | from confirmed Complete Response (CR) or Partial Response (PR) until Progressive Disease (PD) (median 259 days) | 
| Duration of Complete Response | Duration of complete response was the number of days from the date that a complete response was first documented to the date that recurrent or progressive disease was first objectively documented (if patient progressed then censored=no) or to last observation (if patient did not progress then censored=yes). | from confirmed CR until PD (median 259 days) | 
| Duration of Partial Response | Duration of partial response was the number of days from the date that a partial response was first documented to the date that recurrent or progressive disease was first objectively documented (if patient progressed then censored=no) or to last observation (if patient did not progress then censored=yes). | from confirmed PR until PD (median 259 days) | 
| Disease Control (DC) | DC was defined as the total number of subjects whose best response was not progressive disease (PD) (total number of CRs + total number of PRs + total number of Stable Diseases (SD)). The DC at specific time points could also be calculated as the total number of subjects whose response was not PD at that time point. | after start of treatment, at 6 months and 12 months | 
| Duration of Stable Disease | Duration of Stable Disease (DSD), defined as the time from the first documented objective evidence of Stable Disease (SD) to disease progression (DP) or death if death occurred before DP, was assessed in subjects who showed SD as best response. DSD for subjects who had not progressed or died was censored at the date of last tumor assessment. | from start of therapy to PD, only in non-responders (median 259 days) | 
| Time to Response | Time to Response in subjects who achieved an objective response (PR or CR with confirmation) was measured from the date of starting study combination treatment until the earliest date that the response was first documented. | start of therapy to confirmed CR or PR (median 259 days) | 
| Time to Progression | Time to Progression was the number of days from the start of therapy to progression (if patient progressed then censored=no) or to the last observation at which the patient was known to have not progressed, that is, the last observation with a best response of CR, PR, or SD. | From start of treatment until progression (median 259 days) |