Melanoma
Conditions
Brief summary
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).
Interventions
DRUGSorafenib (Nexavar, BAY43-9006)
Sorafenib, 400 mg po (per os), 2 tablets (200 mg each) bid Study Days 2-19
Paclitaxel (225 mg/m\^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1
DRUGPlacebo
Placebo, 2 tablets bid Study Days 2-19
Sponsors
Amgen
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Time from randomization to documented tumor progression or death (median time of 124 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Time from randomization to death (median time of 294 days) | 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 to Progression (TTP) | Time from randomization to documented tumor progression (median time of 126 days) | 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. |
| Duration of Response (DOR) | Time from initial response to documented tumor progression or death (median time of 197 days) | 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. |
| Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | baseline and at visit when best response was noted (maximum treatment duration of 68.3 weeks) | 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). |
Countries
Australia, Canada, France, Germany, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted from May 4 2005 to Jan 08 2009 (first subject's first visit to last subject's last visit) at 54 centers in 7 countries: Australia (6), Canada (6), France (6), Germany (10), Netherlands (2), United Kingdom (8), and United States (16).
Pre-assignment details
Of 315 screened subjects, 270 were randomized (45 failed screening) and were valid for Intent-To-Treat (ITT) analyses (135 in each treatment group). One subject in each group did not receive treatment: 1 died and 1 withdrew consent. Thus, 268 subjects received treatment (134 in each group) and were valid for the safety analyses.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib (Nexavar, BAY43-9006) 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. | 135 |
| Carboplatin/Paclitaxel (C/P) 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. | 135 |
| Total | 270 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Active Follow-up | Adverse Event | 1 | 0 |
| Active Follow-up | Death | 2 | 0 |
| Active Follow-up | Disease progression/recurrence/relapse | 3 | 2 |
| Double-blind (DB) Treatment | Adverse Event | 12 | 4 |
| Double-blind (DB) Treatment | Death | 5 | 2 |
| Double-blind (DB) Treatment | Disease progression/recurrence/relapse | 1 | 0 |
| Double-blind (DB) Treatment | Primary reason with other category | 0 | 1 |
| Double-blind (DB) Treatment | Progression by clinical judgement | 0 | 2 |
| Double-blind (DB) Treatment | Protocol Violation | 0 | 1 |
| Double-blind (DB) Treatment | Radiological and symptomatic progression | 83 | 93 |
| Double-blind (DB) Treatment | Relapse | 1 | 0 |
| Double-blind (DB) Treatment | Withdrawal by Subject | 6 | 8 |
| Long Term Follow-up | Death | 34 | 39 |
| Long Term Follow-up | Disease progression/recurrence/relapse | 2 | 1 |
| Long Term Follow-up | Lost to Follow-up | 1 | 1 |
| Long Term Follow-up | Missing | 10 | 3 |
| Long Term Follow-up | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Sorafenib (Nexavar, BAY43-9006) | Carboplatin/Paclitaxel (C/P) | Total |
|---|---|---|---|
| Age, Continuous | 56.0 years STANDARD_DEVIATION 12.8 | 55.1 years STANDARD_DEVIATION 13 | 55.5 years STANDARD_DEVIATION 57 |
| Age, Customized 65 to 74 years | 29 participants | 39 participants | 68 participants |
| Age, Customized <65 years | 97 participants | 92 participants | 189 participants |
| Age, Customized >=75 years | 9 participants | 4 participants | 13 participants |
| American Joint Committee on Cancer (AJCC) Stage at Study Entry Stage III or IV M1a | 16 participants | 11 participants | 27 participants |
| American Joint Committee on Cancer (AJCC) Stage at Study Entry Stage IV M1b | 27 participants | 31 participants | 58 participants |
| American Joint Committee on Cancer (AJCC) Stage at Study Entry Stage IV M1c | 92 participants | 93 participants | 185 participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 76 participants | 70 participants | 146 participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 59 participants | 65 participants | 124 participants |
| Sex: Female, Male Female | 51 Participants | 48 Participants | 99 Participants |
| Sex: Female, Male Male | 84 Participants | 87 Participants | 171 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 132 / 134 | 134 / 134 |
| serious Total, serious adverse events | 66 / 134 | 65 / 134 |
Outcome results
Primary
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 frame: Time from randomization to documented tumor progression or death (median time of 124 days)
Population: PFS was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) | Progression Free Survival (PFS) | 122 days |
| Carboplatin/Paclitaxel (C/P) | Progression Free Survival (PFS) | 125 days |
p-value: 0.49295% CI: [0.627, 1.31]log rank test
Secondary
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).
Time frame: baseline and at visit when best response was noted (maximum treatment duration of 68.3 weeks)
Population: Change in ECOG PS was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) | Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | missing | 10 participants |
| Sorafenib (Nexavar, BAY43-9006) | Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | better | 9 participants |
| Sorafenib (Nexavar, BAY43-9006) | Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | no change | 70 participants |
| Sorafenib (Nexavar, BAY43-9006) | Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | worse | 46 participants |
| Carboplatin/Paclitaxel (C/P) | Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | worse | 39 participants |
| Carboplatin/Paclitaxel (C/P) | Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | missing | 4 participants |
| Carboplatin/Paclitaxel (C/P) | Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | no change | 82 participants |
| Carboplatin/Paclitaxel (C/P) | Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted | better | 10 participants |
p-value: 0.389Fisher Exact
Secondary
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 frame: Time from initial response to documented tumor progression or death (median time of 197 days)
Population: DOR was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) | Duration of Response (DOR) | 228 days |
| Carboplatin/Paclitaxel (C/P) | Duration of Response (DOR) | 166 days |
p-value: 0.14695% CI: [0.11, 1.437]log rank test
Secondary
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 frame: Time from randomization to death (median time of 294 days)
Population: OS was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) | Overall Survival (OS) | 294 days |
| Carboplatin/Paclitaxel (C/P) | Overall Survival (OS) | 294 days |
p-value: 0.97995% CI: [0.744, 1.333]log rank test
Secondary
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 frame: Time from randomization to documented tumor progression (median time of 126 days)
Population: TTP was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) | Time to Progression (TTP) | 126 days |
| Carboplatin/Paclitaxel (C/P) | Time to Progression (TTP) | 126 days |
p-value: 0.33195% CI: [0.641, 1.162]log rank test