Melanoma
Conditions
Brief summary
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
Issues on Safety outcomes are addressed in the Adverse Event section.
Interventions
DRUGSorafenib (Nexavar, BAY43-9006) + Dacarbazine (DTIC)
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)
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Best Response | during or within 30 days after active therapy | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | from start of treatment until progression or death before progression (median 259 days) | 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. |
| Percentage of Subjects With Progression-free Survival at Specific Time-points | from start of treatment until progression or death before progression after 3, 6 and 12 months | 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. |
| Overall Survival | from start of treatment until death (median 259 days) | Overall Survival was the number of days from the date that combination treatment started until the date of death. |
| Duration of Response | from confirmed Complete Response (CR) or Partial Response (PR) until Progressive Disease (PD) (median 259 days) | 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. |
| Duration of Complete Response | from confirmed CR until PD (median 259 days) | 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). |
| Duration of Partial Response | from confirmed PR until PD (median 259 days) | 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). |
| Disease Control (DC) | after start of treatment, at 6 months and 12 months | 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. |
| Duration of Stable Disease | from start of therapy to PD, only in non-responders (median 259 days) | 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. |
| Time to Response | start of therapy to confirmed CR or PR (median 259 days) | 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. |
| Time to Progression | From start of treatment until progression (median 259 days) | 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. |
Countries
France, United Kingdom
Participant flow
Recruitment details
This study had a 2-stage Simon optimal design consisting of 30 subjects in the first stage and 52 subjects in the second stage for a planned total of 82 subjects. Actually a total of 96 subjects were enrolled and 83 were treated; 32 in the 1st stage and 51 in the second stage. The study was conducted at 8 centers in the UK and 4 centers in France.
Pre-assignment details
Of the 96 enrolled subjects, 13 were screening failures. The reasons for screening failure were violation of inclusion/exclusion criteria (12) and death due to Progressive Disease (PD) (1). The remaining 83 subjects all received at least one dose of sorafenib and dacarbazine.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib + Dacarbazine Dacarbazine 1000 mg/m2 on day one of repeated 21 day cycles, in combination with daily continuous oral Sorafenib (Nexavar, BAY43-9006), 400 mg twice a day (bid) | 83 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Active Follow-up 30(+4) Days Duration | Death | 17 |
| Active Follow-up 30(+4) Days Duration | Study terminated by sponsor | 2 |
| Survival Only Follow-up | Death | 46 |
| Survival Only Follow-up | Lack of Efficacy | 1 |
| Survival Only Follow-up | Study terminated by sponsor | 12 |
| Treatment | Death | 2 |
| Treatment | Study terminated by sponsor | 3 |
Baseline characteristics
| Characteristic | Sorafenib + Dacarbazine |
|---|---|
| Age, Continuous | 53.5 years |
| Clinical disease status Missing | 6 participants |
| Clinical disease status Progressive disease | 74 participants |
| Clinical disease status Stable disease | 3 participants |
| Disease stage (AJCC) M1a Distant subcutaneous or lymphnode metastases | 4 participants |
| Disease stage (AJCC) M1b Lung metastases | 12 participants |
| Disease stage (AJCC) M1c All other visceral metastases | 66 participants |
| Disease stage (AJCC) Missing | 1 participants |
| ECOG status 0 | 52 participants |
| ECOG status 1 | 28 participants |
| ECOG status Missing | 3 participants |
| Histology Acral lentiginous | 2 participants |
| Histology Malignant melanoma | 4 participants |
| Histology Missing | 24 participants |
| Histology Nodular | 29 participants |
| Histology Superfical spreading | 24 participants |
| Lactate dehydrogenase >= 10 percent above the ULN | 26 participants |
| Lactate dehydrogenase Missing | 3 participants |
| Lactate dehydrogenase >= ULN but < 10 percent above ULN | 11 participants |
| Lactate dehydrogenase < Upper Limit of Normal (ULN=325 U/L) | 43 participants |
| Mean time from diagnosis | 1280 days |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 82 / 83 |
| serious Total, serious adverse events | 40 / 83 |
Outcome results
Primary
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.
Time frame: during or within 30 days after active therapy
Population: There were 83 subjects in the intent-to-treat (ITT) population. Of these, 75 were evaluable for Best Response; 8 were not evaluable.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib + Dacarbazine | Overall Best Response | Overall response (CR+PR) | 10 participants |
| Sorafenib + Dacarbazine | Overall Best Response | Complete response (CR) | 1 participants |
| Sorafenib + Dacarbazine | Overall Best Response | Partial response (PR) | 9 participants |
| Sorafenib + Dacarbazine | Overall Best Response | Stable disease (SD) | 31 participants |
| Sorafenib + Dacarbazine | Overall Best Response | Progressive disease (PD) | 34 participants |
Secondary
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.
Time frame: after start of treatment, at 6 months and 12 months
Population: There were 83 subjects in the intent-to-treat (ITT) population. All 83 were included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib + Dacarbazine | Disease Control (DC) | DC at 6 months | 38 participants |
| Sorafenib + Dacarbazine | Disease Control (DC) | DC based on overall best response | 41 participants |
| Sorafenib + Dacarbazine | Disease Control (DC) | DC at 12 months | 38 participants |
Secondary
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).
Time frame: from confirmed CR until PD (median 259 days)
Population: There were 83 subjects in the intent-to-treat (ITT) population. Only the 1 subject who had a CR was included in this analysis (duration 420 days, censored).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib + Dacarbazine | Duration of Complete Response | 420 days |
Secondary
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).
Time frame: from confirmed PR until PD (median 259 days)
Population: There were 83 subjects in the intent-to-treat (ITT) population. Only the 9 subjects who had a PR were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Dacarbazine | Duration of Partial Response | 255 days |
Secondary
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.
Time frame: from confirmed Complete Response (CR) or Partial Response (PR) until Progressive Disease (PD) (median 259 days)
Population: There were 83 subjects in the intent-to-treat (ITT) population. Only the 10 subjects who had a PR or CR were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Dacarbazine | Duration of Response | 327 days |
Secondary
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.
Time frame: from start of therapy to PD, only in non-responders (median 259 days)
Population: There were 83 subjects in the intent-to-treat (ITT) population. Only the 70 subjects who had a Best Response of Stable Disease, ie, those who failed to achieve a Best Response of CR or PR, were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Dacarbazine | Duration of Stable Disease | 93 days |
Secondary
Overall Survival
Overall Survival was the number of days from the date that combination treatment started until the date of death.
Time frame: from start of treatment until death (median 259 days)
Population: There were 83 subjects in the intent-to-treat (ITT) population. All 83 were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Dacarbazine | Overall Survival | 259 days |
Secondary
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.
Time frame: from start of treatment until progression or death before progression after 3, 6 and 12 months
Population: There were 83 subjects in the intent-to-treat (ITT) population. All 83 were included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib + Dacarbazine | Percentage of Subjects With Progression-free Survival at Specific Time-points | PFS at month 3 | 56.63 percentage of participants |
| Sorafenib + Dacarbazine | Percentage of Subjects With Progression-free Survival at Specific Time-points | PFS at month 6 | 33.73 percentage of participants |
| Sorafenib + Dacarbazine | Percentage of Subjects With Progression-free Survival at Specific Time-points | PFS at month 12 | 10.84 percentage of participants |
Secondary
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.
Time frame: from start of treatment until progression or death before progression (median 259 days)
Population: There were 83 subjects in the intent-to-treat (ITT) population. All 83 were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Dacarbazine | Progression-free Survival | 102 days |
Secondary
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.
Time frame: From start of treatment until progression (median 259 days)
Population: There were 83 subjects in the intent-to-treat (ITT) population. Of these 83, 78 were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Dacarbazine | Time to Progression | 102 days |
Secondary
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.
Time frame: start of therapy to confirmed CR or PR (median 259 days)
Population: There were 83 subjects in the intent-to-treat (ITT) population. Only the 10 subjects who had a PR or CR were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib + Dacarbazine | Time to Response | 48 days |