Melanoma
Conditions
Keywords
Metastatic Melanoma
Brief summary
The purpose of this study is to ascertain if the extended schedule of Temozolomide, which allows increased doses and potential depletion of the enzyme underlaying resistance, is a more effective treatment of metastatic melanoma than single agent dacarbazine.
Interventions
DRUGTemozolomide
oral capsule; 150 mg/m2/day PO (by mouth), on 7 consecutive days every 14 days (7 days on / 7 days off continuously); one cycle of temozolomide is defined as a 6-week period; treatment will continue until progression of the disease, unacceptable toxicity, subject refusal, or opinion of the treating physician that it is in the subject's best interest to stop.
DRUGDacarbazine
intravenous solution; dacarbazine 1000 mg/m2 IV (in the vein), on Day 1 +/- 3 days every 3 weeks; one cycle of dacarbazine is defined as a 3-week period; treatment will continue until progression of the disease, unacceptable toxicity, subject refusal, or opinion of the treating physician that it is in the subject's best interest to stop.
Sponsors
European Organisation for Research and Treatment of Cancer - EORTC
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed, stage IV, surgically incurable melanoma * Age 18 years or older * World Health Organization (WHO) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Meets protocol requirements for specified laboratory values * Must be able to take oral medication * Must be disease free from cancer for period of 5 years (except for surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin). * Women of childbearing potential and men must be practicing a medically approved contraception. * Must provide written informed-consent to participate in the study. * Must have full recovery from major surgery or adjuvant treatment * No clinically uncontrolled infectious disease including HIV or AIDS-related illness
Exclusion criteria
* Ocular melanomas * Brain Metastases * Prior cytokine or chemotherapy for stage IV disease * Pregnant or nursing women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | The final analysis was to be performed when at least 616 deaths had occurred. | Overall Survival was defined as the time from the date of randomization to the date of death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Treatment continued until disease progression or unacceptable toxicity. Patients will be followed for survival. | Progression free survival was defined as the time from the date of randomization to the date of disease progression or the date of death regardless of the cause. |
| Objective Response Rate in Subjects With Measurable Lesions | Treatment continued until disease progression or unacceptable toxicity. | Based on investigator's assessment of response in subjects with measurable lesions. Objective response = complete response + partial response. Complete response = disappearance of all target lesions. Partial response = at least a 30% decrease in the sum of longest diameter of target lesions taking as reference the baseline sum longest diameter. |
| Duration of Objective Response | Treatment continued until disease progression or unacceptable toxicity. | Duration of objective response was measured from the time the criteria were met for complete response or partial response to the first date that recurrent or progressive disease was objectively documented. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide temozolomide 150 mg/m2/day PO, on 7 consecutive days every 14 days (7 days on / 7 days off continuously) | 429 |
| Dacarbazine dacarbazine 1000 mg/m2 IV, on Day 1 +/- 3 days every 3 weeks | 430 |
| Total | 859 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death not due to malignancy/toxicity | 1 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Major Protocol Violation | 2 | 0 |
| Overall Study | Medical Decision unrelated toxicity/PD | 10 | 22 |
| Overall Study | Ongoing (still on treatment) | 8 | 12 |
| Overall Study | Other Reason | 6 | 13 |
| Overall Study | Subject's Refusal unrelated to toxicity | 14 | 22 |
| Overall Study | Toxicity (Related AE) | 53 | 9 |
Baseline characteristics
| Characteristic | Temozolomide | Dacarbazine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 153 Participants | 169 Participants | 322 Participants |
| Age, Categorical Between 18 and 65 years | 276 Participants | 261 Participants | 537 Participants |
| Sex: Female, Male Female | 179 Participants | 177 Participants | 356 Participants |
| Sex: Female, Male Male | 250 Participants | 253 Participants | 503 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 394 / 419 | 374 / 421 |
| serious Total, serious adverse events | 124 / 419 | 100 / 421 |
Outcome results
Primary
Overall Survival
Overall Survival was defined as the time from the date of randomization to the date of death from any cause.
Time frame: The final analysis was to be performed when at least 616 deaths had occurred.
Population: Intent to Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Overall Survival | 9.13 Months |
| Dacarbazine | Overall Survival | 9.36 Months |
p-value: 0.999995% CI: [0.86, 1.17]Log Rank
Secondary
Duration of Objective Response
Duration of objective response was measured from the time the criteria were met for complete response or partial response to the first date that recurrent or progressive disease was objectively documented.
Time frame: Treatment continued until disease progression or unacceptable toxicity.
Population: All responders
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Duration of Objective Response | 4.34 Months |
| Dacarbazine | Duration of Objective Response | 8.31 Months |
Secondary
Objective Response Rate in Subjects With Measurable Lesions
Based on investigator's assessment of response in subjects with measurable lesions. Objective response = complete response + partial response. Complete response = disappearance of all target lesions. Partial response = at least a 30% decrease in the sum of longest diameter of target lesions taking as reference the baseline sum longest diameter.
Time frame: Treatment continued until disease progression or unacceptable toxicity.
Population: Intent to treat population with measurable disease at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Objective Response Rate in Subjects With Measurable Lesions | 0.14 Ratio |
| Dacarbazine | Objective Response Rate in Subjects With Measurable Lesions | 0.10 Ratio |
p-value: 0.071895% CI: [0.97, 2.12]Cochran-Mantel-Haenszel
Secondary
Progression Free Survival
Progression free survival was defined as the time from the date of randomization to the date of disease progression or the date of death regardless of the cause.
Time frame: Treatment continued until disease progression or unacceptable toxicity. Patients will be followed for survival.
Population: Intent to Treat Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temozolomide | Progression Free Survival | 2.30 Months |
| Dacarbazine | Progression Free Survival | 2.17 Months |
p-value: 0.266395% CI: [0.8, 1.06]Log Rank