Malignant Melanoma, Recurrent Melanoma
Conditions
Brief summary
This study evaluated two chemotherapy regimens with and without the addition of interferon in patients with advanced or recurrent melanoma.
Interventions
DRUGDacarbazine
900 mg / m2 every 3 weeks
DRUGFotemustine
100 mg / m2 every 3 weeks
DRUGInterferon Alfa-2b
5 M units every 3 weeks
Sponsors
National Cancer Institute, Naples
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of malignant melanoma in advanced stage or recurrent after surgery, and not amenable to further surgery or local therapy. * Presence of measurable disease * Age \> or = 18 years and \< or = 75 years * Performance status (ECOG) 0 - 2 (Appendix 2) * Life expectancy ³ 3 months * Adequate bone marrow function (ANC ³ 2,000/mmc; PTL ³ 100,000/mmc; Hb ³ 10 gr/dl), normal liver and renal function (bilirubin \< 1.25 x N, creatinine \< 1.25 x N, SGOT, SGPT \< 3 times upper normal limit of testing laboratory. * Written, informed consent prior to study specific procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice. * Prior surgery \> 3 weeks from initiating . * If palliative radiation is needed, in case of non target lesions, it must be given prior to initiating chemotherapy. If palliative radiation is required during the study the patient should be permanently discontinued from further treatment. * Adequate contraceptive measures during study participation for sexually active patients of child bearing potential must implement.
Exclusion criteria
* Previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-site of the cervix and basal or squamous cell carcinoma of the skin. * Prior chemo-immunotherapy ( previous adjuvant immunotherapy is allowed) * Known HIV disease. * Concurrent treatment with other experimental drugs. * Concurrent chemotherapy, immunotherapy, hormonal therapy (excluding contraceptives and replacement steroids), radiation therapy * Pregnant or lactating females Previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-site of the cervix and basal or squamous cell carcinoma of the skin. Prior chemo-immunotherapy ( previous adjuvant immunotherapy is allowed) Known HIV disease. Concurrent treatment with other experimental drugs. Concurrent chemotherapy, immunotherapy, hormonal therapy (excluding contraceptives and replacement steroids), radiation therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 24 months | Overall Survival was defined as the time from the date of randomisation to the date of death from any cause or the date of last follow-up for living patients. OS curves were estimated with the Kaplan - Meier (K-M) method and treatments were compared with a two - sided log - rank test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 12 months | Progression Free Survival (PFS) was defined as the time from the date of randomisation to the date of progression of disease or death from any cause, whichever occurred first, or date of last follow-up for patients without progression and alive at the end of the study. PFS curves were estimated with the Kaplan - Meier (K-M) method and treatments were compared with a two-sided log-rank test. |
| Overall Response Rate (ORR) | 18 weeks from start of therapy | Overall Response Rate (ORR) included Complete Response (CR) and Partial Response (PR). Complete Response (CR) was defined as disappearance of all symptoms and signs of all measurable disease, lasting for at least four weeks, without appearance of new lesions. Partial Response (PR) was defined as a \> 50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions, lasting for at least four weeks, without appearance of new lesions or enlargement of existing lesions. |
| Treatment Related Toxicity | at end of each 3 week cycle of therapy up to the discontinuation | worst grade CTC toxicity, for each cycle and overall, will be reported for each treatment arm |
Participant flow
Recruitment details
Patients were randomly assigned to one of four treatment groups. Patients were randomized through a computerized procedure of permuted blocks centralized at the coordinating center (Medical Oncology, NCI Napoli), stratified by PS (0-1,2) and site of metastases (visceral, not visceral).
Participants by arm
| Arm | Count |
|---|---|
| A1 - Combination Chemotherapy Without Interferon combination chemotherapy without interferon
Fotemustine: 100 mg / m2 IV on day 1 repeated on a 3 week cycle
Dacarbazine: 900 mg / m2 IV on day 2 repeated on a 3 week cycle | 64 |
| A2 - Combination Chemotherapy With Interferon combination chemotherapy with interferon
Fotemustine: 100 mg / m2 IV on day 1 repeated on a 3 week cycle
Dacarbazine: 900 mg / m2 IV on day 2 repeated on a 3 week cycle
Interferon Alfa-2b: α2b 5 MUI three times per week | 68 |
| B1 - Single Agent Dacarbazine Without Interferon single agent dacarbazine without interferon
Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle | 70 |
| B2 - Single Agent Dacarbazine Plus Interferon single agent dacarbazine plus interferon
Dacarbazine: 900 mg / m2 every 3 weeks
Interferon Alfa-2b: α2b 5 MUI three times per week | 58 |
| Total | 260 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 58 | 60 | 66 | 57 |
| Overall Study | Lost to Follow-up | 3 | 4 | 1 | 1 |
Baseline characteristics
| Characteristic | A1 - Combination Chemotherapy Without Interferon | A2 - Combination Chemotherapy With Interferon | B1 - Single Agent Dacarbazine Without Interferon | B2 - Single Agent Dacarbazine Plus Interferon | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 13 | 50 years STANDARD_DEVIATION 15 | 59 years STANDARD_DEVIATION 15 | 56 years STANDARD_DEVIATION 14 | 55 years STANDARD_DEVIATION 15 |
| Nodular melanoma | 27 Participants | 36 Participants | 36 Participants | 31 Participants | 130 Participants |
| Region of Enrollment Italy | 64 participants | 68 participants | 70 participants | 58 participants | 260 participants |
| Sex: Female, Male Female | 22 Participants | 33 Participants | 28 Participants | 20 Participants | 103 Participants |
| Sex: Female, Male Male | 42 Participants | 35 Participants | 42 Participants | 38 Participants | 157 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 62 | 25 / 67 | 16 / 71 | 13 / 52 |
| serious Total, serious adverse events | 14 / 62 | 27 / 67 | 8 / 71 | 10 / 52 |
Outcome results
Primary
Overall Survival (OS)
Overall Survival was defined as the time from the date of randomisation to the date of death from any cause or the date of last follow-up for living patients. OS curves were estimated with the Kaplan - Meier (K-M) method and treatments were compared with a two - sided log - rank test.
Time frame: 24 months
Population: Nine patients were lost to follow-up immediately after randomization and, in particular, for FDI + FD 132, instead of 136 randomized (4 lost pts.), for DI + D, 128 instead of 133 (5 lost pts.), for FD1 + DI 126, instead of 131 (5 lost pts.), 134 instead of 138 (4 lost pts.)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine | Overall Survival (OS) | 7.9 Months |
| Dacarbazine/Interferon + Dacarbazine | Overall Survival (OS) | 8.6 Months |
| Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon | Overall Survival (OS) | 9.1 Months |
| Fotemustine/Dacarbazine + Dacarbazine | Overall Survival (OS) | 7.7 Months |
Secondary
Overall Response Rate (ORR)
Overall Response Rate (ORR) included Complete Response (CR) and Partial Response (PR). Complete Response (CR) was defined as disappearance of all symptoms and signs of all measurable disease, lasting for at least four weeks, without appearance of new lesions. Partial Response (PR) was defined as a \> 50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions, lasting for at least four weeks, without appearance of new lesions or enlargement of existing lesions.
Time frame: 18 weeks from start of therapy
Population: Nine patients were lost to follow-up immediately after randomization and, in particular, for FDI + FD 132, instead of 136 randomized (4 lost pts.), for DI + D 128, instead of 133 (5 lost pts.), for FD1 + DI 126, instead of 131 (5 lost pts.), 134, instead of 138 (4 lost pts.).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine | Overall Response Rate (ORR) | 32 participants |
| Dacarbazine/Interferon + Dacarbazine | Overall Response Rate (ORR) | 33 participants |
| Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon | Overall Response Rate (ORR) | 34 participants |
| Fotemustine/Dacarbazine + Dacarbazine | Overall Response Rate (ORR) | 31 participants |
Secondary
Progression Free Survival (PFS)
Progression Free Survival (PFS) was defined as the time from the date of randomisation to the date of progression of disease or death from any cause, whichever occurred first, or date of last follow-up for patients without progression and alive at the end of the study. PFS curves were estimated with the Kaplan - Meier (K-M) method and treatments were compared with a two-sided log-rank test.
Time frame: 12 months
Population: Nine patients were lost to follow-up immediately after randomization and, in particular, for FDI + FD 132, instead of 136 randomized (4 lost pts.), for DI + D, 128 instead of 133 (5 lost pts.), for FD1 + DI 126, instead of 131 (5 lost pts.), 134 instead of 138 (4 lost pts.).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine | Progression Free Survival (PFS) | 2.7 Months |
| Dacarbazine/Interferon + Dacarbazine | Progression Free Survival (PFS) | 2.5 Months |
| Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon | Progression Free Survival (PFS) | 2.8 Months |
| Fotemustine/Dacarbazine + Dacarbazine | Progression Free Survival (PFS) | 2.5 Months |
Secondary
Treatment Related Toxicity
worst grade CTC toxicity, for each cycle and overall, will be reported for each treatment arm
Time frame: at end of each 3 week cycle of therapy up to the discontinuation
Population: It wasn't possible to assess the treatment related toxicity for all the patients included in the study because for some of them, no data were collected.~It's difficult to indicate the exact number of participants affected by the worst grade CTC toxicity because the same patient could be affected by one or more side effects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine | Treatment Related Toxicity | 129 Participants |
| Dacarbazine/Interferon + Dacarbazine | Treatment Related Toxicity | 122 Participants |
| Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon | Treatment Related Toxicity | 119 Participants |
| Fotemustine/Dacarbazine + Dacarbazine | Treatment Related Toxicity | 132 Participants |