SICOG 0109: Fotemustine and Dacarbazine Versus Dacarbazine +/- Alpha Interferon in Advanced Malignant Melanoma

• Sponsor: National Cancer Institute, Naples (Other)
• Overall Status: Completed
• CT.gov ID: NCT01359956
• Collaborator: (none)
• Enrollment: 269
• Arms: 4
• Duration (Months): 106.1

Study Details

Study Description

Brief Summary

This study evaluated two chemotherapy regimens with and without the addition of interferon in patients with advanced or recurrent melanoma.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma; Recurrent Melanoma	Drug: Dacarbazine; Drug: Fotemustine; Drug: Interferon Alfa-2b	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 269 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Fotemustine and Dacarbazine Versus Dacarbazine +/- Alpha Interferon in Advanced Malignant Melanoma: Phase III Study
• Study Start Date: Apr 1, 2002
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Feb 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A1 combination chemotherapy without interferon	Drug: Dacarbazine; 900 mg / m2 every 3 weeks; Drug: Fotemustine; 100 mg / m2 every 3 weeks
Experimental: A2 combination chemotherapy with interferon	Drug: Dacarbazine; 900 mg / m2 every 3 weeks; Drug: Fotemustine; 100 mg / m2 every 3 weeks; Drug: Interferon Alfa-2b; 5 M units every 3 weeks
Active Comparator: B1 single agent dacarbazine without interferon	Drug: Dacarbazine; 900 mg / m2 every 3 weeks
Experimental: B2 single agent dacarbazine plus interferon	Drug: Dacarbazine; 900 mg / m2 every 3 weeks; Drug: Interferon Alfa-2b; 5 M units every 3 weeks

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• National Cancer Institute, Naples

Investigators

• Principal Investigator: Paolo A Ascierto, M.D., Ph.D., NCI Naples
• Principal Investigator: Antonio Daponte, M.D., NCI Naples
• Principal Investigator: Simona Signoriello, M.D., University of Campania "Luigi Vanvitelli"

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute, Naples
• ClinicalTrials.gov Identifier: NCT01359956
• Other Study ID Numbers: SICOG 0109
• First Posted: May 25, 2011
• Last Update Posted: Nov 13, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Melanoma; Interferons; Interferon-alpha; Interferon alpha-2; Dacarbazine; Fotemustine

Study Results

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).

Arm/Group Title	A1 - Combination Chemotherapy Without Interferon	A2 - Combination Chemotherapy With Interferon	B1 - Single Agent Dacarbazine Without Interferon	B2 - Single Agent Dacarbazine Plus Interferon
Arm/Group Description	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	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	single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week
Period Title: Overall Study
STARTED	67	69	71	62
COMPLETED	6	5	4	4
NOT COMPLETED	61	64	67	58

Baseline Characteristics

Arm/Group Title	A1 - Combination Chemotherapy Without Interferon	A2 - Combination Chemotherapy With Interferon	B1 - Single Agent Dacarbazine Without Interferon	B2 - Single Agent Dacarbazine Plus Interferon	Total
Arm/Group Description	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	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	single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week	Total of all reporting groups
Overall Participants	64	68	70	58	260
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54 (13)	50 (15)	59 (15)	56 (14)	55 (15)
Sex: Female, Male (Count of Participants)
Female	22 34.4%	33 48.5%	28 40%	20 34.5%	103 39.6%
Male	42 65.6%	35 51.5%	42 60%	38 65.5%	157 60.4%
Region of Enrollment (participants) [Number]
Italy	64 100%	68 100%	70 100%	58 100%	260 100%
Nodular melanoma (Count of Participants)
Count of Participants [Participants]	27 42.2%	36 52.9%	36 51.4%	31 53.4%	130 50%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine	Dacarbazine/Interferon + Dacarbazine	Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon	Fotemustine/Dacarbazine + Dacarbazine
Arm/Group Description	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 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	single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	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 single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week	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 single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle
Measure Participants	132	128	126	134
Median (Full Range) [Months]	7.9	8.6	9.1	7.7

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine	Dacarbazine/Interferon + Dacarbazine	Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon	Fotemustine/Dacarbazine + Dacarbazine
Arm/Group Description	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 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	single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	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 single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week	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 single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle
Measure Participants	132	128	126	134
Median (Full Range) [Months]	2.7	2.5	2.8	2.5

3. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine	Dacarbazine/Interferon + Dacarbazine	Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon	Fotemustine/Dacarbazine + Dacarbazine
Arm/Group Description	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 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	single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	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 single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week	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 single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle
Measure Participants	132	128	126	134
Number [participants]	32 50%	33 48.5%	34 48.6%	31 53.4%

4. Secondary Outcome

Title	Treatment Related Toxicity
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine	Dacarbazine/Interferon + Dacarbazine	Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon	Fotemustine/Dacarbazine + Dacarbazine
Arm/Group Description	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 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	single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	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 single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week	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 single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle
Measure Participants	129	122	119	132
Count of Participants [Participants]	129 201.6%	122 179.4%	119 170%	132 227.6%

Adverse Events

Arm/Group Title	A1 - Combination Chemotherapy Without Interferon		A2 - Combination Chemotherapy With Interferon		B1 - Single Agent Dacarbazine Without Interferon		B2 - Single Agent Dacarbazine Plus Interferon
Arm/Group Description	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		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		single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle		single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week
All Cause Mortality
	A1 - Combination Chemotherapy Without Interferon		A2 - Combination Chemotherapy With Interferon		B1 - Single Agent Dacarbazine Without Interferon		B2 - Single Agent Dacarbazine Plus Interferon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	A1 - Combination Chemotherapy Without Interferon		A2 - Combination Chemotherapy With Interferon		B1 - Single Agent Dacarbazine Without Interferon		B2 - Single Agent Dacarbazine Plus Interferon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/62 (22.6%)		27/67 (40.3%)		8/71 (11.3%)		10/52 (19.2%)
Blood and lymphatic system disorders
Neutropenia	9/62 (14.5%)	62	27/67 (40.3%)	67	8/71 (11.3%)	72	10/52 (19.2%)	52
Platelets	14/62 (22.6%)	62	23/67 (34.3%)	67	3/71 (4.2%)	72	4/52 (7.7%)	52
Anaemia	4/62 (6.5%)	62	13/67 (19.4%)	67	1/71 (1.4%)	72	2/52 (3.8%)	52
Other (Not Including Serious) Adverse Events
	A1 - Combination Chemotherapy Without Interferon		A2 - Combination Chemotherapy With Interferon		B1 - Single Agent Dacarbazine Without Interferon		B2 - Single Agent Dacarbazine Plus Interferon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/62 (19.4%)		25/67 (37.3%)		16/71 (22.5%)		13/52 (25%)
Gastrointestinal disorders
Nausea/Vomiting	12/62 (19.4%)		25/67 (37.3%)		16/71 (22.5%)		13/52 (25%)
Diarrhoea	3/62 (4.8%)		5/67 (7.5%)		3/71 (4.2%)		0/52 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.