Trial Outcomes & Findings for Fotemustine and Dacarbazine Versus Dacarbazine +/- Alpha Interferon in Advanced Malignant Melanoma (NCT NCT01359956)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

269 participants

Primary outcome timeframe

24 months

Results posted on

2023-04-11

Participant Flow

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).

Participant milestones

Participant milestones
Measure	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	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	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	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
Overall Study STARTED	67	69	71	62
Overall Study COMPLETED	6	5	4	4
Overall Study NOT COMPLETED	61	64	67	58

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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	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	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
Overall Study Death	58	60	66	57
Overall Study Lost to Follow-up	3	4	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	A1 - Combination Chemotherapy Without Interferon n=64 Participants 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	A2 - Combination Chemotherapy With Interferon n=68 Participants 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	B1 - Single Agent Dacarbazine Without Interferon n=70 Participants single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	B2 - Single Agent Dacarbazine Plus Interferon n=58 Participants single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week	Total n=260 Participants Total of all reporting groups
Age, Continuous	54 years STANDARD_DEVIATION 13 • n=99 Participants	50 years STANDARD_DEVIATION 15 • n=107 Participants	59 years STANDARD_DEVIATION 15 • n=206 Participants	56 years STANDARD_DEVIATION 14 • n=7 Participants	55 years STANDARD_DEVIATION 15 • n=31 Participants
Sex: Female, Male Female	22 Participants n=99 Participants	33 Participants n=107 Participants	28 Participants n=206 Participants	20 Participants n=7 Participants	103 Participants n=31 Participants
Sex: Female, Male Male	42 Participants n=99 Participants	35 Participants n=107 Participants	42 Participants n=206 Participants	38 Participants n=7 Participants	157 Participants n=31 Participants
Region of Enrollment Italy	64 participants n=99 Participants	68 participants n=107 Participants	70 participants n=206 Participants	58 participants n=7 Participants	260 participants n=31 Participants
Nodular melanoma	27 Participants n=99 Participants	36 Participants n=107 Participants	36 Participants n=206 Participants	31 Participants n=7 Participants	130 Participants n=31 Participants

PRIMARY outcome

Timeframe: 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.)

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.

Outcome measures

Outcome measures
Measure	Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine n=132 Participants 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	Dacarbazine/Interferon + Dacarbazine n=128 Participants 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	Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon n=126 Participants 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	Fotemustine/Dacarbazine + Dacarbazine n=134 Participants 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
Overall Survival (OS)	7.9 Months Interval 6.6 to 10.2	8.6 Months Interval 6.3 to 10.4	9.1 Months Interval 6.3 to 11.1	7.7 Months Interval 6.3 to 9.7

SECONDARY outcome

Timeframe: 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.).

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.

Outcome measures

Outcome measures
Measure	Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine n=132 Participants 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	Dacarbazine/Interferon + Dacarbazine n=128 Participants 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	Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon n=126 Participants 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	Fotemustine/Dacarbazine + Dacarbazine n=134 Participants 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
Progression Free Survival (PFS)	2.7 Months Interval 2.4 to 3.8	2.5 Months Interval 2.3 to 3.7	2.8 Months Interval 2.4 to 3.9	2.5 Months Interval 2.3 to 2.9

SECONDARY outcome

Timeframe: 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.).

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.

Outcome measures

Outcome measures
Measure	Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine n=132 Participants 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	Dacarbazine/Interferon + Dacarbazine n=128 Participants 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	Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon n=126 Participants 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	Fotemustine/Dacarbazine + Dacarbazine n=134 Participants 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
Overall Response Rate (ORR)	32 participants	33 participants	34 participants	31 participants

SECONDARY outcome

Timeframe: 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.

worst grade CTC toxicity, for each cycle and overall, will be reported for each treatment arm

Outcome measures

Outcome measures
Measure	Fotemustine/Dacarbazine/Interferon + Fotemustine/Dacarbazine n=129 Participants 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	Dacarbazine/Interferon + Dacarbazine n=122 Participants 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	Fotemustine/Dacarbazine/Interferon+Dacarbazine/Interferon n=119 Participants 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	Fotemustine/Dacarbazine + Dacarbazine n=132 Participants 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
Treatment Related Toxicity	129 Participants	122 Participants	119 Participants	132 Participants

Adverse Events

A1 - Combination Chemotherapy Without Interferon

Serious events: 14 serious events

Other events: 12 other events

Deaths: 0 deaths

A2 - Combination Chemotherapy With Interferon

Serious events: 27 serious events

Other events: 25 other events

Deaths: 0 deaths

B1 - Single Agent Dacarbazine Without Interferon

Serious events: 8 serious events

Other events: 16 other events

Deaths: 0 deaths

B2 - Single Agent Dacarbazine Plus Interferon

Serious events: 10 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	A1 - Combination Chemotherapy Without Interferon n=62 participants at risk 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	A2 - Combination Chemotherapy With Interferon n=67 participants at risk 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	B1 - Single Agent Dacarbazine Without Interferon n=71 participants at risk single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	B2 - Single Agent Dacarbazine Plus Interferon n=52 participants at risk single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week
Blood and lymphatic system disorders Neutropenia	14.5% 9/62 • Number of events 62	40.3% 27/67 • Number of events 67	11.3% 8/71 • Number of events 72	19.2% 10/52 • Number of events 52
Blood and lymphatic system disorders Platelets	22.6% 14/62 • Number of events 62	34.3% 23/67 • Number of events 67	4.2% 3/71 • Number of events 72	7.7% 4/52 • Number of events 52
Blood and lymphatic system disorders Anaemia	6.5% 4/62 • Number of events 62	19.4% 13/67 • Number of events 67	1.4% 1/71 • Number of events 72	3.8% 2/52 • Number of events 52

Other adverse events

Other adverse events
Measure	A1 - Combination Chemotherapy Without Interferon n=62 participants at risk 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	A2 - Combination Chemotherapy With Interferon n=67 participants at risk 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	B1 - Single Agent Dacarbazine Without Interferon n=71 participants at risk single agent dacarbazine without interferon Dacarbazine: 900 mg/m2 IV on day 1 repeated on a three-week cycle	B2 - Single Agent Dacarbazine Plus Interferon n=52 participants at risk single agent dacarbazine plus interferon Dacarbazine: 900 mg / m2 every 3 weeks Interferon Alfa-2b: α2b 5 MUI three times per week
Gastrointestinal disorders Nausea/Vomiting	19.4% 12/62	37.3% 25/67	22.5% 16/71	25.0% 13/52
Gastrointestinal disorders Diarrhoea	4.8% 3/62	7.5% 5/67	4.2% 3/71	0.00% 0/52

Additional Information

Paolo A Ascierto, M.D., Ph.D

NCI Naples

Phone: +39 081 5903431

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place