Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation (VEMUPLINT)
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|ClinicalTrials.gov Identifier: NCT01959633|
Recruitment Status : Completed
First Posted : October 10, 2013
Last Update Posted : February 24, 2022
|Condition or disease||Intervention/treatment||Phase|
|Melanoma||Drug: Vemurafenib Drug: Peg-interferon Drug: Cobimetinib||Phase 1 Phase 2|
Phase I A cohort of 3 consecutive patients will be treated at each dose level (first step). Patients are scheduled to receive at least two courses of therapy (cycle every 28 days) at the same dose level. Escalation of the dose to the next higher level proceeds in absence of dose-limiting toxicity (DLT). Drug-related toxicities will be evaluated during each cycle of therapy and graded according to the NCI Common Toxicity Criteria.
Adverse events (AEs) and the activity of the treatment in terms of ORR, will be assessed as primary endpoints, respectively for phase I and phase II; other variables will be compared as secondary endpoints.
The treatment scheme is Peg-Interferon 1/2/3 micrograms/Kg (lyophilized powder 296 and 444 μg vials) one time per week + Vemurafenib film-coated capsules 960 mg b.i.d. + Cobimetinib tablets 60 mg o.d. 21 days on followed by 7 days off.
Interferon treatment should start after 15 days of Vemurafenib + Cobimetinib only.
Phase I will be conducted at Istituto Nazionale per lo Studio e la Cura dei Tumori - Fondazione G. Pascale (PI Paolo Antonio Ascierto) and a minimum of 3 patients per cohort will be enrolled. Groups of 3 patients will be entered at each dose level (vemurafenib 960 mg b.i.d. + Cobimetinib 60 mg o.d. 21 days on followed by 7 days off + Peg-interferon 1/2/3 micrograms/Kg). DLT will be determined after 2 courses of therapy: if all 3 patients treated at a dose level have been observed for 2 courses of therapy without DLT, then the dose will be escalated. If at least 2/3 patients have DLT after the first 2 courses of therapy in each cohort, then the previous dose level will be considered as the MTD. If 1/3 patients have DLT, then 3 more patients will be treated at this dose level. If none of these patients has DLT, then the dose will be escalated. If at least one of the 3 additional patients has DLT, then the previous dose will be considered the MTD.
The maximum tolerated dose (MTD) is then considered the recommended dose for further evaluation (next step).
Patients experiencing toxicities that were not dose-limiting can be retreated at the same dose level upon full recovery.
Special case is represented by patients with liver metastases for whom ALT or AST increases >3xULN (i.e., Grade 2 of the CTCAE) requires a closer monitoring of the liver tests. In such cases patients with AT up to 5xULN may be allowed to participate in the trial. Therefore, a threshold level of ALT or AST >3xBaseline value (vs. the standard >3xULN threshold) is considered to prompt closer monitoring for the whole duration of the treatment. Patients with rapidly rising or high serum ALT or AST or with ALT or AST elevations accompanied by jaundice require urgent evaluation to find treatable causes of hepatocellular necrosis.
Patients will be treated until progression if the MTD is not reached.
Phase II Phase II will be conducted in approximately 10 Investigational sites located in Italy and 42 patients will be enrolled in total (including 3 patients from the phase I).
Treatment will be continued until progression or unacceptable toxicity.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||11 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I-II Study of the Combination Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation|
|Actual Study Start Date :||April 3, 2014|
|Actual Primary Completion Date :||March 26, 2018|
|Actual Study Completion Date :||March 26, 2018|
Experimental: Vemurafenib+Cobimetinib + Peg-interferon
Vemurafenib 960 mg b.i.d. + Cobimetinib 60 mg o.d.(21 days on followed by 7 days off) + Peg-interferon 1/2/3 micrograms/Kg once weekly
Vemurafenib 960 mg b.i.d. for each course of treatment lasting 28 days
Other Name: Brand name= Zelboraf
In the Phase I are included 3 cohorts. Cohort 1) Peg-interferon 1 µg/Kg one time per week s.c. Cohort 2) Peg-interferon 2 µg/Kg one time per week s.c. Cohort 3) Peg-interferon 3 µg/Kg one time per week s.c. Interferon treatment should start after 15 days of Vemurafenib only
In the Phase II is included the cohort selected by phase I due to MTD and expanded at RD.
Other Name: Brand name= Sylatron
Cobimetinib 60 mg o.d. (21 days on followed by 7 days off)
Other Name: Brand name=Cotellic
- Number of participants with adverse events [ Time Frame: up to 24 weeks ]
The NCI CTC-AE (Version 4) will be used to evaluate the clinical safety of the treatment in this study. Patients will be assessed for AEs at each clinical visit up to 24 weeks and as necessary throughout the study.
Hematology and biochemistry will be done as part of regular safety assessments
- Number of Objective tumor responses [ Time Frame: From date of randomization until the date of first documented progression or date of death for many cause, whichever came first, assessed up to week 32 ]Objective tumor response will be measured according to the modified RECIST 1.1 criteria. Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and followed until disease progression. Durable response rate (DRR) will be identified as the percentage of patients that is still in CR and PR at week 32. The results will be tabulated with Clopper-Pearson 95%CI for response rates
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01959633
|Napoli, Italy, 80131|
|Study Chair:||Paolo A Ascierto, MD||Fondazione Melanoma Onlus|