Clinical Trials /

Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation



The hypothesis of this study is to evaluate the safety and the efficacy of Vemurafenib/PEG-interferon combination and the IFNAR1 upregulation lead by this treatment.

Related Conditions:
  • Melanoma
Recruiting Status:



Phase 1/Phase 2

Trial Eligibility



  • Brief Title: Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation
  • Official Title: Phase I-II Study of the Combination Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation

Clinical Trial IDs

  • SECONDARY ID: 2013-003730-33
  • NCT ID: NCT01959633


  • Melanoma


VemurafenibBrand name= ZelborafVemurafenib+Cobimetinib + Peg-interferon
Peg-interferonBrand name= SylatronVemurafenib+Cobimetinib + Peg-interferon
CobimetinibBrand name=CotellicVemurafenib+Cobimetinib + Peg-interferon


The hypothesis of this study is to evaluate the safety and the efficacy of Vemurafenib/PEG-interferon combination and the IFNAR1 upregulation lead by this treatment.

Detailed Description

      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.

Trial Arms

Vemurafenib+Cobimetinib + Peg-interferonExperimentalVemurafenib 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
  • Peg-interferon
  • Cobimetinib

Eligibility Criteria

        Inclusion Criteria:

          1. Patients over 18

          2. Untreated and pretreated (no more than 1 treatment) patients with metastatic melanoma
             at stage unreseactable IIIb-IV, histologically confirmed, that show V600 type BRAF
             mutations. Patients eligible for Phase I may have been pretreated with the
             investigational study treatments.

          3. Patient with measurable disease by RECIST v 1.1

          4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 - 1

          5. Patients who have successfully completed all the secondary side effects to previous
             systemic therapy

          6. Patients with an appropriate hematologic, hepatic and renal functionality, assessed in
             the 7 days preceding the start of therapy, as well as:

               -  Absolute neutrophil count (ANC)> 1.5 X 109 / L

               -  Absolute platelet count > 100 X 109 / L

               -  Hemoglobin > 9 g/dl

               -  Serum creatinine < 1.5 times the normal maximum values or Creatinine Clearance >
                  50 mL/hr (Cockroft-Gault formula)

               -  Transaminase level (AST and ALT) < 2.5 times the normal maximum values

               -  Serum bilirubin < 1.5 times the normal maximum values

          7. Negative pregnancy test performed within 7 days before beginning therapy
             (premenopausal women)

          8. Patients of childbearing age (or with partners of childbearing age) must use effective
             contraception during therapy and for at least 6 months after the effective treatment

          9. Absence of any psychological, familiar or social condition that may affect compliance
             with study protocol and scheduled follow-up

         10. Dated and signed informed consent before any study procedure

        Exclusion Criteria:

          1. Presence of symptomatic brain metastases

          2. Previous malignant cancer during the 2 years preceding the signing of informed consent

          3. Investigational study treatment within 28 days or 5 half-lives, whichever is longer,
             preceding the first dose of study treatments in this study

          4. Pregnancy and/or breast feeding;

          5. Nausea and vomit refractory to therapy, malabsorption, external biliary shunt,
             previous bowel resection, which could impair an adequate absorption

          6. Any of these conditions occurring in the 6 months before the start of Vemurafenib
             therapy: heart attack, unstable angina and/or severe degree, congestive heart failure,
             cerebrovascular accident or transient ischemic attack, pulmonary embolism, arterial
             hypertension not adequately controlled

          7. History of atrial or ventricular arrhythmia, symptomatic> grade 2 (NCI CTCAE)

          8. Hystory of retinopathy

          9. Correct QT interval > 450msec to baseline history of congenital long QT syndrome

         10. Uncontrolled medical condition among which endocrine disorders (such as
             hypothyroidism, hyperthyroidism and diabetes mellitus)

         11. Other severe medical or psychiatric conditions or abnormalities of laboratory tests
             that may increase the risk associated with study participation or the assumption of
             Vemurafenib, or that may interfere with the interpretation of study results, which in
             the judgment of the Investigator can make the patient not eligible for the study

         12. Unwillingness to practice adequate contraception

         13. Prior systemic treatment with BRAFi or MEKi, or interferon alpha
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with adverse events
Time Frame:up to 24 weeks
Safety Issue:
Description: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

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Fondazione Melanoma Onlus

Last Updated

June 11, 2019