Clinical Trials /

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

NCT01959633

Description:

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:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: VEMUPLINT
  • SECONDARY ID: 2013-003730-33
  • NCT ID: NCT01959633

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
VemurafenibBrand name= Zelborafvemurafenib+ Peg-interferon
Peg-interferonBrand name= Sylatronvemurafenib+ Peg-interferon

Purpose

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 will include 9 patients with the common design 3+3+3. This phase will last until MTD
      is reached and patients who were part of the cohort selected due to MTD will be extended at
      phase II. In the phase II, 42 patients will be enrolled.

      Vemurafenib 960 mg b.i.d. + Peg-interferon 1/2/3 micrograms/Kg one time per week (until MTD
      reached) Interferon treatment should start after 15 days of Vemurafenib only. In the Phase I
      groups of 3 patients will be entered at each dose level (vemurafenib 960 mg b.i.d. +
      Peg-interferon 1/2/3 micrograms/Kg). 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, 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 as MTD.

      This phase II is aimed:

      - to verify if the combination Vemurafenib plus PEG-interferon in advanced melanoma patients
      harboring the V600BRAF mutation is more active than the standard therapy (Vemurafenib) as
      reported in literature.

      Therefore, the lowest response probability of interest at 32 weeks is set to .40, and the
      combination treatment will be developed further only if the response at that time is at least
      .60.

      - to verify the upregulation of IFNAR1 expression in patients treated with the combination
      Vemurafenib plus PEG-interferon Therefore, the lowest expression probability of interest at 7
      days is set to .10, and the combination treatment will be developed further only if the
      expression is at least .90.

      Taking in account a 10% drop-out rate, a total of 48 patients will be enrolled to ensure a
      minimum of 42 evaluable patients.
    

Trial Arms

NameTypeDescriptionInterventions
vemurafenib+ Peg-interferonExperimentalVemurafenib 960 mg b.i.d. + Peg-interferon 1/2/3 micrograms/Kg once weekly
  • Vemurafenib
  • Peg-interferon

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

Details

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

Last Updated

January 18, 2017