Clinical Trial to Evaluate the Efficacy of Vemurafenib in Combination With Cobimetinib (Continuous and Intermittent) in BRAFV600-mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

February 14, 2020 updated by: Grupo Español Multidisciplinar de Melanoma

A Randomized Phase II Study of Vemurafenib Plus Cobimetinib Continuous Versus Intermittent, in Previously Untreated BRAFV600- Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

The purpose of this study is to evaluate the efficacy and safety of two different schedules of administration of vemurafenib in combination with cobimetinib (continuous and intermittent) in previously untreated BRAFV600- mutation positive patients with unresectable locally advanced or metastatic melanoma.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

70

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Barcelona, Spain
        • Hospital Clinic de Barcelona
      • Barcelona, Spain
        • Hospital del Mar
      • Barcelona, Spain
        • Hospital Universitario Vall d'Hebron
      • Las Palmas de Gran Canaria, Spain
        • Hospital Insular de Gran Canaria
      • Lugo, Spain
        • Hospital Universitario Lucus Augusti
      • Madrid, Spain
        • Hospital Universitario 12 de Octubre
      • Madrid, Spain
        • Hospital Universitario La Paz
      • Málaga, Spain
        • Hospital Regional Universitario de Malaga
      • Salamanca, Spain
        • Hospital Clínico Universitario de Salamanca
      • Sevilla, Spain
        • Hospital Universitario Virgen Macarena
      • Tenerife, Spain
        • Hospital Universitario de Canarias
      • Valencia, Spain
        • Hospital Universitario y Politecnico La Fe
      • Valencia, Spain
        • Hospital General Universitario de Valencia
      • Valencia, Spain
        • Hospital Universitario Doctor Peset
      • Vigo, Spain
        • Hospital Álvaro Cunqueiro (Complejo Hospitalario Universitario de Vigo)
      • Zaragoza, Spain
        • Hospital Universitario Miguel Servet
    • Guipuzcoa
      • Donostia - San Sebastián, Guipuzcoa, Spain
        • Hospital Universitario Donostia
    • Murcia
      • Cartagena, Murcia, Spain
        • Hospital General Universitario Santa Lucía

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Disease-Specific Inclusion Criteria:

  1. Patients with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma.
  2. Patients must be naïve to treatment for locally advanced unresectable or metastatic disease.
  3. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue.
  4. Measurable disease per RECIST v1.1.
  5. ECOG performance status of 0 or 1.

  6. Additionally, patients to be included in the biomarker sub- study should meet the following criteria:

    • Consent to provide archival tissue for biomarker analyses.
    • Consent to undergo tumor biopsies.

    General Inclusion Criteria:

  7. Male or female patient aged major or equal 18 years.
  8. Able to participate and willing to give written informed.
  9. Life expectancy mayor o igual 12 weeks.

  10. Adequate hematologic and end organ function, within 14 days prior to first dose of study drug treatment:

    • ANC major or equal 1.5 × 109/L.
    • Platelet count major or equal 100 × 109/L.
    • Hemoglobin major or equal 9 g/dL.
    • Albumin major or equal 2.5 g/dL.
    • Bilirubin minor or equal 1.5 × the upper limit of normal (ULN).
    • AST, ALT, and alkaline phosphatase minor or equal 3 × ULN, with the following exceptions:
    • Patients with documented liver metastases: AST and/or ALT minor or equal 5 × ULN.
    • Patients with documented liver or bone metastases alkaline phosphatase minor o equal 5 × ULN.
    • Serum creatinine minor o equal 1.5 × ULN or CrCl major or equal 40 mL/min on the basis of measured CrCl from a 24- hour urine collection.
  11. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use 2 effective forms of contraception during the course of this study and for at least 6 months after completion of study therapy.
  12. Negative serum pregnancy test within 10 days prior to commencement of dosing in women of childbearing potential.
  13. Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol and follow-up after treatment discontinuation schedule.

Exclusion Criteria:

Cancer-Related Exclusion Criteria:

  1. History of prior RAF or MEK pathway inhibitor treatment.
  2. Palliative radiotherapy within 14 days prior to the first dose of study treatment.
  3. Major surgery or traumatic injury within 14 days prior to first dose of study treatment.

  4. Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Patients with a previous malignancy within the past 3 years are excluded except for patients with resected BCC or SCC of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast. History of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer is allowed.

    Exclusion Criteria Based on Ocular Function:

  5. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration.

    The risk factors for RVO are listed below. Patients will be excluded if they have the following conditions:

    • Uncontrolled glaucoma with intra-ocular pressures > 21 mmHg.
    • Serum cholesterol major or equal Grade 2.
    • Hypertriglyceridemia major or equal Grade 2.
    • Hyperglycemia (fasting) major or equal Grade 2.

    Exclusion Criteria Based on Cardiac Function:

  6. History of clinically significant cardiac dysfunction, including the following:

    • Current unstable angina.
    • Symptomatic congestive heart failure of New York Heart Association class 2 or higher.
    • History of congenital long QT syndrome or mean (average of triplicate measurements) QTcF > 450 msec at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus). If not automated, calculation of QTcF must be done through the following formula: QTcF = (QT interval in ms) / [(60 / heart rate in bpm) )^(1/3)]
    • Uncontrolled hypertension major or equal Grade 2 (patients with a history hypertension controlled with anti-hypertensives to minor or equal Grade 1 are eligible).
    • Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%.

    Exclusion Criteria Based on Central Nervous System Function:

  7. Patients with active CNS lesions (including melanomatous meningitis) are excluded. However, patients are eligible if:

    • All known CNS lesions have been treated with stereotactic therapy or surgery, AND
    • There has been no evidence of clinical and radiographic disease progression in the CNS for major or equal 3 weeks after radiotherapy or surgery.

    Whole brain radiotherapy is not allowed, with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal brain lesions.

    General Exclusion Criteria:

  8. Current severe, uncontrolled systemic disease.
  9. History of malabsorption or other condition that would interfere with absorption of study drugs.
  10. Pregnant or lactating.
  11. Unwillingness or inability to comply with study and follow- up procedures.

  12. The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:

    • St. Johns wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer).
    • Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A - Continuous Administration
960 mg of vemurafenib po, bid, days 1 to 28 and 60 mg of cobimetinib po, od, days 1 to 21, for each 28-days' cycle.
Drug: vemurafenib and cobimetinib
Comparison between different treatment regimens
Experimental: B - Intermittent Administration
960 mg of vemurafenib po, bid, days 1 to 28 and 60 mg of cobimetinib po, od, days 1 to 21, for each 28-days' cycle, during 12 weeks. After that period, patients will be treated with both drugs at the same doses indicated previously, but with an intermittent pattern: vemurafenib days 1 to 28 followed by 14 days off (4 weeks on and 2 weeks off) and cobimetinib days 1 to 21 followed by 21 days off (3 weeks on and 3 weeks off)
Drug: vemurafenib and cobimetinib
Comparison between different treatment regimens

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Progression Free Survival (PFS)
Time Frame: Through study completion, up to 42 months
Through study completion, up to 42 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Overall Response Rate (ORR)
Time Frame: Through study completion, up to 42 months
Through study completion, up to 42 months
Progression Free Survival (PFS) at one and two years
Time Frame: At one and two years
At one and two years
Overall Survival (OS) at one and two years
Time Frame: At one and two years
At one and two years
Adverse Events (AE) occurrence
Time Frame: Through study completion, up to 42 months
Through study completion, up to 42 months
Serious Adverse Events (SAE) occurrence
Time Frame: Through study completion, up to 42 months
Through study completion, up to 42 months
Adverse Events of Special Interest (AESI) occurrence
Time Frame: Through study completion, up to 42 months
Through study completion, up to 42 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
BRAF mutation determination (Translational sub-study)
Time Frame: Through study completion, up to 42 months
Analysis of prognostic and predictive value of BRAF mutation in cell-free DNA (cfDNA) samples, and its role in disease evolution monitoring.
Through study completion, up to 42 months
Analysis of resistance mechanisms to the combination of vemurafenib and cobimetinib (Translational sub-study)
Time Frame: Through study completion, up to 42 months
Non-invasive monitorization of resistance mechanisms, through selected gene expression cuantification from blood mRNA.
Through study completion, up to 42 months
Analysis of disease's resistance mechanisms (Translational sub-study)
Time Frame: Through study completion, up to 42 months
Determination of resistance mechanisms in secuential biopsies of the disease.
Through study completion, up to 42 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Grupo Español Multidisciplinar de Melanoma

Collaborators

Roche Farma, S.A
Pivotal S.L.

Investigators

  • Principal Investigator: José Antonio López-Martín, MD, PhD, Hospital Universitario 12 de Octubre
  • Principal Investigator: Alfonso Berrocal, MD, PhD, Hospital General Universitario de Valencia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 30, 2015

Primary Completion (Actual)

September 30, 2019

Study Completion (Actual)

September 30, 2019

Study Registration Dates

First Submitted

October 8, 2015

First Submitted That Met QC Criteria

October 20, 2015

First Posted (Estimate)

October 22, 2015

Study Record Updates

Last Update Posted (Actual)

February 17, 2020

Last Update Submitted That Met QC Criteria

February 14, 2020

Last Verified

July 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GEM-01-15
  • 2014-005277-36 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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