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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

Primary Purpose

Melanoma

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
vemurafenib and cobimetinib
Sponsored by
Grupo Español Multidisciplinar de Melanoma
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Hospital Universitario Donostia
  • Hospital General Universitario Santa Lucía
  • Hospital Clínic de Barcelona
  • Hospital del Mar
  • Hospital Universitario Vall d'Hebron
  • Hospital Insular de Gran Canaria
  • Hospital Universitario Lucus Augusti
  • Hospital Universitario 12 de Octubre
  • Hospital Universitario La Paz
  • Hospital Regional Universitario de Málaga
  • Hospital Clínico Universitario de Salamanca
  • Hospital Universitario Virgen Macarena
  • Hospital Universitario de Canarias
  • Hospital General Universitario de Valencia
  • Hospital Universitario Doctor Peset
  • Hospital Universitario y Politécnico La Fe
  • Hospital Álvaro Cunqueiro (Complejo Hospitalario Universitario de Vigo)
  • Hospital Universitario Miguel Servet

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

A - Continuous Administration

B - Intermittent Administration

Arm Description

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.

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)

Outcomes

Primary Outcome Measures

Progression Free Survival (PFS)

Secondary Outcome Measures

Overall Response Rate (ORR)
Progression Free Survival (PFS) at one and two years
Overall Survival (OS) at one and two years
Adverse Events (AE) occurrence
Serious Adverse Events (SAE) occurrence
Adverse Events of Special Interest (AESI) occurrence

Full Information

First Posted
October 8, 2015
Last Updated
February 14, 2020
Sponsor
Grupo Español Multidisciplinar de Melanoma
Collaborators
Roche Farma, S.A, Pivotal S.L.
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1. Study Identification

Unique Protocol Identification Number
NCT02583516
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
June 30, 2015 (Actual)
Primary Completion Date
September 30, 2019 (Actual)
Study Completion Date
September 30, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grupo Español Multidisciplinar de Melanoma
Collaborators
Roche Farma, S.A, Pivotal S.L.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
70 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A - Continuous Administration
Arm Type
Experimental
Arm Description
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.
Arm Title
B - Intermittent Administration
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
vemurafenib and cobimetinib
Intervention Description
Comparison between different treatment regimens
Primary Outcome Measure Information:
Title
Progression Free Survival (PFS)
Time Frame
Through study completion, up to 42 months
Secondary Outcome Measure Information:
Title
Overall Response Rate (ORR)
Time Frame
Through study completion, up to 42 months
Title
Progression Free Survival (PFS) at one and two years
Time Frame
At one and two years
Title
Overall Survival (OS) at one and two years
Time Frame
At one and two years
Title
Adverse Events (AE) occurrence
Time Frame
Through study completion, up to 42 months
Title
Serious Adverse Events (SAE) occurrence
Time Frame
Through study completion, up to 42 months
Title
Adverse Events of Special Interest (AESI) occurrence
Time Frame
Through study completion, up to 42 months
Other Pre-specified Outcome Measures:
Title
BRAF mutation determination (Translational sub-study)
Description
Analysis of prognostic and predictive value of BRAF mutation in cell-free DNA (cfDNA) samples, and its role in disease evolution monitoring.
Time Frame
Through study completion, up to 42 months
Title
Analysis of resistance mechanisms to the combination of vemurafenib and cobimetinib (Translational sub-study)
Description
Non-invasive monitorization of resistance mechanisms, through selected gene expression cuantification from blood mRNA.
Time Frame
Through study completion, up to 42 months
Title
Analysis of disease's resistance mechanisms (Translational sub-study)
Description
Determination of resistance mechanisms in secuential biopsies of the disease.
Time Frame
Through study completion, up to 42 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Disease-Specific Inclusion Criteria: Patients with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma. Patients must be naïve to treatment for locally advanced unresectable or metastatic disease. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue. Measurable disease per RECIST v1.1. ECOG performance status of 0 or 1. 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: Male or female patient aged major or equal 18 years. Able to participate and willing to give written informed. Life expectancy mayor o igual 12 weeks. 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. 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. Negative serum pregnancy test within 10 days prior to commencement of dosing in women of childbearing potential. 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: History of prior RAF or MEK pathway inhibitor treatment. Palliative radiotherapy within 14 days prior to the first dose of study treatment. Major surgery or traumatic injury within 14 days prior to first dose of study treatment. 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: 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: 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: 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: Current severe, uncontrolled systemic disease. History of malabsorption or other condition that would interfere with absorption of study drugs. Pregnant or lactating. Unwillingness or inability to comply with study and follow- up procedures. 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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
José Antonio López-Martín, MD, PhD
Organizational Affiliation
Hospital Universitario 12 de Octubre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alfonso Berrocal, MD, PhD
Organizational Affiliation
Hospital General Universitario de Valencia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Universitario Donostia
City
Donostia - San Sebastián
State/Province
Guipuzcoa
Country
Spain
Facility Name
Hospital General Universitario Santa Lucía
City
Cartagena
State/Province
Murcia
Country
Spain
Facility Name
Hospital Clínic de Barcelona
City
Barcelona
Country
Spain
Facility Name
Hospital del Mar
City
Barcelona
Country
Spain
Facility Name
Hospital Universitario Vall d'Hebron
City
Barcelona
Country
Spain
Facility Name
Hospital Insular de Gran Canaria
City
Las Palmas de Gran Canaria
Country
Spain
Facility Name
Hospital Universitario Lucus Augusti
City
Lugo
Country
Spain
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
Country
Spain
Facility Name
Hospital Universitario La Paz
City
Madrid
Country
Spain
Facility Name
Hospital Regional Universitario de Málaga
City
Málaga
Country
Spain
Facility Name
Hospital Clínico Universitario de Salamanca
City
Salamanca
Country
Spain
Facility Name
Hospital Universitario Virgen Macarena
City
Sevilla
Country
Spain
Facility Name
Hospital Universitario de Canarias
City
Tenerife
Country
Spain
Facility Name
Hospital General Universitario de Valencia
City
Valencia
Country
Spain
Facility Name
Hospital Universitario Doctor Peset
City
Valencia
Country
Spain
Facility Name
Hospital Universitario y Politécnico La Fe
City
Valencia
Country
Spain
Facility Name
Hospital Álvaro Cunqueiro (Complejo Hospitalario Universitario de Vigo)
City
Vigo
Country
Spain
Facility Name
Hospital Universitario Miguel Servet
City
Zaragoza
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
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http://www.groupgem.org/
Description
Spanish Multidisciplinary Melanoma Group Web

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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

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