Clinical trial NCT02583516: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Melanoma
Lead sponsor: Grupo Español Multidisciplinar de Melanoma
Sponsor class: OTHER
Collaborators: name: Roche Farma, S.A
name: Pivotal S.L.
First posted: 2015-10-22
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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).

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Through study completion, up to 42 months
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Through study completion, up to 42 months
measure: Progression Free Survival (PFS) at one and two years
timeFrame: At one and two years
measure: Overall Survival (OS) at one and two years
timeFrame: At one and two years
measure: Adverse Events (AE) occurrence
timeFrame: Through study completion, up to 42 months
measure: Serious Adverse Events (SAE) occurrence
timeFrame: Through study completion, up to 42 months
measure: Adverse Events of Special Interest (AESI) occurrence
timeFrame: Through study completion, up to 42 months
Other outcomes:
measure: BRAF mutation determination (Translational sub-study)
timeFrame: Through study completion, up to 42 months
measure: Analysis of resistance mechanisms to the combination of vemurafenib and cobimetinib (Translational sub-study)
timeFrame: Through study completion, up to 42 months
measure: Analysis of disease's resistance mechanisms (Translational sub-study)
timeFrame: Through study completion, up to 42 months
Locations:
city: Donostia - San Sebastián
country: Spain
facility: Hospital Universitario Donostia
state: Guipuzcoa
city: Cartagena
country: Spain
facility: Hospital General Universitario Santa Lucía
state: Murcia
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Insular de Gran Canaria
city: Lugo
country: Spain
facility: Hospital Universitario Lucus Augusti
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Málaga
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Tenerife
country: Spain
facility: Hospital Universitario de Canarias
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitario Doctor Peset
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Vigo
country: Spain
facility: Hospital Álvaro Cunqueiro (Complejo Hospitalario Universitario de Vigo)
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital Universitario 12 de Octubre
name: José Antonio López-Martín, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital General Universitario de Valencia
name: Alfonso Berrocal, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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