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.
- Conditions
- BRAFV600-mutation positive patients with unresectable locally advanced or metastatic melanoma.MedDRA version: 17.1 Level: LLT Classification code 10053571 Term: Melanoma System Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2014-005277-36-ES
- Lead Sponsor
- Grupo Español Multidisciplicinar de Melanoma (GEM)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Not specified
- Target Recruitment
- 116
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 creatinina 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 116
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 116
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.
5. History of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer is allowed.
Exclusion Criteria Based on Organ Function Ocular:
6. 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.
7. 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.
Cardiac:
8. 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).
- 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%.
Central Nervous System:
9. Patients with active CNS lesions (including carcinomatous 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:
10. Current severe, uncontrolled systemic disease.
11. History of malabsorption or other condition that would interfere with absorption of study drugs.
12. Pregnant or lactating.
13. Unwillingness or inability to comply with study and follow- up procedures.
14. The following foods/supplements are prohibited at least 7 days prior to in
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate the efficacy (in terms of PFS) of two 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.;<br> Secondary Objective: - Efficacy of both schedule of treatment:<br> * % overall response rate.<br> * SLP rate at 1 an d 2 years<br> * Global supervivence at 1 and 2 years.<br> - Toleralibility of both schedule of treatmen (AEs, SAEs..)<br> ;Primary end point(s): Primary Endpoint PFS ( Progression free survival).;Timepoint(s) of evaluation of this end point: Until progression
- Secondary Outcome Measures
Name Time Method <br> Timepoint(s) of evaluation of this end point: - Progression free survival (PFS) at one and two years<br> - Overall survival (OS) at one and two years.<br><br> The rest of variables at the end of study.<br> ;<br> Secondary end point(s): - Overall response rate (ORR)<br> - Progression free survival (PFS) at one and two years<br> - Overall survival (OS) at one and two years.<br> - Safety (AEs, SAEs and other of special interest).<br> - Associated translational sub-study.<br>