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

Phase 2

Completed

• Conditions: Melanoma
• Interventions: Drug: vemurafenib and cobimetinib

• Registration Number: NCT02583516
• Lead Sponsor: Grupo Español Multidisciplinar de Melanoma

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2015-06-30
• Study First Submitted: 2015-10-08
• Study First Submitted QC: 2015-10-20
• Study First Posted: 2015-10-22
• Status Verified: 2019-07
• Primary Completion: 2019-09-30
• Study Completion: 2019-09-30
• Last Update Submitted: 2020-02-14
• Last Update Posted: 2020-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 70

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.

Read More

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).

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
A - Continuous Administration	vemurafenib and cobimetinib	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.
B - Intermittent Administration	vemurafenib and cobimetinib	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)

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Through study completion, up to 42 months

Secondary Outcome Measures

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

Trial Locations

Locations (18)

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Universitario de Canarias; 🇪🇸 Tenerife, Spain

Hospital Clínico Universitario de Salamanca; 🇪🇸 Salamanca, Spain

Hospital Universitario Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

Hospital Insular de Gran Canaria; 🇪🇸 Las Palmas de Gran Canaria, Spain

Hospital del Mar; 🇪🇸 Barcelona, Spain

Hospital Universitario Doctor Peset; 🇪🇸 Valencia, Spain

Hospital Álvaro Cunqueiro (Complejo Hospitalario Universitario de Vigo); 🇪🇸 Vigo, Spain

Hospital Clínic de Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitario Donostia; 🇪🇸 Donostia - San Sebastián, Guipuzcoa, Spain

Hospital Regional Universitario de Málaga; 🇪🇸 Málaga, Spain

Hospital General Universitario Santa Lucía; 🇪🇸 Cartagena, Murcia, Spain

Hospital Universitario Lucus Augusti; 🇪🇸 Lugo, Spain

Hospital Universitario Virgen Macarena; 🇪🇸 Sevilla, Spain

Hospital Universitario y Politécnico La Fe; 🇪🇸 Valencia, Spain

Hospital Universitario Miguel Servet; 🇪🇸 Zaragoza, Spain

Hospital General Universitario de Valencia; 🇪🇸 Valencia, Spain