Evaluating the Efficacy and Safety of a Sequencing Schedule of Cobimetinib Plus Vemurafenib Followed by Immunotherapy With an Anti- PD-L1 Antibody in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

NCT02902029 | Completed Phase 2

• 1 other identifier: ImmunoCobiVem_2015
• Study Type: interventional
• Target: 186
• Locations: 4 countries
• Sites: 27

Brief Summary

Most patients with locally advanced or metastatic tumors succumb to their disease. Thus, there is a substantial need for novel therapeutic strategies to improve the outcome for patients with advanced or metastatic melanoma. Targeting the the Ras/Raf signalling pathway by BRAF and MEK inhibition as well as targeting immunologic checkpoint control with an antiPD-L1 antibody have emerged as treatment option. In this study the best timing for sequential use of both treatment options (BRAF/MEK inhibition and antiPD-L1 antibody) in patients with unresectable or metastatic BRAFV600 mutant melanoma will be assessed.

Conditions

Malignant Melanoma

Keywords

unresectable stage IIIB, IIIC, IV melanoma

Outcome Measures

Primary Outcomes (1)

• Time to First Documented Disease Progression

  Time to first documented disease progression (PFS1) defined as time from start of run-in phase (date of first intake of study drug) to first documented disease progression date according to RECIST v. 1.1. (PD1) or death by any cause, whichever occurs first.

  4 years

Secondary Outcomes (11)

• Time to Second Objective Disease Progression (PFS2)

  4 years

• Adverse events according to CTCAE Version 4.03 criteria (Safety / Toxicity)

  Until 90 days of discontinuation of dosing of the investigational product

• Overall survival

  4 years

• Overall survival 12 months

  1 year

• Overall survival 24 months

  2 years

Study Arms (2)

Arm A

EXPERIMENTAL

After a 3 months run-in period with vemurafenib and cobimetinib \[960 mg vemurafenib twice daily (BID), 28/0; 60 mg cobimetinib daily (QD), 21/7\], all patients who do not show disease progression or definite treatment interruption (e.g. due to unacceptable toxicity) for more than 28 days will be randomized. Further treatment with vemurafenib and cobimetinib (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7). After progression of disease patients in Arm A will subsequently receive atezolizumab treatment (1200 mg/ q3w).

Drug: Vemurafenib; Drug: Cobimetinib; Drug: Atezolizumab

Arm B

EXPERIMENTAL

After a 3 months run-in period with vemurafenib and cobimetinib (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7), all patients who do not show disease progression or definite treatment interruption (e.g. due to unacceptable toxicity) for more than 28 days will be randomized. Further treatment with atezolizumab. Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on day 1 of each 21 day-cycle. After progression of disease patients in Arm B will cross back to vemurafenib and cobimetinib treatment (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7).

Drug: Vemurafenib; Drug: Cobimetinib; Drug: Atezolizumab

Interventions

Vemurafenib DRUG

960 mg vemurafenib BID until progression or unacceptable toxicity develops

Arm A; Arm B

Cobimetinib DRUG

60 mg cobimetinib QD, 21/7 until progression or unacceptable toxicity develops

Arm A; Arm B

Atezolizumab DRUG

1200 mg atezolizumab administered intravenously on day 1 of each 21 day-cycle. Will be given until progression or unacceptable toxicity develops

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be willing and able to provide written informed consent for the trial.
• Male or female patient being ≥18 years of age on day of signing informed consent.
• Histologically confirmed diagnosis of locally advanced, unresectable or metastatic melanoma AJCC (unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c) without active or untreated brain metastases; all known CNS lesions must have been treated with stereotactic therapy or surgery at least 4 weeks prior to the first dose of trial treatment AND the patient must be without evidence of clinical or radiographic disease progression in the CNS for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms must have returned to baseline, the patient must have no evidence of new or enlarging brain metastases, and the patient must not have used steroids for at least 3 weeks prior to trial treatment.
• No previous therapy for the advanced or metastatic stage. Prior adjuvant therapy is permitted (e.g. Interferon, Interleukin-2-therapy, chemo- or radiotherapy). Prior adjuvant therapy has to be terminated (last dose) at least 28 days before enrolment. Patients who are in follow-up period of a clinical trial in adjuvant setting and progressing may be enrolled / randomized.
• Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1, for the definition of a measureable lesion.
• Presence of BRAF mutation (V600) in tumor tissue.
• Performance status of 0 or 1 on the ECOG Performance Scale.
• Adequate organ function.
• Adequate cardiac function.
• Able to take oral medications.
• Female subject of childbearing potential should have a negative pregnancy test within 72 hours prior to receiving the first dose of study medication.
• Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to CTFG during the course of this study and for at least 6 months after completion of study therapy.

You may not qualify if:

• Use of any investigational or non-registered product within the 30 days before registration.
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study Day 1.
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Prior therapy with a BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib and / or MEK inhibitor
• Prior major surgery.
• Known additional malignancy that is progressing or requires active treatment within 5 years prior to the study.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• History of leptomeningeal metastases.
• History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to RVO or CSR.
• History of retinal degenerative disease.
• History of allogenic bone marrow transplantation or organ transplantation.
• History of Gilbert's syndrome.
• Impaired cardiovascular function or clinically significant cardiovascular diseases.
• Uncontrolled arterial hypertension despite medical treatment.
• Impairment of gastrointestinal function or gastrointestinal disease.

Sponsors & Collaborators

• University Hospital, Essen: lead

Study Sites (27)

Hôpital Ambroise-Paré

Boulogne-Billancourt, 92104, France

Location

Hospital Claude Huriez

Lille, 59000, France

Location

Hôpital de la Timone

Marseille, 13885, France

Location

CHU de Nantes

Nantes, 44093, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69310, France

Location

National Centre for Tumour Diseases (NCT)

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

SLK-Kliniken Heilbronn GmbH

Heilbronn, Baden-Wurttemberg, 74078, Germany

Location

University Hospital Mannheim, Clinic for Dermatology

Mannheim, Baden-Wurttemberg, 68167, Germany

Location

University Hospital Essen, Department of Dermatology, Skin Cancer Center

Essen, North Rhine-Westphalia, 45122, Germany

Location

HELIOS Klinikum Erfurt

Erfurt, Thuringia, 99089, Germany

Location

Charité-Universitätsmedizin Berlin

Berlin, 10117, Germany

Location

Elbe Kliniken Stade - Buxtehude

Buxtehude, 21614, Germany

Location

Universitätsklinikum Köln

Cologne, 50937, Germany

Location

Universitätsklinik Dresden

Dresden, 01307, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Universitätsklinikum des Saarlandes

Homburg/Saar, 66421, Germany

Location

Universitäts-Hautklinik Kiel

Kiel, 24105, Germany

Location

Universitätsklinikum Leipzig

Leipzig, 04103, Germany

Location

Gesellschaft für Klinische Forschung Ludwigshafen mbH

Ludwigshafen, 67063, Germany

Location

Universitätsklinikum Schleswig-Holstein

Lübeck, 23538, Germany

Location

Universitätsklinikum Mainz

Mainz, 55131, Germany

Location

Johannes Wesling Klinikum Minden

Minden, 32429, Germany

Location

Klinikum der Universität München

München, 80337, Germany

Location

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

Location

Uniklinikum Würzburg

Würzburg, 97080, Germany

Location

"LAIKO" General Hospital of Athens

Athens, 11527, Greece

Location

Military Medical Academy

Belgrade, 11000, Serbia

Location

MeSH Terms

Conditions

Melanoma

Interventions

Vemurafenib; cobimetinib; atezolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Dirk Schadendorf, Prof. Dr.

  University Hospital, Essen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: September 12, 2016
• First Posted: September 15, 2016
• Study Start: November 1, 2016
• Primary Completion: March 1, 2024
• Study Completion: March 1, 2024
• Last Updated: April 9, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (20); FR (5); GR (1); SE (1)