Vemurafenib and Cobimetinib Combination in BRAF Mutated Melanoma With Brain Metastasis

NCT02537600 | Completed Phase 2 DMC

• 2 other identifiers: 2013-TL-MEL-Th2014-001671-30
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 17

Brief Summary

The purpose of this study is to determine wether cobimetinib + vemurafenib combination treatment is effective in the treatment of BRAFV600-mutated melanoma patients with brain metastasis

Conditions

Malignant Melanoma

Keywords

BRAF mutation; Brain metastasis; Cobimetinib + Vemurafenib combination treatment

Outcome Measures

Primary Outcomes (1)

• Complete or partial intracranial response rate in cohort A on the evaluation of each patient's best tumor response by the centralized review committee according to modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria.

  From baseline up to 36 months

Secondary Outcomes (7)

• Complete or partial intracranial response rates in cohorts B and C based on the evaluation of each patient's best tumor response by the centralized review committee according to modified RECIST 1.1 criteria.

  Up to 36 months

• Intracranial duration of response (DR) in cohorts A, B and C.

  Up to 36 months

• Overall response rate of cohorts A, B and C

  Up to 36 months

• Overall survival in cohorts A, B and C

  Up to 36 months

• Frequency of Adverse events

  Up to 36 months

Other Outcomes (2)

• Ratio between cerebrospinal fluid concentration and plasmatic exposure of vemurafenib and cobimetinib

  At Day15 Cycle 1

• BRAF mutation rate in circulating DNA tumor

  From baseline up to treatment stop or progression. An average of 8 cycles of treatment is expected.

Study Arms (1)

Cobimetinib + Vemurafenib combination

EXPERIMENTAL

Every patients will be treated with : Vemurafenib 1920 mg / day from day 1 to day 28 continuously Cobimetinib 60 mg / day from day 1 to day 21 One cycle = 28 days Intervention = Cobimetinib + Vemurafenib combination treatment. Only one arm.

Drug: Cobimetinib + Vemurafenib combination treatment

Interventions

Cobimetinib + Vemurafenib combination treatment DRUG

Patients will be treated from day 1 to day 28 with Vemurafenib and from day 1 to day 21 with Cobimetinib. Day 1 to Day 28 corresponds to one cycle of treatment.

Also known as: Vemurafenib = Zelboraf (commercial name), Cobimetinib = code number RO5514041/F04

Cobimetinib + Vemurafenib combination

Eligibility Criteria

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

You may qualify if:

• Men and women ≥ 18 years of age.
• Histologically confirmed metastatic cutaneous melanoma, mucous melanoma, or melanoma of unknown primary origin (stage IV).
• Documented BRAFV600 mutation determined in a hospital center specializing in the molecular genetics of cancer that is certified by the French national cancer institute (INCa).
• Presence of Brain Metastases (BM) for which surgical resection is not a reasonable treatment option but that may be amenable to treatment with targeted therapy, to be decided in the onco-dermatology and/or neuro-oncology multidisciplinary team meeting (MDTM).
• At least one measurable BM in at least one dimension between 5 and 40 mm on magnetic resonance imaging (MRI) with gadolinium (modified RECIST 1.1).
• Patients having previously received a maximum of two systemic therapies during the metastatic phase, except BRAF, Map ERK Kinase (MEK) or Extracellular signal Regulated Kinase (ERK) inhibitors or tyrosine kinase pan-inhibitors (TKIs); prior ipilimumab therapy is allowed if patients have documented cerebral progression 12 weeks after the last injection of treatment and if MRI confirms progression at least 4 weeks later. A period of at least 6 weeks must be observed between the last dose of ipilimumab and the first administration of the study treatments. Prior treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed.
• Patients with symptomatic or asymptomatic BM.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Patients must have recovered from all the side effects (grade ≤ 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events, NCI-Common Toxicity Criteria for Adverse Event (CTCAE), version 4.03) of their most recent systemic or local treatment (except alopecia).
• Signed and dated informed consent before carrying out any procedures that are specific to the trial and are not procedures (examinations) conducted as part of normal patient care.
• Patients willing and able to comply with scheduled visits, treatment schedule, laboratory testing and other trial procedures.
• Negative serum pregnancy test within 10 days of the first dose of the study treatment for women of childbearing age. Women of non-childbearing potential may be included if they are surgically sterile or postmenopausal for ≥ 1 year.
• Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after the last administration of the study treatment. Effective methods of contraception are defined as those that have a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as injectable implants combined with oral contraception or intra-uterine devices, or as total abstinence in cases where the lifestyle of the patient ensures compliance.
• Adequate hematologic, renal and hepatic function within 14 days of the administration of treatment:
• Hematologic Leucocytes \> 2.0 x 109/L Neutrophils \> 1.0 x 109/L Hemoglobin (transfusion allowed) \> 9 g/dL Platelets \> 100 x 109/L Liver Total bilirubin \< 1.5 x upper limit of normal (ULN) (\< 3.0 mg/dL for patients with Gilbert syndrome) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN (\< 5 x ULN if there is liver metastasis) Alkaline phosphatase (ALP) \< 3 x ULN (\< 5 x ULN if there is liver or bone metastasis) Kidney Creatinine Or creatinine clearance \< 1.5 x ULN ≥ 40 mL/min (Cockcroft-Gault formula)

You may not qualify if:

• Uveal melanoma. Patients with mucous melanoma or melanoma of unknown primary origin are eligible if BRAFV600 mutation is confirmed.
• Symptomatic or diffuse leptomeningeal involvement.
• Indication for urgent neurosurgery or radiotherapy.
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been treated to complete remission or untreated stage I chronic lymphoid leukemia.
• Known human immunodeficiency virus (HIV) infection.
• Prior treatment with BRAF, MEK, or ERK inhibitors or pan-TKIs.
• Concurrent administration of any anticancer therapies other than those administered in this study.
• Treatment with any cytotoxic and/or investigational drug or targeted therapy within 4 weeks of the first dose of the study treatment, or ipilimumab, anti-PD-1 or anti-PD-L1 immunotherapy within 8 weeks of the study treatment and/or radiation therapy within 2 weeks of the study treatment.
• Pregnant or breastfeeding women.
• Refractory nausea and vomiting, intestinal malabsorption, or significant bowel resection that would preclude adequate absorption or cause an inability to swallow tablets.
• Ulcerative colitis, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticula or other gastrointestinal condition increasing the risk of perforation.
• Any of the following within the 6 months prior to the first dose of study treatment:
• myocardial infarction,
• severe/unstable angina,
• symptomatic congestive heart failure (New York Heart Association grade ≥2),

Sponsors & Collaborators

• Center Eugene Marquis: lead

Study Sites (17)

CHU de Bordeaux

Bordeaux, 33000, France

Location

CHU Ambroise Paré

Boulogne, 92104, France

Location

CHU Brest - Hôpital Morvan

Brest, France

Location

CHU Caen - Hôpital Clémenceau

Caen, 14033, France

Location

Hôpital Henri Mondor

Créteil, 94010, France

Location

CHU de Dijon

Dijon, France

Location

CHU Albert Michallon

Grenoble, 38014, France

Location

Centre Hospitalier du Mans

Le Mans, 72037, France

Location

CHRU Lille

Lille, 59037, France

Location

Centre Hospitalier Lyon Sud

Lyon, 69495, France

Location

CHU de Nantes

Nantes, 44093, France

Location

Groupe Hospitalier l'Archet

Nice, 06202, France

Location

Hôîtal St louis

Paris, 75010, France

Location

Hôpital Cochin

Paris, 75014, France

Location

Hôpital Bichat

Paris, 75018, France

Location

Centre Eugène Marquis

Rennes, 35042, France

Location

CHU Tours

Tours, 37044, France

Location

MeSH Terms

Conditions

Melanoma; Brain Neoplasms

Interventions

cobimetinib

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; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Thierry Lesimple, MD

  Centre Eugène Marquis

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2015
• First Posted: September 1, 2015
• Study Start: December 1, 2015
• Primary Completion: November 6, 2019
• Study Completion: November 6, 2019
• Last Updated: January 27, 2020

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (17)