Cobimetinib for BRAF-wild-type or Mutated Histiocytoses

NCT ID: NCT04007848

Last Updated: 2025-01-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-25
• Study Completion Date: 2022-03-14

Brief Summary

COBRAH is a randomized double-blind 2-steps controlled superiority trial, with 2 parallel groups.

Patients will be randomly assigned in a 2:1 ratio to receive Cobimetinib orally or placebo during the first 12-weeks step, allowing the determination of the primary criteria.

Detailed Description

Histiocytoses are rare multisystemic disorders characterized by accumulation of histiocytes in various organs. Virtually all the patients have a somatic mutation in the RAS-RAF-MEK-ERK pathway. BRAF inhibitors are efficacious to treat BRAF-mutated patients but one third of the patients are BRAF-wild type. For these patients, preliminary data have shown an efficacy of the MEK inhibitor cobimetinib. This trial aims to evaluate the efficacy of cobimetinib for treating BRAF-wild type or mutated patients with L or R group histiocytoses.

The primary objective of the COBRAH trial is to demonstrate that the rate of objective metabolic response (complete or partial) according to PERCIST criteria is higher under Cobimetinib versus placebo.

The objective metabolic response according to PERCIST criteria (Haroche, et al. 2015) is defined by the Positron Emission Tomography (PET) response and will be used to evaluate the overall therapeutic response at month 3 (Week 12).

For PERCIST criteria, a quantitative analysis of uptake will be performed using the standard uptake value (SUV). Fitting regions of interest covering pathologic uptake will be used to define target lesions. PERCIST will be used to classify the patients as complete metabolic response, partial metabolic response (reduction of a minimum of 30% in target lesions), stable metabolic disease or progressive metabolic disease.

Conditions

Disease or R Group Histiocytoses

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Cobimetinib

Experimental group : 36 histiocytoses's patients without or with BRAF V600E will be randomised in cobimetinib group

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Cobimetinib will be given at the dose of 40 milligrams once a day (21 days/28). Cobimetinib is available as 20 milligrams film-coated tablets

Placebo

Control group : 18 histiocytoses's patients without or with BRAF V600E will be randomised in the placebo group

Group Type: PLACEBO_COMPARATOR

Placebo oral tablet

Intervention Type: DRUG

Placebo will be given at the dose of 40 milligrams once a day (21 days/28). Placebo is available as 20 milligrams film-coated tablets

Interventions

Cobimetinib

Cobimetinib will be given at the dose of 40 milligrams once a day (21 days/28). Cobimetinib is available as 20 milligrams film-coated tablets

Intervention Type: DRUG

Placebo oral tablet

Placebo will be given at the dose of 40 milligrams once a day (21 days/28). Placebo is available as 20 milligrams film-coated tablets

Intervention Type: DRUG

Other Intervention Names

COTELLIC; PLACEBO

Eligibility Criteria

Inclusion Criteria

• Eligible patients should be at least 18 years of age,
• Have a histologically confirmed L or R group histiocytoses without BRAFV600E mutation detected with the use of a real-time polymerase chain reaction or with BRAFV600E mutation AND a contra-indication to BRAF inhibitors
• Have a measurable disease according to the PERCIST criteria with presence of at least one severe organ involvement (heart, vascular, central nervous system) OR a multisystemic disease with ≥3 organ involvement AND failure of a first-line treatment or contra-indication to these treatments,
• Accepting effective contraception during treatment duration (men and women childbearing potential) and 3 months after.
• Signed informed consent

Exclusion Criteria

• Patients with severe hepatic, renal and cardiac outcomes
• Patients with myopathies at baseline
• Patients with retinal detachment at baseline
• Patients with inherited disorders of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
• Patients with high bleeding risk.
• Allergies to iodized contrast media
• Simultaneous participation in another medical research
• Pregnancy or breast-feeding.
• No affiliation to the French Health Care System "sécurité sociale" OR no affiliation of European Health within the scope of Regulations (EEC) n° 1408/71 and 574/72 coordinating social security systems.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Fleur Dr COHEN AUBART

Role: PRINCIPAL_INVESTIGATOR

APHP

Locations

Service de Médecine interne - La Pitié Salpêtrière

Paris, Paris, France

Countries

France

References

Jouenne F, Benattia A, Tazi A. Mitogen-activating protein kinase pathway alterations in Langerhans cell histiocytosis. Curr Opin Oncol. 2021 Mar 1;33(2):101-109. doi: 10.1097/CCO.0000000000000707.

Reference Type: DERIVED

PMID: 33315630 (View on PubMed)

Other Identifiers

P170932J - 2018-00222-23

Identifier Type: -

Identifier Source: org_study_id