Cobimetinib for BRAF-wild-type or Mutated Histiocytoses (COBRAH)

Assistance Publique - Hôpitaux de Paris

Status and phase

Completed

Phase 3

Conditions

Disease or R Group Histiocytoses

Treatments

Drug: Placebo oral tablet

Drug: Cobimetinib

Study type

Interventional

Funder types

Other

Identifiers

NCT04007848

P170932J - 2018-00222-23

Details and patient eligibility

About

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.

Full 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.

Enrollment

54 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.