Clinical trial NCT04007848: Cobimetinib for BRAF-wild-type or Mutated Histiocytoses
Official title: Cobimetinib for BRAF-wild-type or Mutated Histiocytoses : a Randomized, Placebo-controlled, Double Blind Study" COBRAH Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Disease or R Group Histiocytoses
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2019-07-05
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: The objective metabolic responses
timeFrame: at month 3
Secondary outcomes:
measure: Overall survival
timeFrame: every 12 weeks up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group
measure: Progression-free survival
timeFrame: every 12 weeks up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group
measure: Number of participants with adverse events as assessed by CTCAE v4.0
timeFrame: From the randomisation up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group.
measure: Overall response of Cobimetinib (metabolic and tumor assessment)
timeFrame: From the evaluation performed just before the treatment (Day 0 for Cobimetinib group, Week 12 for Placebo group)
measure: CRP levels
timeFrame: At Baseline, Week 12, Week 24, Week 36 and Week 48 (for Placebo group)
Other outcomes:
Locations:
city: Paris
country: France
facility: Service de Médecine interne - La Pitié Salpêtrière
Study officials:
affiliation: APHP
name: Fleur Dr COHEN AUBART
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.