Cobimetinib for BRAF-wild-type Histiocytoses

Cobimetinib for BRAF-wild-type Histiocytoses : a Randomized, Placebo-controlled, Double Blind Study" COBRAH Study

Sponsors

Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Source Assistance Publique - Hôpitaux de Paris
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 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.

Overall Status Recruiting
Start Date July 25, 2019
Completion Date June 22, 2023
Primary Completion Date September 22, 2021
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
The objective metabolic responses at month 3
Secondary Outcome
Measure Time Frame
Overall survival every 12 weeks up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group
Progression-free survival every 12 weeks up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group
Number of participants with adverse events as assessed by CTCAE v4.0 From the randomisation up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group.
Overall response of Cobimetinib (metabolic and tumor assessment) From the evaluation performed just before the treatment (Day 0 for Cobimetinib group, Week 12 for Placebo group)
CRP levels At Baseline, Week 12, Week 24, Week 36 and Week 48 (for Placebo group)
Enrollment 54
Condition
Intervention

Intervention Type: Drug

Intervention Name: Cobimetinib

Description: 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

Arm Group Label: Cobimetinib

Other Name: COTELLIC

Intervention Type: Drug

Intervention Name: Placebo oral tablet

Description: 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

Arm Group Label: Placebo

Other Name: 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,

- 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"

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Fleur Dr COHEN AUBART Principal Investigator APHP
Overall Contact

Last Name: Fleur Dr COHEN AUBART

Phone: +33142178242

Email: [email protected]

Location
Facility: Status: Contact: Service de Médecine interne - La Pitié Salpêtrière Fleur Dr COHEN AUBART +33142178242 [email protected]
Location Countries

France

Verification Date

June 2019

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Cobimetinib

Type: Experimental

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

Label: Placebo

Type: Placebo Comparator

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

Acronym COBRAH
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov