Description:
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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
P170932J - 2018-00222-23
- NCT ID:
NCT04007848
Conditions
- Disease or R Group Histiocytoses
Interventions
| Drug | Synonyms | Arms |
|---|
| Cobimetinib | COTELLIC | Cobimetinib |
| Placebo oral tablet | PLACEBO | Placebo |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Cobimetinib | Experimental | Experimental group : 36 histiocytoses's patients without or with BRAF V600E will be randomised in cobimetinib group | |
| Placebo | Placebo Comparator | Control group : 18 histiocytoses's patients without or with BRAF V600E will be randomised in the placebo group | |
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | The objective metabolic responses |
| Time Frame: | at month 3 |
| Safety Issue: | |
| Description: | The objective metabolic responses is the percentage of patients with a complete metabolic response, partial metabolic response (reduction of a minimum of 30% in target lesions), stable metabolic disease or progressive metabolic disease according to PERCIST criteria (Haroche, et al. 2015) at Month 3. PERCIST criteria is defined by the PET response and will be used to evaluate the overall therapeutic response at month 3.
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 patients metabolic response. |
Secondary Outcome Measures
| Measure: | Overall survival |
| Time Frame: | every 12 weeks up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group |
| Safety Issue: | |
| Description: | Overall survival is defined as the time between the date of randomisation and the death. |
| Measure: | Progression-free survival |
| Time Frame: | every 12 weeks up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group |
| Safety Issue: | |
| Description: | Progression-free survival is defined as the time between the date of randomisation and the first documented event of disease progression according to PERCIST criteria (Haroche, et al. 2015). |
| Measure: | Number of participants with adverse events as assessed by CTCAE v4.0 |
| Time Frame: | From the randomisation up to 36 weeks for Cobimetinib group and 48 weeks for Placebo group. |
| Safety Issue: | |
| Description: | All adverse events from clinical evaluations and laboratory measurements assessed by CTCAE v4.0 |
| Measure: | Overall response of Cobimetinib (metabolic and tumor assessment) |
| Time Frame: | From the evaluation performed just before the treatment (Day 0 for Cobimetinib group, Week 12 for Placebo group) |
| Safety Issue: | |
| Description: | Overall response of Cobimetinib (metabolic and tumor assessment) assessed after 36 weeks of Cobimetinib treatment or until Cobimetinib stop. |
| Measure: | CRP levels |
| Time Frame: | At Baseline, Week 12, Week 24, Week 36 and Week 48 (for Placebo group) |
| Safety Issue: | |
| Description: | CRP levels assessed from blood samples |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Assistance Publique - Hôpitaux de Paris |
Last Updated
July 20, 2021
