Single-agent Cobimetinib for Adults With Histiocytic Disorders

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to find out what effects, good or bad, Cobimetinib has in patients with histiocytosis. Cobimetinib is an investigational oral medication that blocks MEK1.

Official Title
-----------------
Phase II Trial of Single-agent Cobimetinib for Adults With Histiocytic Disorders

Conditions
-----------------
Histiocytic Disorders

Intervention / Treatment
-----------------
* Drug: Cobimetinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed histiocytic disorder or histologic findings compatible with a histiocytic disorder in the context of confirmatory radiologic findings confirmed by the enrolling institution. One of the following: Documentation of BRAF V600E mutation and inability to access of BRAF inhibitor or prior treatment with a BRAF inhibitor discontinued due intolerable side effects or toxicity prior to progression, -OR- Documentation of wild-type BRAF V600 mutational status Patients with BRAF-mutated ECD/LCH who have had disease progression on BRAF inhibitor therapy would be eligible but would require tissue biopsy (or available tissue) for genotyping before participating. Measurable disease according to PET Response Criteria, confirmed by the MSK investigator radiologist, with the exception of patients with cutaneous disease that can be measured and followed by RECIST criteria Histiocytic disorder must be (a) multi-system disease or (b) disease that is recurrent or refractory to standard therapies, or (c) single-system disease with that is unlikely to benefit from conventional and less toxic therapies, based on the best available evidence (for example, CNS or cardiac infiltration, retroperitoneal fibrosis, prior chemotherapy, or other medical history or co-morbidities, etc) Life expectancy > 12 weeks Age ≥ 16 years ECOG performance status ≤ 3 (May be converted from Karnofsky Performance Status) Adequate bone marrow function as indicated by the following: ANC > 1000/uL Platelets ≥ 50,000/uL Hemoglobin ≥ 8.5 g/dL. Patients with cytopenias below these thresholds deemed to be the result of disease will be considered eligible. Adequate renal function, as indicated by: creatinine ≤ 1.5 the upper limit of normal (ULN) -OR- Estimated creatinine clearance of > 50 ml/min As for #7, patients with renal dysfunction deemed to be the result of disease will be considered eligible. Adequate liver function, as defined by bilirubin ≤ 1.5 ULN AND AST/ALT < 3 ULN Ability to swallow pills Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year. Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Patients must be willing to consent for protocol #12-245 for IMPACT testing (for MSK patients ONLY). Exclusion Criteria: Prior treatment with a MEK inhibitor Active infection requiring intravenous antibiotics Pregnant, lactating or breast feeding women Prior radiation therapy within the last 14 days Unwillingness or inability to comply with study and follow-up procedures. Any foods/supplements that are strong inhibitors or inducers of CYP3A are prohibited at least 7 days prior to initiation of and during study treatment History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, RVO, or neovascular macular degeneration The risk factors for RVO are listed below. Exclusion should be considered by clinical discretion if they have the following conditions: Uncontrolled glaucoma with intra-ocular pressures > 21mmHg Serum cholesterol ≥ Grade 2 Hypertriglyceridemia ≥ Grade 2 Hyperglycemia ≥ Grade 2 History of clinically significant cardiac dysfunction, unless deemed to be the direct result of disease, including the following: Current unstable angina Symptomatic congestive heart failure of NYHA class 2 or higher Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 2 are eligible). Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or below 50% Uncontrolled arrhythmias Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cobimetinib<br>This is an open-label, multicenter, phase II study exploring the efficacy and safety of single-agent Cobimetinib in patients with histiocytic disorders whose tumors are 1) BRAFV600 wildtype or 2) BRAFV600E mutant and are intolerant to, or unable to access, BRAF inhibitors. Visits during the treatment period are to be completed on Day 1, Day 15 (this visit can be by telephone), Day 29, and every 28 days thereafter. For patients treated on the study for six months, at the discretion of the Principal Investigator, visits can be spaced out to every 56 days (every 2 cycles instead of every cycle). After 24 cycles of treatment, if imaging demonstrates sustained stability in the opinion of the principal investigator, tumor assessments can be performed ever 1 year. | Drug: Cobimetinib<br>* Cobimetinib will be administered at a dose of 60mg daily for 21 days on, then 7 days off, in a 28 day treatment cycle. Patients will have the option to discontinue treatment after 12 cycles and will be monitored for disease relapse for an additional 12 months. In the event that disease relapse occurs within the 12 month monitoring period, patients will restart treatment and continue on study. Upon restarting, the assessment schedule will restart at rechallenge cycle 1(RC-1) and all assessments will occur at the frequency and intervals. Cycle 1 Day 15 visits will not be required for patients that restart treatment after relapse. Participants will re-sign consent upon rechallenging.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | by PET Response Criterial (PRC), with a dichotomous BOR of CR or PR versus neither of those. Assuming we use this binary endpoint of response, defined as best overall response of CR or PR versus not using the PET Response Criteria (PRC), a sample size of 18 patients provides 90% power to test the hypothesis that the response rate is promising (defined as 35% or higher) against a non-promising rate of 10% or lower. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cobimetinib, 15-216