Single-agent Cobimetinib for Adults With Histiocytic Disorders

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 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