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.

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

1 year