Cobimetinib in Refractory Langerhans Cell Histiocytosis (LCH), and Other Histiocytic Disorders

Exclusion Criteria

• •\- Prior and Concomitant Use of Drugs with CYP3A4 inducing/inhibiting activity: Patient taking strong inducers or inhibitors of CYP3A4 within 14 days prior to study enrollment, including but not limited to the following: erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John's wort.
• •Prior Therapy Restrictions Completion of previous chemotherapy, immunotherapy, radiotherapy, or targeted therapy for LCH (or other histiocytic disorder) at least 28 days (except where specified below) prior to study enrollment, with resolution of all associated toxicity to ≤ Grade 1 prior to study enrollment (exception for alopecia and ototoxicity which do not need to be resolved ≤ Grade 1). Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the laboratory eligibility criteria are met, the patient is considered to have recovered adequately. See below for specific consideration of prednisone and corticosteroids prior to enrollment.
• •* Radiation therapy within the 14 days prior to enrollment.
• •* Any prior treatment with Cobimetinib.
• •* Treatment with a long-acting hematopoietic growth factor within 14 days prior to initiation of study drug or a short-acting hematopoietic growth factor within 7 days prior to enrollment.
• •* Treatment with hormonal therapy (except hormone replacement therapy or oral contraceptives), immunotherapy, biologic therapy, investigational therapy, or herbal cancer therapy within 28 days or \< 5 half-lives, whichever is longer, prior to study enrollment.
• •* For patients with brain tumors (intracranial masses), use of anticoagulants within 7 days prior to enrollment.
• •* Corticosteroid therapy less than or equal to 0.5 mg/kg/day averaged during the 28 days prior to study enrollment is permissible. Patients receiving corticosteroids must be on a stable or decreasing dose for 14 days prior to enrollment and discontinue once study treatment has started.
• •* Patient has received treatment with investigational therapy within 4 weeks prior to initiation of study drug.
• •* Patients taking anticoagulants or have a pre-existing bleeding disorder unrelated to histiocytic disease.
• •Exclusions for other illness
• •* Other active malignancy or history of secondary malignancy.
• •* Refractory nausea and vomiting, malabsorption, external biliary shunt
• •* Infection: Patients who have a known active infection (excluding documented fungal infection of the nail beds) within 28 days prior to enrollment that has not completely resolved.
• •* Major surgical procedure or significant traumatic injury within 28 days prior to enrollment, or anticipation of need for major surgical procedure during the course of the study. Placement of a vascular access device or minor surgery is permitted within fourteen (14) days prior to study enrollment (provided that the wound has healed).
• •* History of significant bowel resection that would preclude adequate absorption or other significant malabsorptive disease.
• •* History of pneumonitis.
• •* Any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that in the opinion of the investigator contraindicates use of an investigational drug or places the patient at unacceptable risk from treatment complications.
• •History of clinically significant cardiac dysfunction, including the following:
• •* Clinically significant cardiac arrhythmias including brady-arrhythmias and/or patients who require anti-arrhythmic therapy (with the exception of beta blockers or digoxin). Patients with controlled atrial fibrillation are not excluded.
• •* Unstable arrhythmia
• •* Unstable angina, or new-onset angina within 3 months prior to initiation of study treatment
• •* Symptomatic congestive heart failure, defined as New York Heart Association Class II or higher
• •* Myocardial infarction within 3 months prior to initiation of study treatment
• •Known chronic human immunodeficiency virus (HIV).
• •History of Grade ≥ 2 CNS hemorrhage or history of any CNS hemorrhage within 28 days of enrollment.
• •Female patients who are pregnant or lactating. Pregnant or lactating women will not be entered on this study because there is no available information regarding human fetal or teratogenic toxicities.