Cobimetinib in Extracranial Arteriovenous Malformations (COBI-AVM Study)

Inclusion Criteria:

• 2 years to 80 years of age

• Extracranial AVM with volumetric measurable disease AVM Tissue from a prior biopsyalong with the corresponding pathology report will be required. If not available, abiopsy will be performed per standard of care

• Patient must be able to take an enteral dose and formulation of medication. Studymedication is only available as an oral suspension or tablet, which may be taken bymouth or other enteral route such as nasogastric or gastric tube

• Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16years of age

• ANC ≥ 0.75 x 109/L (unsupported/without growth factor stimulant in past 7 days)Platelet count ≥ 75 x 109/L (unsupported/without transfusion in past 7 days)Hemoglobin ≥ 8 g/dL (unsupported/without transfusion in past 7 days)

• Calculated creatinine clearance (or radioisotope GFR) ≥ 70 mL/min/1.73m2 or serumcreatinine based on age/gender as follows:

• Age 2 < 6 years: Male 0.8; Female 0.8

• Age 6 to < 10 years: Male1; Female 1

• Age 10 to < 13 years: Male 1.2; Female 1.2

• Age 13 to < 16 years: Male 1.5; Female 1.4

• Age >/= 16 years: Male 1.7; Female 1.4

• AST and ALT ≤ 2.5 x upper limit of normal (ULN) for age Bilirubin (sum of conjugated

• unconjugated) ≤ 1.5 x ULN for age

• Fractional shortening (FS) of ≥ 30% or ejection fraction of ≥ 50% by echocardiogram (ECHO) at Baseline, as determined by echocardiography within 21 days prior to studyentry

• Female patients of childbearing potential (FOCBP) require a negative urine or serumpregnancy test at Baseline, within one week prior to the start of each cycle, at theEnd of Treatment (EOT) visit, and at the 28-Day Post-Treatment Safety Follow-Up (Safety Follow-Up) visit

• Female patients of childbearing potential and female partners of male patients whoare pregnant or could become pregnant (i.e., females childbearing potential) mustagree to follow the contraceptive requirements using two forms of effectivecontraceptive methods (one of which must be a barrier method) for the duration ofthe study treatment and for at least 3 months after the last dose of cobimetinib toavoid pregnancy and/or potential adverse effects on a developing embryo. Agreementto true abstinence (not periodic abstinence or withdrawal method) is an acceptablemethod of birth control

• Patients must also agree not to donate eggs (female patients) or sperm (malepatients) during this study and for at least 3 months after the last dose ofcobimetinib

Exclusion Criteria:

• Patients taking strong inducers or inhibitors of CYP3A4 within 14 days prior tostudy entry, including but not limited to erythromycin, clarithromycin,ketoconazole, azithromycin, itraconazole, grapefruit juice, or St. John's Wort.Appendix A includes a list of other known CYP3A4 inducers and inhibitors that shouldbe discontinued at least 14 days prior to initiation of cobimetinib and avoidedduring study participation, if reasonable alternatives exist

• Completion of previous chemotherapy, immunotherapy, or targeted therapy forextracranial AVM with resolution of all associated toxicity to ≤ Grade 1 (except foralopecia and ototoxicity, which do not need to be resolved ≤ Grade 1) at least 28days prior to study entry (except if otherwise specified below). Patients must havefully recovered from the acute toxic effects of all prior anti-cancer therapy andmust meet the following minimum duration from prior anti-cancer directed therapyprior to study entry. If, after the required timeframe, the laboratory eligibilitycriteria are met, the patient is considered to have recovered adequately

• Treatment with a long-acting hematopoietic growth factor within 14 days prior toinitiation of cobimetinib or a short-acting hematopoietic growth factor within 7days prior to study entry

• Treatment with hormonal therapy (except hormone replacement therapy or oralcontraceptives), immunotherapy, biologic therapy, investigational therapy, or herbalcancer therapy within 28 days or < 5 half-lives, whichever is longer, prior to studyentry

• Corticosteroid therapy < 0.5 mg/kg/day averaged during the month prior to studyentry is permissible but must be discontinued 14 days prior to study entry

• Active malignancy or history of secondary malignancy

• History of severe hypersensitivity reactions to components of cobimetinib

• Refractory nausea and vomiting, malabsorption, external biliary shunt

• Patients who have a known active infection (excluding documented fungal infection ofthe nail beds) within 28 days prior to study entry that has not completely resolved

• Major surgical procedure or significant traumatic injury within 28 days prior tostudy entry, or anticipation of the need for major surgical procedure during thecourse of the study. Placement of a vascular access device or minor surgery ispermitted within 14 days of study entry (provided the wound has healed)

• History of significant bowel resection that would preclude adequate absorption orother significant malabsorptive disease

• History of pneumonitis

• Ophthalmologic considerations: Patients with known significant ophthalmologicconditions or known risk factors for retinal vein occlusion are not eligible.Specifically, patients with a history of retinal vein occlusion (RVO), retinaldetachment, retinal pathology on ophthalmologic exam, retinopathy of prematurity,central serous chorioretinopathy (CSSCR), neovascular retinopathy, intraocularpressure > 21 mmHg, and predisposing factors to RVO (e.g., uncontrolledhypertension, diabetes, or hyperlipidemia, coagulopathy) will be excluded

• Any other disease, metabolic or psychological dysfunction, physical examination orclinical laboratory finding giving reasonable suspicion of a disease or conditionthat in the opinion of the Investigator's judgement contraindicates use of aninvestigational drug or places the patient at unacceptable risk from treatmentcomplications

• Clinically significant cardiac arrhythmias or unstable arrhythmia includingbradyarryhthmias and/or patients who require anti-arrhythmic therapy (with theexception of beta-blockers or digoxin). Patients with controlled atrial fibrillationare not excluded.

• Unstable angina, or new-onset angina within 3 months prior to initiation ofcobimetinib

• Symptomatic congestive heart failure, defined as New York Heart Association Class IIor higher

• Myocardial infarction within 3 months prior to initiation of cobimetinib

• Known chronic human immunodeficiency virus (HIV)

• History of ≥ Grade 2 central nervous system (CNS) hemorrhage or history of any CNShemorrhage within 28 days of study entry

• Female patients who are pregnant or lactating. Pregnant or lactating women will notbe enrolled in this study because there is no available information regarding humanfetal or teratogenic toxicities.

• Patient has received treatment with investigational therapy within 4 weeks prior toinitiation of cobimetinib.