Cobimetinib in Newly Diagnosed or HMA-treated CMML Patients With RAS Pathway Mutations

Inclusion Criteria:

• Male or female subject aged ≥ 18 years.

• Newly diagnosed or hypomethylating agent (HMA) refractory chronic myelomonocyticleukemia (CMML -0/-1/-2; 2016 WHO classification) with RAS pathway activation asdetermined by standard of care hematopoietic cell sequencing results on peripheralblood or bone marrow demonstrating NRAS, KRAS, PTPN11, FLT3, CBL, JAK2, BRAF or NF1mutations at variant allele frequency ≥ 5%. BMBx, NGS, FISH or BCR-ABL1 PCR, andcytogenetics should be done at the primary trial site within 21 days prior to C1D1. 5.1.2 If the patient is FLT3-ITD positive, the FLT3-ITD PCR allelic ratio must be ≥ 0.05 on testing done on screening biopsy (NOTE: cannot quantitate FLT3-ITD VAF byNGS, must be a separate PCR test).

• ECOG Performance Status ≤ 3.

• Adequate organ function as defined as:

• Hepatic:

• Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

• Unless elevation is related to Gilbert's syndrome, hemolysis, or thoughtto be due to leukemic hepatic involvement.

• AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN ----Unless elevation isrelated to leukemic hepatic involvement.

• Renal: ---Serum creatinine ≤ 2x ULN

• OR

• Estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula:

• Males: ((140-age)×weight[kg])/(serum creatinine [mg/dL]×72)

• Females: (((140-age)×weight[kg])/(serum creatinine [mg/dL]×72))×0.85

• Left ventricular function ≥ 50% as assessed by echocardiogram.

• Negative pregnancy test for women of childbearing potential or evidence ofpost-menopausal status. Women will be considered post-menopausal if they have beenamenorrheic for 12 months without an alternative medical cause. The followingage-specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy).

• Women ≥50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy).

• Highly effective contraception for both male and female subjects throughout thestudy and at least 3 months after the last dose of study therapy as described inSection 7.4 of the protocol.

• Recovery to baseline or Grade ≤ 1 CTCAE v5.0 from toxicities related to any priortreatments, unless AE(s) are clinically nonsignificant and/or stable on supportivetherapy.

• Able to provide informed consent and willing to sign an approved consent form thatconforms to federal and institutional guidelines.

Exclusion Criteria:

• Previous exposure to experimental MEK inhibitors for CMML.

• Grade 2 or greater QTc prolongation on screening electrocardiogram (ECG) orclinically significant cardiovascular disease (uncontrolled or symptomatic atrialarrhythmias, congestive heart failure, myocardial infarction/CABG/PCI within 6months of screening, uncontrolled arterial hypertension or history of ventriculararrhythmia)

• Clinical or laboratory evidence of central nervous system (CNS) leukemia.

• Major surgery within 4 weeks prior to study drug initiation.

• History of interstitial lung disease.

• History of retinal detachment, central serous retinopathy (CSR), retinal veinocclusion (RVO), or at high risk for CSR or RVO following screening ophthalmologicexam at discretion of PI/Sub-I following review of exam findings, and, if necessary,consultation with ophthalmology provider.

• Patients with muscular and/or neuromuscular disorders associated with elevated CPK (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, orspinal muscular atrophy).

• Any active significant gastrointestinal dysfunction as determined by the clinicalinvestigator to interfere with the patient's ability to swallow or absorb the studytreatment, (i.e. refractory nausea and vomiting, malabsorption and external biliaryshunt).

• Pregnant or nursing (lactating) women.

• On chronic treatment with strong CYP3A inhibitors or patients taking St. John'sWort, carbamazepine, efavirenz, phenytoin, rifampin, and other strong and moderateCYP3A inducers.

• Diagnosis of any other malignancy within 2 years before study enrollment, except foradequately treated basal cell or squamous cell skin cancer, carcinoma in situ of thebreast, bladder or cervix, low-grade (Gleason 6 or below) prostate cancer onsurveillance with no plans for treatment intervention (eg, surgery, radiation, orcastration), or prostate cancer that has been adequately treated with prostatectomyor radiotherapy and currently with no evidence of disease or symptoms, or any solidtumor malignancy that has been adequately treated for which there is no evidence ofdisease. Patients with monoclonal gammopathy of undetermined significance (MGUS) arepermitted to enroll.

• Known HIV infection with a detectable viral load at the time of screening.

--Note: Patients on effective antiretroviral therapy with an undetectable viral loadat the time of screening are eligible for this trial.

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination, and radiographic findings, and TB testing in linewith local practice), hepatitis B (known positive HBV surface antigen (HBsAg)result), or hepatitis C.

--Note: Patients with a past or resolved HBV infection (defined as the presence ofhepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA.

• Subjects taking prohibited medications as described in Section 6.3.2. A washoutperiod of prohibited medications for a period of at least 5 half-lives or asclinically indicated should occur before the start of treatment.

• Known prior severe hypersensitivity to cobimetinib or any component in itsformulations (NCI CTCAE v5.0 Grade ≥ 3).

• Medical, psychiatric, cognitive, or other conditions that may compromise thesubject's ability to understand the subject information, give informed consent,comply with the study protocol or complete the study.