Cobimetinib for the Treatment of RAS Pathway-Mutated Newly Diagnosed or Refractory Chronic Myelomonocytic Leukemia

Inclusion Criteria

• Male or female subject aged >= 18 years
• Untreated or hypomethylating agent (HMA) refractory chronic myelomonocytic leukemia (CMML-1/-2; 2022 WHO classification) with RAS pathway activation as determined by standard-of-care hematopoietic cell sequencing results on peripheral blood or bone marrow demonstrating NRAS, KRAS, PTPN11, FLT3, CBL, JAK2, BRAF or NF1 mutations at a variant allele frequency >= 5%. Bone marrow biopsy (BMBx), next-generation sequencing (NGS), fluorescence in situ hybridisation (FISH), or BCR-ABL1 PCR and cytogenetics should be done at the primary trial site within 21 days prior to cycle 1 day 1 (C1D1). Results from a previous NGS panel completed within 60 days of registration may be used for the purpose of confirming eligibility. * If the patient is FLT3-ITD positive, the FLT3-ITD PCR allelic ration must be >= 0.05 on testing done on screening biopsy (NOTE: cannot quantitate FLT3-ITD variant allele frequency [VAF] by NGS, must be a separate PCR test).
• Eastern Cooperative Oncology Group (ECOG) performance status =< 3
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) * Unless elevation is related to Gilbert’s syndrome, hemolysis, or thought to be due to leukemic hepatic involvement
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN * Unless elevation is related to leukemic hepatic involvement
• Serum creatinine =< 2 x ULN OR estimated creatinine clearance >= 30 mL/min by Cockcroft-Gault formula
• Left ventricular function >= 50% as assessed by echocardiogram or multigated acquisition scan (MUGA)
• Negative pregnancy test for women of childbearing potential or evidence of post-menopausal status. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) * Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
• Highly effective contraception for both male and female subjects throughout the study and at least 3 months after the last dose of study therapy
• Recovery to baseline or grade =< 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines

Exclusion Criteria

• Previous exposure to experimental MEK inhibitors for CMML
• Grade 2 or greater Fridericia's Correction Formula (QTcF) prolongation on screening electrocardiogram (ECG) or clinically significant cardiovascular disease (uncontrolled or symptomatic atrial arrhythmias, congestive heart failure, myocardial infarction/coronary artery bypass surgery [CABG]/percutaneous coronary intervention [PCI] within 6 months of screening, uncontrolled arterial hypertension or history of ventricular arrhythmia)
• 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 or pneumonitis
• History of retinal detachment, central serous retinopathy (CSR), retinal vein occlusion (RVO), or at high risk for CSR or RVO following screening ophthalmologic exam 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, or spinal muscular atrophy)
• Any active significant gastrointestinal dysfunction as determined by the clinical investigator to interfer with the patient’s ability to swallow or absorb the study treatment, (i.e refractory nausea and vomiting, malabsorption and external biliary shunt)
• Pregnant or nursing (lactating) women
• On chronic treatment with strong CYP3A inhibitors or patients taking St. John’s wort, carbamazepine, efavirenz, phenytoin, rifampin, and other strong and moderate CYP3A inducers
• Treatment for any other malignancy within 2 years of study enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or cervix, low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation, or castration), prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms, or any solid tumor malignancy that has been adequately treated for which there is no evidence of active disease within the last 2 years. Patients with monoclonal gammopathy of undetermined significance (MGUS) are permitted to enroll
• Known human immunodeficiency virus (HIV) infection with a detectable viral load at the time of screening * Note: Patients on effective antiretroviral therapy with an undetectable viral load at the time of screening are eligible for this trial
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C. Active, controlled infections that, in the opinion of the PI, do not increase risk or interfere with study participation are allowed with prior medical monitor approval * Note: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
• Subjects taking prohibited medications. A washout period of prohibited medications for a period of at least 5 half-lives or as clinically indicated should occur before the start of treatment
• Known prior severe hypersensitivity to cobimentinib or any component in its formulations (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]5.0 grade >= 3)
• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study