Cobimetinib for the Treatment of RAS Pathway-Mutated Newly Diagnosed or Refractory Chronic Myelomonocytic Leukemia
- Subject aged >= 18 years
- Newly diagnosed or hypomethylating agent (HMA) refractory chronic myelomonocytic leukemia (CMML-0/-1/-2; 2016 World Health Organization [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%
- 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
- 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 2 weeks month 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
- Previous exposure to experimental MEK inhibitors for CMML
- Grade 2 or greater corrected QT (QTc) 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
- History of retinal detachment, central serous retinopathy (CSR), retinal vein occlusion (RVO), or at risk for CSR or RVO following screening ophthalmologic exam
- 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 interfering with the patient’s ability to swallow or absorb the study treatment
- 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
- Diagnosis of any other malignancy within 2 years before 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 (e.g., surgery, radiation, or castration), or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms
- 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 tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), or hepatitis C * 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
Salt Lake City
I. To assess the efficacy of cobimetinib in patients with newly diagnosed and hypomethylating agent (HMA)-refractory chronic myelomonocytic leukemia (CMML).
I. To assess the safety of cobimetinib treatment in CMML.
II. To assess the complete response (CR) + partial response (PR) rate (as defined by the 2015 Myelodysplastic Syndrome [MDS]/Myeloproliferative Neoplasm [MPN]-International Working Group [IWG] criteria) with cobimetinib treatment in CMML.
III. To assess the long term efficacy of cobimetinib treatment in CMML.
I. To assess the effect of cobimetinib treatment on molecular and phenotypic disease characteristics and characterize mechanisms of resistance.
Patients receive cobimetinib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 36 months.
Trial Phase Phase II
Trial Type Treatment
Huntsman Cancer Institute / University of Utah
- Primary ID HCI132394
- Secondary IDs NCI-2020-11637
- Clinicaltrials.gov ID NCT04409639