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

NCT04409639 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 1 other identifier: HCI132394
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 3

Brief Summary

This is an open-label, nonrandomized phase 2 trial to assess the efficacy of cobimetinib in RAS pathway activated CMML. All eligible patients will be treated daily with cobimetinib in 28-day cycles. Cobimetinib will be administered for three weeks followed by a one week break prior to the start of the following cycle. Patients will remain on study therapy until treatment discontinuation criteria is met.

Conditions

Chronic Myelomonocytic Leukemia (CMML)

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR)

  To assess the efficacy of cobimetinib in patients with newly diagnosed and HMA- refractory chronic myelomonocytic leukemia (CMML). Overall response rate (ORR) is defined as the proportion of patients achieving complete remission, complete cytogenetic remission, partial remission, marrow response, and clinical benefit according to the 2015 MDS/MPN-IWG criteria. This was assessed from the dose of study medication to the decision to end treatment or up to 12 months of treatment, whichever came first.

  From 1st dose of study medication to decision to end treatment or up to 12 months of treatment, whichever came first

Secondary Outcomes (4)

• Related Grade 3-5 Adverse Events

  From the start of study treatment to the last dose of study treatment, up to 2.3 years

• Count of Patients Achieving Complete Response Complete Response (CR) or Partial Response (PR)

  From the start of study treatment, until the last disease assessment, up to 2.6 years

• Progression-free Survival (PFS)

  up to 36 months after the start of therapy, the time of progression, initiation of alternative treatment or death, whichever came first

• Overall Survival (OS)

  Study anticipated to be 60 months.

Study Arms (1)

Treatment: all patients

EXPERIMENTAL

Cobimetinib is taken on a 28-day cycle. Each dose consists of three 20 mg tablets (60 mg) and should be taken once daily for 21 consecutive days (Days 1 to 21-treatment period); followed by a 7-day break (Days 22 to 28-treatment break). Each subsequent cobimetinib treatment cycle should start after a 7-day treatment break has elapsed.

Drug: Cobimetinib

Interventions

Cobimetinib DRUG

Cobimetinib is taken on a 28-day cycle. Each dose consists of three 20 mg tablets (60 mg) and should be taken once daily for 21 consecutive days (Days 1 to 21-treatment period); followed by a 7-day break (Days 22 to 28-treatment break). Each subsequent cobimetinib treatment cycle should start after a 7-day treatment break has elapsed.

Treatment: all patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subject aged ≥ 18 years.
• Newly diagnosed or hypomethylating agent (HMA) refractory chronic myelomonocytic leukemia (CMML -0/-1/-2; 2016 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 variant allele frequency ≥ 5%. BMBx, NGS, FISH or BCR-ABL1 PCR, and cytogenetics 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 by NGS, 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 thought to be due to leukemic hepatic involvement.
• AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN ----Unless elevation is related to leukemic hepatic involvement.
• Renal:
• Serum creatinine ≤ 2x ULN
• 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 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:

You may not qualify if:

• Previous exposure to experimental MEK inhibitors for CMML.
• Grade 2 or greater QTc prolongation on screening electrocardiogram (ECG) or clinically significant cardiovascular disease (uncontrolled or symptomatic atrial arrhythmias, congestive heart failure, myocardial infarction/CABG/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 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 interfere 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.
• 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 (eg, 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, or any solid tumor malignancy that has been adequately treated for which there is no evidence of disease. Patients with monoclonal gammopathy of undetermined significance (MGUS) are permitted 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 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.
• 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 RNA.

Sponsors & Collaborators

• University of Utah: lead
• Genentech, Inc.: collaborator

Study Sites (3)

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Huntsman Cancer Institute at University of Utah

Salt Lake City, Utah, 84112, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Chronic

Interventions

cobimetinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: IIT Data Management Team
• Organization: Research Compliance Office, Huntsman Cancer Institute

IITDataManagement@hci.utah.edu

801-213-6215

Study Officials

• Ami Patel, MD

  Huntsman Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: open-label, nonrandomized phase 2 trial

Study Record Dates

• First Submitted: May 20, 2020
• First Posted: June 1, 2020
• Study Start: January 12, 2021
• Primary Completion: April 2, 2025
• Study Completion (Estimated): August 1, 2026
• Last Updated: April 24, 2026
• Results First Posted: April 24, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)