ACTIVE_NOT_RECRUITING

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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

Phase 2 Trial of Cobimetinib in Newly Diagnosed or HMA-treated CMML Patients With RAS Pathway Mutations

Quick Facts

Study Start:2021-01-12

Study Completion:2026-08

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:ACTIVE_NOT_RECRUITING

Study ID

NCT04409639

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
* 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: * 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 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 as described in Section 7.4 of the protocol. * Recovery to baseline or Grade ≤ 1 CTCAE v5.0 from toxicities related to any prior treatments, unless 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 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. * 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. * Subjects taking prohibited medications as described in Section 6.3.2. 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 cobimetinib or any component in its formulations (NCI CTCAE v5.0 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.

Inclusion Criteria

Exclusion Criteria

* 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:
* 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 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 as described in Section 7.4 of the protocol.
* Recovery to baseline or Grade ≤ 1 CTCAE v5.0 from toxicities related to any prior treatments, unless 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 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.
* 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.
* Subjects taking prohibited medications as described in Section 6.3.2. 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 cobimetinib or any component in its formulations (NCI CTCAE v5.0 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.

Contacts and Locations

Principal Investigator

Ami Patel, MD

PRINCIPAL_INVESTIGATOR

Huntsman Cancer Institute

Study Locations (Sites)

Oregon Health and Science University

Portland, Oregon, 97239

United States

Huntsman Cancer Institute at University of Utah

Salt Lake City, Utah, 84112

United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109

United States

Collaborators and Investigators

Sponsor: University of Utah

Ami Patel, MD, PRINCIPAL_INVESTIGATOR, Huntsman Cancer Institute

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2021-01-12

Study Completion Date2026-08

Study Record Updates

Study Start Date2021-01-12

Study Completion Date2026-08

Terms related to this study

Additional Relevant MeSH Terms

Chronic Myelomonocytic Leukemia (CMML)