Treatment of CMML patients with RAS mutations using cobimetinib

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

This study is testing if the drug cobimetinib can help people with chronic myelomonocytic leukemia who have RAS mutations, including those who are newly diagnosed and those who haven't responded to other treatments.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 29 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Utah (other)
• Drugs / interventions: cobimetinib, chemotherapy, radiation
• Locations: 3 sites (Portland, Oregon and 2 other locations)
• Trial ID: NCT04409639 on ClinicalTrials.gov

What this trial studies

This open-label, nonrandomized phase 2 trial evaluates the efficacy of cobimetinib in patients with chronic myelomonocytic leukemia (CMML) who have RAS pathway mutations. The trial consists of two cohorts: newly diagnosed patients and those who are refractory to hypomethylating agents. Patients will receive cobimetinib daily for three weeks followed by a one-week break in 28-day cycles, continuing until treatment discontinuation criteria are met. The study employs Simon's two-stage design to assess treatment responses in both cohorts.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with newly diagnosed or HMA-refractory CMML and confirmed RAS pathway mutations.

Not a fit: Patients without RAS pathway mutations or those with other types of leukemia may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with RAS pathway activated CMML.

How similar studies have performed: Other studies have shown promise in targeting RAS pathway mutations, suggesting potential for success in this approach.

Eligibility criteria

Inclusion 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:

    ---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 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.

Exclusion Criteria:

* 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.
* 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.

Where this trial is running

Portland, Oregon and 2 other locations

• Oregon Health and Science University — Portland, Oregon, United States (RECRUITING)
• Huntsman Cancer Institute at University of Utah — Salt Lake City, Utah, United States (RECRUITING)
• Fred Hutchinson Cancer Research Center — Seattle, Washington, United States (RECRUITING)

Study contacts

• Principal investigator: Ami Patel, MD — Huntsman Cancer Institute
• Study coordinator: Braxton Smith

Conditions: Chronic Myelomonocytic Leukemia