Clinical Trials /

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

NCT04409639

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.

Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cobimetinib in Newly Diagnosed or HMA-treated CMML Patients With RAS Pathway Mutations
  • Official Title: Phase 2 Trial of Cobimetinib in Newly Diagnosed or HMA-treated CMML Patients With RAS Pathway Mutations

Clinical Trial IDs

  • ORG STUDY ID: HCI132394
  • NCT ID: NCT04409639

Conditions

  • Chronic Myelomonocytic Leukemia (CMML)

Interventions

DrugSynonymsArms
CobimetinibTreatment: all patients

Purpose

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.

Detailed Description

      This is an open-label, nonrandomized phase 2 trial to assess the efficacy of cobimetinib in
      RAS pathway activated CMML. Two cohorts of patients will be accrued using Simon's two-stage
      design (Simon, 1989) for both cohorts. Cohort 1 will enroll nine newly diagnosed patients in
      the first stage and if four or more responses are observed five additional patients will be
      enrolled in the second stage. Cohort 2 will enroll six HMA refractory patients in the first
      stage and if one or more responses are observed then nine additional patients will be
      enrolled in the second stage.

      All eligible patients will be treated daily with cobimetinib in 28-day cycles. Cobimetinib
      will be administered consecutively 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment: all patientsExperimentalCobimetinib 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.
  • Cobimetinib

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%.

          -  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 2 weeks month 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 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 (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.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate 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
Time Frame:From 1st dose of study medication to decision to end treatment or up to 12 months of treatment, whichever came first
Safety Issue:
Description:assess the efficacy of cobimetinib in patients with newly diagnosed and HMA- refractory chronic myelomonocytic leukemia (CMML)

Secondary Outcome Measures

Measure:Frequency of adverse events characterized by seriousness, severity (CTCAEv5.0), duration and relationship to study therapy.
Time Frame:Until decision to end treatment or up to 12 months of treatment, whichever came first
Safety Issue:
Description:assess the safety of cobimetinib treatment in CMML
Measure:Proportion of patients achieving complete response complete response (CR) + partial response (PR)
Time Frame:Until decision to end treatment or up to 12 months of treatment, whichever came first
Safety Issue:
Description:Assessment of complete response (CR) + partial response (PR) rate (defined by 2015 MDS/MPN-IWG criteria)
Measure:Progression-free survival (PFS)
Time Frame:up to 36 months after the start of therapy, the time of progression, initiation of alternative treatment or death, whichever came first
Safety Issue:
Description:Assessment of long-term efficacy
Measure:Overall Survival (OS)
Time Frame:Study anticipated to be 60 months.
Safety Issue:
Description:Assessment of long-term efficacy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Utah

Last Updated

November 12, 2020