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

Primary Purpose

Chronic Myelomonocytic Leukemia (CMML)

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cobimetinib
Sponsored by
University of Utah
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Myelomonocytic Leukemia (CMML)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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, and cytogenetics should be done at the primary trial site within 21 days prior to C1D1. The FLT3-ITD PCR allelic ration 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.

Sites / Locations

  • Oregon Health and Science UniversityRecruiting
  • Huntsman Cancer Institute at University of UtahRecruiting
  • Fred Hutchinson Cancer Research CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment: all patients

Arm Description

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.

Outcomes

Primary Outcome Measures

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
assess the efficacy of cobimetinib in patients with newly diagnosed and HMA- refractory chronic myelomonocytic leukemia (CMML)

Secondary Outcome Measures

Frequency of adverse events characterized by seriousness, severity (CTCAEv5.0), duration and relationship to study therapy.
assess the safety of cobimetinib treatment in CMML
Proportion of patients achieving complete response complete response (CR) + partial response (PR)
Assessment of complete response (CR) + partial response (PR) rate (defined by 2015 MDS/MPN-IWG criteria)
Progression-free survival (PFS)
Assessment of long-term efficacy
Overall Survival (OS)
Assessment of long-term efficacy

Full Information

First Posted
May 20, 2020
Last Updated
August 1, 2023
Sponsor
University of Utah
Collaborators
Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04409639
Brief Title
Cobimetinib in Newly Diagnosed or HMA-treated CMML Patients With RAS Pathway Mutations
Acronym
CONCERTO
Official Title
Phase 2 Trial of Cobimetinib in Newly Diagnosed or HMA-treated CMML Patients With RAS Pathway Mutations
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 12, 2021 (Actual)
Primary Completion Date
August 15, 2025 (Anticipated)
Study Completion Date
August 15, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Utah
Collaborators
Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Myelomonocytic Leukemia (CMML)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
open-label, nonrandomized phase 2 trial
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment: all patients
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cobimetinib
Intervention Description
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.
Primary Outcome Measure Information:
Title
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
Description
assess the efficacy of cobimetinib in patients with newly diagnosed and HMA- refractory chronic myelomonocytic leukemia (CMML)
Time Frame
From 1st dose of study medication to decision to end treatment or up to 12 months of treatment, whichever came first
Secondary Outcome Measure Information:
Title
Frequency of adverse events characterized by seriousness, severity (CTCAEv5.0), duration and relationship to study therapy.
Description
assess the safety of cobimetinib treatment in CMML
Time Frame
Until decision to end treatment or up to 12 months of treatment, whichever came first
Title
Proportion of patients achieving complete response complete response (CR) + partial response (PR)
Description
Assessment of complete response (CR) + partial response (PR) rate (defined by 2015 MDS/MPN-IWG criteria)
Time Frame
Until decision to end treatment or up to 12 months of treatment, whichever came first
Title
Progression-free survival (PFS)
Description
Assessment of long-term efficacy
Time Frame
up to 36 months after the start of therapy, the time of progression, initiation of alternative treatment or death, whichever came first
Title
Overall Survival (OS)
Description
Assessment of long-term efficacy
Time Frame
Study anticipated to be 60 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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, 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Braxton Smith
Phone
801-213-8431
Email
Braxton.Smith@hci.utah.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ami Patel, MD
Organizational Affiliation
Huntsman Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mai-Lee Yap
Phone
503-494-2055
Email
yap@ohsu.edu
First Name & Middle Initial & Last Name & Degree
Elie Traer, MD
Facility Name
Huntsman Cancer Institute at University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Braxton Smith
Phone
801-213-8431
Email
Braxton.Smith@hci.utah.edu
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gabriella Sghia-Hughes
Phone
206-667-4270
Email
gsghiahu@fredhutch.org
First Name & Middle Initial & Last Name & Degree
Joachim Deeg, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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