Phase II Study of Adding the Anti-PD-1 Pembrolizumab to Tyrosine Kinase Inhibitors in Patients With Chronic Myeloid Leukemia and Persistently Detectable Minimal Residual Disease
Overview
- Phase
- Phase 2
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- Sponsor
- ECOG-ACRIN Cancer Research Group
- Enrollment
- 40
- Locations
- 575
- Primary Endpoint
- Proportion of patients on tyrosine kinase inhibitor (TKI) who convert to undetectable minimal residual disease (UMRD)
- Status
- Active, not recruiting
- Last Updated
- 29 days ago
Overview
Brief Summary
This phase II trial studies how well pembrolizumab and dasatinib, imatinib mesylate, or nilotinib work in treating patients with chronic myeloid leukemia and persistent detection of minimal residual disease, defined as the levels of a gene product called bcr-abl in the blood. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Dasatinib, imatinib mesylate, and nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and dasatinib, imatinib mesylate, or nilotinib may work better in treating patients with chronic myeloid leukemia.
Detailed Description
PRIMARY OBJECTIVES: I. Assess the proportion of chronic myelogenous leukemia (CML) patients on stable-dose tyrosine kinase inhibitor (TKI) who convert to undetectable minimal residual disease (UMRD) (molecular response \[MR\]\^4.5) during or within 2 years of initiating pembrolizumab therapy. SECONDARY OBJECTIVES: I. Among patients who have converted to UMRD (MR\^4.5), assess the proportion of CML patients who maintain UMRD for 6 months and 12 months. II. Among patients who have converted to UMRD (MR\^4.5), assess the proportion of CML patients who discontinue their TKI. III. Among patients who have converted to UMRD (MR\^4.5), assess the proportion of CML patients who are UMRD and TKI-free at 2 years from first determined UMRD. IV. Assess the proportion of CML patients who develop grade 3 or 4 immune related adverse events related to pembrolizumab treatment during the first 2 years after registration (not including grade 3 events that respond to corticosteroids and improve to grade 1 or less within 4 weeks). OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and dasatinib, imatinib mesylate, or nilotinib orally (PO) as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 6 years from the date of registration.
Investigators
Eligibility Criteria
Inclusion Criteria
- •PREREGISTRATION (STEP 0): Patient has pathologically-confirmed chronic phase-CML on a first line TKI and must meet the following criteria:
- •The patient has to be on first-line TKI therapy (the same TKI) for at least 2 years prior to pre-registration
- •Has been in MMR (i.e. MR\^3) but still have detectable BCR-ABL transcript by a standard real-time quantitative polymerase chain reaction (RQ-PCR) assay with a limit of detection (sensitivity) of 4.5 for at least 12 months from the first documentation of the MMR
- •Patient has not achieved MR\^4.5 (complete molecular remission \[CMR\]) within the time of initiation of TKI therapy and pre-registration
- •PREREGISTRATION (STEP 0): Patient must be scheduled to undergo a standard of care bone marrow biopsy within 7 days of step 0 registration
- •PREREGISTRATION (STEP 0): Peripheral blood must be collected for submission to Fred Hutchinson Cancer Research Center for central assessment of the establishment of BCR/ABL status to confirm patient?s eligibility for registration to Step 1; Fred Hutchinson will forward results within 1-2 business days of receipt of the peripheral blood to the submitting institution
- •REGISTRATION TO TREATMENT (STEP 1): Institution has received central BCR-ABL test results confirming MRD positive status
- •REGISTRATION TO TREATMENT (STEP 1): Patients have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •REGISTRATION TO TREATMENT (STEP 1): No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment; patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation
- •REGISTRATION TO TREATMENT (STEP 1): No current use of corticosteroids; EXCEPTION: Low doses of steroids (\< 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is permitted
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)
Patients receive pembrolizumab IV over 30 minutes on day 1 and dasatinib, imatinib mesylate, or nilotinib PO as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)
Patients receive pembrolizumab IV over 30 minutes on day 1 and dasatinib, imatinib mesylate, or nilotinib PO as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Imatinib Mesylate
Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)
Patients receive pembrolizumab IV over 30 minutes on day 1 and dasatinib, imatinib mesylate, or nilotinib PO as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Pembrolizumab
Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)
Patients receive pembrolizumab IV over 30 minutes on day 1 and dasatinib, imatinib mesylate, or nilotinib PO as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Dasatinib
Treatment (pembrolizumab, dasatinib, imatinib, nilotinib)
Patients receive pembrolizumab IV over 30 minutes on day 1 and dasatinib, imatinib mesylate, or nilotinib PO as clinically indicated per the treating physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity. Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Nilotinib
Outcomes
Primary Outcomes
Proportion of patients on tyrosine kinase inhibitor (TKI) who convert to undetectable minimal residual disease (UMRD)
Time Frame: Up to 2 years of initiating pembrolizumab
Will be reported with exact confidence intervals. The binomial test will be used to test the null hypothesis that this proportion is 0.2 with the alternative hypothesis being that this proportion is greater than 0.2.
Secondary Outcomes
- Proportion of patients who maintain UMRD for 6 and 12 months(Up to 6 years)
- Proportion of patients who meet the criteria for discontinuing TKI(Up to 6 years)
- Proportion of patients who maintain UMRD for 6 months(Up to 6 years)
- Proportion of patients who develop grade 3 or 4 immune related adverse events (not including grade 3 events that respond to corticosteroids and improve to grade 1 or less within 4 weeks)(Up to 6 years)
- Proportion of patients who maintain UMRD for 2 years after first achieving UMRD(Up to 6 years)