This phase I/II trial studies the best dose of venetoclax when given together with ponatinib and dexamethasone and to see how well they work in treating participants with Philadelphia chromosome or BCR-ABL positive acute lymphoblastic leukemia or chronic myelogenous leukemia that has come back or does not respond to treatment. Drugs used in chemotherapy, such as venetoclax and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ponatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax, ponatinib, and dexamethasone may work better in treating participants with acute lymphoblastic leukemia or chronic myelogenous leukemia.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of venetoclax, ponatinib, and dexamethasone in patients with relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) or lymphoid blastic phase (BP)-chronic myelogenous leukemia (CML). (Phase I) II. To determine the efficacy of the regimen, as defined by the rate of complete remission (CR) or CR with incomplete count recovery (CRi). (Phase II) SECONDARY OBJECTIVES: I. To determine efficacy outcomes, including rate of minimal residual disease negativity by polymerase chain reaction (PCR) for BCR-ABL1 transcripts, median relapse-free survival (RFS), and median overall survival (OS). II. To determine the proportion of patients proceeding to allogeneic stem cell transplant (ASCT). III. To preliminarily determine the safety of the combination regimen. EXPLORATORY OBJECTIVES: I. To evaluate the effect of single-agent ponatinib on apoptotic proteins and Bcl-2 dependency. II. To correlate apoptotic protein expression and Bcl-2 dependency on response and resistance to the combination regimen. III. To assess impact of baseline genomics on outcomes with the combination regimen. OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study. INDUCTION (COURSE 1): Participants who have not received ponatinib within 2 weeks of the anticipated start date receive ponatinib orally (PO) daily on days 1-35, venetoclax PO daily on days 8-35, and dexamethasone PO or intravenously (IV) over 15 minutes on days 8-11. Participants who have received ponatinib within 2 weeks of the anticipated start date receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Participants with CD20 expression receive rituximab IV over 2-6 hours on days 14 and 21 at the discretion of the treating physician after the maximum dose of venetoclax has been reached. CONSOLIDATION (COURSES 2-4): Participants receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Participants with CD20 expression receive rituximab IV over 2-6 hours for up to 2 doses each course at the discretion of the treating physician after the maximum dose of venetoclax has been reached. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE (COURSES 5+): Participants receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Participants achieving remission undergo ASCT at the discretion of the treating physician. After completion of study treatment, participants are followed up at 30 days.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
9
M D Anderson Cancer Center
Houston, Texas, United States
Maximum Tolerated Dose (MTD) of Venetoclax When Given in Combination With Ponatinib and Dexamethasone (Phase I)
MTD is defined as the highest dose level where a dose limiting toxicity (DLT) occurs within at most one out of six patients treated. The MTD is defined as the highest dose studied for which the observed incidence of DLT is less than 33%. Frequencies of toxicities will be tabulated according to the National Cancer Institute (NCI) Common Toxicity Criteria. Patients will be continued to be followed for one year for evidence of late toxicity.
Time frame: Up to 1 year
Number of Participants With a Response Complete Response (CR) + CR With Incomplete Count Recovery (CRi)
Overall response rate, defined as the rate or complete response (CR) + CR with incomplete count recovery (CRi). Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR. Complete remission without recovery of counts (CRi): Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L; neutrophils \< 1 x 10\^9/L).
Time frame: 9 weeks
Event Free Survival (EFS)
Time from date of treatment start until the date of failure or death from any cause.
Time frame: Monthly up to 5 years, 11 months and 7 days
Number of Participants Achieving Minimal Residual Disease Negativity
The proportion of patient achieving minimal residual disease negativity (as assessed by polymerase chain reaction PCR for BCR-ABL transcripts) after 2 cycles of therapy will be estimated.
Time frame: After 2 cycles of therapy
Proportion of Patients Proceeding to Allogeneic Stem Cell Transplant (ASCT) a
All patients assessed for allogeneic stem cell transplant.
Time frame: Up to 1 year
Overall Survival (OS)
Time from date of treatment start until date of death due to any cause or last Follow-up.
Time frame: From treatment initiation to death or last follow-up, up to 5 years, 11 months and 7 days
Relapse-free Survival (RFS)
Relapse-free survival is the time from documented CR/CRi until relapse or death. Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR. Complete remission without recovery of counts (CRi): Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L; neutrophils \< 1 x 10\^9/L).
Time frame: Monthly up to 5 years, 11 months and 7 days
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