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 patients with Philadelphia chromosome or BCR-ABL positive acute lymphoblastic leukemia or chronic myelogenous leukemia that has come back (relapsed) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as venetoclax, 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. Anti-inflammatory drugs, such as dexamethasone lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. Giving venetoclax, ponatinib, and dexamethasone may work better in treating patients with acute lymphoblastic leukemia or chronic myelogenous leukemia.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03576547.
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 (CYCLE 1): Patients 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. Patients 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. Patients 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 (CYCLES 2-4): Patients receive ponatinib PO and venetoclax PO daily on days 1-28 and dexamethasone PO or IV over 15 minutes on days 1-4. Patients with CD20 expression receive rituximab IV over 2-6 hours for up to 2 doses each cycle 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 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE (CYCLES 5+): Patients 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 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving remission undergo ASCT at the discretion of the treating physician.
After completion of study treatment, patients are followed up at 30 days.
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorFarhad Ravandi-Kashani
