Venetoclax, Ponatinib, and Dexamethasone in Participants With Philadelphia Chromosome or BCR-ABL Positive Relapsed or Refractory Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia
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|ClinicalTrials.gov Identifier: NCT03576547|
Recruitment Status : Recruiting
First Posted : July 3, 2018
Last Update Posted : May 20, 2019
|Condition or disease||Intervention/treatment||Phase|
|Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Philadelphia Chromosome Positive Recurrent Acute Lymphoblastic Leukemia Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive Refractory Acute Lymphoblastic Leukemia Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive t(9;22)||Drug: Dexamethasone Drug: Ponatinib Hydrochloride Biological: Rituximab Drug: Venetoclax||Phase 1 Phase 2|
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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)
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.
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 (Clinical Trial)|
|Estimated Enrollment :||38 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I/II Study of the Combination of Venetoclax, Ponatinib and Corticosteroids in Patients With Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia and Lymphoid Blast Phase Chronic Myelogenous Leukemia|
|Actual Study Start Date :||June 26, 2018|
|Estimated Primary Completion Date :||January 31, 2020|
|Estimated Study Completion Date :||January 31, 2020|
Experimental: Treatment (ponatinib, venetoclax, dexamethasone, rituximab)
See Detailed Description
Given PO or IV
Drug: Ponatinib Hydrochloride
- Maximum tolerated dose (MTD) of venetoclax when given in combination with ponatinib and dexamethasone (Phase I) [ Time Frame: Up to 1 year ]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.
- Overall response rate [ Time Frame: 9 weeks ]Overall response rate, defined as the rate or complete response (CR) + CR with incomplete count recovery (CRi)
- Rate of minimal residual disease negativity assessed by polymerase chain reaction (PCR) for BCR-ABL transcripts [ Time Frame: 9 weeks ]
- Proportion of patients proceeding to allogeneic stem cell transplant (ASCT) a [ Time Frame: Up to 1 year ]
- Overall survival (OS) [ Time Frame: From treatment initiation to death or last follow-up, assessed up to 1 year ]Kaplan-Meier curves will be used to estimate unadjusted OS distribution.
- Relapse-free survival (RFS) [ Time Frame: Up to 1 year ]Kaplan-Meier curves will be used to estimate unadjusted RFS distribution.
- Incidence of adverse events evaluated according to NCI Common Toxicity Criteria [ Time Frame: Up to 1 year ]Toxicity type, severity, and attribution will be summarized for each patient using frequency tables.
- Median time to allogeneic stem cell transplant (ASCT) [ Time Frame: Up to 1 year ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03576547
|Contact: Farhad Ravandi-Kashanifirstname.lastname@example.org|
|United States, Texas|
|M D Anderson Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Farhad Ravandi-Kashani 713-745-0394|
|Principal Investigator: Farhad Ravandi-Kashani|
|Principal Investigator:||Farhad Ravandi-Kashani||M.D. Anderson Cancer Center|