A Phase II Study of the Combination of Decitabine, Venetoclax, and Ponatinib in Patients With Philadelphia Chromosome-Positive Acute Myeloid Leukemia or Myeloid Blast Phase Chronic Myelogenous Leukemia
Overview
- Phase
- Phase 2
- Intervention
- Decitabine
- Conditions
- Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Overall response rate
- Status
- Active, not recruiting
- Last Updated
- 5 months ago
Overview
Brief Summary
This phase II trial studies how well the combination of decitabine, venetoclax, and ponatinib work for the treatment of Philadelphia chromosome-positive acute myeloid leukemia or myeloid blast phase or accelerated phase chronic myelogenous leukemia. Drugs used in chemotherapy such as decitabine, 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. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Ponatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving decitabine, venetoclax, and ponatinib may help to control Philadelphia chromosome-positive acute myeloid leukemia or myeloid blast phase or accelerated phase chronic myelogenous leukemia.
Detailed Description
PRIMARY OBJECTIVE: I. To determine the efficacy of the regimen, as defined by the rate of complete remission (CR) or CR with incomplete count recovery (CRi). SECONDARY OBJECTIVES: I. To determine efficacy outcomes, including rate of minimal residual disease negativity by flow cytometry and polymerase chain reaction (PCR) for BCR-ABL1 transcripts, median relapse-free survival, and median overall survival. 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. OUTLINE: Patients recently (within 2 weeks of anticipated start date) treated with ponatinib receive ponatinib orally (PO) daily on days 1-21 of cycle 1 and days 1-28 of subsequent cycles, venetoclax PO daily on days 1-21, and decitabine intravenously (IV) over 60 minutes on days 1-5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients who have not been recently (within 2 weeks of anticipated start date) treated with ponatinib may receive ponatinib monotherapy PO daily on days 1-7 before starting combination therapy with venetoclax in cycle 1. After completion of ponatinib lead-in, patients will receive ponatinib PO daily on days 1-21 of cycle 1 and on days 1-28 of subsequent cycles, venetoclax PO daily on days 8-28 of cycle 1 and days 1-21 of subsequent cycles, and decitabine IV over 60 minutes on days 8-12 of cycle 1 and days 1-5 of subsequent cycles. For these patients, cycle 1 is 35 days in duration and cycles 2-24 repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days then every 6 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with Philadelphia (Ph)+ acute myeloid leukemia (AML) or myeloid accelerated phase (AP)-chronic myelogenous leukemia (CML) or blast phase (BP)-CML (either t\[9;22\] and/or BCR-ABL1 positive by fluorescent in situ hybridization or polymerase chain reaction). Both untreated and relapsed/refractory patients are eligible
- •Performance status =\< 3 (Eastern Cooperative Oncology Group \[ECOG\] scale)
- •Total serum bilirubin =\< 2 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the principal investigator (PI)
- •Alanine aminotransferase (ALT) =\< 1.5 x ULN, unless due to the underlying leukemia approved by the PI
- •Aspartate aminotransferase (AST) =\< 1.5 x ULN unless due to the underlying leukemia approved by the PI
- •Creatinine clearance \>= 30 mL/min
- •Serum lipase =\< 1.5 x ULN
- •Amylase =\< 1.5 x ULN
- •Ability to swallow
- •Signed informed consent
Exclusion Criteria
- •Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment)
- •History of acute pancreatitis within 6 months of study or history of chronic pancreatitis
- •Uncontrolled hypertriglyceridemia (triglycerides \> 450 mg/dL)
- •Active secondary malignancy that in the investigator's opinion will shorten survival to less than 1 year
- •Active grade III-V cardiac failure as defined by the New York Heart Association criteria
- •Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
- •Myocardial infarction (MI), stroke, revascularization, unstable angina or transient ischemic attack within 6 months
- •Left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards prior to enrollment
- •Diagnosed or suspected congenital long QT syndrome
- •Clinically significant atrial or ventricular arrhythmias (such as uncontrolled, clinically significant atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes) as determined by the treating physician
Arms & Interventions
Treatment (ponatinib, venetoclax, decitabine)
See Detailed Description.
Intervention: Decitabine
Treatment (ponatinib, venetoclax, decitabine)
See Detailed Description.
Intervention: Ponatinib
Treatment (ponatinib, venetoclax, decitabine)
See Detailed Description.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Overall response rate
Time Frame: End of cycle 2 (each cycle is 28 days)
Defined as the proportion of patients achieving complete remission (CR) + CR with incomplete count recovery (CRi) occurring at the end of 2 cycles of treatment. Will be estimated along with the 95% credible interval. Patients who drop out of the study before completing 2 cycles and have been treated will be censored for the primary endpoint analysis.
Secondary Outcomes
- Proportion of patients proceeding to allogeneic stem cell transplant(Up to 4.5 years)
- Rate of minimal residual disease negativity(Up to 4.5 years)
- Relapse-free survival (RFS)(From the date of treatment initiation to the date of documented treatment relapses from CR/CRi or death from any cause, whichever occurs first, assessed up to 4.5 years)
- Overall survival (OS)(From treatment start till death or last follow-up, assessed up to 4.5 years)
- Incidence of adverse events(Up to 4.5 years)