Description:
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.
Title
- Brief Title: Decitabine, Venetoclax, and Ponatinib for the Treatment of Philadelphia Chromosome-Positive Acute Myeloid Leukemia or Myeloid Blast Phase or Accelerated Phase Chronic Myelogenous Leukemia
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
2019-0610
- SECONDARY ID:
NCI-2019-07594
- SECONDARY ID:
2019-0610
- NCT ID:
NCT04188405
Conditions
- Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- Acute Myeloid Leukemia
- Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- Recurrent Acute Myeloid Leukemia
- Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- Refractory Acute Myeloid Leukemia
- Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Interventions
Drug | Synonyms | Arms |
---|
Decitabine | 5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, Dezocitidine | Treatment (ponatinib, venetoclax, decitabine) |
Ponatinib | AP-24534, AP24534 | Treatment (ponatinib, venetoclax, decitabine) |
Venetoclax | ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto | Treatment (ponatinib, venetoclax, decitabine) |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (ponatinib, venetoclax, decitabine) | Experimental | See Detailed Description. | - Decitabine
- Ponatinib
- Venetoclax
|
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
- Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 480 msec)
unless corrected after electrolyte replacement
- History of venous thromboembolism including deep venous thrombosis or pulmonary
embolism within the past 3 months, excluding line-associated deep venous
thrombosis (DVT) of the upper extremity
- Uncontrolled hypertension (diastolic blood pressure > 100 mmHg; systolic > 150
mmHg)
- Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days
prior to starting venetoclax
- Treatment with any investigational antileukemic agents or chemotherapy agents in the
last 7 days before study entry, unless full recovery from side effects has occurred or
patient has rapidly progressive disease judged to be life-threatening by the
investigator. Prior recent treatment with corticosteroids, hydroxyurea, or a Food and
Drug Administration (FDA)-approved BCR-ABL tyrosine kinase inhibitor (TKI) is
permitted
- Pregnant and lactating women will not be eligible; women of childbearing potential
should have a negative pregnancy test prior to entering on the study and be willing to
practice methods of contraception throughout the study period. Women do not have
childbearing potential if they have had a hysterectomy or are postmenopausal without
menses for 12 months. In addition, men enrolled on this study should understand the
risks to any sexual partner of childbearing potential and should practice an effective
method of birth control
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Overall response rate |
Time Frame: | End of cycle 2 (each cycle is 28 days) |
Safety Issue: | |
Description: | 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 Outcome Measures
Measure: | Rate of minimal residual disease negativity |
Time Frame: | Up to 4.5 years |
Safety Issue: | |
Description: | Will be estimated along with the 95% credible interval. |
Measure: | Proportion of patients proceeding to allogeneic stem cell transplant |
Time Frame: | Up to 4.5 years |
Safety Issue: | |
Description: | Will be estimated along with the 95% credible interval. |
Measure: | Relapse-free survival (RFS) |
Time Frame: | 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 |
Safety Issue: | |
Description: | The distribution of RFS will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests. |
Measure: | Overall survival (OS) |
Time Frame: | From treatment start till death or last follow-up, assessed up to 4.5 years |
Safety Issue: | |
Description: | The distribution of OS will be estimated using the method of Kaplan and Meier. Comparisons by important subgroups will be made using the log-rank tests. |
Measure: | Incidence of adverse events |
Time Frame: | Up to 4.5 years |
Safety Issue: | |
Description: | Safety data will be summarized by category, severity and frequency. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | M.D. Anderson Cancer Center |
Last Updated
April 20, 2021