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Decitabine, Venetoclax, and Ponatinib for the Treatment of Philadelphia Chromosome-Positive Acute Myeloid Leukemia or Myeloid Blast Phase Chronic Myelogenous Leukemia

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ClinicalTrials.gov Identifier: NCT04188405
Recruitment Status : Recruiting
First Posted : December 5, 2019
Last Update Posted : July 15, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
To determine the efficacy of the regimen, as defined by the rate of complete remission (CR) or CR with incomplete count recovery (CRi)

Condition or disease Intervention/treatment Phase
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 Drug: Decitabine Drug: Ponatinib Drug: Venetoclax Phase 2

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 1-28, 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 17, 2020
Estimated Primary Completion Date : September 1, 2024
Estimated Study Completion Date : September 1, 2024


Arm Intervention/treatment
Experimental: Treatment (ponatinib, venetoclax, decitabine)
See Detailed Description.
Drug: Decitabine
Given IV
Other Names:
  • 5-Aza-2''-deoxycytidine
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Drug: Ponatinib
Given PO
Other Names:
  • AP-24534
  • AP24534

Drug: Venetoclax
Given PO
Other Names:
  • ABT-0199
  • ABT-199
  • ABT199
  • GDC-0199
  • RG7601
  • Venclexta
  • Venclyxto




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Rate of minimal residual disease negativity [ Time Frame: Up to 4.5 years ]
    Will be estimated along with the 95% credible interval.

  2. Proportion of patients proceeding to allogeneic stem cell transplant [ Time Frame: Up to 4.5 years ]
    Will be estimated along with the 95% credible interval.

  3. 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 ]
    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.

  4. Overall survival (OS) [ Time Frame: From treatment start till death or last follow-up, assessed up to 4.5 years ]
    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.

  5. Incidence of adverse events [ Time Frame: Up to 4.5 years ]
    Safety data will be summarized by category, severity and frequency.


Other Outcome Measures:
  1. Apoptotic protein expression and Bcl-2 dependency on response and resistance [ Time Frame: Up to 4.5 years ]
    The correlation between response and patient's clinical information such as apoptotic protein expression, etc. will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with Philadelphia (Ph)+ acute myeloid leukemia (AML) or myeloid blast phase (BP)-chronic myelogenous leukemia (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:

  • Prior history of treatment with venetoclax. Prior ponatinib and/or hypomethylating agents are allowed
  • 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 1 year 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

Information from the National Library of Medicine

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): NCT04188405


Contacts
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Contact: Nicholas Short 713-563-4485 nshort@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Nicholas Short    713-563-4485    nshort@mdanderson.org   
Principal Investigator: Nicholas Short         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Nicholas Short M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04188405    
Other Study ID Numbers: 2019-0610
NCI-2019-07594 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2019-0610 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: December 5, 2019    Key Record Dates
Last Update Posted: July 15, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Blast Crisis
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Decitabine
Venetoclax
Ponatinib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Protein Kinase Inhibitors