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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Intervention / Treatment: Drug: Decitabine; Drug: Venetoclax; Drug: Ponatinib

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nicholas Short; Phone Number: 713-563-4485; Email: nshort@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (ponatinib, venetoclax, decitabine); See Detailed Description.	Drug: Decitabine; Given IV; Other Names: Dacogen; Decitabine for Injection; Deoxyazacytidine; Dezocitidine; 5-Aza-2''-deoxycytidine; Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Drug: Ponatinib; Given PO; Other Names: AP-24534; AP24534

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	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.	End of cycle 2 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of minimal residual disease negativity	Will be estimated along with the 95% credible interval.	Up to 4.5 years
Proportion of patients proceeding to allogeneic stem cell transplant	Will be estimated along with the 95% credible interval.	Up to 4.5 years
Relapse-free survival (RFS)	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.	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)	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.	From treatment start till death or last follow-up, assessed up to 4.5 years
Incidence of adverse events	Safety data will be summarized by category, severity and frequency.	Up to 4.5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apoptotic protein expression and Bcl-2 dependency on response and resistance	The association 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.	Up to 4.5 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: Nicholas Short, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2020
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: November 25, 2019
• First Submitted That Met QC Criteria: December 3, 2019
• First Posted (Actual): December 5, 2019

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Cell Transformation, Neoplastic; Carcinogenesis; Chromosome Aberrations; Translocation, Genetic; Chronic Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Leukemia, Myeloid, Accelerated Phase; Philadelphia Chromosome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Decitabine; Venetoclax; Ponatinib
• Other Study ID Numbers: 2019-0610 (Other Identifier: M D Anderson Cancer Center); NCI-2019-07594 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No