Clinical Trials /

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

NCT04188405

Description:

This phase II trial studies how well decitabine, venetoclax, and ponatinib work for the treatment of Philadelphia chromosome-positive acute myeloid leukemia or myeloid blast phase chronic myelogenous leukemia. Drugs used in chemotherapy such as decitabine and venetoclax 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. 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 the disease.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Decitabine, Venetoclax, and Ponatinib for the Treatment of Philadelphia Chromosome-Positive Acute Myeloid Leukemia or Myeloid Blast 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
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04188405

Conditions

  • 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

DrugSynonymsArms
Decitabine5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (ponatinib, venetoclax, decitabine)
PonatinibAP-24534, AP24534Treatment (ponatinib, venetoclax, decitabine)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (ponatinib, venetoclax, decitabine)

Purpose

This phase II trial studies how well decitabine, venetoclax, and ponatinib work for the treatment of Philadelphia chromosome-positive acute myeloid leukemia or myeloid blast phase chronic myelogenous leukemia. Drugs used in chemotherapy such as decitabine and venetoclax 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. 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 the disease.

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 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 treated with
      ponatinib 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

NameTypeDescriptionInterventions
Treatment (ponatinib, venetoclax, decitabine)ExperimentalPatients recently treated with ponatinib receive ponatinib PO daily on days 1-28, venetoclax PO daily on days 1-21, and decitabine 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 treated with ponatinib 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.
  • Decitabine
  • Ponatinib
  • Venetoclax

Eligibility 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
      
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.

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:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 3, 2019