Clinical Trials /

Venetoclax in Combination With Decitabine and Cedazuridine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

NCT04975919

Description:

This phase II trial studies the effects of venetoxlax in combination with decitabine and cedazuridine in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Chemotherapy drugs, such as venetoclax and 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. Cedazuridine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving venetoxlax in combination with decitabine and cedazuridine may help to control acute myeloid leukemia.

Related Conditions:
  • Acute Bilineal Leukemia
  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax in Combination With Decitabine and Cedazuridine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: A Phase II Study of Venetoclax in Combination With 10-day Oral Decitabine in Relapsed/Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 2021-0248
  • SECONDARY ID: NCI-2021-05744
  • SECONDARY ID: 2021-0248
  • NCT ID: NCT04975919

Conditions

  • Recurrent Acute Biphenotypic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Biphenotypic Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Decitabine and CedazuridineASTX727, CDA Inhibitor E7727/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Tablet, InqoviTreatment (decitabine and cedazuridine, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (decitabine and cedazuridine, venetoclax)

Purpose

This phase II trial studies the effects of venetoxlax in combination with decitabine and cedazuridine in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Chemotherapy drugs, such as venetoclax and 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. Cedazuridine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving venetoxlax in combination with decitabine and cedazuridine may help to control acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the overall response rate (complete remission [CR], complete remission with
      incomplete count recovery [CRi], MLFS and partial response [PR]) of 10-days decitabine and
      cedazuridine (oral decitabine) and venetoclax in patients with refractory/relapsed acute
      myeloid leukemia (AML).

      SECONDARY OBJECTIVES:

      I. To determine the duration of response, event-free survival (EFS), and overall survival
      (OS) of patients with refractory/relapsed AML treated with this combination.

      II. To determine the number of patients who achieve a hematologic improvement (HI) in
      platelets, hemoglobin, or ANC and the number of patients who achieve > 50% reduction in
      blasts on therapy with venetoclax/10-day oral decitabine.

      III. To determine the safety of venetoclax in combination with 10-day oral decitabine in
      patients with refractory/ relapsed AML.

      IV. To determine the number of patients who transition towards stem cell transplantation upon
      achieving response with the combination venetoclax/10-day oral decitabine regimen.

      V. To determine the incidence of infectious complications per cycle with venetoclax in
      combination with 10-day oral decitabine.

      EXPLORATORY OBJECTIVE:

      I. To investigate global gene expression profiles, cytometry by time of flight (CyTOF), BH3
      profiling and other potential prognostic markers to explore predictors of antitumor activity
      and/or resistance to treatment.

      OUTLINE:

      Patients receive decitabine and cedazuridine orally (PO) once daily (QD) on days 1-10.
      Patients who achieve CR/CRi during consolidation/maintenance may receive decitabine and
      cedazuridine PO QD on days 1-5. Patients also receive venetoclax PO QD on days 1-28 of cycle
      1 and days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine and cedazuridine, venetoclax)ExperimentalPatients receive decitabine and cedazuridine PO QD on days 1-10. Patients who achieve CR/CRi during consolidation/maintenance may receive decitabine and cedazuridine PO QD on days 1-5. Patients also receive venetoclax PO QD on days 1-28 of cycle 1 and days 1-21 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Decitabine and Cedazuridine
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with a diagnosis of relapsed or refractory AML (or biphenotypic or bilineage
             leukemia including a myeloid component). Patients with isolated extramedullary AML are
             eligible

          -  Age >= 18 years

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Creatinine < 2 unless related to the disease

          -  Direct bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's
             disease or leukemic involvement

          -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN
             unless considered due to leukemic involvement

          -  In the absence of rapidly proliferative disease, the interval from prior treatment to
             time of initiation will be at least 7 days for cytotoxic or non-cytotoxic
             (immunotherapy) agents. Oral hydroxyurea and/or cytarabine (up to 2 g/m^2) for
             patients with rapidly proliferative disease is allowed before the start of study
             therapy, as needed, for clinical benefit and after discussion with the principal
             investigator (PI). Concurrent therapy for central nervous system (CNS) prophylaxis or
             continuation of therapy for controlled CNS disease is permitted

          -  Male subjects must agree to refrain from unprotected sex and sperm donation from
             initial study drug administration until 90 days after the last dose of study drug

          -  Willing and able to provide informed consent

        Exclusion Criteria:

          -  Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia
             (French-American-British [FAB] class M3-AML)

          -  Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant
             (patients without active GVHD on chronic suppressive immunosuppression and/or
             phototherapy for chronic skin GVHD are permitted after discussion with the PI)

          -  Patients with any severe gastrointestinal or metabolic condition which could interfere
             with the absorption of oral study medications as determined by the investigator

          -  Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia

          -  Active and uncontrolled comorbidities including active uncontrolled infection,
             uncontrolled hypertension despite adequate medical therapy, active and uncontrolled
             congestive heart failure New York Heart Association (NYHA) class III/IV, clinically
             significant and uncontrolled arrhythmia as judged by the treating physician

          -  Known active hepatitis B (HBV) or hepatitis C (HCV) infection or known human
             immunodeficiency virus (HIV) infection

          -  Subject has a white blood cell count > 10 x 10^9/L. (Note: Hydroxyurea is permitted to
             meet this criterion)

          -  Any other medical, psychological, or social condition that may interfere with study
             participation or compliance, or compromise patient safety in the opinion of the
             investigator

          -  Nursing women, women of childbearing potential (WOCBP) with positive urine or serum
             pregnancy test, or women of childbearing potential who are not willing to maintain
             adequate contraception

               -  Appropriate highly effective method(s) of contraception include oral or
                  injectable hormonal birth control, intrauterine device (IUD), and double barrier
                  methods (for example a condom in combination with a spermicide)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Within 4 cycles of treatment (each cycle is 28 days)
Safety Issue:
Description:Defined as the proportion of patients who had complete remission (CR), complete remission with incomplete count recovery (CRi), partial response (PR) or MLFS. Will estimate the ORR for the combination treatment, along with the Bayesian 95% credible interval.

Secondary Outcome Measures

Measure:Proportion of achieving HI
Time Frame:Up to 2 years
Safety Issue:
Description:Will estimate for the combination treatment, along with the Bayesian 95% credible interval.
Measure:Number of patients who transition towards stem cell transplantation
Time Frame:Up to 2 years
Safety Issue:
Description:Will estimate for the combination treatment, along with the Bayesian 95% credible interval.
Measure:Incidence of infectious complications
Time Frame:Up to 2 years
Safety Issue:
Description:Will estimate for the combination treatment, along with the Bayesian 95% credible interval.
Measure:Event-free survival (EFS)
Time Frame:Time interval between treatment start until disease progression, relapse/refractory, or death due to any cause, assessed up to 2 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the survival probabilities of time-to-event variables such as EFS. Log-rank tests will be used to compare among subgroups of patients in terms of the time-to-event variables.
Measure:Overall survival (OS)
Time Frame:Time interval between treatment start until death due to any cause, assessed up to 2 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the survival probabilities of time-to-event variables such as OS. Log-rank tests will be used to compare among subgroups of patients in terms of the time-to-event variables.
Measure:Duration of response
Time Frame:Time from response till progression, relapse/refractory, or death, assessed up to 2 years
Safety Issue:
Description:
Measure:Gene expression profiles
Time Frame:Up to 2 years
Safety Issue:
Description:Will examine the association between gene expression profiles and prognostic markers and overall response and/or resistance will be assessed through logistic regression analyses. Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

July 26, 2021