Clinical Trials /

Venetoclax and Decitabine in Treating Participants With Relapsed/Refractory Acute Myeloid Leukemia or Relapsed High-Risk Myelodysplastic Syndrome

NCT03404193

Description:

This phase II trial studies how well venetoclax and decitabine work in treating participants with acute myeloid leukemia that has come back or does not respond to treatment, or with high-risk myelodysplastic syndrome that has come back. Drugs used in chemotherapy, 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.

Related Conditions:
  • Acute Bilineal Leukemia
  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
  • Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Chronic Myelomonocytic Leukemia
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and Decitabine in Treating Participants With Relapsed/Refractory Acute Myeloid Leukemia or Relapsed High-Risk Myelodysplastic Syndrome
  • Official Title: A Phase II Study of Venetoclax in Combination With 10-Day Decitabine in Newly Diagnosed Elderly or Relapsed/Refractory Acute Myeloid Leukemia and Relapsed High-Risk Myelodysplastic Syndrome and Blastic Plasmacytoid Dendritic Cell Neoplasm

Clinical Trial IDs

  • ORG STUDY ID: 2017-0912
  • SECONDARY ID: NCI-2018-00752
  • SECONDARY ID: 2017-0912
  • NCT ID: NCT03404193

Conditions

  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Chronic Myelomonocytic Leukemia
  • Mixed Phenotype Acute Leukemia
  • Myelodysplastic Syndrome
  • Recurrent Acute Biphenotypic Leukemia
  • Recurrent Acute Myeloid Leukemia
  • Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Mixed Phenotype Acute Leukemia
  • Refractory Acute Myeloid Leukemia
  • Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm
  • Refractory Chronic Myelomonocytic Leukemia
  • Refractory Mixed Phenotype Acute Leukemia

Interventions

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

Purpose

This phase II trial studies how well venetoclax and decitabine work in treating participants with acute myeloid leukemia that has come back or does not respond to treatment, or with high-risk myelodysplastic syndrome that has come back. Drugs used in chemotherapy, 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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the overall response rate (ORR) of venetoclax in combination with 10-day
      decitabine in patients with refractory/relapsed acute myeloid leukemia (AML); elderly (> 60
      year old) patients with newly diagnosed AML not eligible for intensive chemotherapy; patients
      with high-risk myelodysplastic syndrome (MDS) with bone marrow blasts between 10% and 20%,
      relapsed or refractory to prior hypomethylating agent (HMA) therapy, or chronic
      myelomonocytic leukemia (CMML) with bone marrow blasts >= 10% regardless of prior therapy;
      AML patients with prior history of MDS or CMML who received therapy for the MDS or CMML and
      progressed to AML, and younger patients with newly diagnosed AML with poor risk complex
      karyotype and/or TP53 deletions/mutations and patients with blastic plasmacytoid dentritic
      cell neoplasm (BPDCN).

      SECONDARY OBJECTIVES:

      I. To determine the duration of response, disease-free survival (DFS), 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 absolute neutrophil count (ANC) and the number of patients who
      achieve > 50% reduction in blasts on therapy with venetoclax/10-day decitabine.

      III. To determine the safety of venetoclax in combination with 10-day 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 decitabine regimen.

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

      EXPLORATORY OBJECTIVES:

      I. To investigate possible relationships between baseline protein and gene expression
      signatures/mutation profile and BH3 profiling in predicting clinical response to the
      combination.

      II. To characterize the pharmacokinetic (PK) profiles of venetoclax in combination with
      decitabine and antifungals in plasma samples.

      OUTLINE:

      Participants receive decitabine intravenously (IV) over 1 hour on days 1-10 and may also
      receive decitabine on days 1-5 after achieving complete remission/complete remission with
      incomplete count recovery during consolidation/maintenance. Participants also receive
      venetoclax orally (PO) daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles.
      Treatment repeat every 28 days for up to 24 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, participants are followed up every 3 to 6 months for up
      to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, venetoclax)ExperimentalParticipants receive decitabine IV over 1 hour on days 1-10 and may also receive decitabine on days 1-5 after achieving complete remission/complete remission with incomplete count recovery during consolidation/maintenance. Participants also receive venetoclax PO daily on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles. Treatment repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with AML, BPDCN, biphenotypic or bilineage leukemia (including a myeloid
             component) or mixed phenotype acute leukemia (MPAL) who have failed prior therapy;
             patients with AML should have failed prior therapy or have relapsed after prior
             therapy; patients with isolated extramedullary AML are eligible

          -  Elderly (> 60 year old) patients with newly diagnosed AML, BPDCN, or mixed phenotype
             acute leukemia (MPAL) not eligible for intensive chemotherapy

          -  Patients with newly diagnosed AML with poor risk complex karyotype and/or TP53
             deletions/mutations equal or younger than 60 year old

          -  AML or BPDCN patients with prior history of MDS or CMML who received any therapy or no
             therapy for the MDS or CMML and progressed to AML, are eligible at the time of
             diagnosis of AML regardless of any prior therapy for MDS; the World Health
             Organization (WHO) classification will be used for AML

          -  Patients with high-risk MDS with bone marrow blasts between 10% and 20%, relapsed or
             refractory to prior hypomethylating agent (HMA) therapy, defined as prior receipt of 4
             cycles of HMA therapy with failure to attain a response, or relapse after prior
             response to HMA therapy; patients with high risk chronic myelomonocytic leukemia
             (CMML) with bone marrow blasts >= 10% regardless of prior therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 3

          -  White blood cell count =< 10,000

          -  Adequate renal function including creatinine < 2 unless related to the disease

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

          -  Alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement

          -  Provision of written informed consent

          -  Oral hydroxyurea and/or one dose of cytarabine (up to 2 g/m^2) for patients with
             rapidly proliferative disease is allowed before the start of study therapy and while
             the patient is on active study treatment through cycle 1, 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

          -  Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
             at least 12 months) or if of childbearing potential, must have a negative serum or
             urine pregnancy test within 72 hours before the start of the treatment

          -  Women of childbearing potential must agree to use an adequate method of contraception
             during the study and until 3 months after the last treatment; males must be surgically
             or biologically sterile or agree to use an adequate method of contraception during the
             study until 3 months after the last treatment

        Exclusion Criteria:

          -  Patients having received any prior BCL2 inhibitor therapy

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

          -  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

          -  Patients with known infection with human immunodeficiency virus (HIV) or active
             hepatitis B or C

          -  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

          -  Pregnant or breastfeeding
      
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:Up to 4 cycles (112 days)
Safety Issue:
Description:Will be defined as the proportion of patients who had CR (complete remission), CRp (complete remission with incomplete platelet recovery), CRi (complete remission with incomplete count recovery), PR (partial response) or marrow clearance of blasts within 3 months of treatment initiation among adult patients with acute myeloid leukemia (AML); and complete remission (CR), partial remission (PR) or marrow CR (mCR) lasting at least 4 weeks for patients with myelodysplastic syndrome (MDS). Descriptive statistics including plots, mean, median and standard deviations will be used to summarize data. Will estimate the ORR for the combination treatment, along with the 95% confidence interval. The association between ORR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Toxicity type, severity and attribution will be summarized for each patient using frequency tables.
Measure:Duration of response
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log rank tests.
Measure:Disease free survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log rank tests.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier. Comparisons of time-to-event endpoints by important subgroups will be made using the log rank tests.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

July 23, 2020