Clinical Trials /

Venetoclax in Combination With Intensive Induction and Consolidation Chemotherapy in Treatment Naïve AML



This research study is studying the combination of venetoclax and chemotherapy as a possible treatment for acute myelogenous leukemia (AML). The drugs involved in this study are: - Venetoclax - Daunorubicin - Cytarabine

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:



Phase 1

Trial Eligibility



  • Brief Title: Venetoclax in Combination With Intensive Induction and Consolidation Chemotherapy in Treatment Naïve AML
  • Official Title: Phase 1b Study of Venetoclax in Combination With Intensive Induction and Consolidation Chemotherapy in Treatment Naïve Subjects With Acute Myelogenous Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 18-351
  • NCT ID: NCT03709758


  • Acute Myeloid Leukemia




This research study is studying the combination of venetoclax and chemotherapy as a possible treatment for acute myelogenous leukemia (AML). The drugs involved in this study are: - Venetoclax - Daunorubicin - Cytarabine

Detailed Description

      This research study is a Phase I clinical trial, which tests the safety of an investigational
      drug and also tries to define the appropriate dose of the investigational drug to use for
      further studies. "Investigational" means that the drug is being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved venetoclax for this specific
      disease but it has been approved for other uses.

      In this research study, the investigators are combining the use of venetoclax (the
      investigational drug being studied) with chemotherapy drugs daunorubicin and cytarabine. The
      investigators are looking to determine the highest dose of venetoclax that can be given
      safely in combination with these chemotherapy drugs.

      Depending on when the participant join the study, the participant may participate in part 1
      (induction with venetoclax escalation), part 2 (consolidation with venetoclax escalation), or
      part 3 (an expansion cohort utilizing the maximum tolerated doses identified in parts 1 and
      2). The study doctor will tell the participant which part of the study they will join.

Trial Arms

Venetoclax+Daunorubicin+CytarabineExperimentalVenetoclax administered orally on days 1 to 11 daily Daunorubicin administered intravenously on days 2-4 Cytarabine administered on days 2-8 by continuous IV infusion
  • Venetoclax
  • Daunorubicin
  • Cytarabine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with AML who are newly diagnosed according to the WHO 2016 Classification and
             previously untreated with the exception of hydroxyurea. ATRA pretreatment for
             suspected APL for less than 5 days is allowed. Eligible patients with AML arising from
             an antecedent hematologic disease (AHD) including MDS, may have been treated for their
             prior hematologic disease (except for allogenic transplant).

          -  AML patients include de-novo AML, AML evolving from MDS or other AHD and AML after
             previous cytotoxic therapy or radiation (secondary AML).

               -  For a diagnosis of AML, a bone marrow or peripheral blast count of 20% or more is

               -  In AML with monocytic or myelomonocytic differentiation, monoblasts and
                  promonocytes, but not abnormal mature monocytes, are counted as blast

          -  Patients must be ≥18 and ≤60 years old.

          -  Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2. (See protocol
             Appendix D.)

          -  LVEF ≥ 45% by MUGA or ECHO at screening.

          -  Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 50
             mL/min; determined via urine collection for 24-hour creatinine clearance or by the
             Cockcroft Gault formula.

          -  Adequate liver function as demonstrated by:

               -  aspartate aminotransferase (AST) ≤ 2.5 × ULN*

               -  alanine aminotransferase (ALT) ≤ 2.5× ULN*

               -  total bilirubin ≤ 1.5 × ULN*

          -  Unless considered due to leukemic organ involvement.

          -  Subjects with Gilbert's Syndrome may have a total bilirubin > 1.5 × ULN per discussion
             with the overall study PI

          -  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.

          -  Females of childbearing potential (i.e., not postmenopausal for at least 1 year or not
             surgically sterile) must have negative results by a serum pregnancy test performed
             within 7 days of day 1.

          -  Subject must voluntarily sign and date an informed consent, approved by an Independent
             Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of
             any screening or study-specific procedures.

        Exclusion Criteria:

          -  Subject has acute promyelocytic leukemia, inversion16, t(8;21) or FLT3 mutant AML as
             described below. Contact PI with questions.

               -  Inversion 16 and t(8;21): CBF chromosomal abnormalities may be assessed by
                  molecular (PCR), metaphase cytogenetics, or FISH

               -  FLT3: ITD or a point mutation in the TKD loop of variant allele fractions ≥5% by
                  PCR, capillary electrophoresis, or NGS panel capable of defining FLT3 allelic

          -  Subject has known active CNS involvement with AML.

          -  Subject has tested positive for HIV (due to potential drug-drug interactions between
             antiretroviral medications and venetoclax, as well as anticipated venetoclax
             mechanism-based lymphopenia that may potentially increase the risk of opportunistic
             infections). Note: HIV testing is not required.

          -  Subject is known to be positive for hepatitis B or C infection with the exception of
             those with an undetectable viral load within 3 months. (Hepatitis B or C testing is
             not required). Subjects with serologic evidence of prior vaccination to HBV [i.e., HBs
             Ag-, and anti-HBs+] are allowed.

          -  Subject has received the following within 7 days prior to the initiation of study

               -  Strong or moderate CYP3A inducers (see Appendix C)

               -  Strong and moderate CYP3A inhibitors (see Appendix C)

          -  Subject has consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges) or Star fruit within 3 days prior to the
             initiation of study treatment.

          -  Subject has a cardiovascular disability status of New York Heart Association Class ≥
             2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but
             ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.

          -  Subject has a significant history of renal, neurologic, psychiatric, endocrinologic,
             metabolic, immunologic, hepatic, cardiovascular disease, or any other medical
             condition that in the opinion of the investigator would adversely affect his/her
             participating in this study.

          -  Subject has chronic respiratory disease that requires continuous oxygen use.

          -  Subject has a malabsorption syndrome or other condition that precludes enteral route
             of administration.

          -  Subject exhibits evidence of other clinically significant uncontrolled condition(s)
             including, but not limited to: uncontrolled systemic infection.

          -  Subject has a history of other malignancies prior to study entry, with the exception

               -  Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of

               -  Basal cell carcinoma of the skin or localized squamous cell carcinoma of the

               -  Previous malignancy confined and surgically resected (or treated with other
                  modalities) with curative intent.

               -  Prior malignancies treated with (surgery+/- chemotherapy+/- radiation) that have
                  remained disease free for at least two years after completion of therapy

          -  Subject has a white blood cell count > 25 × 109/L. Note: Hydroxyurea is permitted to
             meet this criterion.

          -  Subject treated with any form of chemotherapy, immunotherapy, or investigative agent
             within 1 month of enrollment.
Maximum Eligible Age:60 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (Induction)
Time Frame:2 years
Safety Issue:
Description:To determine a safe and tolerable dose of venetoclax that can be given in combination with standard induction therapy to patients with newly diagnosed AML.

Secondary Outcome Measures

Measure:Complete Response Rate
Time Frame:2 years
Safety Issue:
Description:1. To obtain preliminary data as to the efficacy (Complete Remission (CR), Complete remission with incomplete platelet recovery (CRp), Complete remission with incomplete hematologic recovery (CRi), and minimal residual disease (MRD) negative CR) of combining venetoclax with standard induction and consolidation chemotherapy for AML.
Measure:Exploratory analysis concerning the impact of BH3 profiling on response when venetoclax is combined with standard induction and consolidation chemotherapy in AML.
Time Frame:2 years
Safety Issue:
Description:BH3 profiling will be performed at the time of screening, and on PB blasts just prior to start of IV chemotherapy on day 2 of induction. These studies will determine if BH3 profile changes are induced by venetoclax exposure. Exploratory research analyses may not be included in the clinical study report.
Measure:Determine the pharmacodynamic effects of combo venetoclax with standard chemotherapy in AML on apoptosis and other intracellular events in AML blasts exposed in patients to a combination of venetoclax plus standard induction chemo.
Time Frame:2 years
Safety Issue:
Description:A reduction in leukocytosis or blast counts will be evaluated as a measure of venetoclax-induced pharmacodynamic activity.
Measure:Exploratory analysis concerning the impact of pre-therapy disease factors including mutational profile on outcome in AML patients who receive venetoclax in combination with standard chemotherapy.
Time Frame:2 years
Safety Issue:
Description:Single cell mass cytometry (CyTOF) will be used to observe changes in the levels of BCL-2 and associated proteins before therapy, at time of response assessment, upon recovery from consolidation (if applicable) and at relapse if feasible. Exploratory research analyses may not be included in the clinical study report.


Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Acute Myeloid Leukemia

Last Updated

March 17, 2021