Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03709758
Recruitment Status : Recruiting
First Posted : October 17, 2018
Last Update Posted : June 24, 2019
Sponsor:
Collaborators:
AbbVie
Genentech, Inc.
Information provided by (Responsible Party):
Richard Stone, MD, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE October 12, 2018
First Posted Date  ICMJE October 17, 2018
Last Update Posted Date June 24, 2019
Actual Study Start Date  ICMJE October 15, 2018
Estimated Primary Completion Date June 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
  • Maximum Tolerated Dose (Induction) [ Time Frame: 2 years ]
    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.
  • Maximum Tolerated Dose (Consolidation) [ Time Frame: 2 years ]
    To determine a safe and tolerable dose of venetoclax and that can be given with a cycle of high dose cytarabine in consolidation after achievement of remission with induction therapy at the established MTD of venetoclax.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03709758 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
  • Complete Response Rate [ Time Frame: 2 years ]
    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.
  • Partial Response Rate [ Time Frame: 2 years ]
    1. To obtain preliminary partial response rate data as to the efficacy of combining venetoclax with standard induction and consolidation chemotherapy for AML.
  • Minimal Residual Disease [ Time Frame: 2 years ]
    1. To obtain minimal residual disease (MRD) response rate data as to the efficacy of combining venetoclax with standard induction and consolidation chemotherapy for AML.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Venetoclax in Combination With Intensive Induction and Consolidation Chemotherapy in Treatment Naïve AML
Official Title  ICMJE Phase 1b Study of Venetoclax in Combination With Intensive Induction and Consolidation Chemotherapy in Treatment Naïve Subjects With Acute Myelogenous Leukemia
Brief Summary

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: Venetoclax
    Venetoclax blocks an important pathway that promotes cell survival in tumor cells that overexpress BCL-2, so venetoclax causes cells to die
    Other Name: Venclexta
  • Drug: Daunorubicin
    Chemotherapy is most effective at killing cells that are rapidly dividing.
    Other Name: Cerubidine
  • Drug: Cytarabine
    Chemotherapy is most effective at killing cells that are rapidly dividing.
    Other Name: Cytosar-U
Study Arms  ICMJE Experimental: Venetoclax+Daunorubicin+Cytarabine
  • Venetoclax 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
Interventions:
  • Drug: Venetoclax
  • Drug: Daunorubicin
  • Drug: Cytarabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 21, 2019)
64
Original Estimated Enrollment  ICMJE
 (submitted: October 16, 2018)
58
Estimated Study Completion Date  ICMJE June 1, 2025
Estimated Primary Completion Date June 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 required.
    • In AML with monocytic or myelomonocytic differentiation, monoblasts and promonocytes, but not abnormal mature monocytes, are counted as blast equivalents.
  • 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 burden
  • 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 treatment:

    • 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 of:

    • Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
    • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
    • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Richard Stone, MD 617-632-5157 Richard_Stone@dfci.harvard.edu
Contact: Jeremy Stewart 617-582-8063 jstewart13@partners.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03709758
Other Study ID Numbers  ICMJE 18-351
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Richard Stone, MD, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Dana-Farber Cancer Institute
Collaborators  ICMJE
  • AbbVie
  • Genentech, Inc.
Investigators  ICMJE
Principal Investigator: Richard Stone, MD Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP