Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02287233
Recruitment Status : Active, not recruiting
First Posted : November 10, 2014
Last Update Posted : May 16, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
AbbVie

Tracking Information
First Submitted Date  ICMJE November 6, 2014
First Posted Date  ICMJE November 10, 2014
Last Update Posted Date May 16, 2019
Actual Study Start Date  ICMJE December 30, 2014
Estimated Primary Completion Date May 12, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 14, 2019)
  • Number of participants with adverse events [ Time Frame: From participant's first dose until 30 days after participant's last dose of study drug; up to 3 years following last participant first dose ]
    Participants will be monitored for clinical and laboratory evidence of adverse events throughout the study.
  • Time to maximum observed plasma concentration (Tmax) of venetoclax [ Time Frame: Blood samples will be taken at 0 (pre-dose), 2, 4, 6 ,8 and 24 hours post-dose on Days 10 and 18. ]
    The time at which the maximum plasma concentration (Cmax) is observed.
  • Maximum tolerated dose (MTD) of venetoclax in combination with cytarabine [ Time Frame: Minimum first cycle of dosing (28 days) ]
    Venetoclax will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicity information from all participants.
  • Recommended phase two dose (RPTD) of venetoclax in combination with cytarabine [ Time Frame: Minimum first cycle of dosing (28 days) ]
    Venetoclax will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicity information from all participants.
  • Maximum observed plasma concentration (Cmax) of cytarabine [ Time Frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10. ]
    The highest concentration that a drug achieves in the blood after administration in a dosing interval
  • Area under the plasma concentration-time curve from time 0 to 6 hours post-dose (AUC6) of cytarabine. [ Time Frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10. ]
    The area under the plasma concentration-time curve over a 6- hour dose interval.
  • Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC24) of venetoclax [ Time Frame: Blood samples will be taken at 0 (pre-dose), 2, 4, 6, 8, and 24 hours post-dose on Days 10 and 18. ]
    The area under the plasma concentration-time curve over a 24-hour dose interval.
  • Overall Response Rate- In Cohort C, overall response rate (ORR) will be evaluated for subjects allowed additional supportive meds (e.g strong CYP3A inhibitor) if medically indicated. [ Time Frame: Measured up to 3 years after the last participant has enrolled in the study. ]
    Overall response rate will be defined as the proportion of participants who achieve a complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) per the International Working Group (IWG) for AML.
  • Time to maximum observed plasma concentration (Tmax) of cytarabine. [ Time Frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10. ]
    The time at which the maximum plasma concentration (Cmax) is observed.
  • Maximum observed plasma concentration (Cmax) of venetoclax [ Time Frame: Blood samples will be taken at 0 (pre-dose), 2, 4, 6, 8 and 24 hours post-dose on Days 10 and 18. ]
    The highest concentration that a drug achieves in the blood after administration in a dosing interval.
Original Primary Outcome Measures  ICMJE
 (submitted: November 6, 2014)
  • Number of participants with adverse events [ Time Frame: From participant's first dose until 30 days after participant's last dose of study drug; up to 2 years following last participant first dose ]
    Participants will be monitored for clinical and laboratory evidence of adverse events throughout the study.
  • Maximum observed plasma concentration (Cmax) of ABT-199 [ Time Frame: Blood samples will be taken at 0 (pre-dose) 2, 4, 6, 8, and 24 hours post-dose on Days 10 and 18. ]
    The highest concentration that a drug achieves in the blood after administration in a dosing interval.
  • Time to maximum observed plasma concentration (Tmax) of ABT-199 [ Time Frame: Blood samples will be taken at 0 (pre-dose) 2, 4, 6, 8, and 24 hours post-dose on Days 10 and 18. ]
    The time at which the maximum plasma concentration (Cmax) is observed.
  • Area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC24) of ABT-199 [ Time Frame: Blood samples will be taken at 0 (pre-dose) 2, 4, 6, 8, and 24 hours post-dose on Days 10 and 18. ]
    The area under the plasma concentration-time curve over a 24-hour dose interval.
  • Maximum tolerated dose (MTD) of ABT-199 in combination with cytarabine [ Time Frame: Minimum first cycle of dosing (28 days) ]
    ABT-199 will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicity information from all participants.
  • Recommended phase two dose (RPTD) of ABT-199 in combination with cytarabine [ Time Frame: Minimum first cycle of dosing (28 days) ]
    ABT-199 will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicity information from all participants.
  • Overall response rate (ORR) [ Time Frame: Measured up to 2 years after the last participant has enrolled in the study. ]
    Overall response rate will be defined as the proportion of participants who achieve a complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) per the International Working Group (IWG) for AML.
  • Time to progression (TTP) [ Time Frame: Measured up to 2 years after the last participant has enrolled in the study. ]
    Time to progression will be defined as the number of days from the date of enrollment to the date of earliest disease progression.
  • Maximum observed plasma concentration (Cmax) of cytarabine [ Time Frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10. ]
    The highest concentration that a drug achieves in the blood after administration in a dosing interval
  • Time to maximum observed plasma concentration (Tmax) of cytarabine [ Time Frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10. ]
    The time at which the maximum plasma concentration (Cmax) is observed.
  • Area under the plasma concentration-time curve from time 0 to 6 hours post-dose (AUC6) of cytarabine [ Time Frame: Blood samples will be taken 0 (pre-dose); 15 and 30 minutes; and 1, 3, and 6 hours after subcutaneous injection on Days 1 and 10. ]
    The area under the plasma concentration-time curve over a 6- hour dose interval.
Change History Complete list of historical versions of study NCT02287233 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2019)
  • The number of participants who undergo transplant [ Time Frame: Measured up to 3 years after the last participant has enrolled in the study. ]
    The proportion of subjects who undergo a subsequent bone marrow or stem cell transplant will be summarized.
  • Duration of response (DOR) [ Time Frame: Measured up to 3 years after the last participant has enrolled in the study. ]
    Duration of response will be defined as the number of days from the date of first response (CR, CRi, or PR) per the IWG criteria for AML to the earliest recurrence or progressive disease (PD).
  • Overall survival (OS) [ Time Frame: Measured up to 3 years after the last participant has enrolled in the study. ]
    Overall survival will be defined as the number of days from the date of first dose to the date of death.
  • Hematologic response rate to venetoclax/cytarabine combination therapy [ Time Frame: Measured up to 3 years after the last participant has enrolled in the study. ]
    Hematologic response rate will be defined as the proportion of participants who achieve a complete remission (CR) or CRh (complete remission with partial hematologic recovery)
Original Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2014)
  • Duration of response (DOR) [ Time Frame: Measured up to 2 years after the last participant has enrolled in the study. ]
    Duration of response will be defined as the number of days from the date of first response (CR, CRi, or PR) per the IWG criteria for AML to the earliest recurrence or progressive disease (PD).
  • Progression-free survival [ Time Frame: Measured up to 2 years after the last participant has enrolled in the study. ]
    Progression-free survival will be defined as the number of days from the date of enrollment to the date of earliest disease progression or death.
  • Overall survival (OS) [ Time Frame: Measured up to 2 years after the last participant has enrolled in the study. ]
    Overall survival will be defined as the number of days from the date of enrollment to the date of death.
  • The percentage of participants with minimal residual disease (MRD) negativity [ Time Frame: Measured up to 2 years after the last participant has enrolled in the study. ]
    Minimal residual disease negativity will be defined as the presence of less than one AML cell per 10,000 leukocytes in either peripheral blood and/or bone marrow.
  • The number of participants who undergo transplant [ Time Frame: Measured up to 2 years after the last participant has enrolled in the study. ]
    The proportion of subjects who undergo a subsequent bone marrow or stem cell transplant will be summarized.
  • Leukemia response rates to ABT-199/cytarabine combination therapy [ Time Frame: Measured up to 2 years after the last participant has enrolled in the study. ]
    Leukemia response rates of CR, CRi, PR, resistant disease (RD), PD, and hematologic response (HR) will be calculated.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia
Official Title  ICMJE A Phase 1/2 Study of Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia Who Are Greater Than or Equal to 60 Years of Age and Who Are Not Eligible for Standard Anthracycline-Based Induction Therapy
Brief Summary This study consists of two portions: The first portion- Phase 1, or dose-escalation portion, that will evaluate the safety and pharmacokinetic profile of venetoclax in combination with low-dose cytarabine (LDC), define the maximum tolerated dose (MTD), and generate data to support a recommended Phase 2 dose (RPTD) in treatment-naïve subjects with Acute Myelogenous Leukemia (AML). Second portion, initial Phase 2 that will evaluate if the RPTD has sufficient efficacy and acceptable toxicity to warrant further development of the combination therapy. Subsequently, Phase 2 Cohort C, will evaluate the overall response rate (ORR) for subjects allowed additional supportive medications (strong CYP3A inhibitors) if medically indicated.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myelogenous Leukemia
  • AML
Intervention  ICMJE
  • Drug: Venetoclax
    Venetoclax will be taken orally once daily on Days 1 through 28 of each cycle. This is a dose escalation study, therefore the dose of venetoclax will change.
    Other Names:
    • GDC-0199
    • ABT-199
  • Drug: Cytarabine
    Cytarabine will be administered subcutaneously on Days 1 to 10 of each 28-day cycle.
Study Arms  ICMJE Experimental: Venetoclax + low-dose cytarabine
Treatment Naive Acute Myelogenous Leukemia
Interventions:
  • Drug: Venetoclax
  • 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 Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: May 14, 2019)
91
Original Estimated Enrollment  ICMJE
 (submitted: November 6, 2014)
65
Estimated Study Completion Date  ICMJE May 12, 2021
Estimated Primary Completion Date May 12, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participant must be greater than or equal to 65 years of age in Phase 1 and 2. Participants enrolled in Cohort C must be either:

    • greater than or equal to 75 years of age; OR
    • greater than or equal to 60 to 74 years will be eligible if the participants has at least one of the following co-morbidities, which make the participant unfit for intensive chemotherapy:
  • ECOG Performance Status of 2 - 3;
  • Cardiac history of CHF requiring treatment or Ejection Fraction less than or equal to 50% or chronic stable angina;
  • DLCO less than or equal to 65% or FEV1 less than or equal to 65%;
  • Creatinine clearance greater than or equal to 30 mL/min to less than 45 ml/min (calculated by Cockcroft-Gault formula)
  • Moderate hepatic impairment with total bilirubin greater than 1.5 to less than or equal to 3.0 × ULN
  • Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the study medical monitor before study enrollment
  • Participant must have a projected life expectancy of at least 12 weeks.
  • Participant must have histological confirmation of AML and be ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidity or other factors.
  • Participant must have received no prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Participant may have been treated for prior Myelodysplastic Syndrome.
  • Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status;

    • of 0 to 2 for participants greater than equal to 75 years of age
    • of 0 to 3 for participants greater than equal to 60 to 74 years of age, if 0 - 1 another co-morbidity is required to make participant eligible.
  • Participant must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.

Note: Investigators should consider measuring a 24-hour creatinine clearance for subjects who are morbidly obese, have fluctuating renal function, or who in the investigator's clinical judgment may yield a more accurate clearance when measured than when calculated.

  • Participant must have adequate liver function as demonstrated by:

    • aspartate aminotransferase (AST) less than or equal to 2.5 × upper limit of normal (ULN)*
    • alanine aminotransferase (ALT) less than or equal to 2.5 × ULN*
    • bilirubin less than or equal to 1.5 × ULN for all participants age 75 and older* Participants who are less than 75 years of age must have a bilirubin of less than 3.0 × ULN * Unless considered due to leukemic organ involvement. Note: Participants with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per discussion between the investigator and AbbVie medical monitor.
  • Male participants must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 180 days after the last dose of study drug.
  • Participant 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.
  • If female, participant must be either:

    • Postmenopausal defined as no menses for 12 or more months without an alternative medical cause OR
    • Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

Exclusion Criteria:

  • Participant has received treatment with cytarabine for a pre-existing myeloid disorder.
  • Participant has acute promyelocytic leukemia (French-American-British Class M3 AML).
  • Participant has known active central nervous system (CNS) involvement with AML.
  • Participant has tested positive for human immunodeficiency virus (HIV).
  • Participant has received the following within 7 days prior to the initiation of study treatment: strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort.
  • Participant has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
  • Participant has a cardiovascular disability status of New York Heart Association Class greater than 2.
  • Participant 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.
  • Participant has chronic respiratory disease that requires continuous oxygen use.
  • Participant has a malabsorption syndrome or other condition that precludes enteral route of administration.
  • Participant exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to: uncontrolled systemic infection requiring IV therapy (viral, bacterial or fungal).
  • Participant has a history of other malignancies prior to study entry, with the exception of: adequately treated in situ carcinoma of the breast or cervix uteri; basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; or previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
  • Participant has a white blood cell count greater than 25 × 10^9/L. Hydroxyurea is permitted to meet this criterion.
  • Participant is a candidate for a bone marrow or stem cell transplant within 12 weeks after study enrollment.
  • Participant has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Germany,   Italy,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02287233
Other Study ID Numbers  ICMJE M14-387
2014-002610-23 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Genentech, Inc.
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date May 2019

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