We updated the design of this site on December 18, 2017. Learn more.
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 1 of 6 for:    venetoclax cytarabine
Previous Study | Return to List | Next Study

A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia (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. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02287233
Recruitment Status : Active, not recruiting
First Posted : November 10, 2014
Last Update Posted : January 17, 2018
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
AbbVie

Brief Summary:
This study consists of three 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.

Condition or disease Intervention/treatment Phase
Acute Myelogenous Leukemia AML Drug: Venetoclax Drug: Cytarabine Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 94 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia Who Are ≥ 60 Years of Age and Who Are Not Eligible for Standard Anthracycline-Based Induction Therapy
Actual Study Start Date : January 2, 2015
Estimated Primary Completion Date : September 13, 2018
Estimated Study Completion Date : May 9, 2019


Arm Intervention/treatment
Experimental: Venetoclax + low-dose cytarabine
Treatment Naive Acute Myelogenous Leukemia
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.



Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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 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.

  10. 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.

  11. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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).

  3. Leukemia response rates to venetoclax/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 and MLFS will be calculated.

  4. 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.

  5. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   60 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject must be greater than or equal to 65 years of age in Phase 1 and 2. Subjects 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 subjects has at least one of the following co-morbidities, which make the subject 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
  • Subject must have a projected life expectancy of at least 12 weeks.
  • Subject 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.
  • Subject must have received no prior treatment for AML with the exception of hydroxyurea, allowed through the first cycle of study treatment. Note: Subject may have been treated for prior Myelodysplastic Syndrome.
  • Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status;

    • of 0 to 2 for subjects greater than equal to 75 years of age
    • of 0 to 3 for subjects greater than equal to 60 to 74 years of age, if 0 - 1 another co-morbidity is required to make subject eligible.
  • Subject 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.

  • Subject 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 subjects age 75 and older* Subjects 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: Subjects with Gilbert's Syndrome may have a bilirubin greater than 1.5 × ULN per discussion between the investigator and AbbVie medical monitor.
  • Male subjects 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.
  • 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.
  • If female, subject 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.
  • Subject has a history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02287233


Locations
United States, Kansas
Univ Kansas Med Ctr
Kansas City, Kansas, United States, 66160
United States, New York
Columbia University Medical Center-OB/GYN Department
New York, New York, United States, 10032
United States, Pennsylvania
UPMC
Pittsburgh, Pennsylvania, United States, 15260
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232-0011
United States, Washington
Fred Hutchinson Cancer Researc
Seattle, Washington, United States, 98109
Australia, New South Wales
Calvary Mater Newcastle
Waratah, New South Wales, Australia, 2298
Australia, Victoria
Alfred Health
Melbourne, Victoria, Australia, 3004
Germany
Univ Klinik Eppendorf Hamburg
Hamburg, Germany, 20246
Italy
A.O. Policlinico S. Orsola Malpighi
Bologna, Emilia-Romagna, Italy, 40138
Sponsors and Collaborators
AbbVie
Genentech, Inc.
Investigators
Study Director: AbbVie Inc. AbbVie

Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT02287233     History of Changes
Other Study ID Numbers: M14-387
2014-002610-23 ( EudraCT Number )
First Posted: November 10, 2014    Key Record Dates
Last Update Posted: January 17, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by AbbVie:
Myelogenous Leukemia
Treatment Naive AML
Untreated AML

Additional relevant MeSH terms:
Cytarabine
Venetoclax
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs