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Trial record 1 of 5 for:    venetoclax cytarabine
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A Study Evaluating Venetoclax in Combination With Low-Dose Cytarabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia (AML)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
AbbVie
ClinicalTrials.gov Identifier:
NCT02287233
First received: November 6, 2014
Last updated: August 3, 2017
Last verified: August 2017
  Purpose
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 Intervention Phase
Acute Myelogenous Leukemia AML Drug: Venetoclax Drug: Cytarabine Phase 1

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by AbbVie:

Primary Outcome Measures:
  • 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 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.


Secondary Outcome Measures:
  • 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).

  • 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 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.


Estimated Enrollment: 91
Study Start Date: April 4, 2014
Estimated Study Completion Date: May 10, 2019
Estimated Primary Completion Date: September 13, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Eligibility

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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02287233

Locations
United States, Kansas
University of Kansas Medical Center /ID# 131175
Westwood, Kansas, United States, 66205
United States, New York
New York Presbyterian Hospital /ID# 131170
New York, New York, United States, 10021
United States, Pennsylvania
UPMC Hillman Cancer Center /ID# 131168
Pittsburgh, Pennsylvania, United States, 15232
United States, Tennessee
Vanderbilt University Medical Center /ID# 131177
Nashville, Tennessee, United States, 37232
United States, Washington
Fred Hutchinson Cancer Research Center /ID# 131178
Seattle, Washington, United States, 98109
Australia
Alfred Health /ID# 131180
Melbourne, Australia, 3004
Calvary Mater Newcastle /ID# 136076
Waratah, Australia, 2298
Germany
Universitaetsklinikum Eppendorf Hamburg-CeDeF /ID# 133979
Hamburg, Germany, 20246
Italy
Policlinico Universitario S. Orsola Malpighi /ID# 131183
Bologna, Italy, 40138
Sponsors and Collaborators
AbbVie
Genentech, Inc.
Investigators
Study Director: John Hayslip, MD AbbVie
  More Information

Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT02287233     History of Changes
Other Study ID Numbers: M14-387
2014-002610-23 ( EudraCT Number )
Study First Received: November 6, 2014
Last Updated: August 3, 2017

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

Additional relevant MeSH terms:
Cytarabine
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

ClinicalTrials.gov processed this record on August 22, 2017