Study of ABT-199 (GDC-0199) in Combination With Azacitidine or Decitabine (Chemo Combo) in Subjects With Acute Myelogenous Leukemia (AML)

• ClinicalTrials.gov Identifier: NCT02203773
• Recruitment Status: Active, not recruiting
• First Posted: July 30, 2014
• Last Update Posted: December 22, 2020
• Sponsor: AbbVie
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: July 10, 2014
• First Posted Date: July 30, 2014
• Last Update Posted Date: December 22, 2020
• Actual Study Start Date: October 6, 2014
• Estimated Primary Completion Date: September 27, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 20, 2020)

• Complete Remission Rate [ Time Frame: Measured up to 1 year after the last subject last dose ]
  Complete Remission Rate will be determined by the number of subjects who achieve a Complete Remission.
• The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration.
• Complete Remission with incomplete blood count recovery rate [ Time Frame: Measured up to 1 year after the last subject last dose ]
  Complete Remission with incomplete blood count recovery Rate will be determined by the number of subjects who achieve a Complete Remission with incomplete blood count recovery.
• half-life (t1/2) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  The time required for the concentration of the drug to reach half of its original value.
• Maximum observed plasma concentration (Cmax) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  Maximum observed concentration, occurring at Tmax.
• Overall Response Rate [ Time Frame: Measured up to 1 year after the last subject last dose ]
  Overall response rate will be defined as the proportion of subjects who achieve a complete remission (CR), complete remission incomplete (CRi), or partial remission(PR) per the International Working Group criteria for AML.
• Clearance (CL) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  Clearance is defined as the rate at which drug is cleared from the blood.
• AUC from 0-24 (AUC0-24) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  The area under the plasma concentration-time curve (AUC) over a 24-hour dose interval.
• Time to Cmax (peak time, Tmax), [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  The time at which maximum plasma concentration (Cmax) is observed.
• AUC from 0 to infinity (AUC∞) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  Area under the plasma concentration-versus-time curve from time zero to infinity.
• Overall Survival [ Time Frame: Measured up to 1 year after the last subject last dose ]
  Overall survival will be defined as the number of days from the date of enrollment to the date of death.

Original Primary Outcome Measures (submitted: July 28, 2014)

• Adverse Event (AE) monitoring of ABT-199 in combination with decitabine and azacitidine [ Time Frame: Measured from Day 1 up to 2 years after the last subject has enrolled ]
  AE monitoring will be assessed by evaluation of study drug exposure, AEs , serious AEs, all deaths, as well as laboratory determinations and vital sign parameters.
• Maximum observed plasma concentration (Cmax) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  Maximum observed concentration, occurring at Tmax.
• The time to Cmax (peak time, Tmax), [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  The time at which maximum plasma concentration (Cmax) is observed.
• The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  The area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration.
• AUC from 0-24 (AUC0-24) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  The area under the plasma concentration-time curve (AUC) over a 24-hour dose interval.
• half-life (t1/2) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  The time required for the concentration of the drug to reach half of its original value.
• AUC from 0 to infinity (AUC∞) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  Area under the plasma concentration-versus-time curve from time zero to infinity.
• Clearance (CL) [ Time Frame: For approximately 5 days following a single dose of ABT-199. ]
  Clearance is defined as the rate at which drug is cleared from the blood.

Current Secondary Outcome Measures (submitted: March 20, 2020)

• Percent of subjects who move on to stem cell transplant [ Time Frame: Measured up to 1 year after the last subject last dose ]
  The percent of subjects who move on to stem cell transplant will be summarized.
• Duration of Response [ Time Frame: Measured up to 1 year after the last subject last dose ]
  Duration of response will be defined as the number of days from the date of first response per the IWG criteria for AML to the earliest recurrence or progressive disease (PD).
• Event Free Survival [ Time Frame: Measured up to 1 year after the last subject last dose ]
  Event-free survival (EFS) will be defined as the number of days from the date of first dose to the date of earliest evidence of relapse, subsequent treatment other than stem cell transplant while in composite complete response (CR + CRi), or death.

Original Secondary Outcome Measures (submitted: July 28, 2014)

• Overall response rate [ Time Frame: Measured up to 2 years after the last subject has enrolled. ]
  Overall response rate will be defined as the proportion of subjects who achieve a complete remission (CR), complete remission incomplete (CRi), or partial remission(PR) per the International Working Group criteria for AML.
• Duration of Response [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  Duration of response will be defined as the number of days from the date of first response per the IWG criteria for AML to the earliest recurrence or progressive disease (PD).
• Time to Progression [ Time Frame: Measured up to 2 years after the last subject 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.
• Progression-Free Survival [ Time Frame: Measured up to 2 years after the last subject 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 or death.
• Overall Survival [ Time Frame: Measured up to 2 years after the last subject 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.
• Minimal Residual Disease (MRD) Negativity Rate [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  The presence of less than one AML cell per 10,000 leukocytes in either peripheral blood and/or bone marrow.
• Changes in clinical laboratory test results [ Time Frame: Measured from Day 1 up to 2 years after the last subject has enrolled in the study. ]
  chemistry, hematology, and urinalysis
• Changes in physical exam findings, including vital signs. [ Time Frame: Measured from Day 1 up to 2 years after the last subject has enrolled in the study. ]
  Body temperature, weight, blood pressure, heart rate, and respiratory rate
• Percent of subjects who move on to stem cell transplant [ Time Frame: Measure up to 2 years after the last subject has enrolled in the study. ]
  The percent of subjects who move on to stem cell transplant will be summarized.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of ABT-199 (GDC-0199) in Combination With Azacitidine or Decitabine (Chemo Combo) in Subjects With Acute Myelogenous Leukemia (AML)
• Official Title: A Phase 1b Study of ABT-199 (GDC-0199) in Combination With Azacitidine or Decitabine in Treatment-Naive Subjects With Acute Myelogenous Leukemia Who Are Greater Than or Equal to 60 Years of Age and Who Are Not Eligible for Standard Induction Therapy
• Brief Summary: This is a Phase 1b, open-label, non-randomized, multicenter study to evaluate the safety and pharmacokinetics of orally administered ABT-199 combined with decitabine or azacitidine and the preliminary efficacy of these combinations. In addition, there is a drug-drug interaction (DDI) sub-study only at a single site, to assess the pharmacokinetics and safety of ABT-199 in combination with posaconazole.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Myelogenous Leukemia
• Myelogenous Leukemia
• Treatment Naive AML

Intervention

• Drug: Posaconazole
  Posaconazole will be administered orally twice a day on Cycle 1 Day 21 and once daily from Cycle 1 Day 22 to Cycle 1 Day 28.
• Drug: ABT-199
  ABT-199 is taken orally once daily starting on Day 2 of cycle 1 and begin on day 1 of every other cycle thereafter. This is a dose escalation study, therefore the dose of ABT-199 will change.
• Drug: Decitabine
  Decitabine will be administered by IV infusion over 1 hour beginning on Day 1 thru Day 5 of each Cycle for a minimum of 4 Cycles
• Drug: Azacitidine
  Azacitidine will be administered by IV infusion over 10 to 40 minutes or subcutaneously based on the institutional guidelines, beginning on Day 1 through Day 7 of each Cycle, for a minimum of 4 Cycles.

Study Arms

• Experimental: ABT-199 + Azacitidine
  Treatment Naive Acute Myelogenous Leukemia
  Interventions:

  • Drug: ABT-199
  • Drug: Azacitidine
• Experimental: ABT-199 + Decitabine
  Treatment Naive Acute Myelogenous Leukemia
  Interventions:

  • Drug: ABT-199
  • Drug: Decitabine
• Experimental: ABT-199+Decitabine+Posaconazole
  Treatment Naive Acute Myelogenous Leukemia
  Interventions:

  • Drug: Posaconazole
  • Drug: ABT-199
  • Drug: Decitabine

Publications *

• DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7-17. doi: 10.1182/blood-2018-08-868752. Epub 2018 Oct 25.
• DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman M, Arellano M, Frattini MG, Kantarjian H, Popovic R, Chyla B, Xu T, Dunbar M, Agarwal SK, Humerickhouse R, Mabry M, Potluri J, Konopleva M, Pollyea DA. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb;19(2):216-228. doi: 10.1016/S1470-2045(18)30010-X. Epub 2018 Jan 12.
• Agarwal SK, DiNardo CD, Potluri J, Dunbar M, Kantarjian HM, Humerickhouse RA, Wong SL, Menon RM, Konopleva MY, Salem AH. Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments. Clin Ther. 2017 Feb;39(2):359-367. doi: 10.1016/j.clinthera.2017.01.003. Epub 2017 Feb 1.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: December 18, 2020): 260
• Original Estimated Enrollment (submitted: July 28, 2014): 89
• Estimated Study Completion Date: September 27, 2021
• Estimated Primary Completion Date: September 27, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subjects must have confirmation of Acute Myeloid Leukemia (AML) by WHO criteria 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
• Subjects must have Eastern Cooperative Oncology Group (ECOG) Performance Status of ) to 2 for subjects greater than or equal to 75 years of age, or 0 to 3 for subjects greater than or equal to 60 to 74 years of age
• Subject must have adequate kidney and liver function as described in the protocol

Exclusion Criteria:

• Subject has received treatment with the following hypomethylating agent and/or chemo therapeutic agent for for an antecedent hematologic disorder (AHD) (Subjects may have been treated with other agents for AHD i.e., Myelodysplastic syndrome [MDS])
• Subject has history of Myeloproliferative Neoplasm (MPN).
• Subject has favorable risk cytogenetics as categorized by the National Comprehensive Cancer Network Guidelines Version 2, 2014 for AML.
• Subject has t(8;21), inv(16), t(16;16) or t(15;17) karyotype abnormalities.
• Subject has acute promyelocytic leukemia.
• Subject has known active central nervous system involvement with AML.
• Subject has received a strong and/or moderate CYP3A inducer within 7 days prior to the initiation of study treatment.

• 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.
• Subject has a white blood cell count > 25 × 10^9/L. Note: Hydroxyurea is permitted to meet this criterion.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Germany, United States

Administrative Information

• NCT Number: NCT02203773
• Other Study ID Numbers: M14-358; 2014-000687-18 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• 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)
• 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: AbbVie
• Collaborators: Genentech, Inc.

Investigators

• Study Director: AbbVie Inc.; AbbVie

• PRS Account: AbbVie
• Verification Date: December 2020