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

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

This is a Phase 1b, open-label, non-randomized, multicenter study to evaluate the safety and pharmacokinetics of orally administered venetoclax (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 venetoclax (ABT-199) in combination with posaconazole.

Study Overview

• Status: Terminated
• Conditions: Acute Myelogenous Leukemia; Myelogenous Leukemia; Treatment Naive AML
• Intervention / Treatment: Drug: ABT-199; Drug: Azacitidine; Drug: Decitabine; Drug: Posaconazole

• Study Type: Interventional
• Enrollment (Actual): 212
• Phase: Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital /ID# 130356
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Ctr /ID# 130352
    • Melbourne, Victoria, Australia, 3004
      • Alfred Health /ID# 130353
• France
  • Paris, France, 75010
    • AP-HP - Hopital Saint-Louis /ID# 130349
  • Gironde
    • Pessac CEDEX, Gironde, France, 33604
      • Hopital Haut-Lévêque /ID# 134388
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • Duplicate_Hopital Universitaire Purpan /ID# 134389
• Germany
  • Dresden, Germany, 01307
    • Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 130342
  • Munich, Germany, 81675
    • Duplicate_Klinikum Rechts der Isar /ID# 130347
  • Baden-Wuerttemberg
    • Ulm, Baden-Wuerttemberg, Germany, 89081
      • Universitaetsklinikum Ulm /ID# 130341
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Universitaetsklinikum Leipzig /ID# 130346
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope /ID# 129718
    • Sacramento, California, United States, 95817
      • University of California, Davis Comprehensive Cancer Center /ID# 129719
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Univ of Colorado Cancer Center /ID# 127859
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Midtown Infectious Disease Clinic /ID# 129715
  • Illinois
    • Chicago, Illinois, United States, 60611-2927
      • Northwestern University Feinberg School of Medicine /ID# 128741
    • Chicago, Illinois, United States, 60637-1443
      • The University of Chicago Medical Center /ID# 128742
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University /ID# 129699
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute /ID# 127857
  • New York
    • New York, New York, United States, 10032-3729
      • Columbia University Medical Center /ID# 130289
  • North Carolina
    • Durham, North Carolina, United States, 27710-3000
      • Duke Cancer Center /ID# 129720
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center /ID# 127860
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center /ID# 141581
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington /ID# 129717

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 0 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ABT-199 + Azacitidine; Treatment Naive Acute Myelogenous Leukemia	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: 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.
Experimental: ABT-199 + Decitabine; Treatment Naive Acute Myelogenous Leukemia	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
Experimental: ABT-199+Decitabine+Posaconazole; Treatment Naive Acute Myelogenous Leukemia	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: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Adverse Events (AEs)	An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug.	Measured up to 1 year after the last subject last dose
Maximum observed plasma concentration (Cmax)	Maximum observed concentration, occurring at Tmax.	For approximately 5 days following a single dose of ABT-199.
Time to Cmax (peak time, Tmax),	The time at which maximum plasma concentration (Cmax) is observed.	For approximately 5 days following a single dose of ABT-199.
The area under the plasma concentration-time curve (AUC) from 0 to 24 hours (AUC0-24)	The area under the plasma concentration-time curve (AUC) over a 24-hour dose interval.	For approximately 5 days following a single dose of ABT-199.
Half-Life (t1/2)	The time required for the concentration of the drug to reach half of its original value.	For approximately 5 days following a single dose of ABT-199.
Clearance (CL)	Clearance is defined as the rate at which drug is cleared from the blood.	For approximately 5 days following a single dose of ABT-199.
Complete Remission Rate	Complete Remission Rate will be determined by the number of subjects who achieve a Complete Remission.	Measured up to 1 year after the last subject last dose
Complete Remission with incomplete blood count recovery rate	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.	Measured up to 1 year after the last subject last dose
Overall Response Rate	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.	Measured up to 1 year after the last subject last dose
Overall Survival	Overall survival will be defined as the number of days from the date of first dose to the date of death.	Measured up to 1 year after the last subject last dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival	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.	Measured up to 1 year after the last subject last dose
Duration of Response	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).	Measured up to 1 year after the last subject last dose

Collaborators and Investigators

• Sponsor: AbbVie
• Collaborators: Genentech, Inc.
• Investigators: Study Director: ABBVIE INC., AbbVie

Publications and helpful links

General Publications

• Badawi M, Chen X, Marroum P, Suleiman AA, Mensing S, Koenigsdorfer A, Schiele JT, Palenski T, Samineni D, Hoffman D, Menon R, Salem AH. Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet. Clin Drug Investig. 2022 Aug;42(8):657-668. doi: 10.1007/s40261-022-01172-4. Epub 2022 Jul 13.
• Konopleva M, Thirman MJ, Pratz KW, Garcia JS, Recher C, Pullarkat V, Kantarjian HM, DiNardo CD, Dail M, Duan Y, Chyla B, Potluri J, Miller CL, Wei AH. Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naive Acute Myeloid Leukemia. Clin Cancer Res. 2022 Jul 1;28(13):2744-2752. doi: 10.1158/1078-0432.CCR-21-3405.
• Pollyea DA, DiNardo CD, Arellano ML, Pigneux A, Fiedler W, Konopleva M, Rizzieri DA, Smith BD, Shinagawa A, Lemoli RM, Dail M, Duan Y, Chyla B, Potluri J, Miller CL, Kantarjian HM. Impact of Venetoclax and Azacitidine in Treatment-Naive Patients with Acute Myeloid Leukemia and IDH1/2 Mutations. Clin Cancer Res. 2022 Jul 1;28(13):2753-2761. doi: 10.1158/1078-0432.CCR-21-3467.
• 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.

Helpful Links

• clinical study report synopsis

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2014
• Primary Completion (Actual): June 16, 2022
• Study Completion (Actual): June 16, 2022

Study Registration Dates

• First Submitted: July 10, 2014
• First Submitted That Met QC Criteria: July 28, 2014
• First Posted (Estimate): July 30, 2014

Study Record Updates

• Last Update Posted (Actual): May 16, 2023
• Last Update Submitted That Met QC Criteria: May 12, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: AML; Venetoclax; ABT-199; Venclexta; GDC-0199; Acute Myelogenous Leukemia; Untreated AML; Myelogenous Leukemia; Treatment Naive AML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Decitabine; Venetoclax; Azacitidine; Posaconazole
• Other Study ID Numbers: M14-358; 2014-000687-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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