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

Sponsor

AbbVie (Industry)

Overall Status

Terminated

CT.gov ID

NCT02203773

Collaborator

Genentech, Inc. (Industry)

212

Enrollment

Locations

Arms

92.3

Actual Duration (Months)

9.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia Myelogenous Leukemia Treatment Naive AML	Drug: Posaconazole Drug: ABT-199 Drug: Decitabine Drug: Azacitidine	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

212 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 6, 2014

Actual Primary Completion Date :

Jun 16, 2022

Actual Study Completion Date :

Jun 16, 2022

Arms and Interventions

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: 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

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: 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

Outcome Measures

Primary Outcome Measures

Number of Participants Experiencing Adverse Events (AEs) [Measured up to 1 year after the last subject last dose]
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.
Maximum observed plasma concentration (Cmax) [For approximately 5 days following a single dose of ABT-199.]
Maximum observed concentration, occurring at Tmax.
Time to Cmax (peak time, Tmax), [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 24 hours (AUC0-24) [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) [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.
Clearance (CL) [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.
Complete Remission Rate [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.
Complete Remission with incomplete blood count recovery rate [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.
Overall Response Rate [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.
Overall Survival [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 first dose to the date of death.

Secondary Outcome Measures

Event Free Survival [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.
Duration of Response [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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

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