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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Myelogenous Leukemia, Myelogenous Leukemia, Treatment Naive AML

Intervention / Treatment
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* Drug: Posaconazole
* Drug: ABT-199
* Drug: Decitabine
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABT-199 + Azacitidine<br>Treatment Naive Acute Myelogenous Leukemia | Drug: ABT-199<br>* 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.<br>Drug: Azacitidine<br>* 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.<br>|
| Experimental: ABT-199 + Decitabine<br>Treatment Naive Acute Myelogenous Leukemia | Drug: ABT-199<br>* 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.<br>Drug: Decitabine<br>* 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<br>|
| Experimental: ABT-199+Decitabine+Posaconazole<br>Treatment Naive Acute Myelogenous Leukemia | Drug: Posaconazole<br>* 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.<br>Drug: ABT-199<br>* 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.<br>Drug: Decitabine<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myelogenous Leukemia, AML, Myelogenous Leukemia, ABT-199, GDC-0199, Treatment Naive AML, Untreated AML, Venetoclax, Venclexta