A Phase 2 Study of ABT-199 in Subjects With Acute Myelogenous Leukemia (AML)

Phase 2

Completed

• Conditions: Acute Myelogenous Leukemia; AML; Acute Myeloid Leukemia
• Interventions: Drug: ABT-199

• Registration Number: NCT01994837
• Lead Sponsor: AbbVie

Brief Summary

This was a Phase 2, open-label, multicenter study evaluating the preliminary efficacy and safety of venetoclax (ABT-199) administered orally in participants with acute myelogenous leukemia (AML).

Detailed Description

The primary objective was to evaluate the preliminary efficacy of venetoclax administered orally in participants with relapsed and/or refractory (R/R) acute myelogenous leukemia (AML) or frontline therapy in patients with AML who were unfit for intensive therapy. The secondary objective was to evaluate the preliminary safety of venetoclax administered orally in patients with AML. The first portion of the study was to consist of 19 participants with the objective of evaluating anti-tumor effects and confirming the safety of the regimen. The second portion (expansion) was to consist of 35 additional subjects to evaluate anti-tumor effects and safety and was to commence if an adequate efficacy signal (i.e., ≥ 5/19 achieved complete remission \[CR\], CR with incomplete bone marrow recovery \[CRi\] or partial remission \[PR\]) had been observed in the first portion of the study. The criterion for success would have been met if ≥ 16 of 54 participants achieved remission. The efficacy signal from first portion of the study was deemed insufficient for enrollment into the second portion of the study, as 4 of the 19 subjects achieved CR/CRi. During the trial, a number of participants were in screening at the point of the interim analysis. Given the early signs of clinical activity of venetoclax, disease severity, and prognosis of these participants without available options for therapy, they were allowed to initiate treatment ahead of completion of the interim analysis. Therefore, 32 participants were enrolled. No additional participants were screened or treated after the interim analysis was completed.

Study Timeline

• Study Start: 2013-11
• Study First Submitted: 2013-11-20
• Study First Submitted QC: 2013-11-20
• Study First Posted: 2013-11-26
• Primary Completion: 2014-12
• Study Completion: 2014-12
• Disposition First Submitted: 2015-12-18
• Disposition First Submitted QC: 2015-12-18
• Disposition First Posted: 2016-01-22
• Results First Submitted: 2017-12-15
• Status Verified: 2018-01
• Results First Submitted QC: 2018-01-18
• Results First Posted: 2018-01-23
• Last Update Submitted: 2018-05-02
• Last Update Posted: 2018-06-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

1. Histological or cytological confirmation of relapsed or refractory acute myelogenous leukemia (AML) (by World Health Organization [WHO] classification) or untreated AML in participants who are unfit for intensive therapy.

2. Participant has an Eastern Cooperative Oncology Group (ECOG) Performance score of 0 to 2.

3. Participant must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 50 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula using ideal body mass (IBM) instead of mass.

4. Participant must have adequate liver function as demonstrated by:

   • aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN)*
   • alanine aminotransferase (ALT) ≤ 3.0 × ULN*
   • bilirubin ≤ 1.5 × ULN* *unless considered due to leukemic organ involvement. (Participants with Gilbert's Syndrome may have had a bilirubin > 1.5 × ULN per discussion between the investigator and AbbVie medical monitor)

Exclusion Criteria

1. Participant has received acute anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any investigational therapy within 14 days or 5 half-lives (whichever is shorter) prior to first dose of ABT-199.
2. Participant has received a monoclonal antibody for anti-neoplastic intent within 8 weeks prior to the first dose of study drug.
3. Participant has received potent Cytochrome P450, family 3, subfamily A (CYP3A) inducers (such as rifampin, carbamazepine, phenytoin and St. John's wort) and warfarin or requires the use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin and complications of this effect) within 7 days prior to the first dose of study drug.
4. Participant has received CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 5 days prior to the first dose of study drug.
5. Participant has a white blood cell count > 25 x 10^9/L.
6. Participant has acute promyelocytic leukemia (French-American-British Class M3 AML).
7. Participants with known active central nervous system (CNS) disease.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ABT-199	ABT-199	Continuous dosing of venetoclax (ABT-199) QD (once daily) beginning with dose-escalation on Week 1 Day 1. Participants received a dose of 20 mg of ABT-199 on Week 1 Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 800 mg on Day 6 and QD thereafter.

Primary Outcome Measures

Name	Time	Method
Objective Remission Rate	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	The objective remission rate (ORR) was defined as the percentage of participants who achieved complete remission (CR), complete remission with incomplete bone marrow recovery (CRi), or partial remission (PR) per the International Working Group criteria for AML. Complete remission (CR) was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts. Complete remission with incomplete bone marrow recovery (CRi) was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL. Partial remission (PR) was defined as normalization in peripheral blood neutrophil and platelet counts with at least a 50% decrease in blasts persisting in bone marrow versus baseline.

Secondary Outcome Measures

Name	Time	Method
Rate of Minimal Residual Disease (MRD) Negativity	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	The rate of minimal residual disease (MRD) response was defined as the percentage of participants who had MRD negative status. Only participants with a reported MRD assessment (negative or positive) from the local laboratory at the investigator site were used in the calculation of MRD response rate.
Complete Remission With Incomplete Marrow Recovery (CRi) Rate	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	The complete remission with incomplete bone marrow recovery (CRi) rate was defined as the percentage of participants who achieved CRi per the International Working Group criteria for AML. Complete remission with incomplete bone marrow recovery was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL.
Complete Remission Rate and Complete Remission With Incomplete Marrow Recovery (CRi) Rate	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	The complete remission rate and the complete remission with incomplete marrow recovery rate (Cri) was defined as the percentage of participants who achieved complete remission (CR) or complete remission with incomplete bone marrow recovery (CRi), per the International Working Group criteria for AML. Complete remission (CR) was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts. Complete remission with incomplete bone marrow recovery (CRi) was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL.
Percentage of Participants Who Received Subsequent Stem Cell Transplant	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	The percentage of participants who received a subsequent allogenic (from a healthy donor) stem cell transplant was summarized.
Complete Remission Rate	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	The complete remission (CR) rate was defined as the percentage of participants who achieved CR per the International Working Group criteria for AML. Complete remission was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts.
Duration of Remission	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	Duration of remission was defined as the number of days from the date of first remission (CR, CRi, or PR) per the International Working Group criteria for AML to the earliest recurrence or progressive disease (PD). In this study, the duration of remission analysis was not performed because of the low remission rate, per the Statistical Analysis Plan.
Progression-free Survival	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	Progression-free survival was defined as the number of months from the date of enrollment to the date of earliest progression or death. If a participant did not experience disease progression or death, then the data was censored at the date of the last disease assessment.
Overall Survival	Measured up to 2 years after the last subject had enrolled in the study.	Overall survival was defined as the number of months from the date of enrollment to the date of death for all dosed participants. For participants who did not die, their data were censored at the date of last study visit or the last known date to be alive, whichever was later.
Time to Progression	When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier	Time to progression was defined as the number of months from the date of enrollment to the date of earliest disease progression. If a participant did not experience disease progression, then the data for that participant was censored at the date of the last disease assessment.