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

• ClinicalTrials.gov Identifier: NCT01994837
• Recruitment Status: Completed
• First Posted: November 26, 2013
• Results First Posted: January 23, 2018
• Last Update Posted: June 6, 2018
• Sponsor: AbbVie
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: November 20, 2013
• First Posted Date: November 26, 2013
• Results First Submitted Date: December 15, 2017
• Results First Posted Date: January 23, 2018
• Last Update Posted Date: June 6, 2018
• Study Start Date: November 2013
• Actual Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 18, 2018)

Objective Remission Rate [ Time Frame: 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.

Original Primary Outcome Measures (submitted: November 20, 2013)

Efficacy will be measured by overall response rate (ORR) [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]

To evaluate the preliminary efficacy of ABT-199 administered orally in patients with relapsed/refractory AML or frontline in patients with AML who are unfit for intensive therapy.

Current Secondary Outcome Measures (submitted: January 18, 2018)

• Complete Remission Rate [ Time Frame: 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 [ Time Frame: 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.
• Time to Progression [ Time Frame: 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.
• Progression-free Survival [ Time Frame: 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 [ Time Frame: 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.
• Percentage of Participants Who Received Subsequent Stem Cell Transplant [ Time Frame: 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.
• Rate of Minimal Residual Disease (MRD) Negativity [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: November 20, 2013)

• Complete response (CR) rate [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  Complete response rate will be defined as the proportion of subject who achieved a complete response per the International Working Group (IWG) 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 progression.
• Progression-free Survival [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  Progression-free survival will be defined as the number of days from the date of enrollment to the date of earliest progression or death. If the subject does not experience disease progression or death, then the data will be censored at the date of the last disease assessment.
• 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 for all dosed subjects
• Percent of subjects who move on to stem cell transplant [ Time Frame: Measured 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.
• Rate of Minimal Residual Disease (MRD) negativity in subjects [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  The rate of Minimal Residual Disease (MRD) negativity will be defined as the number of subjects who had MRD negativity status.
• Number of subjects with adverse events [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  Subjects will be monitored for clinical and laboratory evidence of adverse events throughout the study.
• Change 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.
• Change 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, urinalysis
• Percentage of subjects with adverse events [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  Subjects will be monitored for clinical and laboratory evidence of adverse events throughout the study.
• Complete response with incomplete marrow recovery (CRi) [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  Complete response with incomplete marrow recovery (CRi) will be defined as the proportion of subjects who achieve a CRi based on the IWG criteria for AML.
• Partial response (PR) [ Time Frame: Measured up to 2 years after the last subject has enrolled in the study. ]
  Partial response will be defined as the proportion of subjects who achieved a PR per the IWG criteria for AML.

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

Descriptive Information

• Brief Title: A Phase 2 Study of ABT-199 in Subjects With Acute Myelogenous Leukemia (AML)
• Official Title: A Phase 2 Study of ABT-199 in Subjects With Acute Myelogenous Leukemia (AML)
• 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Myelogenous Leukemia
• AML
• Acute Myeloid Leukemia

Intervention

Drug: ABT-199

Tablet

Other Name: ABT-199 also known as venetoclax

Study Arms

Experimental: 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.

Intervention: Drug: ABT-199

• Publications *: Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, McKeegan E, Salem AH, Zhu M, Ricker JL, Blum W, DiNardo CD, Kadia T, Dunbar M, Kirby R, Falotico N, Leverson J, Humerickhouse R, Mabry M, Stone R, Kantarjian H, Letai A. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016 Oct;6(10):1106-1117. Epub 2016 Aug 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 16, 2015): 32
• Original Estimated Enrollment (submitted: November 20, 2013): 54
• Actual Study Completion Date: December 2014
• Actual Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: United States

Administrative Information

• NCT Number: NCT01994837
• Other Study ID Numbers: M14-212
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: AbbVie
• Study Sponsor: AbbVie
• Collaborators: Genentech, Inc.

Investigators

• Study Director: Jalaja Potluri, MD; AbbVie

• PRS Account: AbbVie
• Verification Date: January 2018