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

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).

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.

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.