A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible for Standard Induction Therapy

Introduction: Overexpression of the antiapoptotic protein BCL-2 has been implicated in the maintenance and survival of acute myelogenous leukemia (AML) cells and associated with resistance to chemotherapy. Elderly AML patients (pts) respond poorly to standard chemotherapy, with low overall survival and poor outcomes. Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor that has demonstrated single-agent activity in AML cell lines, primary pt samples, and relapsed/refractory AML pts. VEN has also been shown to synergize with hypomethylating agents in preclinical models, suggesting that the combination of VEN with decitabine (DEC) or 5-azacitidine (AZA) may be a promising approach for AML treatment (Tx).

Methods: This is an ongoing phase 1b, open-label, nonrandomized, dose-escalation trial of VEN in combination with DEC or AZA in older (≥65 years) Tx-naive AML pts (NCT02203773). Eligibility includes pts with ECOG PS ≤2 and not eligible for standard induction therapy. Pts receive standard DEC (Arm A: 20 mg/m²; intravenous [iv]) daily on days (D) 1−5 or AZA (Arm B: 75 mg/m²; subcutaneous or iv) daily on D1−7 of each 28-D cycle (C), for a minimum of 4 C in combination with once-daily continuous oral VEN on D2−28 in C1, and on D1−28 from C2 and beyond. VEN dose escalation follows a 3+3 design and is currently at the 800-mg dose level. Tumor lysis syndrome (TLS) prophylaxis was implemented in all pts prior to and during week 1 C1 of VEN with a dose ramp-up from 20 mg to the designated cohort dose. Dual primary objectives are safety and pharmacokinetic (PK) profile of VEN in combination with DEC or AZA. Secondary objectives include preliminary efficacy evaluations. Adverse events (AEs) were monitored throughout the study and dose-limiting toxicities (DLTs) were assessed during C1 and up to D42. Response assessments occurred on D1 of C2, C5, and every 12 weeks thereafter using International Working Group (IWG) criteria.

Results: As of June 11, 2015, 22 pts (36% male; median age 74 years [range: 65–85]) have been enrolled into Cohort 1 (n=10) and Cohort 2 (n=12) in 2 dose level cohorts. Table 1 shows an overview of pt enrollment and best response results. Twelve pts received DEC + VEN, with a designated dose of VEN at 400 mg (Cohort 1, n=6) and 800 mg (Cohort 2, n=6). Ten pts received AZA + VEN with VEN at 400 mg (Cohort 1, n=4) and 800 mg (Cohort 2, n=6). Median time on study is 95.5 D (range: 6−205). Currently, 9 pts (75%) in Arm A and 5 pts (50%) in Arm B remain active. Three pts discontinued DEC + VEN Tx (Cohort 1): 2 prior to completion of C1 (1 for noncompliance, 1 due to multiorgan failure not related to Tx), and 1 elected hospice care. In the AZA + VEN arm, 5 pts discontinued Tx: 3 in Cohort 1 to undergo an allogeneic stem cell transplant, and 2 in Cohort 2; 1 pt withdrew consent after achieving a complete remission (CR) and 1 due to central nervous system leukemia prior to completion of C1. Tx-emergent AEs (TEAEs; ≥30%) are shown in Table 2. The most common grade 4 TEAEs (Arm A/B) were a decrease in platelet count (8%/30%), neutrophil count (8%/20%), and white blood cell count (8%/20%). The most frequent serious AE was febrile neutropenia (33%/30%). Most pts (n=15) had grade 1–2 cytopenias at baseline; 5 in Arm A and 4 in Arm B progressed to grade 3–4 cytopenia; study drug interruption was necessitated in 12 pts (55%). No events of clinical/laboratory TLS or DLTs were reported. Four deaths occurred: 3 in Arm A (all after treatment discontinuation) and 1 in Arm B (disease progression-related AE). Preliminary PK results (n=14) showed that PK profiles of VEN in the absence and presence of AZA and DEC are similar.

Nineteen of 22 pts completed C1 and were response evaluable. Overall response rate (CR/CR with incomplete marrow recovery/partial remission) using the intent-to-treat population was 75% (9/12 pts) in Arm A and 70% (7/10 pts) in Arm B. Best response was obtained at completion of C1 in 9 pts and prior to or at end of C4 in the remaining 7 pts. Three pts without objective response by IWG criteria have experienced decreases in bone marrow blast counts at end of C1. None of the pts with objective response experienced relapse of AML.

Conclusions: Combination therapy of VEN with DEC or AZA demonstrates a tolerable safety profile. Rapid responses were observed in both Tx arms and across all cohorts, with no reported relapses. The maximum tolerated dose has not been reached in either arm and dose escalation is ongoing.