P567: phase 1b omniverse trial: safety and tolerability of oral azacitidine in combination with venetoclax for treatment of acute myeloid leukemia

Background: Safer and more effective lower-intensity treatment options are needed for patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). The combination of venetoclax (VEN), an oral BCL-2 inhibitor, and injectable AZA (Inj AZA), a hypomethylating agent, is indicated in IC-ineligible patients with newly diagnosed (ND) AML and has shown significantly improved response and survival rates vs. Inj AZA alone (DiNardo et al., N Engl J Med 2020). Oral azacitidine (Oral-AZA) allows for extended dosing schedules vs. Inj AZA. Aims: This study will evaluate the safety/tolerability and efficacy and determine the maximum tolerated dose of Oral-AZA + VEN in patients with AML. Methods: OMNIVERSE (NCT04887857) is an ongoing, phase 1b, multicenter, open-label, dose-determination study evaluating Oral-AZA + VEN in patients with relapsed/refractory (R/R; part 1) and ND AML (part 2). This abstract presents data from part 1. Eligible patients are adults with R/R AML (WHO 2016 criteria) not eligible for further IC, with an ECOG performance status of ≤ 2. The starting dose level (DL 1) is Oral-AZA 300 mg QD x 14 days (d) per 28d treatment cycle + VEN 400 mg QD x 28d. DL can be de-escalated, depending on dose-limiting toxicities (DLTs), to Oral-AZA 200 mg QD x 14d per 28d cycle + VEN 400 mg QD x 28d (DL –1) or Oral-AZA 200 mg QD x 14d per 28d cycle + VEN 400 mg QD x 21d (DL –2). Dosing decisions are guided by a modified toxicity probability interval 2 (mTPI-2) design. The primary endpoint is to evaluate safety/tolerability and establish the maximum tolerated dose (MTD) of Oral-AZA + VEN in R/R AML (starting dose for part 2). Secondary endpoints are to assess preliminary investigator-determined response rates per ELN 2017 AML response criteria (Döhner et al., Blood 2017) for complete remission (CR), CR with partial hematologic recovery, CR with incomplete blood count recovery (CRi), morphologic leukemia-free state, overall response, and measurable residual disease (plus conversion rate). Results: Patient enrollment began in December 2021 and is ongoing; data from part 1 are available for 5 patients (3 female; aged 51–80 years). Three patients had 1 prior line of treatment and 2 patients had 2 prior lines of treatment. Oral-AZA + VEN was given for 1–12 cycles. Of the 5 patients, 3 reported ≥ 1 any grade drug-related adverse event, the most common of which were grade 1–3 diarrhea (2 patients) and grade 1–2 nausea (2 patients). Grade 3 febrile neutropenia, which was not deemed drug-related, was reported in 4 patients (6 episodes total). In 1 patient, Oral-AZA was reduced to 200 mg QD x 14d from cycle 4 due to grade 1 diarrhea and VEN to 70 mg QD x 28d from cycle 3 due to co-treatment with a strong CYP3A inhibitor (per protocol). Three patients died after treatment discontinuation. No DLTs were observed and MTD of Oral-AZA + VEN was determined to be Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d. As of January 2023, 2 patients remained on treatment. Best response achieved was CRi in 2 patients and stable disease in 3 patients. Summary/Conclusion: These results indicate that a MTD of Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d has a manageable safety profile consistent with known profiles of the individual agents. Further evaluation in AML is warranted. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved. Keywords: Venetoclax, Clinical trial, Acute myeloid leukemia, Hypomethylating agents