P499: THE PHASE 1B OMNIVERSE TRIAL OF ORAL AZACITIDINE IN COMBINATION WITH VENETOCLAX FOR TREATMENT OF RELAPSED/REFRACTORY OR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (TRIAL IN PROGRESS)

Abstract

Background: For older patients (pts) with acute myeloid leukemia (AML) who are ineligible for standard intensive chemotherapy (IC) regimens, traditional lower-intensity AML treatment (Tx) options include low-dose cytarabine (LDAC) or hypomethylating agents (HMAs; azacitidine [AZA] and decitabine), which are generally well tolerated but associated with suboptimal outcomes vs IC [Vey 2020]. Therefore, there remains a need for less toxic and more efficacious lower-intensity AML Tx regimens, especially agents that can be administered in the outpatient setting, which may increase convenience and reduce resource utilization. Venetoclax (VEN) is an oral, selective, small-molecule BCL2 inhibitor that has demonstrated considerable activity when combined with LDAC or HMAs in older pts with AML. In a recent phase 3 trial, VEN + injectable AZA significantly improved response and survival vs AZA alone in IC-ineligible pts with newly diagnosed (ND) AML [DiNardo 2020]. In the USA, VEN is approved in combination with an HMA or LDAC for Tx of pts with ND AML ≥ 75 years (y) of age or who cannot use IC due to comorbidities. Oral-AZA (CC-486) is approved for pts with AML in first remission (CR1) after IC who are ineligible for transplant or other curative therapies. In the randomized, phase 3 QUAZAR AML-001 trial of Oral-AZA in pts with AML in CR1 after IC, Oral-AZA 300 mg QD for 14 days (d)/28d Tx cycle was generally well tolerated and associated with significantly improved overall survival vs placebo. Gastrointestinal symptoms were the most common adverse events reported with Oral-AZA [Wei 2020]. Oral-AZA has also shown clinical activity in pts with active AML [Savona 2015]. As incorporation of AZA into DNA is S-phase-restricted, extended Oral-AZA dosing regimens (> 7d/28d Tx cycle) increase drug incorporation into cycling tumor cells to prolong epigenetic activity throughout the Tx cycle [Laille 2015]. An all-oral VEN + Oral-AZA combination regimen allows for outpatient administration and thus improves pt adherence [Eek 2016]. Aims: Describe the study design and objectives of the OMNIVERSE trial of Oral-AZA + VEN in older pts with ND AML or pts with AML relapsed/refractory (R/R) to prior Tx. Methods: OMNIVERSE (NCT04887857) is a multicenter, open-label, 2-part phase 1b trial (Figure). The key objectives of the trial are to assess safety and determine the maximum tolerated dose of Oral-AZA + VEN in pts with R/R AML (WHO 2016 criteria) ineligible to receive further IC (part I), and then in pts with ND AML ≥ 75 y of age, or those ≥ 18–74 y of age ineligible for IC or HSCT due to comorbidities (part 2). Main eligibility criteria include an ECOG performance status of 0–2 (ECOG 3 is allowed for pts ≥ 18–74 y of age with comorbidities) and an unfavorable cytogenetic risk profile for pts with ND AML. The initial dose of Oral-AZA is 300 mg QD × 14d/28d cycle, with de-escalation to 200 mg × 14d/28d cycle allowed for dose-limiting toxicities. VEN 400 mg is taken orally QD in continuous 28d cycles (or for 21d/cycle for dose level –2). A modified toxicity probability interval-2 design is used to evaluate the planned dose levels. The sample size is dependent on the dose levels included in the study (≤ 18 pts/part). Results: N/A Image:Summary/Conclusion: Study enrollment began in 2021. The trial is ongoing at clinical sites in the United States and Australia.