OMNIVERSE: A Phase 1b/2 Study of Oral Azacitidine Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed (ND) Acute Myeloid Leukemia (AML)
Authors: Ravandi Farhad , Carraway Hetty E. , Taningco Lilia , Dilley Kimberley , Laille Eric , Gong Jing , Lopes de Menezes Daniel , Wei Andrew H. 
Published: November 2021

Abstract
Background: Novel AML treatments (Tx) have improved the tolerability and clinical outcomes for older patients (pts) with AML, especially since standard intensive chemotherapy (IC) regimens are associated with risks of toxicity and mortality. Lower-intensity Tx options for IC-ineligible pts include low-dose cytarabine (LDAC) or hypomethylating agents (HMAs; azacitidine [AZA] and decitabine), which are generally well tolerated, but have been associated with inferior outcomes vs IC [Vey 2020]. As such, the development of less-toxic regimens with better efficacy has been a priority, and increased focus has been given to optimizing Tx regimens in the outpatient setting for convenience, independence, and quality of life (QoL).
The oral formulation of AZA (Oral-AZA [CC-486]) is approved in the United States, European Union, and Canada for Tx of pts with ND AML in first remission after IC who are not able to complete curative therapy (eg, HSCT). In a pivotal phase 3 trial, Oral-AZA 300 mg QD for 14 days (d)/28d Tx cycle was well tolerated and improved overall survival (OS) vs placebo in pts with AML in CR/CRi after IC. Oral-AZA has also shown preliminary clinical efficacy in pts with active AML [Savona 2015].
Novel regimens based on LDAC or HMAs in combination with newer agents, including the BCL2 inhibitor, venetoclax (VEN), have demonstrated promising activity in older pts with AML. Although only modest clinical benefits were achieved with single-agent VEN in pts with R/R AML [Konopleva 2016], the combination of VEN + AZA in pts with ND AML shows synergistic anti-leukemic activity via AZA-mediated inhibition of MCL1 and BCL-XL, enhancing BCL2 dependence in leukemic cells. In IC-ineligible ND AML, VEN + injectable AZA significantly improved remission rates and OS vs AZA alone [DiNardo 2020]. Consequently, VEN, in combination with an HMA or LDAC, was approved in the US for Tx of pts with ND AML aged ≥ 75 years (y) or those with comorbidities precluding use of IC.
Given S-phase-restricted DNA incorporation of AZA, extended Oral-AZA dosing regimens (&gt; 7d/28d Tx cycle) increases the opportunity for cycling cells to incorporate the drug, thereby sustaining epigenetic activity [Laille 2015]. An outpatient VEN + AZA oral combination regimen may also increase the likelihood of pt adherence [Eek 2016]. Here, we describe the study design and objectives of the OMNIVERSE trial of Oral-AZA + VEN in older pts with ND AML or pts with AML R/R to prior Tx.
Study Design and Methods: OMNIVERSE (NCT04887857) is a multicenter, open-label, phase 1b/2 trial conducted in 3 sequential study parts (Figure). Key objectives of the 2-part, dose-finding phase 1b portion are to evaluate safety and establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of Oral-AZA + VEN, first in pts with R/R AML (World Health Organization [WHO] 2016 criteria) ineligible to receive further IC (part 1), and subsequently in pts with ND AML (WHO 2016) aged ≥ 75 y, or those aged ≥ 18-74 y with comorbidities that preclude use of IC or HSCT (part 2). Key pt eligibility criteria include an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (ECOG 3 is allowed for pts aged ≥ 18-74 y with comorbidities), and an unfavorable cytogenetic risk profile for pts with ND AML. The starting dose of Oral-AZA is 300 mg QD × 14d cycle, which can be escalated to 300 mg × 21d or de-escalated to 200 mg × 14d/28d cycle depending on dose-limiting toxicities experienced; oral VEN is taken QD continuously (or 21d/cycle for dose level -2). A modified toxicity probability interval-2 (mTPI-2) design is used to evaluate the planned dose levels. The sample size of the phase 1b portion depends on the dose levels utilized (≤ 18 pts in each part).
In phase 2, pts with ND AML (same inclusion criteria as for phase 1b-part 2) will receive Oral-AZA + VEN at the RP2D. The primary endpoint is the rate of complete remission (CR) plus CR with partial hematologic recovery (CRh). Key secondary endpoints include safety, duration of CR/CRh, overall response rate (per European Leukemia Net criteria), and longitudinal minimal residual disease (MRD) profiling for CR/CRh responders. Key exploratory objectives are to characterize DNA methylation patterns and BCL2 family member expression profiles. The phase 2 expansion will enroll ~100 pts, which is calculated based on the response rates from the M14-358 (NCT02203773) and VIALE-A (NCT02993523) studies.
Enrollment is planned to begin in 2021.
Figure 1 Figure 1.

Disclosures
Ravandi: Amgen: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Carraway: Takeda: Other: Independent review committee; Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astex: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Taningco: Bristol Myers Squibb: Current Employment. Dilley: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Laille: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Wei: Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Servier: Consultancy; Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding.