Phase I and Expansion Study of Eprenetapopt (APR-246) in Combination with Venetoclax (VEN) and Azacitidine (AZA) in TP53-Mutant Acute Myeloid Leukemia (AML)
Authors: Garcia-Manero Guillermo , Goldberg Aaron D , Winer Eric S. , Altman Jessica K. , Fathi Amir T. , Odenike Olatoyosi , Roboz Gail J. , Gallacher Phillip , Wennborg Anders , Kaylor Hickman Denice , Attar Eyal C. , Sallman David A. 
Published: November 2021

Abstract
Background
Mutations in the tumor suppressor gene TP53 are found in up to 20% of patients with AML, 30-40% of pts with secondary AML, and are associated with extremely poor overall survival (OS) of &lt; 6 months. VEN + hypomethylating agent (HMA) combinations are associated with a 20-25% complete remission (CR) rate in TP53 mutant AML (Wei, 2018; DiNardo, 2020) though VEN + HMA has not improved OS over AZA alone. Eprenetapopt, a small molecule p53 stabilizer, targets cellular redox balance resulting in tumor cell apoptosis and ferroptosis as well as immune modulation of the tumor microenvironment. Pre-clinically, eprenetapopt interacts synergistically with AZA and VEN to induce myeloid cell death in vitro and significantly reduces tumor burden when combined with AZA in a murine AML xenotransplant model.
Methods
This is a multi-center, open-label, dose-finding and expansion study to determine the safety and preliminary efficacy of eprenetapopt in combination with VEN and AZA in TP53 mutant AML. This study included two 3+3 dose-finding safety lead in cohorts of pts with previously untreated TP53 mutant AML followed by an expansion. Dose limiting toxicities (DLTs) were assessed during C1 and included prolonged myelosuppression in the absence of disease and grade ≥3 non-hematologic toxicity not recovering to grade ≤1. Pts in Safety Cohort 1 (SC1) received 1 prior line of HMA therapy for MDS and Safety Cohort 2 (SC2) had no prior HMA. Treatment consisted of concurrent eprenetapopt at 4.5 g/day D 1-4 with VEN 400 mg PO QD for SC1 while SC2 also received AZA 75 mg/m 2 IV/SC D 1-7. Cycles were 28 days. Following the safety cohorts, Expansion Cohort 2 (eprenetapopt + AZA + VEN) enrolled pts with previously untreated AML without prior HMA. Primary endpoints include determination of DLTs, frequency and severity of treatment-emergent adverse events (TEAEs), and recommended eprenetapopt dose for expansion. Secondary endpoints include rates of CR and CR+ CRi (CR with incomplete blood count recovery).
Results
As of the data cutoff date of 22 June 2021, 47 pts were enrolled, 44 received at least 1 dose of eprenetapopt, and 9 remained on the triplet combination The median age was 67 years (27-81), 52.3% were male, 77% had performance status ≤1, 55% had secondary AML, and 30% had therapy-related AML. Median aspirate blasts was 28%, ANC 0.42 K/uL, hemoglobin 79 g/L, and plts 24.5 K/uL. Complex karyotype (≥3) was detected in 36/39 pts (92%) and abnormal chromosomes 5, 7, and 17 in 28 (72%), 12 (31%), and 20 pts (51%), respectively. Median TP53 VAF was 48% (0,87) with 71%, 16%, 7%, and 5% having missense, frameshift, nonsense, and splice mutations, respectively.
Across all cohorts, disease progression or relapse (19) and hematopoietic stem cell transplant (7) were the primary reasons for treatment discontinuation.
There were no DLTs observed in the 6 pts in SC1 and in the 6 pts in SC2. All-grade TEAEs in ≥30% included nausea (66%), febrile neutropenia (52%), diarrhea (50%), decreased appetite (41%), constipation and vomiting (39% each), hypokalemia (36%), hypotension, platelet count decreased, and peripheral edema (32% each), and dizziness and cough (30% each). Grade ≥3 TEAEs in ≥20% were febrile neutropenia (52%), platelet count decreased (30%), and anemia (21%). Four pts (9%) experienced TEAEs leading to study treatment discontinuation. Eleven pts experienced a TEAE leading to death, with sepsis (n=2) being the only fatal TEAE reported in &gt;1 pt. No fatal TEAE was assessed as treatment related. The 30-day mortality rate was 9%.
There was 1 CR and 1 CRi among the 6 pts who received eprenetapopt + VEN. Preplanned efficacy analysis of the first 30 efficacy evaluable pts who received eprenetapopt + VEN + AZA demonstrated CR rate of 37% and CR +CRi rate of 53% with median duration 118 days (95% CI 60, NE) and 128 days (95% CI 57, NE), respectively. Based on the number of reported CRs, 11, the study met the Simon 2-stage efficacy criteria discriminating a target CR rate of &gt;40% from a failure CR rate of &lt;20%.
Conclusions
Eprenetapopt plus VEN with and without AZA was tolerated by pts as demonstrated by absence of DLTs across safety cohorts and by an emerging safety profile consistent with events attributable to the underlying disease as well as those known to occur with VEN and AZA therapy. In addition, the triplet regimen demonstrated highly encouraging efficacy data and met the Simon-2 stage CR threshold, warranting further study in this population with unmet medical need.

Disclosures
Goldberg: Arog: Research Funding; Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; DAVA Oncology: Honoraria; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Winer: Takeda: Consultancy; Novartis: Consultancy; Abbvie: Consultancy. Altman: Astellas: Honoraria, Research Funding; Aptos: Research Funding; Loxo: Research Funding; Aprea: Research Funding; Biosight: Membership on an entity's Board of Directors or advisory committees, Other: reimbursement for travel, Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos Therapeutics: Research Funding; ImmunoGen: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; ALX Oncology Inc.: Research Funding; Fujifilm: Research Funding; Glycomimetics: Other: data monitoring committee; Abbvie: Honoraria, Research Funding. Fathi: AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Foghorn: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Roboz: Astellas: Consultancy; Celgene: Consultancy; Mesoblast: Consultancy; Actinium: Consultancy; Blueprint Medicines: Consultancy; AstraZeneca: Consultancy; Astex: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Helsinn: Consultancy; Janssen: Research Funding; Jasper Therapeutics: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Agios: Consultancy; Bayer: Consultancy; Jazz: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Glaxo SmithKline: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Gallacher: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wennborg: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kaylor Hickman: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Attar: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sallman: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Takeda: Consultancy.

OffLabel Disclosure:
This study discusses the off-label use of eprenetapopt in the treatment of TP53 mutant AML.