Siremadlin in Combination with Venetoclax (VEN) Plus Azacitidine (AZA) in Adult Patients with Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy: A Phase Ib/II Trial

Background: Patients with AML who are ineligible for intensive chemotherapy have limited treatment options. Adding VEN to standard-of-care hypomethylating agents (HMAs) improves remission rates and survival for these patients. However, relapse rates with VEN+HMA are high, and many patients do not achieve a complete remission (CR)/CR with incomplete hematological recovery (CRi), or do so and remain measurable residual disease-positive (DiNardo CD, N Engl J Med, 2020), which is associated with poor outcomes. Murine double minute 2 (MDM2) is a key negative regulator of tumor protein 53 (p53; encoded by the TP53 gene). Inhibition of the p53-MDM2 interaction upregulates the tumor suppressor effects of p53. Siremadlin (HDM201) is a selective inhibitor of the p53-MDM2 interaction. In combination with VEN, siremadlin had durable antitumor responses in p53-wild-type AML patient-derived xenograft models (Wang Y, Cancer Res, 2019). Siremadlin was tolerable and demonstrated preliminary single-agent antitumor activity in patients with relapsed/refractory AML in a first-in-human Phase I trial (Stein EM, Clin Cancer Res, 2021; NCT02143635). In combination with VEN, siremadlin also demonstrated promising preliminary antileukemic activity in a Phase Ib trial in patients with relapsed/refractory AML (Wei AH, ASH 2021; NCT03940352).

Study design: This international, multicenter, Phase Ib/II, open-label, dose-confirmation, proof-of-concept trial will provide a dosing recommendation and assess the preliminary efficacy of siremadlin in combination with VEN+AZA in adults (≥18 years) with AML who are ineligible for intensive chemotherapy (NCT05155709). For this Phase Ib/II trial, patients must have an Eastern Cooperative Oncology Group performance status of 0-2 (if age ≥75 years) or 0-3 (if age ≥18-74 years) with at least 1 predefined comorbidity rendering the patient ineligible for intensive chemotherapy. Patients with TP53 mutations, chromosomal del17p, or prior MDM2-inhibitor or FLT3-inhibitor treatment are ineligible. Patients will be enrolled into 2 arms: (Arm 1) patients who have received 2-4 cycles of first-line VEN+AZA without achieving a best response of CR, CR with partial hematological recovery (CRh), CRi, or morphologic leukemia-free state, and (Arm 2) newly diagnosed patients with adverse genetic risk as defined in Figure 1. The trial has 2 parts: (Part 1) a safety run-in to assess the safety and confirm the recommended Phase II dose (RP2D) of siremadlin+VEN+AZA and (Part 2) an expansion phase to evaluate the preliminary efficacy of siremadlin in combination with VEN+AZA.

Treatment will be administered in 28-day cycles until disease progression, relapse, or unacceptable toxicity. In Part 1, 3-6 patients per arm will receive the starting dose of siremadlin (20 mg; once-daily oral capsule) from Day 1 to Day 5 in each 28-day treatment cycle in combination with VEN+AZA. For Arm 1, VEN and AZA will be administered at doses determined prior to trial enrollment. For Arm 2, VEN will be administered once daily at 400 mg on each day of the cycle, following a 3-day ramp-up, and AZA will be administered intravenously or subcutaneously at 75 mg/m² either on Days 1-7, or Days 1-5 and Days 8-9 (according to standard local clinical practice). If the starting dose of siremadlin is deemed safe, an additional ~6-9 patients will receive dose level +1 (30 mg) of siremadlin to determine the RP2D for Part 2. Approximately 26 patients will receive siremadlin at the RP2D in combination with VEN+AZA in Part 2.

Two primary outcomes will be assessed: in Arms 1 and 2, the proportion of patients with dose-limiting toxicities reported during the first cycle (28 days); and in Arm 1 only, the proportion of patients at the expansion dose who achieve CR. Secondary outcomes include, in Arm 2 only, proportion of patients who achieve CR, and in Arms 1 and 2, duration of CR; proportion of patients who achieve CR, or CRh, or CRi; duration of CR/CRh and CR/CRi; overall survival; pharmacokinetics; proportion of CR-MRD negative overall and MRD negativity in patients achieving a CR, CR/CRh, and CR/CRi.

Conclusions: This Phase Ib/II trial investigates siremadlin in combination with VEN+AZA in patients with AML who are ineligible for intensive chemotherapy and will aid in the understanding of the effectiveness of an MDM2 inhibitor with venetoclax combination in patients with AML. The trial is in progress and expected to enroll approximately 55 patients.

Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Wei:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Macrogenics: Honoraria; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, and Expenses, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding; Pfizer: Honoraria; BeiGene: Consultancy; Shoreline: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria, Research Funding; Syndax: Research Funding; Astex: Research Funding; Astellas: Honoraria, Speakers Bureau; Gilead: Honoraria; Agios: Honoraria; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Servier: Consultancy, Honoraria, Other: Travel, Accommodations, and Expenses, Patents & Royalties: Filing Date: 21/07/2017. Combination of a BCL-2 inhibitor and a MCL-1 inhibitor, uses and pharmaceutical compositions thereof. A. Wei, D. Moujalled, G. Pomilio, A.L. Maragno, O. Geneste, A. Claperon, H. Maacke, E. Halilovic, D. Porter, E. Morris, Y. Wang, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau. Stein:PTC Therapeutics and Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; PinotBio, Bristol Myers Squibb, Jazz Pharmaceuticals, Foghorn Therapeutics, Blueprint Medicines, Gilead Sciences, Janssen Pharmaceuticals: Consultancy; Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Auron Therapeutics: Current equity holder in private company; Amgen, AbbVie, Seattle Genetics, and Biotheryx: Consultancy; Bayer: Research Funding. DeAngelo:Glycomimetics: Research Funding; Servier: Consultancy; Kite, a Gilead Company: Consultancy; Pfizer: Consultancy; AbbVie: Research Funding; Takeda: Consultancy; Shire: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Incyte: Consultancy; Gilead: Consultancy; Forty-Seven: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Autolos: Consultancy; Amgen: Consultancy; Agios: Consultancy. Pathak:Novartis Pharma AG: Current Employment. Xu:Novartis Pharmaceuticals Corporation: Current Employment. Grzesiak:Novartis Pharma AG: Current Employment. Venditti:Servier: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy; Jazz Pharmaceuticals: Honoraria, Research Funding; Janssen & Cylag: Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; astrazeneca: Honoraria; abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.