Siremadlin (HDM201) Is Well Tolerated and Demonstrates Clinical Activity in Patients with Acute Myeloid Leukemia Who Have Relapsed after Allogeneic Stem Cell Transplantation: A Subset Analysis of Safety and Preliminary Efficacy
Authors: Stein Eytan M. , Chromik Jörg , Carpio Cecilia , Mous Rogier , Kiladjian Jean-Jacques , Alatrash Gheath , Curti Antonio , Craddock Charles , Schmid Christoph , Zeiser Robert , Eldjerou Lamis K. , Weber Hans-Jochen Jochen , Fabre Claire , Scott Jeffrey , DeAngelo Daniel J. 
Published: November 2021

Abstract
Introduction:
Siremadlin is an oral (PO), potent and selective 2 nd generation inhibitor of Murine Double Minute-2 (MDM2i), resulting in a p53-dependent anti-proliferative effect. Siremadlin has a well-characterized safety profile and encouraging single-agent anti-leukemic activity in relapsed refractory (R/R) acute myeloid leukemia (AML) (Stein 2021, provisionally accepted, NCT02143635). More recently, MDM2i including siremadlin, have been shown to possess potent immunomodulatory effects (IME) in murine AML and solid tumor models (Wang 2021, Fang 2019). These data suggest that IME of siremadlin could be exploited to prevent relapse in AML patients (pts) in remission after allogeneic stem cell transplantation (SCT).
Here we report the results of an exploratory post-hoc analysis of safety and preliminary efficacy in a subset of pts with relapsed AML post SCT and subsequently treated with siremadlin monotherapy.
Methods:
From the first-in-human study, CHDM201X2101 (NCT02143635), among 91 R/R AML pts treated with siremadlin monotherapy, a subset of pts (n= 19) who had undergone SCT before study entry were identified for inclusion in this analysis.
Eligible pts were ≥ 18 years with wild-type TP53 AML have failed prior therapies. Siremadlin was administered PO according to 4 treatment regimens: 1A, 250 mg or 350 mg or 400 mg on day 1 of a 3-week (-W) cycle (n= 6); 1B, 120 mg or 150 mg on days 1 and 8 of a 4-W cycle (n= 4); 2A, 20 mg or 30 mg daily for the first 2 weeks of a 4-W cycle (n= 2); and 2C, 45 mg daily for the first week of a 4-W cycle (n= 7).
Grading of adverse events (AEs) was per CTCAE version 4.03. Response evaluation was per investigator's assessment based on the International Working Group for AML (Cheson 2003).
Results:
Nineteen pts with R/R AML after ≥1 SCT had received siremadlin as salvage therapy for active disease. The median age was 64 years (range: 30-72), and median interval from most recent SCT to start of siremadlin was 308 days (range, 119-1105). Median number of prior lines of antineoplastic therapy between most recent SCT and study entry was 1 (range, 0-3), 3 patients had received prior donor lymphocyte infusion [Table 1].
The median duration of exposure to siremadlin was 60 days (range, 21-203), median dose intensity was 52.5 mg/day (range, 13.4-200), and the median cumulative dose was 630 mg (range, 250-1710). Sixteen (84.2%) and 14 (73.7%) pts experienced grade (G) ≥3 AEs and treatment-related AEs, respectively; 14 (73.7%) and 12 (63.2%) pts experienced serious AEs (SAEs) and treatment-related SAEs, respectively. Nine pts had AEs leading to siremadlin dose adjustment or interruption, and 1 pt had an AE leading to treatment discontinuation (fungal sinusitis, G3, not suspected to be related to siremadlin). The most common G 3/4 non-hematological AEs were febrile neutropenia (n=11, 57.9%), hypokalemia (n=5, 26.3%), and tumor lysis syndrome (n=3, 15.8%).
Graft vs host disease (GvHD) was observed in 4 pts (21.1%): G3, n=2 (10.5%); G2 and G1, each n=1 (5.3%) [Table 2]. Three of these 4 pts had a history of GvHD prior to commencement of siremadlin. Siremadlin was continued safely at full dose (n=3) or dose-reduced (n=1) in all four pts. For 1 pt treated with 400 mg in Reg 1A, chronic GvHD was declared a dose-limiting toxicity. Overall, the safety profile was consistent with what was observed in the overall X2101 study population of hematologic malignancies (n=93) including n=91 R/R AML pts [Table 3].
Of note, 3 out of 19 patients achieved a major clinical response: 2 achieved complete remission (CR) and 1 CR with incomplete hematologic recovery (CRi).
Conclusions:
The safety of siremadlin monotherapy in pts with relapsed AML following prior SCT(s) appears to be consistent with that previously defined in R/R AML. No excessive GvHD was reported and siremadlin could be continued safely at full or reduced dose. Preliminary efficacy data indicate anti-leukemic activity. Despite the limitation of this post-hoc analysis in a small cohort of patients, these results and recently identified IME provide evidence to support further exploration of siremadlin post SCT as a potential maintenance or preemptive treatment in AML pts with high risk of relapse to enhance the allogeneic graft vs leukemia, an important and potent therapy against AML relapse.
Figure 1 Figure 1.

Disclosures
Stein: Blueprint Medicines: Consultancy; Daiichi Sankyo: Consultancy; PinotBio: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Syndax Pharmaceuticals: Consultancy; Genentech: Consultancy; Gilead Sciences, Inc.: Consultancy; Astellas: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy. Carpio: Regeneron, TAKEDA, Celgene, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Curti: Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeiser: Incyte, Mallinckrodt, Novartis: Honoraria, Speakers Bureau. Eldjerou: Novartis Pharmaceuticals: Current Employment. Weber: Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Fabre: Novartis: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Scott: Novartis Pharmaceuticals: Current Employment. DeAngelo: Abbvie: Research Funding; Takeda: Consultancy; Servier: Consultancy; Glycomimetrics: Research Funding; Blueprint: Research Funding; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Amgen: Consultancy; Agios: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy.