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4595 R289, a Dual Irak 1/4 Inhibitor, in Patients with Relapsed/Refractory (R/R) Lower-Risk Myelodysplastic Syndrome (LR-MDS): Initial Results from a Phase 1b Study

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research
Monday, December 9, 2024, 6:00 PM-8:00 PM

Guillermo Garcia-Manero, MD1, Yazan F Madanat, MD2, Mikkael A. Sekeres, MD3, Hetty E. Carraway, MD, MBA4, Mike Cusnir, MD5, James McCloskey, MD6, Kiran Naqvi, MD, MPH7, Gary J. Schiller, MD8, Lucy Yan, MD, PhD9*, Toufigh Gordi, PhD, MBA9*, Lisa Rojkjaer, MD10 and Lewis R. Silverman, MD11

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX
3Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
4Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
5Mount Sinai Comprehensive Cancer Ctr., Miami Beach, FL
6John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
7Department of Medicine, Division of Hematology Oncology, Chao Family Comprehensive Cancer Center,, University of California Irvine Health, Orange, California, USA, Orange, CA
8David Geffen School of Medicine, UCLA, Los Angeles, CA
9Rigel Pharmaceuticals, Inc., South San Francisco, CA
10Rigel, Rancho Santa Fe, CA
11Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY

Introduction: Interleukin receptor-associated kinases (IRAK) 1 and 4 are critical for downstream signaling of IL-1R family and most toll-like receptors (TLR), promoting proinflammatory cytokine production, bone marrow inflammation and cell death. In addition, IRAK 1/4 exhibit complementary and compensatory dependencies via MyD88-independent pathways in MDS and acute myeloid leukemia, inhibiting hematopoietic cell differentiation. Co-targeting both IRAK 1/4 may be necessary to maximally suppress inflammation and leukemic stem/progenitor cell function and restore hematopoiesis in MDS.

R835 is a selective dual inhibitor of IRAK 1/4 that blocks TLR4 and IL-1R-dependent cytokine release in vitro and in vivo. We report the initial dose escalation results from a phase 1b, open-label, single arm dose escalation/expansion study evaluating the safety and preliminary activity of the oral IRAK 1/4 inhibitor R289, a prodrug of R835, in LR-MDS pts (NCT05308264).

Methods: Eligible pts were ≥18 years of age with R/R LR-MDS [very low, low, or intermediate-risk per the Revised International Prognostic Scoring System (IPSS-R)] and either symptomatic anemia (hemoglobin ≤9.0 g/dL) and no RBC transfusions within the prior 16 weeks (wks) [non-TD (NTD)] or TD-anemia [≥2 units (u) RBCs within 8 wks during the 16-wk pre-enrollment period]. Baseline (BL) RBC transfusion burden (TB) within 16 wks prior to study treatment was defined as high (HTB, ≥8 u RBCs) or low (LTB, 3-7 u RBCs). Those with del (5q) must be R/R to lenalidomide. A 3+3 design was used to determine the maximum tolerated dose or recommended dose for expansion. Primary/secondary objectives were safety/PK and preliminary efficacy, respectively. R289 was administered orally in 28-day cycles (250 mg QD, 500 mg QD, 750 mg QD, 250 mg BID). Hematologic improvement-erythroid (HI-E) responses were assessed per IWG 2018 criteria and other responses per IWG 2006 criteria, starting at week 8.

Results: As of the data cutoff date (15 July 2024),19 pts were enrolled [IPSS-R score: very low (n=4, 21%), low (n=9, 47%), intermediate (n=6, 32%)]. Median age was 76 (range 50-83); 68% were males. Most pts had MDS with multilineage dysplasia [n=7, (37%)]. The median number of prior therapies was 4 (range 1-8). Prior therapies included luspatercept [n=15 (79%)], hypomethylating agent (HMA) [n=15 (79%)]. At BL, 15 pts (79%) were HTB, 2 pts (11%) were LTB, and 2 pts (11%) were non-TD. Mean BL absolute neutrophil count (ANC) was 2.52 × 109/L; 3 pts (16%) had an ANC <1 × 109/L. Mean BL platelet count was 153 × 109/L [<100 × 109/L in 4 pts (21%)]. The most frequent (≥20%) treatment emergent adverse events (TEAEs) were diarrhea and fatigue (both n=5; 26%) and nausea (n=4; 21%); all grade (G)1/2. The most frequent G3/4 AEs were pneumonia, anemia, ALT increase and upper GI hemorrhage (all n=2; 10%). Two pts discontinued therapy due to an AE. At doses ≥500 mg QD, R835 plasma concentrations at steady state reached or exceeded concentrations correlating with 50% (n=6) or 90% (n=3) LPS-induced cytokine inhibition as observed in HV.

Fourteen of 19 pts were evaluable for efficacy (received ≥1 dose of study drug with ≥1 efficacy assessment) at the data cutoff; 1 pt withdrew due to an AE, 4 had < 8 wks follow-up (too early to evaluate for response). No responses occurred at 250 mg QD (n=3). Three pts achieved RBC-transfusion independence (RBC-TI) ≥8 wks: 1/6 at 500 mg QD and 2/5 at 750 mg QD. The median duration of RBC-TI was 29 wks (range 12.4-35.9 wks). RBC-TI >24 wks was achieved in 2 HTB pts (28.9 and 35.9 wks) following 3 and 5 prior therapies, including an HMA. One HTB pt at 500 mg QD had a minor HI-E response. One LTB pt achieving TI (750 mg QD) also attained a marrow complete response (BL blasts: 4%).

Conclusions: At data cutoff, R289 was well-tolerated in this heavily pretreated LR-MDS patient population, the majority of whom were HTB. The incidence of G3/4 cytopenias and infections was low. Preliminary efficacy data suggest an on-target biologic drug effect, with RBC-TI/HI-E responses occurring in 36% of patients receiving R289 doses ≥500 mg QD. The responses were durable (>24 weeks) in 2 HTB pts thus far. Further evaluation of 250 mg BID and a 500/250 mg daily split dose is ongoing. An expansion cohort is planned to confirm a recommended phase 2 dose.

Disclosures: Garcia-Manero: Genentech: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Astex: Research Funding; Curis: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; Aprea: Research Funding; Astex: Other: Personal fees; Helsinn: Other: Personal fees; Helsinn: Research Funding; Amphivena: Research Funding; Genentech: Other: Personal fees. Madanat: Taiho Oncology, Rigel Pharmaceuticals, Novartis: Consultancy; Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences and Novartis: Other: Advisory Board; OncLive, MD Education, Sierra Oncology, Stemline, MorphoSys: Consultancy; Blueprint Medicines, MD Education, and Morphosys: Other: travel; BMS, Kura Oncology, BluePrint Medicines, Geron: Consultancy. Sekeres: Kurome: Membership on an entity's Board of Directors or advisory committees; Schroedinger: 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, Research Funding. Carraway: Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees. McCloskey: BluePrint Health: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy; Stemline Therapeutics: Speakers Bureau; Blueprint Medicines: Consultancy; Bristol-Myers Squibb/Pfizer: Consultancy; Amgen: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Takeda: Speakers Bureau; BluPrint Oncology: Honoraria. Yan: Rigel: Current Employment, Current equity holder in publicly-traded company. Gordi: Rigel: Current Employment, Current equity holder in publicly-traded company. Rojkjaer: Rigel Pharmaceuticals: Current Employment; Viracta Therapeutics: Ended employment in the past 24 months. Silverman: Celgene: Research Funding; BMS: Research Funding.

*signifies non-member of ASH