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626 Phase 1/2 Study of TP-3654, a Selective PIM1 Kinase Inhibitor: Preliminary Data Showed Clinical Activity and Cytokine Reductions in Relapsed/Refractory Myelofibrosis Patients

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Myelofibrosis: New Therapeutic Frontiers
Hematology Disease Topics & Pathways:
Research, clinical trials, adult, Clinical Research, drug development, Therapies, Study Population, Human
Sunday, December 10, 2023: 4:45 PM

Lindsay A.M Rein, MD1, Firas El Chaer, MD2, Junichiro Yuda, MD, PhD3, Kazuya Shimoda, MD, PhD4, James McCloskey, MD5, Akiyoshi Takami, MD, PhD6, Tamanna Haque, MD7*, Michiko Ichii, MD, PhD8*, Shuichi Shirane, MD, PhD9*, Masafumi Fukaya, MD10*, Joseph M. Scandura, MD, PhD, MS11, Terrence Bradley, MD12, Pankit Vachhani, MD13, Takayuki Tabayashi, MD, PhD14*, Steven Green, MD15*, Stanley Cheung, MD, PhD16*, Prithviraj Bose, MD17, Sharad Khurana, MD, MSc18, Casey L. O'Connell, MD19, Idoroenyi Amanam, MD20, David M. Ross, MBBS, PhD, FRACP, FRCPA21*, Sujan Kabir, MD22*, Masataka Seki, MS23*, Mark Wade, PhD22*, Vishnu Peddagali, MD22*, Zhonggai Li, PhD22*, Jatin Shah, MD22 and Raajit K. Rampal, MD, PhD7

1Duke University, Durham, NC
2University of Virginia Health System, Charlottesville, VA
3National Cancer Center Hospital East, Kashiwa, Japan
4University of Miyazaki, Miyazaki, Japan
5The John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ
6Aichi Medical University School of Medicine, Nagakute, Japan
7Memorial Sloan Kettering Cancer Center, New York, NY
8Osaka University Graduate School of Medicine, Suita, Japan
9Juntendo University School of Medicine, Bunkyo-ku, Japan
10Shizuoka Cancer Center, Nagaizumi, Japan
11Weill Cornell Medical College, New York, NY
12University of Miami Sylvester Comprehensive Cancer Center, Miami, FL
13University of Alabama at Birmingham, Birmingham, AL
14Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
15Roswell Park Comprehensive Cancer Center, Buffalo, NY
16ICON Cancer Care, Kurralta Park, Australia
17MD Anderson Cancer Center, The University of Texas, Houston, TX
18University of Arizona Cancer Center, Tucson, AZ
19USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA
20City of Hope National Medical Center, Duarte, CA
21Royal Adelaide Hospital, Adelaide, SA, Australia
22Sumitomo Pharma America, Inc., Boston, MA
23Sumitomo Pharma Co., Ltd., Chuo-Ku, Japan

Background: PIM1 expression is significantly upregulated in hematologic malignancies including myelofibrosis (MF) and has been shown to play a role in modulating the activity of cytokine induced PI3K/AKT and JAK/STAT pathways. The distinct clinical features of MF are partly attributed to the elevated circulating cytokines; a subset of which are shown to correlate with poor prognosis. TP-3654, an oral investigational highly selective PIM1 kinase inhibitor, is currently being evaluated in a phase 1/2 study in patients (pts) with relapsed/refractory MF. In preclinical studies, TP-3654 alone and in combination with ruxolitinib showed spleen size and bone marrow (BM) fibrosis reduction in murine MF models. Importantly, TP-3654 also showed reduction of cytokine response genes and serum TGF-β in progenitor cells and JAK2V617F murine MF model, respectively.

Methods: This phase 1/2 study evaluates the safety and efficacy of TP-3654 monotherapy in pts with MF (NCT04176198). Key eligibility criteria include primary or secondary MF; previously treated with or ineligible for JAK inhibitor treatment; DIPSS intermediate 1, 2 or high-risk MF; platelet ≥25x109/L; splenomegaly (≥450 cm3 by imaging); and ≥2 measurable symptoms per MFSAF v4. The study aims to identify the MTD and/or RP2D of TP-3654 monotherapy and to assess safety, clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement), PK, and PD markers (cytokine profile, BM fibrosis etc.). We investigated the patterns of similarity of 43 cytokines changes after 12 weeks of TP-3654 treatment using principal component analysis (PCA).

Results: As of 20 June 2023, a total of 23 pts enrolled across 5 dose levels in the phase 1 dose escalation part. At baseline, median age 73 years (range 61, 80), spleen volume 2008.2 cm3 (range 609, 6006), TSS 20.8 (range 4, 62), platelet 115 x109/L (range 64, 520), hemoglobin 10.1 g/dL (range 5.9, 13.7; 5 pts requiring transfusion). All pts, except one, had received ≥1 prior JAK inhibitor treatment (median 12.9 months [range 2.3, 81.0]). Median duration of TP-3654 treatment was 14.9 weeks (range 2, 96). No DLT occurred. Treatment-related adverse events (TRAEs) occurring in ≥20% of pts included grade 1/2 nausea, vomiting, and diarrhea. Grade 3 TRAEs were diarrhea (n=1) and platelet count decreased (n=2). Mean hemoglobin and platelet counts remained stable throughout the 24-week treatment period. SVR observed in 10 of 13 evaluable pts treated for ≥12 weeks (median best change -11%, range +97% to -63%); 3 pts showed ≥35% SVR. TSS improvement were observed in 12 of 13 evaluable pts (median best change -70%, range +9 to -100%); 7 pts showed ≥50% TSS response (Fig 1A); 5 pts had durable response for ≥12 weeks. Broad reductions in cytokines observed as early as within the first 24 hours after TP-3654 treatment. At week 12, pts with higher cytokine reductions correlated with greater TSS improvement. Two components of the PCA, PC1 and PC7, include MF associated cytokines such as IL-8, IL-18, CD40, ENRAGE amongst others, were reduced with TP-3654 treatment and these reductions correlated with symptom improvement (Fig 1B). BM fibrosis was reduced in one pt who also achieved spleen and symptom responses, showed MF associated cytokine reductions, and is on active treatment for 2 years.

Conclusions: This preliminary data of TP-3654 in relapsed/refractory MF pts showed early signs of clinical activity including spleen volume reduction, TSS improvement, and correlating cytokine reductions. TP-3654 is well tolerated with limited myelosuppressive adverse events. Enrollment is ongoing as monotherapy and current data support the development of TP-3654 in combination with JAK inhibitors given the preliminary clinical activity and minimal cytopenia.

Disclosures: Rein: DAVA Oncology: Other: Speaker, travel ; CTI BioPharma/Sobi: Consultancy; Abbvie: Consultancy; Blueprints Medicine: Research Funding; PharmaEssentia: Research Funding; Geron: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy, Research Funding; Merck: Research Funding; Incyte: Consultancy, Research Funding; Sumitomo Pharma: Consultancy, Research Funding; Cogent: Research Funding; Protagonist: Research Funding. El Chaer: BioSight: Research Funding; PharmaEssentia: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding; Arog Pharmaceuticals: Research Funding; Association of Community Cancer Centers: Consultancy; DAVA Oncology: Other: Travel grant; CTI Biopharma: Consultancy; AbbVie: Consultancy; MorphoSys: Consultancy; Sanofi: Research Funding; Sumitomo Pharma Oncology: Consultancy, Research Funding; Fibrogen: Research Funding; Amgen: Consultancy, Research Funding; Bristol Myers Squib: Research Funding; Celgene: Research Funding. McCloskey: Stemline Therapeutics: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb/Pfizer: Consultancy, Honoraria, Speakers Bureau; BluPrint Oncology: Honoraria; Jazz Pharmaceuticals: Speakers Bureau; BluePrint Health: Speakers Bureau; Incyte: Speakers Bureau; Blueprint Medicines: Consultancy; Novartis: Consultancy. Bradley: NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron Corporation: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees. Vachhani: LAVA therapeutics: Consultancy; MorphoSys: Consultancy; Stemline: Consultancy; Servier: Consultancy; Genentech: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; GlaxoSmith Kline: Consultancy; Daiichi Sankyo: Consultancy; CTI BioPharma Corp: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Cogent Biosciences: Consultancy; Blueprint Medicines: Consultancy, Speakers Bureau; Amgen: Consultancy; AbbVie: Consultancy. Tabayashi: Chugai: Research Funding; Janssen: Honoraria. Cheung: Novartis: Consultancy. Bose: Kartos, Telios, Disc, Janssen, Geron: Research Funding; GSK, Novartis, Karyopharm, AbbVie, Pharma Essentia, Jubilant, Morphic: Honoraria; Incyte, BMS, CTI, Morphosys, Blueprint, Cogent, Sumitomo, Ionis: Honoraria, Research Funding. O'Connell: Genentech: Other: Prior research support. Provision of drug for the study ; Astex Pharmaceuticals, Inc: Other: Prior research support. Provision of drug for the study . Kabir: Sumitomo Pharma America, Inc.: Current Employment. Seki: Sumitomo Pharma Co., Ltd.: Current Employment. Wade: Sumitomo Pharma America, Inc.: Current Employment. Peddagali: Sumitomo Pharma America, Inc.: Current Employment. Li: Sumitomo Pharma America, Inc.: Current Employment. Shah: Sumitomo Pharma America, Inc.: Current Employment. Rampal: Incyte: Research Funding; Constellation: Research Funding; Servier: Consultancy; Ryvu: Research Funding; Zentalis: Consultancy; Zentalis: Research Funding; Karyopharm: Consultancy; Kartos: Consultancy; Dainippon: Consultancy; Sumitomo: Consultancy; Morphosys/Constellation: Consultancy; GSK-Sierra: Consultancy; Pharmaessentia: Consultancy; Galecto: Consultancy; CTI BioPharma Corp: Consultancy; Celgene-BMS: Consultancy; Stemline: Research Funding; Incyte: Consultancy.

*signifies non-member of ASH