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240 Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Latest Data for Combination and Emerging Targeted Therapies in Myelofibrosis
Hematology Disease Topics & Pathways:
clinical trials, Research, Clinical Research
Saturday, December 10, 2022: 3:15 PM

Firas El Chaer, MD1, James McCloskey, MD2*, Lindsay A.M. Rein, MD3, Randy A. Brown, MD4, Steven D. Green, MD5*, Jeffrey J. Pu, MD, PhD6, Shuichi Shirane, MD, PhD7*, Kazuya Shimoda, MD, PhD8, Michiko Ichii, MD, PhD9*, Junichiro Yuda, MD, PhD10*, Joseph Scandura, MD, PhD11, Sujan Kabir, MD12*, Jason M Foulks, PhD13*, Jian Mei, PharmD12*, Huyuan Yang, PhD12*, Mark Wade, PhD14*, Carl Stapinski, PharmD12*, Claudia Lebedinsky, MD12 and Raajit K Rampal, MD, PhD15

1Division of Hematology/Oncology, University of Virginia Health System, Charlottesville, VA
2John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
3Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC
4Division of Hematology & Oncology, Department of Medicine, Shands HealthCare & University of Florida, Gainesville, FL
5Department of Medicine, Leukemia Division, Roswell Park Comprehensive Cancer Center, Buffalo, NY
6University of Arizona Cancer Center, Tucson, AZ
7Division of Hematology, Juntendo University School of Medicine, Tokyo, Japan
8University of Miyazaki, Miyazaki, Japan
9Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita City, Japan
10Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan
11Richard T. Silver, M.D. Myeloproliferative Neoplasms (MPN) Center, Weill Cornell Medicine, New York, NY
12Sumitomo Pharma Oncology, Inc., Marlborough, MA
13Sumitomo Pharma Oncology, Lehi, UT
14Sumitomo Pharma Oncology, Inc., Lehi, UT
15Memorial Sloan Kettering Cancer Center, New York, NY

Introduction: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. Expression of PIM-1 is significantly upregulated in MF hematopoietic cells, supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a highly selective oral investigational PIM-1 kinase inhibitor. When administered alone and in combination with ruxolitinib, TP-3654 reduced spleen size and BM fibrosis in JAK2V617F and MPLW515L murine MF models (Dutta, 2021). In addition, TP-3654 decreased cytokine response genes and serum TGF-b in progenitor cells and JAK2V617F mice, respectively. TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation.

Methods: This Phase I/II study evaluates the safety and efficacy of TP-3654 monotherapy in patients with MF (NCT04176198). Key eligibility criteria include primary or secondary MF; intermediate or high-risk MF per DIPSS; previously treated with or ineligible for JAK inhibitor treatment; grade ≥2 BM fibrosis; platelet count ≥25x109/L; absolute neutrophil count ≥1x109/L; splenomegaly; and ≥2 measurable symptoms. The study aims to identify the maximum tolerated dose and/or recommended Phase II dose using a Bayesian logistic regression model (BLRM) with overdose control, and to assess clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement, and BM fibrosis reduction), safety, pharmacokinetic, and pharmacodynamic markers in peripheral blood and BM biopsies.

Results: As of 11 July 2022, 8 patients were enrolled across 5 dose levels in the dose escalation phase. At baseline, median age was 70 years (range, 61 to 77), median spleen volume was 2370 cm3 (range, 1189 to 4407), median total symptom score was 19 (range, 4 to 62), median platelet count was 120 x109/L (range 68 to 237), median hemoglobin was 10.1 g/dL (range, 5.9 to 13.7), and two patients were transfusion-dependent. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitor treatment was 35 weeks (range, 13 to 269). Six patients had JAK2V16F mutation, 2 patients had CALR mutation. The median duration of TP-3654 treatment was 21 weeks (range, 1 to 45). No dose-limiting toxicities occurred. Treatment-related adverse events (TRAEs) occurring in >20% of patients included mild to moderate nausea, vomiting, and diarrhea. Grade ≥ 3 TRAEs included only 1 case of vomiting. No hematological TRAEs were reported. No discontinuation due to AE occurred. SVR was observed in 5 out of 6 evaluable patients (median best change -14%, range -3.2% to -35%) (Figure 1). Symptom improvement was observed in 5 out of 6 evaluable patients (median best change -70%, range -32 to -100%). A panel of cytokines were evaluated in plasma samples obtained at baseline and during TP-3654 treatment. Reductions in cytokines (TGF-b, IL-18, VEGF, RANTES, MMP-9, and TIMP-1) were observed after TP-3654 treatment (Figure 2). Patients with higher cytokine reductions correlated with higher reduction in total symptom score. Enrollment is ongoing, updated data will be presented.

Conclusions: The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors.

Disclosures: McCloskey: AbbVie, CTI BioPharma, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, Bristol Myers Squibb, Incyte, Jazz Pharmaceuticals, Stemline, and Takeda: Speakers Bureau. Rein: Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprints Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Scandura: MPN-RF: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma Oncology, Inc: Consultancy; European Leukemia net: Honoraria, Other: Travel fees; CR&T: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Research Funding. Kabir: Sumitomo Pharma Oncology, Inc.: Current Employment. Foulks: Sumitomo Pharma Oncology, Inc.: Current Employment, Patents & Royalties: WO2021102343A1; CA3103995A1; US11040038B2. Mei: Sumitomo Pharma Oncology, Inc.: Current Employment. Yang: umitomo Pharma Oncology, Inc.: Current Employment. Wade: umitomo Pharma Oncology, Inc.: Current Employment. Stapinski: umitomo Pharma Oncology, Inc.: Current Employment. Lebedinsky: Sumitomo Pharma Oncology, Inc.: Current Employment.

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