A Phase 1/2 Study of Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor, in Combination with JAK Inhibitors Ruxolitinib or Momelotinib in Patients with Myelofibrosis

Background: JAK inhibitors are the current standard of care treatment for patients (pts) with myelofibrosis (MF). Ruxolitinib (RUX), the first approved JAK inhibitor in 2011, showed spleen volume reduction (SVR) and symptom improvement in about 40% pts, but is limited by anemia, thrombocytopenia, or lack of disease-modifying effects (Verstovsek S, 2012). Momelotinib (MMB), a recently approved JAK inhibitor for MF pts with anemia in 2023, showed modest symptom and spleen responses in about 25% pts in relapsed/refractory (R/R) setting (Mesa R, 2022). About 60% pts may not achieve spleen or symptom responses after frontline treatment, and up to 75% R/R MF pts do not achieve adequate responses. Recent Phase 3 combination studies of RUX with Pelabresib (Rampal R, 2023) or Navitoclax (Pemmaraju N, 2023) in treatment naïve MF pts with platelet (PLT) count ≥100 x 10⁹/L showed significant increase only in spleen responses; however, did not improve symptoms response, also were limited by overlapping toxicities of thrombocytopenia. Therefore, combination strategies of JAK inhibitors and agents with unique mechanism of action and minimal overlapping toxicities (e.g., cytopenias) are needed to improve response rates and clinical outcomes in MF. PIM1 expression is upregulated in hematologic malignancies including MF. In preclinical models, PIM1 knockout (KO) was shown to prevent MF progression without affecting PLT counts, whereas pan-PIM KO caused decreased PLT counts (Dutta A, 2021; An N, 2013). Nuvisertib (TP-3654), an oral investigational highly selective PIM1 kinase inhibitor, alone and in combination with RUX, showed spleen size and bone marrow (BM) fibrosis reduction and normalization or increase in hematological counts in murine JAK2V617F and MPLW515L mutant MF models. Preliminary results from the ongoing global Phase 1/2 study in R/R MF pts with PLT count ≥25 x 10⁹/L (NCT04176198, Arm 1) showed that TP-3654 monotherapy was well tolerated with limited myelosuppressive adverse events (AEs), and early signs of clinical activity including SVR, total symptom score (TSS) reduction, and cytokine reductions (Rein L, 2023). Current monotherapy and preclinical data support the development of TP-3654 in combination with JAK inhibitors RUX or MMB in MF pts with low (<100 x 10⁹/L) or normal PLT counts.

Methods: The ongoing global Phase 1/2 study of TP-3654 monotherapy (Arm 1) has now been expanded to evaluate TP-3654 add-on to RUX (Arm 2) or in combination with MMB (Arm 3) in pts with MF (NCT04176198). The study aims to identify the MTD and/or RP2D of TP-3654 when given with RUX or MMB, and to assess the safety, clinical activity (SVR and TSS reduction), PK and PD markers. Study population include primary or secondary MF; DIPSS intermediate 1, 2 or high-risk; splenomegaly (≥450 cm³ by imaging); ≥2 measurable symptoms with each score ≥3 or a total average score of ≥10 per the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0); PLT count ≥50 x 10⁹/L; adequate hepatic functions (ALT and AST ≤3x ULN [ALT and AST ≤5x ULN if liver involvement secondary to MF], direct bilirubin ≤2x ULN); and adequate renal function (serum creatinine ≤1.5x ULN or creatinine clearance ≥30 mL/min). For TP-3654 add-on to RUX (Arm 2), pts that have been on RUX treatment for ≥6 months and on a stable dose of RUX for ≥8 weeks, but have either lost response or had a suboptimal or plateau in response. For TP-3654 in combination with MMB (Arm 3), pts that have been previously treated with an approved JAK inhibitor (except MMB) for ≥12 weeks, or ≥4 weeks if JAK inhibitor therapy was complicated by a transfusion requirement of ≥4 units of RBC in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma. Combination arms are currently recruiting pts.

Mascarenhas:Bristol Myers Squibb: Research Funding; Merck: Consultancy; Ariad: Speakers Bureau; PharmaEssentia: Consultancy, Research Funding; MorphoSys: Consultancy; Icahn School of Medicine at Mount Sinai: Current Employment; Ajax: Research Funding; Pfizer: Research Funding; Celgene: Consultancy, Other: Travel Support, Speakers Bureau; AbbVie: Consultancy, Research Funding; Blueprint Medicines: Consultancy; Kartos: Consultancy, Research Funding; Sumitomo: Consultancy; Novartis: Consultancy, Other: Travel Support , Research Funding, Speakers Bureau; CTI BioPharma/SOBI: Consultancy, Research Funding; Karyopharm: Consultancy; Keros: Consultancy; Disc: Consultancy; Incyte Corporation: Consultancy, Speakers Bureau; GSK: Consultancy; Roche: Consultancy; Geron: Consultancy, Research Funding; NS Pharma: Research Funding; Astellas: Research Funding. Rampal:Servier: Consultancy; Ryvu: Research Funding; Zentalis: Consultancy, Research Funding; Karyopharm: Consultancy; Kartos: Consultancy; Sumitomo Dainippon: Consultancy; Cogent: Consultancy; Protagonist: Consultancy; Sierra Oncology/GSK: Consultancy; Constellation/MorphoSys: Consultancy, Research Funding; Jubilant: Consultancy; PharmaEssentia: Consultancy; Galecto: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; CTI BioPharma: Consultancy; AbbVie: Consultancy; Blueprint: Consultancy; Celgene/BMS: Consultancy; Incyte Corporation: Consultancy, Research Funding; Disc Medicine: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Promedior: Consultancy. El Chaer:Bristol Meyers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; PharmaEssentia: Consultancy, Research Funding; ACCC: Consultancy; Sumitomo Pharma America, Inc.: Consultancy, Research Funding; Geron: Consultancy; Sobi: Consultancy; AbbVie: Consultancy; CTI Biopharma: Consultancy; MorphoSys: Consultancy; DAVA Oncology: Consultancy, Other: Travel Grant; Celgene: Research Funding; Sanofi: Research Funding; FibroGen: Research Funding; BioSight: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding. Gupta:BMS/Celgene: Consultancy, Other: Participation on a data safety or advisory board; Novartis: Consultancy; Constellation: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Other: Participation on a data safety or advisory board; Pfizer: Consultancy, Other: Participation on a data safety or advisory board; GSK: Consultancy, Honoraria, Other: support for attending meetings and/or travel; Daiichi Sankyo: Consultancy, Other: Participation on a data safety or advisory board; Sumitomo Pharm: Consultancy; Sierra Oncology: Consultancy, Other: Participation on a data safety or advisory board; CTI Biopharma: Consultancy, Other: Participation on a data safety or advisory board; Roche: Membership on an entity's Board of Directors or advisory committees. Shimoda:Novartis Pharma KK: Honoraria; AbbVie GK: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Taisho Pharmaceutical Co: Research Funding; Sumitomo Dainippon Pharma Co Ltd: Research Funding; Shinogi & Co Ltd: Research Funding; PharmaEssentia Japan KK: Research Funding; Otsuka Pharmaceutical Co Ltd: Research Funding; Nippon Kayaku Co Ltd: Research Funding; Mochida Pharmaceutical Co Ltd: Research Funding; Kyowa Kirin Co Ltd: Research Funding; Eisai Co Ltd: Research Funding; Daiichi Sankyo Co Ltd: Research Funding; Chugai Pharmaceutical Co Ltd: Research Funding; Sierra Oncology: Consultancy. Kiladjian:GSK: Consultancy; Abbvie: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; AOP Orphan: Honoraria, Speakers Bureau; PharmaEssentia: Honoraria; Novartis: Consultancy. Passamonti:Abbvie: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; AOP: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau; Karyiopharma: Honoraria, Speakers Bureau; Kyowa Kirin: Honoraria, Speakers Bureau; MEI: Honoraria, Speakers Bureau; Sumitomo: Honoraria, Speakers Bureau; BMS/Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Kartos Therapeutics Inc.: Honoraria, Speakers Bureau. Bose:GSK: Honoraria; Astellas: Research Funding; Novartis: Honoraria; Karyopharm: Honoraria; Ionis Pharmaceuticals: Research Funding; Cogent: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Disc Medicine: Research Funding; PharmaEssentia: Honoraria; Telios: Research Funding; Blueprint: Honoraria, Research Funding; BMS: Honoraria, Research Funding; CTI Biopharma Corp: Honoraria, Research Funding; Kartos: Honoraria, Research Funding; MorphSys: Honoraria, Research Funding; AbbVie: Honoraria; Pfizer: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Scandura:SDP Oncology: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees; Morphic: Consultancy; Medpacto: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calico: Consultancy. Mesa:MorphoSys: Consultancy, Research Funding; Telios: Consultancy, Honoraria; Sierra: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; CTI: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Blueprint: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Rein:Geron: Other: Site Principal Investigator for clinical trial, Research Funding; Blueprints Medicine: Other: Site Principal Investigator for clinical trial, Research Funding; Protagonist: Other: Site Principal Investigator for clinical trial, Research Funding; Cogent Biosciences: Other: Site Principal Investigator for clinical trial, Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: Site Principal Investigator for clinical trial, Research Funding; Incyte: Consultancy, Other: Site Principal Investigator for clinical trial, Research Funding; Morphpsys: Consultancy; Novartis: Consultancy, Honoraria, Other: Site Principal Investigator for clinical trial, Research Funding; DAVA Oncology: Other: Speaker, conference participant; PharmaEssentia: Other: Site Principal Investigator for clinical trial, Research Funding; Merck: Other: Site Principal Investigator for clinical trial, Research Funding; Karyopharm: Other: Site Principal Investigator for clinical trial, Research Funding; Telios Pharma: Research Funding; Silence Therapeutics: Research Funding; Sobi: Consultancy; Abbvie: Consultancy. Yuda:AbbVie: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Chugai: Research Funding; Genmab: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Takeda: Research Funding; BMS: Research Funding; Sumitomo Pharma: Research Funding; MSD: Research Funding; Mitsubishi Tanabe: Research Funding; BrightPath Biotherapeutics Co.,Ltd.: Research Funding. Ross:Menarini: Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Devos:Keros: Consultancy. Talpaz:Arcus: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Imago: Membership on an entity's Board of Directors or advisory committees; KyowaKirin: Membership on an entity's Board of Directors or advisory committees; Sumitomo: Membership on an entity's Board of Directors or advisory committees; SierraOncology: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hoffman:Kymera: Research Funding; Protagonist Therapeutics: Consultancy; Karyopharm therapetics: Research Funding; Cellenkos: Research Funding; Dexcel: Research Funding; Silence Therapeutics: Consultancy. Kabir:Sumitomo Pharma America, Inc.: Current Employment. Li:Sumitomo Pharma America, Inc.: Current Employment. Foulks:Sumitomo Pharma America, Inc.: Current Employment, Patents & Royalties: WO2014062838 A2. PCT/US2013/065296, WO2020023910A1, WO2019195753A1, WO2019200254A1, US20200297698A1, WO2021102343A1, WO2019195759A1. Ansaldo:Sumitomo Pharma America, Inc.: Current Employment. Seki:Sumitomo Pharma America, Inc.: Current Employment. Peddagali:Sumitomo Pharma America, Inc.: Current Employment. Shah:Sumitomo Pharma America: Current Employment. Harrison:IMAGO: Consultancy, Honoraria, Speakers Bureau; Geron: Consultancy; GSK: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Research Funding, Speakers Bureau; Sobi: Consultancy; Galecto: Consultancy; Keros: Consultancy, Honoraria, Speakers Bureau; AOP: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; MorphoSys/Constellation: Consultancy, Honoraria, Other: Research: PI, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Incyte: Consultancy, Honoraria, Other: Teaching and Speaking; Research: PI, Speakers Bureau; CTI: Ended employment in the past 24 months; AbbVie: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Research Funding, Speakers Bureau; MPN voice: Other: Leadership role.