A phase I study of PARP inhibitor (niraparib) plus HSP90 inhibitor (pimitespib) in solid tumors: The NiraPim (EPOC2102) study

BackgroundResistance mechanisms of PARP inhibitors include the restoration of homologous recombination repair (HRR) through reversion mutations, as well as the stabilization of HRR proteins by heat shock protein 90 (HSP90). HSP90, a molecular chaperone, plays a pivotal role in the stability, maturation, and function of various client proteins, including those regulating HRR. HSP90 inhibitors have been shown to destabilize HRR proteins, thereby inducing homologous recombination deficiency (HRD) and enhancing the efficacy of PARP inhibitors in preclinical models resistant to PARP inhibitors. The NiraPim (EPOC2102) study explores the synergistic potential of combining niraparib, a PARP inhibitor, with pimitespib, an HSP90 inhibitor, aiming to overcome such resistance in solid tumors.Trial designThis is a phase 1, open-label, investigator-initiated, multi-center study. It includes a dose-escalation part, following a 3+3 design to determine the recommended dose (RD), and a dose-expansion part to assess the safety and efficacy of the RD. In the dose-escalation part, pimitespib is administered at doses of 80, 120, or 160 mg on a 5-day on/2-day off schedule, in combination with niraparib at 200 mg once daily. In the dose-expansion part, cohort A includes patients with solid tumors resistant to PARP inhibitors (breast, ovarian, prostate, pancreatic cancers) harboring BRCA pathogenic variants, while cohort B includes patients with solid tumors that have not been treated with PARP inhibitors. The primary endpoint is the incidence of dose-limiting toxicities in the dose-escalation part. The secondary endpoints include adverse event rates, objective response rates, and progression-free survival. Tumor tissue and blood samples will be serially collected for multi-omics analysis, conducted as part of both the NiraPim TR study (jRCT1030220300) and the SCRUM-Japan MONSTAR-SCREEN-2 (UMIN000043899). Planned enrollment of 9-18 patients for the dose-escalation part and 30 patients for the dose-expansion part, from September 2022 to August 2024. The dose-escalation part has been completed, the RD has been determined, and the dose-expansion part has commenced.Clinical trial identificationjRCT2031220179.Legal entity responsible for the studyThe authors.FundingTakeda Pharmaceutical Co., Ltd.; Taiho Pharmaceutical Co., Ltd.DisclosureH. Nakajima: Financial Interests, Personal, Invited Speaker: Pfizer, Taiho, Lilly, AstraZeneca, Chugai, Takeda, Ono. T. Eiraku: Financial Interests, Personal, Full or part-time Employment: Kyorin Pharmaceutical Co., Ltd. Y. Komatsu: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., DaiichipSankyo, Taiho, Chugai, Lilly, Merck, MSD, BMS, Takeda, Bayer Yakuhin, Moroo Co., Asahi Kasei, Pfizer, Nippon Zoki Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Incyte Corporation, Zeria Pharmaceutical Co., Ltd., Yakult Honsha, Nipro Corporation, Sanofi/Aventis, Astellas Pharma Inc., Nippon Kayaku Co., Ltd.; Financial Interests, Personal, Writing Engagement: Eli Lilly and Company, Yakult Honsha Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd., Taiho, Chugai, Sanofi, Nipro, Daiichi Sankyo, BMS, Sysmex Corporation, EPS Holdings, Inc., Asahi Kasei Pharma Corporation, Nippon Zoki Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd.; Non-Financial Interests, Member: JSCO, JSMO, ASCO. T. Kato: Financial Interests, Personal, Invited Speaker: MSD. M. Wakabayashi: Financial Interests, Personal, Invited Speaker: Nihon Medi-Physics Co., Ltd. T. Fujisawa: Financial Interests, Personal, Invited Speaker: Amelieff Co Ltd. Y. Nakamura: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Guardant Health AMEA; Financial Interests, Institutional, Funding: Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Roche Diagnostics; Financial Interests, Institutional, Coordinating PI: Seagen. A. Ohashi: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma. Inc.; Financial Interests, Institutional, Research Funding: Daiichi Sankyo, Astellas Pharma; Financial Interests, Personal, Royalties: Takeda Pharmaceutical Company, Ltd. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd, Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., Falco Biosystems Ltd., Merus N.V., Bristol Myers Squibb K.K., Medical & Biological Laboratories Co., Ltd., Takeda Pharmaceutical Co., Ltd. A. Sato: Financial Interests, Institutional, Sponsor/Funding: Taiho Pharmaceutical, Boehringer Ingelheim, Bayer, Chugai Pharma, Eisai, Ono Pharmaceutical, Takeda, Rakuten Medical, Pentax Medical Devices, Daiichi Sankyo/UCB Japan, MSD, FerroptoCure, AstraZeneca, P-minde. Y. Naito: Financial Interests, Personal, Invited Speaker, Speakers Bureau: Chugai, Pfizer, Eli Lilly, Eisai, AstraZeneca, PDR Pharma, Novartis, Guardant, Ono, Takeda, Taiho, Bayer, Nihon Kayaku, Daiichi Sankyo, Bristol, MSD; Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Local PI: AbbVie, Boehringer Ingelheim, Ono, Chugai, Taiho, Pfizer, AstraZeneca, Gilead, Takeda, Eisai; Financial Interests, Personal, Steering Committee Member: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, JCOG: Natera; Non-Financial Interests, Principal Investigator: Myriad. All other authors have declared no conflicts of interest.