Abstract 267TiP
Background
Gastrointestinal stromal tumor (GIST) is a soft-tissue sarcoma of the gastrointestinal tract. Most GISTs have mutations in KIT or PDGFRA, key drivers of the development. Imatinib (IM), a KIT/PDGFRA tyrosine kinase inhibitor, is effective but resistance develops, mainly due to secondary mutations in KIT. Thus, better therapies are needed for IM-refractory GIST patients (pts). Heat shock protein 90 (HSP90) is a molecular chaperone that activates cancer-related proteins like KIT, PDGFRA, and BRAF which are dependent on HSP90 especially in mutant forms. HSP90 inhibitors can lead to degradation of KIT including activated forms and potentially overcome IM-resistance. Pimitespib (PIMI) is a novel HSP90 inhibitor approved in Japan for fourth-line GIST based on a phase III study (CHAPTER-GIST-301). At ESMO 2023 (1917MO), we reported that PIMI effectively inhibited tumor growth in an IM-resistant xenograft model and enhanced the anti-tumor activity when combined with IM. Preliminary efficacy and tolerability were also observed in IM-resistant pts in a dose-escalation part (DEP) of the CHAPTER-GIST-101 study (NCT05245968).
Trial design
This phase I study is for IM-refractory advanced GIST in the second-line setting, with DEP, and its main part, expansion part (ExP). DEP determined the maximum tolerated dose as PIMI 160 mg/day + IM 400 mg/day and the ExP dose as PIMI 120 mg/day + IM 400 mg/day. The ExP is a global, open-label, randomized part evaluating the efficacy and safety with PIMI + IM, PIMI monotherapy followed by IM re-challenging, and sunitinib (SU) in each arm of 20 pts. Pts are randomized 1:1:1 to receive PIMI 120 mg on 5 days on/2 days off with IM 400 mg daily, PIMI 160 mg on 5 days on/2 days off followed by IM 400 mg daily after discontinuation of PIMI, or SU 50 mg on 4 weeks on/2 weeks off. The primary endpoint is progression-free survival (PFS) by independent radiological review. The secondary endpoints include investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, PK, and safety. Exploratory pharmacogenomics analysis is also measured. The study recruits pts from Australia, China, Japan, Singapore, and Taiwan.
Clinical trial identification
NCT05245968.
Legal entity responsible for the study
Taiho Pharmaceutical Co., LTD.
Funding
Taiho Pharmaceutical Co., LTD.
Disclosure
W.P. Yong: Financial Interests, Personal, Invited Speaker: DKSH Singapore Pte Ltd, AstraZeneca Singapore Pte Ltd, Bristol Myers Squibb (S) Pte Ltd, MSD Pharma (Singapore) Pte Ltd, Novartis (S) Pte Ltd; Financial Interests, Personal, Advisory Board: Ipsen Pharma Singapore Pte Ltd, Amgen; Financial Interests, Institutional, Local PI: Novartis (S) Pte Ltd, Amgen. 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, Personal, Principal Investigator, JCOG: Natera; Non-Financial Interests, Personal, Principal Investigator: Myriad. H. Hirano: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical, Teijin Phama, Novartis, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Ono Pharmaceutical, Janssen Pharmaceutical, Merck Biopharma, Bristol Myers Squibb, Pfizer, Eisai, AMGEN, Astellas, Seagen, MSD, Insyte, BeiGene, Novartis, ALX Oncology, PPD, Nippon Boehringer Ingelheim. Y. Kurokawa: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lily, Yakult Honsha, Bristol Myers Squibb, Daiichi Sankyo, Nippon Kayaku, MSD, Astellas Pharma; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical, Ono Pharmaceutical, MSD. Y. Komatsu: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, 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 Company, Limited, 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, Personal, Member: JSCO, JSMO, ASCO. M. Ozaka: Financial Interests, Personal, Invited Speaker: Taiho, Yaklut, MSD, Incyte, Ono, Bayer, Servier. J. Chen: Financial Interests, Personal, Other, Clinical trial Principle investiagator: Amgen, BMS/ONO, Janssen, Merck, MSD, Roche, Taiho; Financial Interests, Personal, Advisory Board, expert advise meeting: Astellas, CStoone; Financial Interests, Personal, Other, Clinical trial Principle investiagatorspeaker: Astrzeneca; Financial Interests, Personal, Invited Speaker: TTY; Financial Interests, Institutional, Other, PI for TaiRx study: TaiRx; Financial Interests, Personal, Other, Study Investigator: Daiichi Sankyo; Non-Financial Interests, Personal, Leadership Role, Presisdent: Taiwan Oncology Society. C. Yen: Financial Interests, Personal and Institutional, Local PI: Deciphera, BioAtla, Rain Therapeutics, ONO, Boehringer Ingelheim, Cogent Biosciences, Polaris, Napo, Taiho, PharmaEssentia, AstraZeneca; Financial Interests, Personal, Steering Committee Member: Daiichi Sankyo; Financial Interests, Personal and Institutional, Other, DSMB member: FullHope Biomedical; Non-Financial Interests, Personal, Member: AACR, ASCO, Taiwan Oncology Society. J.R. Zalcberg: Financial Interests, Personal, Advisory Board: MSD, FiveFusion, Duo Oncology, RevMed; Financial Interests, Institutional, Other, Research: MSD, BMS, Astellas, Taiho, Servier, STA; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Writing Engagement: Servier; Financial Interests, Personal, Member of Board of Directors, NED: ICON, PRAXIS; Financial Interests, Personal, Stocks/Shares: Biomarin, Amarin, Ophthea, Frequency Therapeutics, Gilead, UniQure, Orphazyme, Novavax, CSL; Non-Financial Interests, Personal, Member of Board of Directors, Australian Clinical Trials Alliance: ACTA. A.C. Roy: Financial Interests, Personal, Advisory Board: MSD, BMS, BeiGene, Takeda, Grey Wolf Therapeutics, Medison Pharma, AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD, Ipsen, Pierre Fabre, Limbic Oncology; Financial Interests, Personal, Member of Board of Directors: Southern Oncology SA Private Practice, Southern Oncology Clinical Research Unit; Financial Interests, Institutional, Research Grant: Merck, Specialised Therapeutics. L. Chen: Financial Interests, Personal, Invited Speaker: PharmaEngine (TW), ONO, BMS, Ipsen, Novartis, TTY (TW); Financial Interests, Personal, Other, Medical Monitoring for clinical trial: Taivex (TW); Financial Interests, Personal, Other, DSMC member for clinical trials: OBI (TW); Financial Interests, Personal, Advisory Board: MSD, AstraZeneca; Financial Interests, Personal, Advisory Board, Scientific Advisory Committee: ScinoPharm Taiwan, Onward; Financial Interests, Personal, Full or part-time Employment, Co-affiliated, Distinguished Investigator and Senior Physician Staff: National Institute of Cancer Research, National Health Research Institutes, Taiwan; Financial Interests, Personal, Full or part-time Employment, Professor of Internal Medicine: Kaohsiung Medical Univrsity Hopsital, Kaohsiung Medical University, Kaohsiung, Taiwan; Financial Interests, Personal, Member of Board of Directors, Independent Director: ScinoPharm Taiwan, Ltd.; Financial Interests, Personal, Advisory Board, Alpha-enolase specific antibodies: HuniLife Biotechnology, Inc., Taiwan; Financial Interests, Personal, Steering Committee Member, TOPAZ-1, phase III trial: AstraZeneca; Financial Interests, Personal, Steering Committee Member, ATTRACTIONs trials, ATT-2 (3L), ATT-4 (1L), ATT-5 (Adjuvant) and ATT-6 (1L): Ono; Financial Interests, Personal, Trial Chair, SynCore CT4006, phase III trial: Syncore BioPharma, Taiwan; Financial Interests, Institutional, Trial Chair, Industry-sponsored, phase II bridging trial in TCOG: TTY, Taiwan; Financial Interests, Institutional, Steering Committee Member, C3651003 (Cancer cachexia), Operations steering Committee, country lead: Pfizer; Non-Financial Interests, Personal, Principal Investigator, Investigator-initiated trials: Taiwan Cooperative Oncology Group, National Institute of Cancer Research, Taiwan; Non-Financial Interests, Personal, Leadership Role, President (2021.09 ∼): Taiwan NeuroEndocrine Tumor Society (TNETS); Non-Financial Interests, Personal, Member of Board of Directors: Taiwan Pancreas Society, Taiwan; Non-Financial Interests, Institutional, Product Samples, Medication for TCOG trials: TTY; Non-Financial Interests, Institutional, Product Samples, Targeted Cancer Panel NGS testing: ACTgenomics (TW); Non-Financial Interests, Personal, Other, International Staring Committee Member (ISCM), Academic Planning Committee, JSMO: Japanese Society of Medical Oncology (JSMO); Non-Financial Interests, Personal, Leadership Role, Council Member: Asian Oncology Society (AOS). T. Nishida: Financial Interests, Personal, Invited Speaker, honoraria for lectures: Pfizer, Eisai; Financial Interests, Personal, Advisory Board, Consulting and advisory, and honoraria for lectures: Taiho Pharmaceutical. T. Doi: Financial Interests, Personal, Other, Advisory Role: Noil-Immune Biotech, Oncolys BioPharma, Boehringer Ingelheim, A2 Healthcare, PRA Health Sciences, KAKEN Pharma, Chugai Pharma, Sumitomo Pharma, Shionogi, Otsuka Pharma, Takeda, Kyowa Kirin, Rakuten Medical; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Taiho, MSD, AbbVie, Pfizer, BMS, Janssen Pharma, Daiichi Sankyo, Chugai Pharma, Boehringer Ingelheim, PRA Health Sciences, Amgen, GSK, Shionogi, RIN Institute, Ono Pharma, Bayer, Kyowa Kirin. All other authors have declared no conflicts of interest.