Background: Gastrointestinal stromal tumor (GIST) is soft-tissue sarcoma of the gastrointestinal tract. Most GISTs harbor mutations in KIT or PDGFRA, recognized as key drivers of GIST development and progression. Imatinib (IM), which inhibits KIT/PDGFRA tyrosine kinase, exerts significant clinical activity in GIST, but most GISTs develop resistance to IM, mainly due to secondary kinase-domain mutations in KIT. Therefore, standard therapies for patients (pts) with IM-refractory GIST have room for improvement. Heat shock protein 90 (HSP90) is one of the molecular chaperones. Many of HSP90's client proteins, such as KIT, PDGFRA, and BRAF, have been identified as cancer-related proteins required for tumor development, and their activation, especially in mutant forms, is dependent on HSP90.Therefore, HSP90 inhibitors have a potential to overcome IM-resistance. Pimitespib (PIMI) is a novel HSP90 inhibitor, approved in Japan for pts with fourth line GIST based on the results of the phase 3 study (CHAPTER-GIST-301). We reported at ESMO 2023 (1917MO) that PIMI effectively inhibited tumor growth in an IM-resistant xenograft model, and further enhanced the anti-tumor activity when given with IM, and that PIMI + IM was well tolerated with no dose-limiting toxicity and suggested preliminary efficacy in pts resistant to IM in a dose-escalation part (DEP) of CHAPTER-GIST-101 study. Methods: The CHAPTER-GIST-101 study (NCT05245968) is a global phase 1 study in pts with IM-refractory advanced GIST in the second-line setting, consisting of three parts: the DEP, its expansion part (ExP), and another DEP for Chinese pts. The DEP used a 3+3 design to determine the maximum tolerated dose of PIMI (120 mg/day or 160 mg/day, orally, on 5 days on/2 days off) in combination with IM (400 mg/day once daily) and the ExP is for the efficacy and safety with determined dose of 120 mg/day PIMI + IM. The ExP is a global, open-label, randomized, part evaluating the efficacy and safety of PIMI in combination with IM, PIMI monotherapy, and standard therapy sunitinib (SU) in each arm of 20 pts. Pts are randomized 1:1:1 to receive either PIMI 120 mg on 5 days on/2 days off with IM 400 mg once daily, PIMI 160 mg on 5 days on/2 days off followed by IM 400 mg once 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 the 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 planned. After the DLT evaluation for the DEP, enrollment for the ExP began in March 2023 in Japan, Singapore, Taiwan and Australia, and for the DEP for Chinese pts is also ongoing in China to evaluate tolerability and efficacy of this combination. Clinical trial information: NCT05245968.