1422TiP - Phase II, singlearm, nonrandomized, and multicenter clinical trial of regorafenib (REG) as a single agent in the firstline setting for patients with metastatic and/or unresectable KIT/PDGFR wild-type GIST. A GEIS and ISG study

Abstract

Approximately 10-15% of adults with GIST lack KIT or PDGFRA mutations. This KIT/PDGFRA wild-type (wt) GIST is considered a separate pathological entity and is highly clinically heterogeneous. Because most KIT/PDGFRA wt-GISTs do not respond to imatinib, new treatment approaches are needed. REG is an oral multikinase inhibitor that has been shown to improve progression-free survival (PFS) and disease control rate (DCR) vs placebo in patients with advanced GIST progressing after failure of imatinib and sunitinib (Demetri et al. Lancet 2013). This study was designed to assess the effectiveness of REG in patients with metastatic and/or unresectable KIT/PDGFR wt-GIST in the first-line setting. Trial design: Patients ≥18 years of age with histologically confirmed unresectable and/or metastatic KIT/PDGFR wt-GIST (lack of mutations in KIT exons 11,9,13,17 and PDGFR exons 12,18 confirmed by next-generation sequencing) are eligible. Other inclusion criteria include ≥1 measurable lesion (RECIST v1.1), ECOG PS 0-1, adequate bone marrow, liver, and renal function, not fulfilling any exclusion criteria, and written informed consent. FFPE-tumor blocks are to be provided. Collection of blood and fresh tumor samples for a translational substudy is optional. REG 160 mg will be administered once daily in a 3-weeks on, 1-week off schedule until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw. Thirtythree patients (+ 20%) are to be recruited according to Simon Minmax 2stage Phase II design. Main endpoint is DCR relative to the historical control of imatinib in wt-GIST. Hypothesis 0: p0 = 73% (0% CR + 23% PR + 50% SD). Hypothesis 1: achieving a DCR of p1 = 90% with REG. Using error rates of a = 0.05 and b = 0.20, the first-stage sample size is 31 patients, with 26 patients as the upper limit for firststage drug rejection. Secondary outcomes include PFS, overall survival, response (CHOI criteria), correlation with translational research, early metabolic response by PETscan, and safety (CTCAE 4.03). Clinical trial identification: EudraCT Number: 2015-001048-12 Legal entity responsible for the study: Grupo Español de Investigación en Sarcomas (GEIS)