Phase 1 study of NB003, a broad-spectrum KIT/PDGFRα inhibitor, in patients with advanced gastrointestinal stromal tumors (GIST).

作者：Jian Li, Ping Chi, Yoon‐Koo Kang, Hui Cao, Suzanne George, Jun Zhang, Jian Zhang, Kang Hu, Lijia Zhang, Yanhua Xu · 发表于：Journal of Clinical Oncology · 年份：2024 · DOI：10.1200/jco.2024.42.16_suppl.11518 · 被引用次数：5 · 研究领域：Gastrointestinal Tumor Research and Treatment、Sarcoma Diagnosis and Treatment、Platelet Disorders and Treatments

11518 Background: NB003 is a potent and selective small-molecule tyrosine kinase inhibitor of KIT/PDGFRα. It was designed to inhibit a broad spectrum of primary and acquired imatinib-resistant mutations in KIT/PDGFRα. Methods: This is a first-in-human phase 1 study in patients (pts) with advanced GIST who progressed on or intolerant to imatinib and other SoCs. Pts received oral NB003 twice daily (BID). An accelerated titration followed by a Bayesian optimal interval (BOIN) design was used. After the MTD or MAD was determined, putative RP2D(s) were explored to establish the RP2D. The primary endpoint was safety and tolerability. Other endpoints included PK, efficacy and mutational status by ctDNA. Results: As of Jan 10, 2024, 42 pts (median age 55 y [range 33–81]; 69% male; 71.4% ECOG PS 1; 69% primary mutation in KIT exon 11; median 4 prior TKI therapies [range 2–7]) were treated in dose escalation phase. Seven dose levels (DL) were tested, including 3mg (1 pt), 6mg (1 pt), 12mg (3 pts), 20mg (15 pts), 30mg (15 pts), 35mg (4 pts), 40mg (3 pts). The most frequent treatment-related adverse events (TRAEs) were asymptomatic CPK increased (92.9%), anaemia (78.6%), AST increased, face oedema, WBC decreased (76.2% each), periorbital oedema (66.7%), neutrophil count decreased (64.3%), amylase increased (57.1%), lipase increased (52.4%), platelet count decreased (45.2%), oedema peripheral (38.1%). The most frequent Grade ≥3 TRAEs were anaemia (61.9%), asymptomatic CPK increased (59.5%...