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

• DOI: 10.1200/jco.2024.42.16_suppl.11518
• Publication Date: 2024-06-13T13:56:15Z
• Authors: Jian Li; Ping Chi; Yoon-Koo Kang; Hui Cao; Suzanne George; Jun Zhang; Jian Zhang; Kang Hu; Lijia Zhang; Yanhua Xu
• Keywords: Broad spectrum; Stromal tumor

11518 Background: NB003 is a potent and selective small-molecule tyrosine kinase inhibitor of KIT/PDGFRα. It was designed to inhibit broad spectrum primary acquired imatinib-resistant mutations in Methods: This first-in-human phase 1 study patients (pts) with advanced GIST who progressed on or intolerant imatinib other SoCs. Pts received oral twice daily (BID). An accelerated titration followed by Bayesian optimal interval (BOIN) design used. After the MTD MAD determined, putative RP2D(s) were explored establish RP2D. The endpoint safety tolerability. Other endpoints included PK, efficacy mutational status ctDNA. Results: As Jan 10, 2024, 42 pts (median age 55 y [range 33–81]; 69% male; 71.4% ECOG PS 1; mutation KIT exon 11; median 4 prior TKI therapies 2–7]) treated dose escalation phase. Seven levels (DL) tested, including 3mg (1 pt), 6mg 12mg (3 pts), 20mg (15 30mg 35mg (4 40mg pts). most frequent treatment-related adverse events (TRAEs) asymptomatic CPK increased (92.9%), anaemia (78.6%), AST increased, face oedema, WBC decreased (76.2% each), periorbital oedema (66.7%), neutrophil count (64.3%), amylase (57.1%), lipase (52.4%), platelet (45.2%), peripheral (38.1%). Grade ≥3 TRAEs (61.9%), (59.5%), (23.8%), (21.4%). leading treatment discontinuation reported 2 (fatigue, tumor haemorrhage) at DL, (AST decreased) DL pt (face oedema) respectively. DLTs occurred (febrile neutropenia, rash maculo-papular, increased). In pts, confirmed ORR 26.2% (11/42, 95% CI:13.9, 42.0) per mRECISTv1.1 investigator assessment, DCR 73.8% (31/42, CI:58.0, 86.1). Most responses (7/11) are still ongoing. Tumor observed resistance both ATP-binding site activation loop domain based predose ctDNA (including 3 exon11/13, exon11/17, exon17, exon16, 9/17, not detected). A correlation between changes allele fraction (MAF) size from baseline. Conclusions: heavily pretreated GIST, demonstrated manageable profile encouraging antitumor activity across secondary KIT. RP2D defined as BID overall efficacy. Expansion cohorts different lines currently under enrollment. Clinical trial information: NCT04936178 .