1916MO - A first-in-human phase I trial of NB003, a potent and selective KIT/PDGFRa inhibitor, in patients with advanced gastrointestinal stromal tumors (GIST)

Background

NB003 is a potent and selective small-molecule tyrosine kinase inhibitor (TKI) of KIT and PDGFRα, designed to inhibit a broad range of primary and acquired imatinib-resistant mutations in KIT/PDGFRα in GIST. This study is aimed to determine the safety and tolerability, the MTD, and the RP2D of NB003 in patients (pts) with advanced GIST.

Methods

This is a phase 1, multicenter, open-label, dose-escalation study of adult pts with confirmed GIST who progressed on or intolerant to imatinib and other standard of care treatments. A BOIN dose-escalation design was used; pts received oral NB003 in 7 dose levels (DL), ranging from 3mg to 40mg twice daily (BID). The primary endpoint was safety and tolerability. Other endpoints were PK, PD, and early efficacy signal by mRECIST.

Results

As of 19 April 2023, 23 pts (median age, 56.0) were enrolled; 60.9% were male and 78.3% had ECOG PS 1. 78.3% received at least 4 lines of prior TKIs. The most frequent treatment-related adverse events (TRAEs) were CPK increased (95.7%), AST increased (87.0%), face oedema (82.6%), periorbital oedema (82.6%), WBC decreased (78.3%), anaemia (73.9%), neutrophil count decreased (69.6%), amylase increased (65.2%), platelet count decreased (47.8%), lipase increased (43.5%), ALT increased (34.8%), fatigue (34.8%) and oedema peripheral (34.8%). 2 pts from 40 mg BID DL (Grade 3 fatigue, Grade 3 face oedema) and 1 pt from 30mg BID DL (Grade 3 febrile neutropenia, Grade 3 rash maculo-papular) experienced DLTs. TRAE (face oedema) leading to permanent discontinuation in 1 patient at 40mg BID. 3 of the 19 evaluable pts had confirmed and 2 pts had unconfirmed RECIST partial responses (PRs). The confirmed ORR was 15.8% (3/19), disease control rate (DCR: PR + stable disease [SD]) was 78.9% (15/19). The increase of drug exposure was approximately dose proportional at steady state.

Conclusions

NB003 has a manageable toxicity profile and promising clinical activity in heavily pretreated pts with advanced GIST harboring a broad spectrum of acquired imatinib-resistant mutations. The 20mg and 30mg BID doses are selected for further investigation in the phase I RP2D confirmation cohort.

Clinical trial identification

NCT04936178.

Editorial acknowledgement

Legal entity responsible for the study

Ningbo Newbay Technology Development Co., Ltd.

Funding

Ningbo Newbay Technology Development Co., Ltd.

Disclosure

K. Hu, L. Zhang, Y. Xu: Financial Interests, Institutional, Member: Ningbo Newbay Technology Development Co. Ltd. All other authors have declared no conflicts of interest.