NB003 / AstraZeneca, Ningbo Tai Kang - LARVOL DELTA

The broad-spectrum KIT inhibitor NB003 and activity in advanced gastrointestinal stromal tumors (GIST): Updated results from a phase 1 study (NCT04936178). (ASCO 2025) - P1 | "It was designed to inhibit a broad spectrum of primary and acquired imatinib-resistant mutations in KIT...For ≥3rd-line pts without prior ripretinib, the cORR was 41.2% (95% CI:29.4, 53.8) and the mPFS was NR (95% CI:9.5, NE)... NB003 demonstrated a manageable safety profile, and showed encouraging clinical benefit in GIST pts, as evidenced by mPFS and cORR, across multiple lines of treatment and a broad spectrum of secondary resistance KIT mutations. The promising data from this phase 1 study supports further testing of NB003 in Phase 3 studies."

Metastases • P1 data • Stroma • Anemia • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hematological Disorders • Infectious Disease • Oncology • Pneumonia • Respiratory Diseases • Sarcoma

Phase 1 study of NB003, a broad-spectrum KIT/PDGFRα inhibitor, in patients with advanced gastrointestinal stromal tumors (GIST). (ASCO 2024) - P1 | "It was designed to inhibit a broad spectrum of primary and acquired imatinib-resistant mutations in KIT/PDGFRα... In heavily pretreated pts with advanced GIST, NB003 demonstrated a manageable safety profile with encouraging antitumor activity across a broad spectrum of secondary resistance mutations in KIT. The RP2D was defined as 20mg BID based on overall safety and efficacy. Expansion cohorts in different lines of GIST are currently under enrollment."

Clinical • Metastases • P1 data • Stroma • Anemia • Fatigue • Febrile Neutropenia • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Hematological Disorders • Neutropenia • Oncology • Sarcoma • PDGFRA

A first-in-human phase I trial of NB003, a potent and selective KIT/PDGFRa inhibitor, in patients with advanced gastrointestinal stromal tumors (GIST) (ESMO 2023) - P1 | "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 • Metastases • P1 data • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • KIT • PDGFRA

A Study of NB003 in Patients With Advanced Malignancies (clinicaltrials.gov) - P1 | N=258 | Recruiting | Sponsor: Ningbo Newbay Technology Development Co., Ltd | N=36 ➔ 258 | Trial completion date: Jul 2023 ➔ Dec 2025 | Trial primary completion date: Apr 2023 ➔ Jul 2025

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Characterizing the functional significance of PDGFRAK385I and PDGFRAK385L extracellular domain mutations in the newly defined myxoid glioneuronal tumor (AACR 2023) - "We found that the PDGFRAK385I and PDGFRAK385L mutants were sensitive to inhibitors axitinib, AZD-3229, and avapritinib at therapeutically relevant concentrations. Further, these mutants showed resistance to imatinib, nilotinib, and crenolanib underscoring the importance of pharmacogenomic investigation. No appreciable difference in sensitivity or resistance profiles was observed between the two mutants. In summary, our findings indicate that these previously uncharacterized p.K385I/L extracellular domain mutations in PDGFRA are oncogenic and represent a pharmacologically actionable target that could be harnessed to increase therapeutic options in the setting of myxoid glioneuronal tumors."

Brain Cancer • CNS Tumor • Glioma • Oncology • PDGFRA • STAT3

A Study of NB003 in Patients With Advanced Malignancies (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Ningbo Newbay Technology Development Co., Ltd; Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Solid Tumor • PDGFRA

A Study of NB003 in Patients With Advanced Malignancies (clinicaltrials.gov) - P1; N=36; Not yet recruiting; Sponsor: Ningbo Newbay Technology Development Co., Ltd

Clinical • New P1 trial • Oncology • Solid Tumor • PDGFRA

[VIRTUAL] Comprehensive profile of platelet derived growth factor receptor alpha (PDGFRA) mutations in gastrointestinal stromal tumors (AACR-II 2020) - "Gastrointestinal stromal tumors (GIST) most commonly harbor oncogenic mutations in KIT tyrosine kinase, which can be targeted by the tyrosine kinase inhibitor, imatinib...Using in vitro models, we profiled the sensitivity of avapritinib and other novel inhibitors such as crenolanib, ripretinib (DCC-2618), and AZD3229 against many of the observed PDGFRA mutations...We also modeled and characterized novel secondary mutations in PDGFRA seen in drug resistant tumors. From our results, we have curated a comprehensive data set that can be used to inform clinicians about possible treatment options for PDGFRA-mutant GIST, and also provide implications for treatments of other PDGFRA-mutant cancers."

Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • PDGFRA

Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors. (PubMed, Sci Transl Med) - "AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents-imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST."

Journal • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • KDR

"AZD3229 is potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors. @AstraZeneca https://t.co/mlGQsX6ipS" (@Intestinal_Cell)

Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • PDGFRA

The pharmacokinetic-pharmacodynamic (PKPD) relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of GIST. (PubMed, Clin Cancer Res) - "We demonstrate that AZD3229 warrants clinical investigation as a new treatment for GIST patients based on its ability to inhibit both ATP-binding and A-loop mutations of KIT at clinically relevant exposures."

Journal • PK/PD data • Preclinical

Ningbo Tai Kang Medical Technology Co., Ltd announces global licensing agreement with AstraZeneca (Businesswire) - "Ningbo Tai Kang Medical Technology Co. Ltd. announced....that it has entered into a licensing agreement with AstraZeneca. Tai Kang has been granted the exclusive global rights to further develop and commercialize AZD3229, a small molecule KIT inhibitor that is active against primary, secondary and resistant KIT and PDGFRα mutations observed in gastrointestinal stromal tumor (GIST)."

Licensing / partnership

Discovery of N-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (AZD3229), a potent pan-KIT mutant inhibitor for the treatment of gastrointestinal stromal tumors. (PubMed, J Med Chem) - "Selectivity over KDR can be rationalised predominantly by the interaction of water molecules with the protein and ligand in the active site and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST."

Journal

Exploring the pharmacokinetic-pharmacodynamic relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of gastrointestinal stromal tumors (AACR 2019) - "Exploring the in vivo activity and PK-PD relationship in multiple cell-line derived xenograft and PDX models harboring different mutations provides a benchmark from which to anchor human dose predictions that partly reflect the spectrum of responses likely to be seen in GIST patients."

PK/PD data • Preclinical