First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors

Authors

Sarina A Piha-Paul
Binghe Xu
Ecaterina E Dumbrava
Siqing Fu
Daniel D Karp
Funda Meric-Bernstam
David S Hong
Jordi A Rodon
Apostolia M Tsimberidou
Kanwal Raghav
Jaffer A Ajani
Anthony P Conley
Frank Mott
Ying Fan
Jean Fan
Peng Peng
Hui Wang
Shumao Ni
Caixia Sun
Xiaoyan Qiang
Wendy J Levin
Brenda Ngo
Qinhua Cindy Ru
Frank Wu
Milind M Javle

Publication Date

4-4-2024

Journal

Oncologist

Abstract

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors.

PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy.

RESULTS: Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours.

CONCLUSIONS: Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.

Keywords

Male, Humans, Triple Negative Breast Neoplasms, Bayes Theorem, Prostatic Neoplasms, Castration-Resistant, Vascular Endothelial Growth Factor A, Neoplasms, Antineoplastic Agents, Cholangiocarcinoma, Hypertension, Maximum Tolerated Dose, solid tumors, kinase inhibitor, phase I, tinengotinib, clinical study

Comments

Supplementary Material

PMID: 38297981

DOI

10.1093/oncolo/oyad338

PMID

38297981

PMCID

PMC10994248

PubMedCentral® Posted Date

January 2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes