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Published on: September 18, 2013
First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients
Sarina A Piha-Paul1, Binghe Xu2, Ecaterina E Dumbrava1
1Department of Investigational Cancer Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
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.
Insights
Tinengotinib, a multi-kinase inhibitor, showed good tolerability and promising efficacy in patients with advanced solid tumors, particularly in cholangiocarcinoma and breast cancer.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Tinengotinib (TT-00420) is a novel multi-kinase inhibitor targeting fibroblast growth factor receptors (FGFRs), Janus kinase (JAK), vascular endothelial growth factor receptors (VEGFRs), and Aurora kinases.
- Investigating novel targeted therapies is crucial for improving outcomes in patients with advanced solid tumors.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and preliminary efficacy of tinengotinib in a first-in-human phase I dose-escalation study.
- To determine the maximum tolerated dose (MTD) and recommended dose for expansion (DRDE) of tinengotinib.
Main Methods:
- A phase I, open-label, dose-escalation study using Bayesian modeling with overdose control.
- Patients received daily oral tinengotinib in 28-day cycles.
- Primary endpoints included dose-limiting toxicities (DLTs), MTD, and DRDE; secondary endpoints were pharmacokinetics and efficacy.
Main Results:
- Forty-eight patients were enrolled. The DRDE was determined to be 12 mg daily; MTD was not reached.
- The most common treatment-related adverse event was hypertension (50.0%). Dose-limiting toxicities included palmar-plantar erythrodysesthesia syndrome and hypertension.
- In 43 response-evaluable patients, 30.2% achieved partial response or stable disease ≥24 weeks, notably in cholangiocarcinoma, hormone receptor-positive/HER2-negative breast cancer, triple-negative breast cancer, and castrate-resistant prostate cancer.
Conclusions:
- Tinengotinib demonstrated a favorable safety profile and pharmacokinetic characteristics.
- Preliminary efficacy suggests potential clinical benefit in specific advanced solid tumors, including FGFR inhibitor-refractory cholangiocarcinoma and HER2-negative breast cancer.
- Further investigation in phase II trials is warranted to confirm these findings.
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