Dataset Information

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

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.

SUBMITTER: Piha-Paul SA

PROVIDER: S-EPMC10994248 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Piha-Paul Sarina A SA Xu Binghe B Dumbrava Ecaterina E EE Fu Siqing S Karp Daniel D DD Meric-Bernstam Funda F Hong David S DS Rodon Jordi A JA Tsimberidou Apostolia M AM Raghav Kanwal K Ajani Jaffer A JA Conley Anthony P AP Mott Frank F Fan Ying Y Fan Jean J Peng Peng P Wang Hui H Ni Shumao S Sun Caixia C Qiang Xiaoyan X Levin Wendy J WJ Ngo Brenda B Ru Qinhua Cindy QC Wu Frank F Javle Milind M MM

The oncologist 20240401 4

<h4>Purpose</h4>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.<h4>Patients and methods</h4>Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using es ...[more]

PMID: 38297981

Similar Datasets

Project description:BackgroundThe mouse double minute 2 homolog (MDM2) oncogene exerts oncogenic activities in many cancers and represents a potential therapeutic target. This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, in patients with advanced solid tumors.Patients and methodsPatients with histologically confirmed advanced solid tumors who had progressed to standard treatment or lacked effective therapies were recruited. Alrizomadlin was administered once daily every other day for 21 days of a 28-day cycle until disease progression or intolerable toxicity.ResultsA total of 21 patients were enrolled and treated with alrizomadlin; 57.1% were male and the median age was 47 (25-60) years. The maximum tolerated dose of alrizomadlin was 150 mg and the recommended phase II dose was 100 mg. One patient in the 200-mg cohort experienced dose-limiting toxicity of thrombocytopenia and febrile neutropenia. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (33.3%), lymphocytopenia (33.3%), neutropenia (23.8%), and anemia (23.8%). Alrizomadlin demonstrated approximately linear pharmacokinetics (dose range 100-200 mg) and was associated with increased plasma macrophage inhibitory cytokine-1, indicative of p53 pathway activation. Of the 20 assessable patients, 2 [10%, 95% confidence interval (CI) 1.2% to 31.7%] patients achieved partial response and 10 (50%, 95% CI 27.2% to 72.8%) showed stable disease. The median progression-free survival was 6.1 (95% CI 1.7-10.4) months, which was significantly longer in patients with wild-type versus mutant TP53 (7.9 versus 2.2 months, respectively; P < 0.001). Among patients with MDM2 amplification and wild-type TP53, the overall response rate was 25% (2/8) and the disease control rate was 100% (8/8).ConclusionsAlrizomadlin had an acceptable safety profile and demonstrated promising antitumor activity in MDM2-amplified and TP53 wild-type tumors. This study supports further exploration of alrizomadlin with recommended doses of 100 mg q.o.d. in 21 days on and 7 days off regimen.

Dataset Information

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

Purpose

Patients and methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets