First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors DOI Creative Commons
Sarina A. Piha‐Paul, Binghe Xu,

Ecaterina E. Dumbrava

et al.

The Oncologist, Journal Year: 2024, Volume and Issue: 29(4), P. e514 - e525

Published: Jan. 31, 2024

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 receptors, Aurora A/B, in patients with advanced solid tumors. Patients Methods received orally daily 28-day cycles. Dose escalation was guided by Bayesian modeling using overdose control. The primary objective to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended for expansion (DRDE). Secondary objectives included pharmacokinetics efficacy. Results Forty-eight were enrolled (dose escalation, n = 40; expansion, 8). MTD not reached; DRDE 12 mg daily. DLTs palmar-plantar erythrodysesthesia syndrome (8 mg, 1) hypertension (15 2). most common treatment-related adverse event (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; 7) or stable disease (SD) ≥ 24 weeks (n 6), including 4/11 (36.4%) FGFR2 mutations/fusions cholangiocarcinoma (PR 3; SD 1), 3/3 (100.0%) hormone receptor (HR)-positive/HER2-negative breast cancer 2; 2/5 (40.0%) triple-negative (TNBC; PR 1; 1/1 castrate-resistant prostate (CRPC; PR). Four (33.3%; HR-positive/HER2-negative cancer, TNBC, cholangiocarcinoma) treated at had PRs. Tinengotinib’s half-life 28-34 hours. Conclusions Tinengotinib well favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative (including TNBC), CRPC. Continued evaluation is warranted II trials.

Language: Английский

Clinical and translational relevance of intratumor heterogeneity DOI Creative Commons
Marie-Anne Goyette, Marla Lipsyc-Sharf, Kornélia Polyák

et al.

Trends in cancer, Journal Year: 2023, Volume and Issue: 9(9), P. 726 - 737

Published: May 27, 2023

Language: Английский

Citations

25
Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies DOI Creative Commons

Tongchen He,

Lanbo Xiao, Yuanyuan Qiao

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(8), P. 1336 - 1351.e9

Published: July 18, 2024

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of tuft cell lineage and cell-like small lung cancer (SCLC). Here, we identify a specific dependence POU2F3 molecular subtype SCLC (SCLC-P) on activity mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment SCLC-P cells with proteolysis targeting chimera (PROTAC) degrader mSWI/SNF ATPases evicts its coactivators from attenuates downstream signaling. B malignancies which are dependent POU2F1/2 cofactor, POU2AF1, also sensitive to ATPase degraders, treatment leading eviction POU2AF1 IRF4 decreased signaling in multiple myeloma cells. An orally bioavailable significantly inhibits tumor growth preclinical models without signs toxicity. This study suggests that POU2F-POU2AF-driven have an intrinsic complex, representing therapeutic vulnerability.

Language: Английский

Citations

14
Cancer cell states: Lessons from ten years of single-cell RNA-sequencing of human tumors DOI
Itay Tirosh, Mario L. Suvà

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(9), P. 1497 - 1506

Published: Aug. 29, 2024

Language: Английский

Citations

14
Genetically-engineered mouse models of small cell lung cancer: the next generation DOI
Matthew G. Oser, David MacPherson, Trudy G. Oliver

et al.

Oncogene, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 8, 2024

Language: Английский

Citations

13
First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors DOI Creative Commons
Sarina A. Piha‐Paul, Binghe Xu,

Ecaterina E. Dumbrava

et al.

The Oncologist, Journal Year: 2024, Volume and Issue: 29(4), P. e514 - e525

Published: Jan. 31, 2024

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 receptors, Aurora A/B, in patients with advanced solid tumors. Patients Methods received orally daily 28-day cycles. Dose escalation was guided by Bayesian modeling using overdose control. The primary objective to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended for expansion (DRDE). Secondary objectives included pharmacokinetics efficacy. Results Forty-eight were enrolled (dose escalation, n = 40; expansion, 8). MTD not reached; DRDE 12 mg daily. DLTs palmar-plantar erythrodysesthesia syndrome (8 mg, 1) hypertension (15 2). most common treatment-related adverse event (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; 7) or stable disease (SD) ≥ 24 weeks (n 6), including 4/11 (36.4%) FGFR2 mutations/fusions cholangiocarcinoma (PR 3; SD 1), 3/3 (100.0%) hormone receptor (HR)-positive/HER2-negative breast cancer 2; 2/5 (40.0%) triple-negative (TNBC; PR 1; 1/1 castrate-resistant prostate (CRPC; PR). Four (33.3%; HR-positive/HER2-negative cancer, TNBC, cholangiocarcinoma) treated at had PRs. Tinengotinib’s half-life 28-34 hours. Conclusions Tinengotinib well favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative (including TNBC), CRPC. Continued evaluation is warranted II trials.

Language: Английский

Citations

13