Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors
Poster Presentations - Proffered Abstracts(2021)
摘要
Background: Elevated expression of PIM kinases in various solid and hematologic malignancies is correlated with increased cell survival and reduced apoptosis, implicating inhibition of PIM kinases as attractive targets for disruptive therapy. TP-3654 is an oral, small molecule, investigational PIM kinase inhibitor with favorable selectivity against PIM-1 over other kinases. TP-3654 is currently being evaluated in a phase 1 first-in-human study in patients (pts) with advance solid tumors (NCT03715504). Methods: Pts with advanced metastatic, progressive, or unresectable solid tumors refractory or intolerant of established therapies were treated with TP-3654. Pts took TP-3645 orally once (QD) or twice (BID) daily in a 28-day dosing cycle until unacceptable toxicity or disease progression. Escalating dose levels of TP-3654 were evaluated using a 3+3 design. The primary objective was to determine maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included establishing the pharmacokinetic (PK) profile of oral TP-3654 and any evidence of antitumor activity. An exploratory objective was to study predictive biomarkers in tumor tissues and mechanism-based pharmacodynamic activity in peripheral blood mononuclear cells (PBMCs). Results: As of 31 May 2021, 22 pts were treated with TP-3654 at 480 mg QD (n=3), 720 mg QD (n=3), 1080 mg QD (n=4), 1440 mg QD (n=3), 720 mg BID (n=3), and 960 mg BID (n=6). Median age of 58 years (range: 20–72), 59% (13/22) pts male, and 86% (19/22) pts received ≥3 lines of prior therapy. Median treatment duration is 2 cycles (range: 0.1–24) and 6 pts received treatment for ≥4 cycles. Two pts remain on active study treatment. No DLT was observed. The most common treatment-emergent adverse events (TEAEs) reported in ≥20% of pts were vomiting, diarrhea, nausea, and abdominal pain. No related myelosuppressive AEs were reported. Fifty percent (11/22) of pts reported 18 Grade ≥3 TEAEs, of which only one (alanine aminotransferase increased) was considered related to TP-3654. No related, serious AEs were reported. Two TEAEs resulted in a fatal outcome (acute kidney injury, completed suicide); neither were related to TP-3654. Best response is stable disease (SD) in 67% (10/15) evaluable pts, SD for ≥ 16 weeks in 5 pts, best reduction of tumor size from baseline is -22%. TP-3654 plasma exposure increased with doses up to 1080 mg QD; the BID regimen at the 720 mg dose achieved greater plasma exposure than the 1440 mg QD dosing regimen. Reduced phosphorylation of PIM-1 downstream signal protein pBAD was observed in isolated PBMCs, predominantly in pts with prolonged clinical benefit. Conclusions: Preliminary data suggest that TP-3654 is tolerated as a monotherapy up to 960 mg BID in pts with heavily pretreated, relapsed, and refractory solid tumors. No DLT was observed and MTD was not reached. PK data indicate that the BID dose regimen achieved better plasma exposure than the QD regimen at higher doses. TP-3654 has shown target-specific inhibition of PIM-1 in pts. Updated data will be presented. Citation Format: Ignacio Garrido-Laguna, Patrick M. Dillon, Sujan Kabir, Jian Mei, Mark L. Wade, Huyuan Yang, Carl Stapinski, Jason M. Foulks, Steven L. Warner, Clifford Whatcott, Claudia Lebedinsky, Siqing Fu. Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P223.
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关键词
pim kinase inhibitor,abstract p223,pharmacokinetic,pharmacodynamic study,first-in-human,dose-escalation
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