A Phase 1, Multi-Center, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Evidence of Antitumor Activity of FHND5071 as a Single Agent in Adult Patients With Advanced Solid Tumors
This is a Phase 1, first-in-human, open-label dose-escalation study to determine the MTD and/or recommended Phase 2 dose (RP2D) and assess the DLT of FHND5071. The safety, tolerability, and PK of FHND5071 will be assessed in adult patients with advanced solid tumors. The total number of evaluable subjects in the study will depend upon the number of dose-escalations necessary. It is estimated that approximately 24 evaluable subjects will be enrolled in the dose-escalation part of this study. This multicenter study will be conducted in the United States. Dose-escalation of FHND5071 will follow two sequential parts: a modified accelerated titration design in single subject cohorts with a starting dose level of 40 mg, where the FHND5071 dose would be doubled in each dose cohort until the subject in a current cohort experience a Grade ≥2 adverse event that is at least possibly related to FHND5071 in the opinion of the Investigator and the Medical Monitor; a modified 3+3 escalation design in cohort of 3-6 subjects, where the FHND5071 dose would be escalated in ≤100% increments determined by the Safety Review Committee (SRC) until 2 of 3 or 2 of 6 subjects experience a DLT. In both parts of dose escalation, FHND5071 will be administered orally once daily (QD) in 28-day treatment cycles. Escalation cohorts may explore alternative doses or different schedules, if deemed appropriate by the Safety Review Committee.
2023-08-02·European journal of drug metabolism and pharmacokinetics
Preclinical Pharmacokinetics and in vitro Metabolism of FHND5071, a Novel Selective RET Kinase Inhibitor.
作者: Yiran Han ; Tiantian Wen ; Jia Wang ; Jinmiao Shi ; Yongqiang Zhu
BACKGROUND AND OBJECTIVES:
Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that plays a crucial role in tumorigenesis. FHND5071, a potent and selective RET kinase inhibitor, could exert antitumor effects by inhibiting RET autophosphorylation. The present work aims to profile the pharmacokinetics of FHND5071 in in vivo and in vitro experiments as a ground work for further clinical research.
The absorption, distribution, metabolism, and excretion properties of FHND5071 were examined, along with metabolite production and cytochrome P450 (CYP) phenotyping assay. Additionally, plasma protein binding and pharmacokinetics in mice were investigated.
Microsomal stability assay corroborated moderate to high clearance of FHND5071, and the use of UPLC-Q-TOF-MS identified a total of six metabolites and suggested a possible metabolic pathway involving oxidation, demethylation, and N-dealkylation. Primary contributors to the CYP-mediated metabolism of FHND5071 were found to be CYP2C8 and CYP3A4, and FHND5071 displayed low permeability and acted as a substrate for the P-glycoprotein (P-gp). FHND5071 had a moderate to high binding in plasma and exhibited a moderate absorption degree (absolute bioavailability > 60%) The distribution of FHND5071 in mouse tissues was rapid (mostly peaking at 1-4 h) and wide (detectable in almost all tissues and organs), with the highest exposure in the spleen. A small fraction of FHND5071 was excreted via the urine and feces, and a presumed metabolic pathway involving 20 metabolites in mice is proposed.
Pharmacokinetic characteristics of FHND5071 were systemically profiled, which may lay the foundation for further clinical development as a drug candidate.