Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors

Abstract

NCT01962532.

Population Pharmacokinetics of Total and Free Erdafitinib in Adult Healthy Volunteers and Cancer Patients: Analysis of Phase 1 and Phase 2 Studies

“…The 3 studies conducted in cancer patients were (1) EDI1001 (NCT01703481), a first‐in‐human multiple‐dose study conducted in 4 parts to evaluate the PK, pharmacodynamics, and safety of erdafitinib; identify recommended phase 2 doses; and explore potential clinical activity of these doses; (2) GAC1001 (NCT01962532), a multiple‐dose study to evaluate the safety, PK, pharmacodynamics, and clinical activity of erdafitinib in Asian patients; and (3) BLC2001 (NCT02365597), a multiple‐dose, open‐label study conducted to determine the efficacy and the safety of 2 different dose regimens of erdafitinib in patients with metastatic or surgically unresectable urothelial cancers that harbor selected FGFR genomic aberrations . In the phase 2 study, erdafitinib dose was administered either daily or 7 days on/7 days off in 28‐day cycles, with a pharmacodynamically guided up‐titration after 2 to 4 weeks of erdafitinib treatment.…”

“…Clinical pharmacokinetics (PK) of erdafitinib have been assessed previously in healthy volunteers and in patients with cancer. In the combined single‐/multiple‐ascending‐dose study, the systemic exposure (maximum concentration [C max ] and area under the concentration‐time curve) increased with increasing dose with no consistent deviations from dose proportionality . Apparent terminal half‐life for erdafitinib in cancer patients ranged from 42 to 74 hours.…”

“…In the combined single-/multiple-ascending-dose study, 8 the systemic exposure (maximum concentration [C max ] and area under the concentration-time curve) increased with increasing dose with no consistent deviations from dose proportionality. 9 Apparent terminal halflife for erdafitinib in cancer patients ranged from 42 to 74 hours. Based on total plasma concentration of erdafitinib, the apparent volume of distribution (26 L) and plasma clearance (0.26 L/h) across the doses were relatively low.…”

Recent Advances in the Development of Indazole‐based Anticancer Agents

“…Therefore, identification of potent and selective FGFRs inhibitors is an unmet medical need, although severalF GFR-selective inhibitors have progressed into clinicalt rials, such as NVP-BGJ398, AZD4547, CH5183284, LY2874455, and JNJ-42756493. [29][30][31][32][33] Aw ide range of small molecules bearing an indazole nucleus wered ocumented to have FGFR inhibitory activity. Turner et al described the use of ad enovo-based design approach to identify initial hits andf ound an indazole-based pharmacophore that showed encouraging levels of inhibition toward FGFRs.…”

Grade 3 Hepatotoxicity following Fulvestrant, Palbociclib, and Erdafitinib Therapy in a Patient with ER-Positive/PR-Negative/HER2-Negative Metastatic Breast Cancer: A Case Report

“…There is little existing research on erdafitinib, but so far, the most common adverse events do not include hepatotoxicity [8]. One report details a case of dose-limiting hepatotoxicity occurring on cycle 1 day 15 (C1D15) of therapy.…”