Abstract CT228: Formulation switch and pharmacokinetics/pharmacodynamics of Debio 1347 (CH5183284), a novel FGFR inhibitor, in a first-in-human dose escalation trial in solid tumors patients
Authors: Nicolas-Metral Valerie , Vaslin Anne , Supko Jeffrey G. , Nakai Kiyohiko , Ishii Nobuya , Menetrey Annick , Roubaudi-Fraschini Marie-Claude , Marfurt Judith , Chabaud Sebastien , Layer Andreas , Purcea Daniela , Douchain Jerome , Zanna Claudio 
Published: August 2015

Abstract
Background: Deregulated fibroblast growth factor receptor (FGFR) signaling is associated with tumorigenesis. The oral selective FGFR 1, 2, 3 inhibitor Debio 1347, a Biopharmaceutical Classification System Class II drug, is currently investigated in a phase I trial in selected patients harboring FGFR genetic alterations (NCT01948297). A formulation switch from capsules to tablets was investigated in the course of the dose escalation part of the trial.
Methods: Comparative in vitro dissolution tests and PK data after single dose (20 mg) in Cynomolgus monkeys were generated with capsules and tablets to evaluate the suitability of the new tablet formulation prior to human use. The first-in-human, phase I dose-escalation multiple tumor type “basket” study enrolled patients with advanced solid malignancies harboring defined activating alterations of FGFR 1, 2, or 3. Patients received Debio 1347 orally once daily and were assessed for dose-limiting toxicities (DLT) during the first 4 weeks. With a starting dose level of 10 mg the study followed a 3+3 algorithm with dose-escalation on a modified Fibonacci sequence. Capsules of 10- and 20-mg strength were administered in patients up to the 3rd dose level. At the 4th dose-level, the pharmacokinetic (PK) profile and intra-patient relative oral bioavailability of the new tablet formulation versus the original capsule formulation were determined in a two-period, 7-day washout, cross-over design after single dose in standardized food intake conditions. Debio 1347 plasma levels were measured using a validated LC-MS/MS assay. The pharmacodynamic (PD) profile of Debio 1347 was also assessed by measuring plasma levels of several biomarkers using standardized assays. A comparison of the PK and PD of the two dosage forms and their tolerability was performed prior to selection of the dosage form for pursuing the dose escalation.
Results: Adequate in vitro dissolution profiles were observed for both capsules and tablets. In addition, oral bioavailability of 20-mg tablets was comparable to that of 10- and 20-mg capsules in monkeys. In a majority of solid tumor patients administered with 40 mg of Debio 1347, intra-patient relative oral bioavailability of the tablet versus capsule was &gt; 80%. In addition, PD and safety profiles after 4-week once daily dosing with tablets were comparable to that of capsules.
Conclusion: A formulation switch from capsules (only 10 and 20 mg capsules available) to tablets (20, 30, 50, and 100 mg tablets) of the FGFR inhibitor Debio 1347 was successfully implemented in the course of the first-in-human trial to facilitate dose escalation and improve treatment compliance at high doses by reducing the number of units to be swallowed by solid tumor patients.
Citation Format: Valerie Nicolas-Metral, Anne Vaslin, Jeffrey G. Supko, Kiyohiko Nakai, Nobuya Ishii, Annick Menetrey, Marie-Claude Roubaudi-Fraschini, Judith Marfurt, Sebastien Chabaud, Andreas Layer, Daniela Purcea, Jerome Douchain, Claudio Zanna. Formulation switch and pharmacokinetics/pharmacodynamics of Debio 1347 (CH5183284), a novel FGFR inhibitor, in a first-in-human dose escalation trial in solid tumors patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT228. doi:10.1158/1538-7445.AM2015-CT228