This study aimed to define the clinically relevant supratherapeutic dose of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate potential effects of therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. This was a two‐part phase I study (http://anzctr.org.au ACTRN12618001036202). Part A was a randomized, open‐label, three‐period, single‐dose crossover study (n = 12) with rilzabrutinib 100 mg ± ritonavir 100 mg or rilzabrutinib 1200 mg. Part B was a randomized, double‐blind, placebo‐controlled, four‐way, single‐dose crossover study (n = 39) with matched placebo, rilzabrutinib 400 mg ± ritonavir 100 mg, or moxifloxacin (positive control). Primary objectives: part A – pharmacokinetics (PK) of rilzabrutinib ± ritonavir, safety, and optimal dose for Part B; Part B – effect of rilzabrutinib therapeutic and supratherapeutic concentration on electrocardiogram (ECG) parameters. ECGs and PK samples were serially recorded before and post‐dose. In part A, rilzabrutinib 100 mg + ritonavir led to 17‐fold area under the concentration–time curve (AUC0–∞) and 7‐fold maximum plasma concentration (Cmax) increases over rilzabrutinib alone. Rilzabrutinib 1200 mg was discontinued due to mild‐to‐moderate gastrointestinal intolerance. In Part B, rilzabrutinib 400 mg + ritonavir increased rilzabrutinib mean AUC0–∞ from 454 to 3800 ng h/mL and Cmax from 144 to 712 ng/mL. The concentration–QTc relationship was slightly negative, shallow (−0.01 ms/ng/mL [90% CI −0.016 to −0.001]), and an effect >10 ms on QTcF could be excluded within the observed range of plasma concentrations, up to 2500 ng/mL. Safety was similar to other studies of rilzabrutinib. In conclusion, rilzabrutinib, even at supratherapeutic doses, had no clinically relevant effects on ECG parameters, including the QTc interval.
This single-center, open-label, non-randomized, two-part, phase I study was conducted (1) to evaluate the absolute oral bioavailability of rilzabrutinib 400 mg tablet following an i.v. microtracer dose of ~100 μg [14C]-rilzabrutinib (~1 μCi) and single oral dose of 400 mg rilzabrutinib tablet (part 1), and (2) to characterize the absorption, metabolism, and excretion (AME) of 14C-radiolabeled rilzabrutinib following single oral dose (300 mg) of [14C]-rilzabrutinib (~1000 μCi; administered as a liquid) in healthy male participants (part 2). A total of 18 subjects were enrolled (n = 8 in part 1; n = 10 in part 2). The absolute bioavailability of 400 mg rilzabrutinib oral tablet was low (<5%). In part 1, rilzabrutinib was absorbed rapidly after single oral dose of rilzabrutinib 400 mg tablet with a median (range) time to maximum concentration (T max ) value of 2.03 h (1.83-2.50 h). The geometric mean (coefficient of variation) terminal half-life following the oral dose and i.v. microtracer dose of ~100 μg [14C]-rilzabrutinib, were 3.20 (51.0%) and 1.78 (37.6%) h, respectively. In part 2, rilzabrutinib was also absorbed rapidly following single oral dose of 300 mg [14C]-rilzabrutinib solution with a median (range) T max value of 1.00 h (1.00-2.00 h). The majority of total radioactivity was in the feces for both non-bile collection subjects (92.9%) and bile collection subjects (87.6%), and ~5% of radioactivity was recovered in urine after oral administration. Urinary excretion of unchanged rilzabrutinib was low (3.02%). The results of this study advance the understanding of the absolute bioavailability and AME of rilzabrutinib and can help inform its further investigation. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Rilzabrutinib is a potent, oral, and reversible covalent Bruton's tyrosine kinase inhibitor being developed to treat autoimmune diseases. Rilzabrutinib is currentlyThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Background: FGFR inhibition is a promising and clinically proven therapeutic approach in a number of solid tumors where genetic alterations of FGFR drive oncogenesis. PRN1371 is a highly selective oral, irreversible inhibitor of FGFR1-4 that exhibits high potency in cancer cell lines harboring FGFR alterations, including mutations and fusions. Methods: Part A of this phase 1 open-label, multicenter clinical trial explored ascending doses of PRN1371 in adult patients with advanced solid tumors who had received at least one prior treatment for recurrent, metastatic, and/or locally advanced disease, and for whom no standard therapy options were anticipated to result in a durable remission. The primary objectives were to investigate the safety and tolerability and determine the maximum tolerated dose (MTD). Secondary objectives included determination of the pharmacokinetic (PK) profile. The trial employed a “3 + 3” design, where cohorts of three patients are studied at each dose level until additional patients need to be added to better assess safety. PRN1371 was dosed once or twice daily in continuous, 28-day cycles until disease progression. Elevated serum phosphorus, a known effect of systemic FGFR inhibition, was managed with oral phosphate-binding medications and a low phosphate diet, with dose interruptions and use of acetazolamide if certain thresholds were exceeded. Results: In part A, PRN1371 was administered to 36 patients in cohorts at doses of 15mg, 20mg, 25mg, and 35mg QD as well as BID doses of 15mg and 25mg. The drug has been generally well tolerated. The most common side effect observed was hyperphosphatemia, which was generally managed by administration of phosphate binders, and there were no treatment-related adverse events leading to study drug discontinuation. Five of 36 patients reported treatment-related serious adverse events (SAEs). PRN1371 was well absorbed, exhibited moderate PK variability with minimal accumulation, and was approximately dose proportional between 15 and 35mg doses. Exposure of parent drug in urine exceeded the cellular IC90 at all dose levels, which may be particularly relevant for localized bladder cancer. Part B of the study has been initiated, which will enroll patients with metastatic urothelial cell carcinoma (mUC) with FGFR1, 2, 3, or 4 genetic alterations. Citation Format: Sarina A. Piha-Paul, Cinta Hierro, Ignacio Matos, Valentina Boni, Noah Hahn, Rhonda Bitting, Todd Bauer, Aggarwal Rahul, Funda Meric-Bernstam, Steven Gourlay, Timothy D. Owens, Ken Brameld, Ann Neale, Richard Schwartz, Steve Murray, Sibel Ucpinar, Peter Foote, Eleni Venetsanakos, Josep Tabernero. A phase 1, multicenter, dose-escalation study of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors including metastatic urothelial carcinoma (mUC) [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A19.
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