RESILIENT part 1: Pharmacokinetics of second-line (2L) liposomal irinotecan in patients with small cell lung cancer (SCLC)

Abstract

Background: RESILIENT (NCT03088813) is a two-part phase 2/3 study of the safety, tolerability and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy. Here we describe the pharmacokinetics (PK) of 2L liposomal irinotecan from RESILIENT part 1. Method(s): Part 1 was an open-label, single-arm study comprising dose-finding and dose-expansion phases. Patients aged >= 18 years, with an ECOG performance status of 0/1, received liposomal irinotecan 70 or 85 mg/m2 free base every 2 weeks. Seven PK samples per patient were scheduled. Plasma concentration data for total irinotecan (tIRI) and SN-38 (active metabolite) were analysed using a population PK model updated for SCLC. PK parameters were estimated with non-linear mixed effects modelling. Assessment of model adequacy was based on the uncertainty of parameter estimates and advanced evaluation methods (e.g. visual predictive check). Interindividual variability was examined using potential covariates including patient demographics and UGT1A1*28 genotype status. Derived PK parameters, Caverage and Cmax, were computed by dose from individually predicted PK profiles. Result(s): As of 2 DEC 2019, 30 patients had received liposomal irinotecan (70 mg/m2, n = 25; 85 mg/m2, n = 5). tIRI PK is described by a two-compartment model with first-order elimination. SN-38 is formed directly by a first-order constant from the central compartment of liposomal irinotecan or following a transit compartment. UGT1A1*28 *7/*7 homozygous status (4/30 patients) was not associated with a significant impact on SN-38 clearance. Model evaluation was satisfactory for both tIRI and SN-38. After 70 and 85 mg/m2 respectively, median (coefficient of variation %) Caverage was 5.1 (48) and 5.5 (9) mug/mL for tIRI, and 1.6 (33) and 2.1 (16) ng/mL for SN-38, and Cmax was 36.1 (15) and 40.7 (14) mug/mL for tIRI and 3.7 (32) and 4.4 (10) ng/mL for SN-38. Conclusion(s): The PK of 2L liposomal irinotecan and SN-38 in patients with SCLC is well described by the population model. Findings suggest SN-38 clearance is not associated with UGT1A1*28 *7/*7 homozygous status. RESILIENT part 2 data will be added to the current dataset to enrich the PK characterization. Clinical trial identification: NCT03088813. Editorial acknowledgement: Dr David Gothard of Oxford PharmaGenesis, Oxford, UK, provided medical writing and editorial support, which was sponsored by Ipsen, in accordance with Good Publication Practice guidelines. Legal entity responsible for the study: Ipsen. Funding(s): Ipsen. Disclosure: S. Ponce: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: AstraZeneca. K. Brendel: Full/Part-time employment: Ipsen. D.R. Spigel: Advisory/Consultancy: Aptitude Health; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy: Dracen Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): EMD Sorono; Advisory/Consultancy: Evelo Biosciences; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: GlaxoSmithKline; Advisory/Consultancy: Iksuda Therapeutics; Advisory/Consultancy: Illumina; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Research grant/Funding (institution): Molecular Templates; Advisory/Consultancy, Research grant/Funding (institution): Nektar Therapeutics; Advisory/Consultancy, Research grant/Funding (inst tution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: PharmaMar; Research grant/Funding (institution): Ipsen; Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Takeda; Advisory/Consultancy: Triptych Health Partners; Advisory/Consultancy: TRM Oncology; Advisory/Consultancy: Williams & Connolly; Travel/Accommodation/Expenses: Amgen; Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi Sankyo; Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Travel/Accommodation/Expenses: Spectrum Pharmaceuticals; Research grant/Funding (institution): Aeglea Bio Therapeutics; Research grant/Funding (institution): Astellas. Y. Chen: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Astra Zeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol Myers-Squibb; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Genentech; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution): Guardant Health; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Honoraria (self), Speaker Bureau/Expert testimony: Merck; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Advisory/Consultancy: Array BioPharma; Advisory/Consultancy: Heron Therapeutics; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Helsinn; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Roche. M. Jove Casulleras: Honoraria (self): Boehringer Ingelheim; Travel/Accommodation/Expenses: Merck Sharp & Dohme; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Takeda. O. Juan-Vidal: Advisory/Consultancy: AbbVie; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Takeda. R. Bernabe Caro: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda. A. Navarro: Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony: Oryzon Genomics. A. Dowlati: Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Incuron; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): Regeneron; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Tesaro. B. Zhang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Ipsen. Y. Moore: Leadership role, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Ipsen. J. Kokhreidze: Full/Part-time employment: Ipsen; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Constellation Pharmaceuticals; Advisory/Consultancy: JKMD Global Medical Solutions; Advisory/Consultancy: Tocagen. A. Pedret-Dunn: Full/Part-time employment: Ipsen. L. Paz-Ares: Leadership role: Altum Sequencing; Leadership role: European Medicines Agency Scient fic Advisory Groups; Leadership role: Genomica S.A.U; Honoraria (self): Advanced Accelerator Applications; Honoraria (self): Amgen; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Blueprint Medicines; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Celegene; Honoraria (self): Incyte; Honoraria (self): Ipsen; Honoraria (self): Lilly; Honoraria (self): Merck Serono; Honoraria (self), Travel/Accommodation/Expenses: Merck Sharp & Dohme; Honoraria (self): Novartis; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): PharmaMar; Honoraria (self), Travel/Accommodation/Expenses: Roche/Genentech; Honoraria (self): Sanofi; Honoraria (self): Servier; Honoraria (self): Sysmex; Travel/Accommodation/Expenses: Takeda. All other authors have declared no conflicts of interest.Copyright © 2020