Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer

• Type of Material: Article
• Authors: Chao Li, G1 Therapeutics Inc; Lowell Hart, SCRI; Taofeek Owonikoko, Emory University; Raid Aljumaily, University of Oklahoma; Caio Max Rocha Lima, Wake Forest Baptist Medical Center; Paul R. Conkling, Virginia Oncology Associates; Roy Timothy Webb, Genesis Cancer Center; Robert M. Jotte, Rocky Mountain Cancer Centers; Steven Schuster, Poudre Valley Health System; William J. Edenfield, Prisma Health Cancer Institute; Deborah A. Smith, Nuventra Pharma Science; Mark Sale, Nuventra Pharma Science; Patrick J. Roberts, G1 Therapeutics Inc; Rajesh K. Malik, G1 Therapeutics Inc; Jessica A. Sorrentino, G1 Therapeutics Inc
• Language: English
• Date: 2021-02-17
• Publisher: Springer
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s00280-021-04239-9
• Title of Journal or Parent Work: Cancer Chemotherapy and Pharmacology
• Volume: 87
• Issue: 5
• Start Page: 689
• End Page: 700
• Grant/Funding Information: These studies were funded by G1 Therapeutics, Inc.
• Keywords: Pharmacology & Pharmacy; Chemotherapy-induced myelosuppression; Trilaciclib; Pharmacodynamics; 6 inhibitor; CDK4; Pharmacokinetics; Science & Technology; Myelopreservation; Life Sciences & Biomedicine; Oncology
• Research Categories: Health Sciences, Rehabilitation and Therapy; Health Sciences, Oncology; Health Sciences, Pharmacy; Health Sciences, Pharmacology

Abstract

Purpose Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). Methods A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. Results Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40–50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. Conclusion Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib.