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

• Published in: Cancer chemotherapy and pharmacology 2021-05, Vol.87 (5), p.689-700
• Main Authors: Li, Chao, Hart, Lowell, Owonikoko, Taofeek K., Aljumaily, Raid, Rocha Lima, Caio Max, Conkling, Paul R., Webb, Roy Timothy, Jotte, Robert M., Schuster, Steven, Edenfield, William J., Smith, Deborah A., Sale, Mark, Roberts, Patrick J., Malik, Rajesh K., Sorrentino, Jessica A.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Bone marrow; Cancer Research; Cell cycle; Cells (biology); Chemotherapy; Clinical trials; Clinical Trials as Topic; Cyclin-dependent kinase 4; Exposure; Female; G1 phase; Hematopoietic stem cells; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Middle Aged; NCT; NCT02243150; NCT02499770; NCT02514447; Neoplasm Staging; Oncology; Original; Original Article; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Progenitor cells; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Pyrroles - administration & dosage; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Safety; Small cell lung carcinoma; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - pathology; Toxicity; Young Adult
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-021-04239-9

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/m 2 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/m 2 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/m 2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m 2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m 2 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/m 2 as the RP2D for trilaciclib. ClinicalTrials.gov Identifiers NCT02243150; NCT02499770; NCT02514447.