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.

摘要: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses preclinical clinical data informed selection recommended Phase II dose (RP2D) used trilaciclib trials extensive-stage small lung cancer (ES-SCLC). A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed guided an optimal for bone marrow arrest first-in-human I study (G1T28-1-01). PK, PD, safety, efficacy G1T28-1-01 two Ib/IIa studies (G1T28-02/-03) ES-SCLC were analyzed support RP2D selection. Model simulation based on predicted a ≥ 192 mg/m2 would induce 40–50% decrease total proliferation humans almost 100% cycling HSPCs. Consistent with this model, analysis aspirates healthy volunteers after 192 mg/m2 administration demonstrated HSPCs 40% proliferation, minimal toxicity. G1T28-02/-03 reported similar PK parameters 200 mg/m2 but slightly lower exposures than expected compared volunteers; consequently, 240 280 mg/m2 doses also tested match volunteer exposures. Based relevant safety data, 240 mg/m2 was selected as RP2D, which favored by myelopreservation endpoints G1T28-02/-03. Integrated PK/PD, trilaciclib. NCT02243150; NCT02499770; NCT02514447.