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

Chao Li,Robert M Jotte,Caio Max Rocha Lima,Lowell Hart,Steven Schuster,Roy Timothy Webb,William J Edenfield,Mark Sale,Taofeek K Owonikoko,Rajesh K Malik,Patrick J Roberts,Paul R Conkling,Raid Aljumaily,Jessica A Sorrentino,Deborah A Smith

doi:10.1007/s00280-021-04239-9

Abstract

PurposeTrilaciclib 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).MethodsA 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.ResultsModel 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.ConclusionIntegrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib.ClinicalTrials.gov IdentifiersNCT02243150; NCT02499770; NCT02514447.

Highlights

Damage to hematopoietic stem and progenitor cells (HSPCs) by cytotoxic chemotherapy causes multilineage myelosuppression, which can manifest as neutropenia, anemia, thrombocytopenia, and/or lymphopenia [1,2,3]
Data obtained using murine hematopoietic stem cell (HSC) indicated that a single dose of trilaciclib induced a dose-dependent, reversible cell cycle arrest of all hematopoietic cell types, and that concentrations resulting in the maximum (~ 50%) decrease from baseline in the relative percentage of total bone marrow cycling cells were effective in decreasing the percentage of cycling HSPCs so that almost 100% of HSPCs were arrested in the G1 phase [11]
Since hematopoietic development is well-conserved across species, trilaciclib’s cyclin-dependent kinase 4/6 (CDK4/6) inhibition in humans was expected to be similar to that in mice and dogs, and mouse and dog data infer that a dose level resulting in an approximate 50% decrease in total bone marrow cycling cells would result in an almost 100% decrease in the percentage of cycling HSPCs, representing a therapeutically effective dose

Summary

Introduction

Damage to hematopoietic stem and progenitor cells (HSPCs) by cytotoxic chemotherapy causes multilineage myelosuppression, which can manifest as neutropenia, anemia, thrombocytopenia, and/or lymphopenia [1,2,3]. Trilaciclib is a first-in-class, highly potent, and selective intravenously administered cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, developed to preserve multiple hematopoietic cell lineages from chemotherapy-induced damage. When administered prior to chemotherapy, trilaciclib transiently arrests CDK4/6-dependent proliferating cells in the G1 phase of the cell cycle to prevent CIM [5, 10, 11]. Administration of trilaciclib prior to chemotherapy was shown to protect HSPCs from CIM, resulting in faster recovery of all blood cell lineages and mitigation of bone marrow exhaustion [10, 11]. In a Phase I first-in-human trial (Study G1T28-1-01), trilaciclib transiently inhibited bone marrow HSPC proliferation in healthy human volunteers with minimal toxicity; all moderate adverse events (AEs) spontaneously resolved within 24 h, and no AEs of severe or life-threatening intensity were reported [11, 12]

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