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.
CDK4/6 inhibitor
Chemotherapy-induced myelosuppression
Myelopreservation
Pharmacodynamics
Pharmacokinetics
Trilaciclib
Journal
Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
13
11
2020
accepted:
28
01
2021
pubmed:
18
2
2021
medline:
28
8
2021
entrez:
17
2
2021
Statut:
ppublish
Résumé
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). 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. Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m Integrated PK/PD, safety, and efficacy data support 240 mg/m NCT02243150; NCT02499770; NCT02514447.
Identifiants
pubmed: 33595690
doi: 10.1007/s00280-021-04239-9
pii: 10.1007/s00280-021-04239-9
pmc: PMC8026479
doi:
Substances chimiques
Pyrimidines
0
Pyrroles
0
trilaciclib
U6072DO9XG
Banques de données
ClinicalTrials.gov
['NCT02243150', 'NCT02499770', 'NCT02514447']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
689-700Références
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