G1 Therapeutics, Inc., Research Triangle Park, NC, USA.
Fosun Pharma USA, Inc., Lexington, MA, USA.
Cancer Chemother Pharmacol. 2021 May;87(5):689-700. doi: 10.1007/s00280-021-04239-9. Epub 2021 Feb 17.
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 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 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 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03.
Integrated PK/PD, safety, and efficacy data support 240 mg/m as the RP2D for trilaciclib. CLINICALTRIALS.
NCT02243150; NCT02499770; NCT02514447.
Trilaciclib 是一种首创的 CDK4/6 抑制剂，可将造血干细胞和祖细胞 (HSPC) 暂时阻滞在细胞周期的 G1 期，以防止它们受到化疗引起的损伤（骨髓保护）。我们报告了临床前和临床数据的综合分析，这些数据为 Trilaciclib 在广泛期小细胞肺癌（ES-SCLC）中的临床试验中选择推荐的 II 期剂量（RP2D）提供了信息。
从临床前数据开发的半机制药代动力学/药效学 (PK/PD) 模型指导了首次人体 I 期研究（G1T28-1-01）中 G1 骨髓阻滞的最佳剂量选择。对 G1T28-1-01 和两项 ES-SCLC 中的 Ib/IIa 期研究（G1T28-02/-03）的 PK、PD、安全性和疗效数据进行了分析，以支持 RP2D 的选择。
基于临床前数据的骨髓阻滞模型模拟预测，≥192mg/m 的剂量将在人体内诱导总骨髓增殖减少 40-50%，并使循环 HSPC 几乎完全阻滞在细胞周期 G1 期。与该模型一致，对 Trilaciclib 192mg/m 给药后健康志愿者的骨髓抽吸物进行的分析表明，HSPC 几乎完全阻滞在 G1 期，总骨髓增殖减少 40%，且毒性最小。G1T28-02/-03 报告了与 Trilaciclib 200mg/m 相似的 PK 参数，但与健康志愿者相比，暴露量略低；因此，还测试了 240 和 280mg/m 剂量以匹配健康志愿者的暴露量。基于 PK 和相关安全性数据，选择 240mg/m 作为 RP2D，这也受到 G1T28-02/-03 中骨髓保护终点的青睐。
综合 PK/PD、安全性和疗效数据支持 Trilaciclib 240mg/m 作为 RP2D。临床试验。
NCT02243150；NCT02499770；NCT02514447。
