Evaluation Of Targeted Bone Marrow Arrest By G1t28, A Cdk4/6 Inhibitor In Clinical Development To Reduce Chemotherapy-Induced Myelosuppression.

2529 Background: Myelosuppression is the major dose-limiting toxicity of chemotherapy, which limits dose intensity. G1T28 is a highly potent and selective CDK4/6 inhibitor in development as an IV agent to provide targeted bone marrow chemoprotection in patients with CDK4/6-independent tumors. Hematopoietic stem and progenitor cells (HSPCs) are dependent upon CDK4/6 for proliferation; G1T28 induces a transient G1 cell cycle arrest that renders HSPCs resistant to the cytotoxic effects of chemotherapy. In preclinical models, this results in faster recovery of all blood cell counts following chemotherapy and preservation of long-term hematopoietic function. Methods: To rationally design tolerable and active chemotherapy combination regimens with reduced multi-lineage myelosuppression, the magnitude and duration of G1T28-induced HSPC G1 arrest in human bone marrow was characterized. Data from 3 species (mouse, rat, dog) were used to evaluate dose response relationships for HSPC G1 cell cycle arrest and to construct a cross-species allometrically-scaled PK/PD model. Model simulations and human PK/PD data from a Phase I trial (NCT02243150) were used to predict the biologically effective dose (BED) in humans. In this trial, the BED was assessed by obtaining bone marrow aspirates and evaluating G1 arrest of HSPCs by flow cytometry. Results: Preclinical PK/PD modeling outputs and clinical data predicted the BED in humans to be 192 mg/m2. Specifically, a 15mg/kg dose of G1T28 in dogs produced robust and sustained bone marrow arrest for ~24 hours and had a similar PK exposure to the predicted human BED. A single bone marrow aspirate from 12 subjects following 192 mg/m2 (baseline, n = 5; 24 h post-G1T28, n = 3, or 32 h post-G1T28, n = 4) demonstrated a robust G1 arrest of multiple progenitor subsets at 24 h, with early progenitors persisting in G1 arrest to 32 h. Conclusions: A single IV administration of G1T28 at the BED of 192 mg/m2 produced robust inhibition of HSPCs within the bone marrow for > 24 hours. Based on these results, Phase 1b/2a studies are planned to evaluate the potential of G1T28 in reducing multi-lineage chemotherapy-induced myelosuppression. Clinical trial information: NCT02243150.