First-in-human Phase 1 safety, PK, and PD study of the CDK4/6 inhibitor G1T28.

Article Details

Citation

Tiessen RG, Roberts PJ, Sorrentino JA, White HS, Makhuli KM, Bisi JE, Strum JC, van Hoogdalem E, Malik RK

First-in-human Phase 1 safety, PK, and PD study of the CDK4/6 inhibitor G1T28.

Journal of Clinical Oncology. 2015 May 20;33(15):2527-2527.

PubMed ID
Not Available
Abstract

Background: G1T28 is a highly potent and selective CDK4/6 inhibitor being developed as an IV agent for targeted bone marrow chemoprotection and as an oral antineoplastic agent. The CDK4/6 pathway is critical in regulating cell proliferation of certain tumors. In addition, hematopoietic stem and progenitor cells (HSPCs) are dependent upon CDK4/6 for proliferation. Transient G1T28-induced G1 cell cycle arrest of HSPCs renders them resistant to the cytotoxic effects of chemotherapy. Thus, G1T28 could be used for chemoprotection (reduction of chemotherapy-induced myelosuppression) in patients with CDK4/6-independent tumors, or as an antineoplastic agent in patients with CDK4/6-dependent tumors. Methods: The objective of this study was to assess the safety and tolerability of G1T28, as well as to characterize PK and PD (NCT02243150). Part 1 was a double blind, placebo-controlled, single escalating dose study in healthy volunteers of both sexes, where subjects were randomized (3:1) to receive G1T28 or placebo as a single 30-minute IV infusion. In Part 2, 8 subjects will receive single escalating oral doses of G1T28 in three dosing periods. PD assessments included evaluation of ex vivo stimulation of lymphocytes and bone marrow cell cycle analysis. Results: 45 subjects have enrolled in the study to date. In Part 1, G1T28 was administered at doses of 6, 12, 24, 48, 96 and 192 mg/m2. G1T28 was well tolerated, with no dose limiting toxicities or serious adverse events reported. In Part 1, G1T28 exposure (Cmax and AUC) increased proportionally with dose, while clearance was relatively constant. G1T28 at 96 and 192 mg/m2 demonstrated a robust pharmacodynamic effect with a dose-dependent decrease in phytohemagglutinin (PHA)-stimulated lymphocyte proliferation ex vivo. Conclusions: G1T28, a novel CDK4/6 inhibitor, is well tolerated and demonstrates predictable PK and robust PD activity. Based on these results, IV G1T28 will be investigated in Phase 1b/2a studies in patients with CDK4/6-independent tumors to evaluate its potential as a targeted bone marrow chemoprotectant. In addition, the oral formulation will be assessed as an antineoplastic agent in patients with CDK4/6-dependent tumors. Clinical trial information: NCT02243150.

DrugBank Data that Cites this Article

Drugs