Development of G1T28-1 to Mitigate Hematologic Sequelae of ARS and DEARE
Abstract
One of the nation s top biodefense priorities is the development of an effective and safe therapeutic that can mitigate the key sequelae of acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE). In response to the Peer Reviewed Medical Research Program Technology/Therapeutic Development Award goals addressing Illnesses Related to Radiation Exposure, G1 Therapeutics (G1) has identified a novel approach to mitigate the hematologic effects of ARS and DEARE. G1 has developed a new class of CDK4/6 inhibitors optimized to decrease multi-lineage myelosuppression, which is the principal acute complication faced by immediate survivors of a radiologic disaster. G1 Therapeutics clinical candidate, G1T28-1, is a highly potent, selective, reversible, CDK4/6 inhibitor that temporarily puts bone marrow cells to sleep (known as a cell cycle arrest). This transient, drug-induced cell cycle arrest provides resistance to DNA damage caused by radiation and chemotherapy. Persistent proliferation in the setting of unrepaired DNA damage is toxic to the bone marrow cells. This bone marrow arrest allows for DNA repair of chromosomal damage, prevents the induction of bone marrow cell death, and mitigates the resultant acute and chronic hematologic toxicities from ionizing radiation and chemotherapy. G1T28-1 is currently being evaluated in a First-In-Human Phase I Safety, Pharmacokinetic and Pharmacodynamic study in healthy volunteers (clinicaltrials.gov #NCT02243150). This study will establish the dose and schedule of G1T28-1 to be used in Phase II chemoprotection trials in cancer patients. In this proposal, we plan to expand on our preclinical data around the use of G1T28-1 as a radiomitigant to support the expansion of its clinical development to include radiomitigation. As such, this proposal seeks to (1) determine the optimal dose and schedule of G1T28-1 administration after ionizing radiation; (2) evaluate the efficacy of combined G1T28-1 and G-CSF (Neulasta) treatment regimens administered after ionizing radiation; and (3) determine the impact of single and co-administration of G1T28-1 and G-CSF after ionizing radiation on long-term hematopoietic reserve. Our proposal, if successful, will provide an important deliverable in line with the mission of this award mechanism: an effective way to prevent acquired bone marrow failure an illness related to radiation exposure, specifically addressing ARS and DEARE in both military Service members and the civilian population. Due to the ability to protect all blood cell types, oral administration, minimal toxicity, and high therapeutic index, G1T28-1 will be beneficial in preventing the hematopoietic toxicity and bone marrow failure caused by DNA-damaging total body irradiation from an environmental accidents/disasters or terrorist attack. This award will provide the data needed to justify the clinical development of G1T28-1 as a radiomitigant and more importantly will complete the preclinical data package required to secure further funding (through the Department of Defense or Biomedical Advanced Research and Development Authority) to advance its clinical development for this unmet medical need.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510264
Entities
People
- Patrick Roberts
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army