A Phase I Study To Assess The Safety, Pharmacokinetics (Pk), Pharmacodynamics (Pd), And Anti -Tumor Activity Of Oral Coh29, A Novel Ribonucleotide Reductase (Rnr) Inhibitor In Adult Patients (Pts) With Advanced Solid Tumors.

TPS2600Background: Human RNR catalyzes the rate-limiting step in the formation of deoxyribonucleotide triphosphates (dNTPs) necessary for DNA repair and replication. Rapidly dividing tumor cells are especially sensitive to RNR inhibition due to elevated dNTP requirements. Overexpression of the RNR RRM2 subunit is also associated with neoplasia, metastasis, and poor prognosis. COH29 is an aromatically substituted thiazole compound that is a novel small molecule inhibitor of RNR activity, and exhibits unique mechanisms and target specificity that overcomes the weaknesses of other small molecule RNR inhibitors. Preclinically, it is more potent than hydroxyurea and gemcitabine, and is not associated with iron chelating-related toxicities such as hypoxia. Cell lines deficient in BRCA1 also exhibit greater sensitivity to COH29 than BRCA1 wildtype cell lines, implicating inhibition of DNA repair mechanisms in line with PARP inhibitors. Methods: In this Phase I, single site, dose escalation, safety study pts will...