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.

Abstract

TPS2600 Background: 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 receive oral COH29 twice a day for 21 days of a 28-day cycle. Eligible pts are age ≥ 18 years, ECOG ≤ 2, able to take oral medication, have adequate organ and marrow function, and diagnosed with any solid tumor refractory to standard therapies. Dose escalation will be pursued utilizing a Simon’s accelerated titration design, which allows skipping of dose levels (dose doubling) during the accelerated dose-finding phase. Primary objectives are to determine the maximum tolerated dose of COH29, toxicities per CTCAEv4, and PKs. Secondary objectives include assessment of objective response per RECIST 1.1 every 2 cycles. PD assessment includes measurement of plasma CK18 levels to determine degree of cellular apoptosis, evaluation of dNTP pool levels in peripheral blood mononuclear cells (PBMCs) to evaluate RNR inhibition, as well as measurement of PAR expression in PBMCs to assess PARP inhibition. Quantitation of tumor RRM2 expression using dual-color immunohistochemistry will be explored as a predictive biomarker of anti-tumor response to COH29. Clinical trial information: NCT02112565.