Findings From The Phase I Clinical Trials Of Cx-4945, An Orally Available Inhibitor Of Ck2.

3087 Background: CK2 protein kinase is an attractive target for anticancer therapy because it is essential to the survival and maintenance of the cancer phenotype, it is overexpressed in cancer cells, and it supports multiple oncogenic signaling pathways. CX-4945 is a first-in-class, orally available, small molecule with highly selective inhibition of CK2. Methods: Two phase I clinical studies with CX-4945 were conducted in patients with advanced solid tumors in successive escalating dose cohorts. CX-4945 was administered orally on two different dosing schedules; twice daily or four times daily, for the first 3 consecutive weeks of a 4 week cycle. Therapy was continued until the patient showed signs of intolerance to CX-4945, or evidence of disease progression. All patients studied provided blood samples for pharmacokinetic and pharmacodynamic analyses, including the biomarker measurements of IL-6 and IL-8 levels, phosphoproteins to assess the inhibition of CK2 protein kinase in peripheral blood mononuclear cells, and downstream inhibition of the Akt signaling pathway. Results: Forty-three patients received oral doses with CX-4945 in these phase I studies. The maximum tolerated doses (MTDs) were determined for both dosing schedules, and the drug was deemed generally well tolerated. Diarrhea and hypokalemia are the dose limiting toxicities (DLTs), and these toxicities are reversible with drug discontinuation, antidiarrheal use, and potassium supplementation. The pharmacokinetics of CX-4945 were linear and dose dependent, and evidence of biomarker responses in the inhibition of CK2 and Akt pathways were observed in a drug exposure-related manner. No complete or partial RECIST responses were seen, but stable disease for at least 6 months was evident in 15% of treated patients. Conclusions: These studies established that CX-4945 can be orally administered safely on two different dosing schedules. The pharmacokinetics of CX-4945 were dose dependent, and drug exposure related inhibition of the CK2 and Akt pathways were observed. Disease stabilization was evident with CX-4945 as a single agent. Combination phase Ib/II studies in a number of different cancers are planned.