Archexin, a novel AKT-1–specific inhibitor for the treatment of metastatic renal cancer: Preliminary phase I data.

Abstract

550 Background: Archexin (RX-0201) is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of Archexin's effect on AKT-1 mRNA levels was examined in human renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 cells and resulted in decreased AKT-1 mRNA levels. Methods: The current study is a proof of concept phase Ib/2, multicenter, open label 2-stage study for subjects who progressed on at least 1 VEGF-targeted therapy. Stage 1 is an open-label, dose-escalation phase Ib study of Archexin administered in combination with everolimus. Archexin is administered by a 24 hour continuous intravenous infusion for 14 days followed by 7 days of rest. It is hypothesized that 250 mg/m2/day or a lower dose of Archexin will be identified as safe and well-tolerated when administered in combination with 10 mg of everolimus. The dose of Archexin identified in Stage 1 will be studied further in Stage 2 which is the randomized, open-label, 2-arm study of Archexin in combination with 10 mg of everolimus versus 10 mg of everolimus alone. Plasma concentrations were measured using a validated LC-MS/MS assay, and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Results: Five subjects with metastatic clear cell renal carcinoma received 125 mg/m2/day (n = 3) or 200 mg/m2/day (n = 2) of Archexin with 10 mg of everolimus administered daily. Two subjects have had stable disease for 160 and 257 days. The most frequently reported treatment related adverse events for the combination were thrombocytopenia, vomiting and fatigue; no dose limiting toxicities have been reported currently. At all dose levels post-infusion, Archexin plasma concentrations increased rapidly and quickly reached a virtual plateau. Upon cessation of infusion on Day 14, plasma concentrations declined rapidly. Conclusions: At the dose levels tested, Archexin, in combination with everolimus, appears to be well tolerated in patients with metastatic renal cancer. Dose escalation/modification is ongoing to determine the recommended phase II dose of Archexin to be studied further in Stage 2 (randomized) when combined with everolimus. Clinical trial information: NCT02089334.