A phase I trial of RX-0201 (AKT anti-sense) in patients with an advanced cancer

Abstract

3564 Background: Akt-1, a proto-oncogene, plays a vital role in cancer progression by stimulating proliferation and inhibiting apoptosis of cancer cells. RX-0201, a 20-mer oligonucleotide with sequence complementary to Akt-1 mRNA, is designed to inhibit the expression of Akt-1 within cancer cells in cancer patients (pts). Non-clinical studies conducted on RX-0201 demonstrated that RX-0201 bears significant in vitro and in vivo anti-cancer activities with favorable safety. Purposes: The aims of the current phase I trial were to determine the maximum tolerated dose (MTD) and to establish pharmacokinetic (PK) and safety profiles of RX-0201 in pts with an advanced cancer. Methods: RX-0201 was administered to pts with an advanced cancer by up to 2 cycles of continuous infusion; each cycle of infusion lasted for 14 days which was followed by a 7-day rest. Rapid dose escalation had been used until at least a grade (G) 2 toxicity was observed, and then a traditional dose escalation followed. Entry criteria included Karnofsky Performance Status score =70, advanced cancer, tumor accessible for paired biopsy, and signed informed consent. 17 pts were enrolled and treated at a dose level ranging from 6 to 315 mg/m2/d on D1–14, repeated q 21 d. Results: G 3 fatigue was observed in two pts at the 315 mg/m2/d dose; three pts dosed at 250 mg/m2/d were not noted with any G 3 toxicity, which make this dose (250 mg/m2/d) the recommended phase II trial dose. No other significant, compound-related, adverse events were observed in those 17 pts participated. Pts PK profiles of RX-0201 and AKT-1 immunohistochemistry results on pts’ tumor biopsy samples will also be presented. Conclusion: MTD of RX-0201 is 315 mg/m2/d in pts with an advanced cancer when the compound is administered in the current continuous infusion regimen. No significant financial relationships to disclose.