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A Phase 1 Open-Label, Accelerated Dose-Escalation Study of the Hypoxia-Activated Prodrug AQ4N in Patients with Advanced Malignancies

Authors' Affiliations: ¹ Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas; ² Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New York; and ³ Novacea, Inc., South San Francisco, California

Requests for reprints: Kyriakos P. Papadopoulos, South Texas Accelerated Research Therapeutics, 4319 Medical Drive, Suite 205, San Antonio, TX 78229. Phone: 210-593-5250; Fax: 210-615-1121; E-mail: kyri.papadopoulos{at}start.stoh.com.

Purpose: AQ4N is a novel prodrug that is selectively bioreduced to AQ4, a topoisomerase II inhibitor, in hypoxic tumor. This study assessed the maximum tolerated dose and pharmacokinetics of AQ4N when administered weekly in patients with advanced cancers.

Experimental Design: AQ4N was administered as a 30-minute i.v. infusion on days 1, 8, and 15 of a 28-day cycle in eight dose cohorts ranging from 12 to 1,200 mg/m². Accelerated titration design was used and the maximum tolerated dose was defined as the highest dose at which fewer than two of six patients had a dose-limiting toxicity.

Results: Sixteen patients were treated with cumulative doses of AQ4N ranging from 61.6 through 9,099.1 mg/m². A single patient per cohort was treated up to 384 mg/m² without toxicities. At 1,200 mg/m², two of five patients experienced a dose-limiting toxicity (grade 5 respiratory failure and grade 3 fatigue). Five cohort assigned patients were treated without toxicity at 768 mg/m², establishing this dose as the maximum tolerated dose. Among the most common adverse events observed were fatigue (38%), diarrhea (31%), nausea (25%), vomiting (25%), and anorexia (13%). Anticipated blue coloration of body fluids or skin was observed in all patients. The pharmacokinetics of AQ4N were dose proportional over all doses studied. Three patients experienced stable disease, including a patient with collecting duct renal cancer stable for 25 months.

Conclusion: AQ4N is well tolerated when administered weekly on a 3-of-4-week schedule at 768 mg/m². Further combination studies investigating the safety and efficacy of AQ4N are ongoing.