A phase 1 open-label, accelerated dose-escalation study of the hypoxia-activated prodrug AQ4N in patients with advanced malignancies

Kyriakos P. Papadopoulos, Sanjay Goel, Murali Beeram, Alvin Wong, Kavita Desai, Missak Haigentz, María L. Milián, Sridhar Mani, Anthony Tolcher, Alshad S. Lalani, John Sarantopoulos

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34 Scopus citations


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 9,099.1mg/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.

Original languageEnglish (US)
Pages (from-to)7110-7115
Number of pages6
JournalClinical Cancer Research
Issue number21
StatePublished - Nov 1 2008


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Papadopoulos, K. P., Goel, S., Beeram, M., Wong, A., Desai, K., Haigentz, M., Milián, M. L., Mani, S., Tolcher, A., Lalani, A. S., & Sarantopoulos, J. (2008). A phase 1 open-label, accelerated dose-escalation study of the hypoxia-activated prodrug AQ4N in patients with advanced malignancies. Clinical Cancer Research, 14(21), 7110-7115. https://doi.org/10.1158/1078-0432.CCR-08-0483