TY - JOUR
T1 - A phase 1 open-label, accelerated dose-escalation study of the hypoxia-activated prodrug AQ4N in patients with advanced malignancies
AU - Papadopoulos, Kyriakos P.
AU - Goel, Sanjay
AU - Beeram, Murali
AU - Wong, Alvin
AU - Desai, Kavita
AU - Haigentz, Missak
AU - Milián, María L.
AU - Mani, Sridhar
AU - Tolcher, Anthony
AU - Lalani, Alshad S.
AU - Sarantopoulos, John
PY - 2008/11/1
Y1 - 2008/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-08-0483
DO - 10.1158/1078-0432.CCR-08-0483
M3 - Article
C2 - 18981010
AN - SCOPUS:58149250648
SN - 1078-0432
VL - 14
SP - 7110
EP - 7115
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -