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


METHODS
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/m(2). 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/m(2). A single patient per cohort was treated up to 384 mg/m(2) without toxicities. At 1,200 mg/m(2), 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/m(2), 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.


CONCLUSIONS
AQ4N is well tolerated when administered weekly on a 3-of-4-week schedule at 768 mg/m(2). Further combination studies investigating the safety and efficacy of AQ4N are ongoing.
Papadopoulos
Kyriakos P
KP
Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. kyri.papadopoulos@start.stoh.com
Goel
Sanjay
S
Beeram
Murali
M
Wong
Alvin
A
Desai
Kavita
K
Haigentz
Missak
M
Milián
María L
ML
Mani
Sridhar
S
Tolcher
Anthony
A
Lalani
Alshad S
AS
Sarantopoulos
John
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000880:Anthraquinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014839:Vomiting / Q000139:chemically induced
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011355:Prodrugs; C094428:AQ4N