title: Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours.
abstract: To evaluate the toxicity, pharmacological and biological properties of ATN-161, a five -amino-acid peptide derived from the synergy region of fibronectin, adult patients with advanced solid tumours were enrolled in eight sequential dose cohorts (0.1-16 mg kg(-1)), receiving ATN-161 administered as a 10-min infusion thrice weekly. Pharmacokinetic sampling of blood and urine over 7 h was performed on Day 1. Twenty-six patients received from 1 to 14 4-week cycles of treatment. The total number of cycles administered to all patients was 86, without dose-limiting toxicities. At dose levels above 0.5 mg kg(-1), mean total clearance and volume of distribution showed dose-independent pharmacokinetics (PKs). At 8.0 and 16.0 mg kg(-1), clearance of ATN-161 was reduced, suggesting saturable PKs. Dose escalation was halted at 16 mg kg(-1) when drug exposure (area under the curve) exceeded that associated with efficacy in animal models. There were no objective responses. Six patients received more than four cycles of treatment (>112 days). Three patients received 10 or more cycles (> or =280 days). ATN-161 was well tolerated at all dose levels. Approximately, 1/3 of the patients in the study manifested prolonged stable disease. These findings suggest that ATN-161 should be investigated further as an antiangiogenic and antimetastatic cancer agent alone or with chemotherapy.
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Cianfrocca
authors.forename: K A
authors.initials: KA
authors.lastname: Kimmel
authors.forename: J
authors.initials: J
authors.lastname: Gallo
authors.forename: T
authors.initials: T
authors.lastname: Cardoso
authors.forename: M M
authors.initials: MM
authors.lastname: Brown
authors.forename: G
authors.initials: G
authors.lastname: Hudes
authors.forename: N
authors.initials: N
authors.lastname: Lewis
authors.forename: L
authors.initials: L
authors.lastname: Weiner
authors.forename: G N
authors.initials: GN
authors.lastname: Lam
authors.forename: S C
authors.initials: SC
authors.lastname: Brown
authors.forename: D E
authors.initials: DE
authors.lastname: Shaw
authors.forename: A P
authors.initials: AP
authors.lastname: Mazar
authors.forename: R B
authors.initials: RB
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D020533:Angiogenesis Inhibitors; D009842:Oligopeptides; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide