Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2), 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 À1 ), 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 À1 , mean total clearance and volume of distribution showed dose-independent pharmacokinetics (PKs). At 8.0 and 16.0 mg kg À1 , clearance of ATN-161 was reduced, suggesting saturable PKs. Dose escalation was halted at 16 mg kg À1 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 (4112 days). Three patients received 10 or more cycles (X280 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.

Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma

“…Although multiple inhibitors of the α 5 β 1 integrin have been shown to be safe in preclinical animal studies, specificity for α 5 β 1 over other RGD-binding integrins remains an elusive target, in part because several of these inhibitors were developed as anticancer agents, in which multi-integrin antagonism has been more effective in animal models of tumor invasion. Nevertheless, the inhibitors currently being used in active clinical trials, including ATN-161, do not have significant reported toxicity (46,47), suggesting that new drugs targeting this pathway could be rapidly moved into clinical trials for intervention in asthma.…”

Integrin αvβ3‐targeted cancer therapy

“…[Jain, 2005]. [Color figure can be viewed in the online version] [Delbaldo et al, 2008;Patel et al, 2001;Posey et al, 2001] Phase II [Beekman et al, 2006;Colevas et al, 2004;Hariharan et al, 2007;MacDonald et al, 2008;Nabors et al, 2007;Raguse et al, 2004] ATN-161 Ac-PHSCN-NH 2 α 5 β 1 , α v β 3 Phase II [Cianfrocca et al, 2006;Donate et al, 2008] …”

Integrins as therapeutic targets: lessons and opportunities

“…ATN-161 (Ac-PHSCN-NH 2 ) is a mimetic of the fibronectin sequence PHSRN undergoing clinical development for the treatment of solid tumours 170 . It appears to interact with β sub-units, blocking signalling rather than adhesion, and it is thought that this may be due to inhibition of the rearrangement of disulphide bonds necessary for signalling in a similar manner to inhibitors of thiol isomerase action on integrins 164,171 .…”