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Annals of Oncology Advance Access originally published online on February 3, 2009
Annals of Oncology 2009 20(4):741-745; doi:10.1093/annonc/mdn695
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

phase I and pharmacokinetics

Clinical and pharmacological phase I evaluation of ExherinTM (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumours

A. Perotti1, C. Sessa2, A. Mancuso2, C. Noberasco3, S. Cresta1, A. Locatelli1, M. L. Carcangiu1, K. Passera4, A. Braghetti2, D. Scaramuzza1, F. Zanaboni1, A. Fasolo1, G. Capri1, M. Miani5, W. P. Peters6 and L. Gianni1,*

1 Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
2 Instituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland
3 European Institute of Oncology, Milano
4 Dipartimento di Bioingegneria Politecnico di Milano, Milano
5 Southern Europe New Drug Organization, Milano, Italy
6 Adherex Technologies Inc., Durham, USA

* Correspondence to: Dr L. Gianni, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy. Tel: +39-02-2390-2789; Fax: +39-02-2390-2012; E-mail: luca.gianni{at}istitutotumori.mi.it

Background: Upregulation of N-cadherin promotes dysregulated cell growth, motility, invasiveness, plus maintenance of vascular stability and is associated with cancer progression in several human tumour types. N-cadherin is expressed also on tumour cells and the anti-N-cadherin cyclic pentapeptide ADH-1, tested in the present study, can exert a direct antitumour effect.

Patients and methods: Adult patients with advanced solid malignancies expressing N-cadherin on tumour biopsies carried out in the previous 12 months received escalating i.v. doses of ADH-1 given weekly (initially for 3 of 4 weeks, then every week). Plasma pharmacokinetics (PK) was studied at cycle 1. Blood flow changes were assessed after first dosing in all patients treated in the initial regimen.

Results: In all, 129 patients were screened, 65 (50%) were N-cadherin positive, and 30 were enrolled. The doses ranged from 150 to 2400 mg/m2; no maximum tolerated dose was reached. Treatment was well tolerated with asthenia as the most frequent adverse event. Two patients with ovarian cancer showed prolonged disease stabilisation while one patient with fallopian tube carcinoma achieved a mixed response. PK was linear in the range of doses tested.

Conclusion: ADH-1 is the first anti-N-cadherin compound tested in humans. In N-cadherin-positive patients, ADH-1 showed an acceptable toxicity profile, linear PK and hints of antitumour activity in gynaecological cancers.

Key words: antiangiogenic, N-cadherin, phase I

Received for publication July 23, 2008. Revision received September 30, 2008. Accepted for publication October 2, 2008.


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