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


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/m(2); 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.


CONCLUSIONS
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.
Perotti
A
A
Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
Sessa
C
C
Mancuso
A
A
Noberasco
C
C
Cresta
S
S
Locatelli
A
A
Carcangiu
M L
ML
Passera
K
K
Braghetti
A
A
Scaramuzza
D
D
Zanaboni
F
F
Fasolo
A
A
Capri
G
G
Miani
M
M
Peters
W P
WP
Gianni
L
L
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015820:Cadherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D015820:Cadherins; C541294:N-Ac-CHAVC-NH2; D010456:Peptides, Cyclic