Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors.
OBJECTIVE
A fully human monoclonal antibody to anti-alpha(v) integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors.


METHODS
In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [(18)F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months.


RESULTS
Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell alpha(v) integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days.


CONCLUSIONS
CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.
Mullamitha
Saifee A
SA
Cancer Research, UK. Gordon.Jayson@christie-tr.nwest.nhs.uk
Ton
Nhuan C
NC
Parker
Geoff J M
GJ
Jackson
Alan
A
Julyan
Peter J
PJ
Roberts
Caleb
C
Buonaccorsi
Gio A
GA
Watson
Yvonne
Y
Davies
Karen
K
Cheung
Sue
S
Hope
Lynn
L
Valle
Juan W
JW
Radford
John A
JA
Lawrance
Jeremy
J
Saunders
Mark P
MP
Munteanu
Mihaela C
MC
Nakada
Marian T
MT
Nemeth
Jeffrey A
JA
Davis
Hugh M
HM
Jiao
Qun
Q
Prabhakar
Uma
U
Lang
Zhihui
Z
Corringham
Robert E
RE
Beckman
Robert A
RA
Jayson
Gordon C
GC
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000276:immunology / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D049268:Positron-Emission Tomography; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D039564:Integrin alphaV