Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5).
BACKGROUND
TRA-8 is a murine agonist monoclonal antibody to death receptor 5 (DR5), which is able to trigger apoptosis in DR5 positive human tumor cells without the aid of crosslinking. It has demonstrated cytotoxicity in vitro and in vivo antitumor efficacy to a wide range of solid tumors in murine xenograft models. Tigatuzumab is a humanized IgG1 monoclonal antibody derived from TRA-8.


METHODS
A phase I trial of tigatuzumab in patients with relapsed/refractory carcinomas (n = 16) or lymphoma (n = 1) was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety. Three to six (3-6) patients were enrolled in successive escalating cohorts at doses ranging from 1 to 8 mg/kg weekly.


RESULTS
Seventeen (17) patients enrolled, 9 in the 1-, 2-, and 4-mg/kg dose cohorts (3 in each cohort) and 8 in the 8-mg/kg dose cohort. Tigatuzumab was well tolerated with no DLTs observed, and the MTD was not reached. There were no study-drug-related grade 3 or 4, renal, hepatic, or hematologic toxicities. Plasma half-life was 6-10 days, and no anti-tigatuzumab responses were detected. Seven (7) patients had stable disease, with the duration of response ranging from 81 to 798 days.


CONCLUSIONS
Tigatuzumab is well tolerated, and the MTD was not reached. The high number of patients with stable disease suggests antitumor activity.
Forero-Torres
Andres
A
University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, Alabama 35294-3300, USA.
Shah
Jatin
J
Wood
Tina
T
Posey
James
J
Carlisle
Ronda
R
Copigneaux
Catherine
C
Luo
Feng Roger
FR
Wojtowicz-Praga
Slawomir
S
Percent
Ivor
I
Saleh
Mansoor
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C552861:tigatuzumab