Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study.
OBJECTIVE
To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity.


METHODS
Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized.


RESULTS
Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (+/-13.1) mL/h/m2 and 41.1 (+/-16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses.


CONCLUSIONS
The recommended dose for cantuzumab mertansine is 235 mg/m2 i.v. every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors.
Tolcher
Anthony W
AW
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. atolcher@saci.org
Ochoa
Leonel
L
Hammond
Lisa A
LA
Patnaik
Amita
A
Edwards
Tam
T
Takimoto
Chris
C
Smith
Lon
L
de Bono
Johann
J
Schwartz
Garry
G
Mays
Theresa
T
Jonak
Zdenka L
ZL
Johnson
Randall
R
DeWitte
Mark
M
Martino
Helen
H
Audette
Charlene
C
Maes
Kate
K
Chari
Ravi V J
RV
Lambert
John M
JM
Rowinsky
Eric K
EK
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000493:pharmacokinetics* / Q000494:pharmacology; D008875:Middle Aged; D018396:Mucin-1 / Q000276:immunology; D009369:Neoplasms / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D018796:Immunoconjugates; D018396:Mucin-1; D008453:Maytansine