A phase I study of cantuzumab mertansine administered as a single intravenous infusion once weekly in patients with advanced solid tumors.

Abstract

PURPOSE:

The purpose is to determine the maximum-tolerated dose, assess the toxicities, characterize the pharmacokinetic behavior, and seek preliminary evidence of biological activity of cantuzumab mertansine when administered as a weekly i.v. infusion without interruption.

EXPERIMENTAL DESIGN:

Patients with incurable solid tumors that expressed the target antigen for cantuzumab mertansine, CanAg, were treated with doses of cantuzumab mertansine ranging from 40 to 138 mg/m(2). The maximum-tolerated dose was defined as the highest dose at which no more than 1 of 6 patients experienced dose-limiting toxicity. Plasma concentrations of cantuzumab mertansine and total humanized antibody were determined, and area under the plasma concentration-time curve (to the last measured concentration) was calculated.

RESULTS:

Thirty-nine patients received a total of 280 weekly doses of cantuzumab mertansine. Acute, transient elevation of the hepatic transaminases and reversible fatigue were identified as the dose-limiting toxicities at the highest dose level. The maximum-tolerated dose was determined to be 115 mg/m(2)/week. Evidence of clinical activity was noted in 3 patients. Pharmacokinetic analyses revealed that the pharmacokinetic variability was moderate, without evidence of dose dependency. Furthermore, the drug had a long terminal half-life ( approximately 40 h).

CONCLUSIONS:

This study identified a safe and tolerable dose of the novel immunoconjugate prodrug cantuzumab mertansine. The evidence of antitumor activity suggests that additional clinical development is warranted, with a focus on tumors that express high levels of CanAg and which are known to be sensitive to antimicrotubule agents.

• Authors: Paul R Helft, Richard L Schilsky, Frank J Hoke, Daphne Williams, Hedy L Kindler, Evie Sprague, Mark DeWitte, Helen K Martino, John Erickson, Lini Pandite, Mark Russo, John M Lambert, Maria Howard, Mark J Ratain
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 13 Pg. 4363-8 (Jul 01 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15240523 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Prodrugs
• Maytansine
• cantuzumab mertansine
• Transaminases

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (therapeutic use)
• Area Under Curve
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Humans
• Immunohistochemistry
• Liver (enzymology)
• Male
• Maximum Tolerated Dose
• Maytansine (administration & dosage, analogs & derivatives, therapeutic use)
• Microtubules (metabolism)
• Middle Aged
• Neoplasms (drug therapy)
• Prodrugs
• Time Factors
• Transaminases (metabolism)