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

Paul 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

Research output: Contribution to journalArticle

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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/m2. The maximum-tolerated dose was defined as the highest dose at which no more than I 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/m2/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 (∼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.

Original languageEnglish (US)
Pages (from-to)4363-4368
Number of pages6
JournalClinical Cancer Research
Volume10
Issue number13
DOIs
StatePublished - Jul 1 2004
Externally publishedYes

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Intravenous Infusions
Maximum Tolerated Dose
Neoplasms
Pharmacokinetics
Immunoconjugates
Antibodies, Monoclonal, Humanized
Prodrugs
Transaminases
Fatigue
Half-Life
cantuzumab mertansine
Research Design
Antigens
Liver
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase I study of cantuzumab mertansine administered as a single intravenous infusion once weekly in patients with advanced solid tumors. / Helft, Paul; Schilsky, Richard L.; Hoke, Frank J.; Williams, Daphne; Kindler, Hedy L.; Sprague, Evie; DeWitte, Mark; Martino, Helen K.; Erickson, John; Pandite, Lini; Russo, Mark; Lambert, John M.; Howard, Maria; Ratain, Mark J.

In: Clinical Cancer Research, Vol. 10, No. 13, 01.07.2004, p. 4363-4368.

Research output: Contribution to journalArticle

Helft, P, Schilsky, RL, Hoke, FJ, Williams, D, Kindler, HL, Sprague, E, DeWitte, M, Martino, HK, Erickson, J, Pandite, L, Russo, M, Lambert, JM, Howard, M & Ratain, MJ 2004, 'A phase I study of cantuzumab mertansine administered as a single intravenous infusion once weekly in patients with advanced solid tumors', Clinical Cancer Research, vol. 10, no. 13, pp. 4363-4368. https://doi.org/10.1158/1078-0432.CCR-04-0088
Helft, Paul ; Schilsky, Richard L. ; Hoke, Frank J. ; Williams, Daphne ; Kindler, Hedy L. ; Sprague, Evie ; DeWitte, Mark ; Martino, Helen K. ; Erickson, John ; Pandite, Lini ; Russo, Mark ; Lambert, John M. ; Howard, Maria ; Ratain, Mark J. / A phase I study of cantuzumab mertansine administered as a single intravenous infusion once weekly in patients with advanced solid tumors. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 13. pp. 4363-4368.
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AU - Schilsky, Richard L.

AU - Hoke, Frank J.

AU - Williams, Daphne

AU - Kindler, Hedy L.

AU - Sprague, Evie

AU - DeWitte, Mark

AU - Martino, Helen K.

AU - Erickson, John

AU - Pandite, Lini

AU - Russo, Mark

AU - Lambert, John M.

AU - Howard, Maria

AU - Ratain, Mark J.

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