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 maximumtolerated 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 maximumtolerated 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 (ϳ40 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.

A Phase I Dose Escalation Study with Anti-CD44v6 Bivatuzumab Mertansine in Patients with Incurable Squamous Cell Carcinoma of the Head and Neck or Esophagus

“…With respect to peripheral neuropathy and transaminases, no toxicities of biological significance as noted in the anti-MUC1-mertansine clinical studies were seen (15,16). No other toxicities were seen during the study.…”

Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate

“…These agents bind directly to microtubules in a manner similar to the Vinca alkaloids (24,25). Antibody-maytansinoid conjugates directed toward cancer antigens, such as CanAg (cantuzumab mertansine and IMGN242), prostate-specific membrane antigen (MLN2704), CD56 (IMGN901), CD33 (AVE9633), and CD44v6 (bivatuzumab mertansine) are in early stages of clinical testing (20,(26)(27)(28). Because HER2 is highly differentially expressed on breast tumor cells (1-2 million copies per cell) compared with normal epithelial cells, HER2 represents an ideal target for antibody-drug conjugate (ADC) therapy.…”

Antibody-Drug Conjugates Designed to Eradicate Tumors with Homogeneous and Heterogeneous Expression of the Target Antigen

“…Antibody conjugates with highly cytotoxic compounds, such as calicheamicins, maytansinoids, auristatins, CC1065 analogues (DC drugs), or novel taxoids, exhibit potent and selective killing of target tumor cells in vitro and in animal models (3,4). Several maytansinoid conjugates are currently in clinical development (5,6) and a conjugate of an anti-CD33 antibody with calicheamicin, gemtuzumab ozogamicin (Mylotarg), has been approved for the treatment of relapsed acute myeloid leukemia (7).…”