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Cantuzumab Mertansine, a Maytansinoid Immunoconjugate Directed to the CanAg Antigen: A Phase I, Pharmacokinetic, and Biologic Correlative Study
Abstract
Purpose: 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 (IV) once every 3 weeks and to seek evidence of antitumor activity. Patients and Methods: Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered IV 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/m 2. 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/m 2 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. Conclusion: The recommended dose for cantuzumab mertansine is 235 mg/m 2 IV 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.
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“the majority of clinical trials that tested ADCs targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5; CEA), EGFR and trophoblast cell surface antigen-2 (TROP2) with various cytotoxic payloads showed the insufficiency of ADCs to overcome therapy resistance or have been highly toxic.7178”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [78]
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Self-citationSite-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index
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“For example, the maytansine-derivative DM1, a potent antimicrotubule agent, is used in huN901-DM1 for small-cell lung cancer and huC242-DM1, which targets the CanAg antigen present on various tumors (9).”
BackgroundNatural products to drugs: natural product-derived compounds in clinical trials
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“A subsequent phase II trial confirmed that the response rate was low, although it was noteworthy that active drug could be detected within tumor masses that had undergone biops”
Background
Metadata
- Authors
- Tolcher, A. W., Ochoa, L., Hammond, L. A., Patnaik, A., Edwards, T., Takimoto, C., Smith, L., de Bono, J., Schwartz, G., Mays, T., Jonak, Z. L., Johnson, R., DeWitte, M., Martino, H., Audette, C., Maes, K., Chari, R. V. J., Lambert, J. M., & Rowinsky, E. K.
- Affiliations
- Brooke Army Medical Center (US)
- From the Institute for Drug Development, Cancer Therapy and Research Center and The University of Texas Health Science Center at San Antonio; and Brooke Army Medical Center, San Antonio, TX; GlaxoSmithKline, Collegeville, PA; and ImmunoGen Inc., Cambridge, MA.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2003-01-15
- Volume
- 21
- Issue
- 2
- Pages
- 211-222
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2121080375
- Cited by
- 206
- References
- 16
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 1 · 2023: 5 · 2022: 3 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 8 · 2017: 5 · 2016: 8 · 2015: 19 · 2014: 9 · 2013: 10 · 2012: 16
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- DM1, pharmacokinetics, maximum tolerated dose, hepatotoxicity, colorectal cancer, solid tumors, tumor localization, anticancer activity
- MeSH terms
- Adult, Aged, Antibodies, Monoclonal, Antineoplastic Agents, Phytogenic, Dose-Response Relationship, Drug, Female, Half-Life, Humans, Infusions, Intravenous, Male, Maytansine, Middle Aged, Neoplasms, Mucin-1, Immunoconjugates, Maximum Tolerated Dose
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