This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hartung, G. Articles by Queisser, W. Search for Related Content PubMed PubMed Citation Articles by Hartung, G. Articles by Queisser, W.

Phase I Trial of Methotrexate-Albumin in a Weekly Intravenous Bolus Regimen in Cancer Patients¹

Oncology Center, III. Medical University Clinic Mannheim [G. H., S. H., M. K., W. Q.], I. Medical University Clinic Mannheim [G. S., D. L. H.], German Cancer Research Center, Heidelberg [H. S., A. W., H. H. S., L. E., E. F., W. M-B.], and Clinic for Tumor Biology, University of Freiburg [H. H. F.], Germany, and the Phase I Study Group of the Association for Medical Oncology of the German Cancer Society

Methotrexate-albumin conjugate (MTX-HSA) is a novel human albumin-based prodrug conjugate of methotrexate (MTX). A low MTX loading rate provided optimal tumor targeting and therapeutic efficacy during preclinical testing. The objectives of this first Phase I study of MTX-HSA were to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in a weekly regimen. Seventeen cancer patients who were no longer amenable to standard treatment were enrolled and were evaluable for DLT. Up to eight injections were performed in weekly intervals. Dose escalation was as follows: 20, 40, 50, and then 60 mg/m² MTX-HSA (based on the amount of MTX bound to albumin). Additional MTX-HSA courses were feasible in case of tumor response. DLT (mainly stomatitis, Common Toxicity Criteria grade 3) occurred, beginning at the 50 mg/m² dose level after repeated administrations; in one case, thrombocytopenia was dose-limiting. Two events of DLT occurred at the 60 mg/m² dose level within the first two administrations. Mild anemia, transaminitis, and one case of skin toxicity were found. No significant leukopenia, nausea, renal toxicity, or other toxicities were observed. MTX-HSA was well tolerated. Drug accumulation occurred on the weekly schedule. The half-life of the drug was estimated to be up to 3 weeks. Tumor responses were seen in three patients: (a) a partial response was seen in one patient with renal cell carcinoma (response duration, 30 months, ongoing); (b) a minor response was seen in one patient with pleural mesothelioma (response duration, 31 months, ongoing); and (c) a minor response was seen in one patient with renal cell carcinoma (response duration, 14 months until progression). Poststudy treatment was administered at 2–4-week intervals. No signs of toxicity or drug accumulation were seen. Altered pharmacological properties of MTX-HSA such as plasma half-life, tumor targeting, or intracellular metabolism might have contributed to these responses. The MTD for weekly administration was 4 x 50 mg/m² MTX-HSA during short-term treatment. A regimen with MTX-HSA injections of 50 mg/m² every 2 weeks was recommended for a further clinical Phase I study.

This article has been cited by other articles:

				Y. Nakase, A. Hagiwara, S. Kin, K.-i. Fukuda, T. Ito, T. Takagi, J. Fujiyama, C. Sakakura, E. Otsuji, and H. Yamagishi Intratumoral Administration of Methotrexate Bound to Activated Carbon Particles: Antitumor Effectiveness against Human Colon Carcinoma Xenografts and Acute Toxicity in Mice J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 382 - 387. [Abstract] [Full Text] [PDF]

				C. Fiehn, U. Muller-Ladner, S. Gay, S. Krienke, S. Freudenberg-Konrad, J. Funk, A. D. Ho, H. Sinn, and A. Wunder Albumin-coupled methotrexate (MTX-HSA) is a new anti-arthritic drug which acts synergistically to MTX Rheumatology, September 1, 2004; 43(9): 1097 - 1105. [Abstract] [Full Text] [PDF]

				K. Wosikowski, E. Biedermann, B. Rattel, N. Breiter, P. Jank, R. Loser, G. Jansen, and G. J. Peters In Vitro and in Vivo Antitumor Activity of Methotrexate Conjugated to Human Serum Albumin in Human Cancer Cells Clin. Cancer Res., May 1, 2003; 9(5): 1917 - 1926. [Abstract] [Full Text] [PDF]

				A. Wunder, U. Muller-Ladner, E. H. K. Stelzer, J. Funk, E. Neumann, G. Stehle, T. Pap, H. Sinn, S. Gay, and C. Fiehn Albumin-Based Drug Delivery as Novel Therapeutic Approach for Rheumatoid Arthritis J. Immunol., May 1, 2003; 170(9): 4793 - 4801. [Abstract] [Full Text] [PDF]