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Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors

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Abstract

CEP-2563 dihydrochloride (CEP-2563) is a soluble lysinyl-β-alanyl ester of CEP-751, a potent inhibitor of the trk family of receptor tyrosine kinases and the platelet-derived growth factor (PDGF) receptor tyrosine kinase. CEP-2563 was developed because of the limited aqueous solubility of CEP-751. Preclinical models have demonstrated that both CEP-751 and CEP-2563 have antitumor activity in a variety of tumors. A Phase I clinical trial involving 18 patients was conducted to determine the toxicity profile, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of CEP-2563 in patients with advanced solid tumors refractory to standard therapy. CEP-2563 was administered over 1 hour via a central venous catheter once daily for five consecutive days every three weeks. A rapid dose titration strategy with initial single patient cohorts and 100% dose escalations was used. With the appearance of drug-related toxicity, escalations were decreased to 50% or 25% and cohorts were expanded to 3 or 6 patients until establishment of the MTD. Dose escalation rapidly proceeded to 320 mg/m2/d. The dose limiting toxicities (DLTs) observed were grade 3 hypotension and grade 2 allergic reaction. Other toxicities included anemia, thrombocytopenia, anorexia, asthenia, diarrhea, fatigue, headache, nausea, vomiting, and rash. Pharmacokinetic analysis showed that CEP-2563 is reliably converted to CEP-751. This study demonstrated that single agent CEP-2563 therapy is feasible with acceptable toxicities. The recommended phase II dose is 256 mg/m2/d. Rapid dose escalation with single patient cohorts was a safe and efficient method of conducting this phase I trial.

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Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

    Samir D. Undevia, Linda Janisch & Sridhar Mani

  2. Department of Medicine, Section of Hematology/Oncology and Cancer Research Center, University of Chicago, Chicago, IL, USA

    Nicholas J. Vogelzang & Ann M. Mauer

  3. Department of Medicine, Section of Hematology/Oncology, Cancer Research Center, and Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA

    Mark J. Ratain

Authors
  1. Samir D. Undevia
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  2. Nicholas J. Vogelzang
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  3. Ann M. Mauer
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  4. Linda Janisch
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  5. Sridhar Mani
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Undevia, S.D., Vogelzang, N.J., Mauer, A.M. et al. Phase I clinical trial of CEP-2563 dihydrochloride, a receptor tyrosine kinase inhibitor, in patients with refractory solid tumors. Invest New Drugs 22, 449–458 (2004). https://doi.org/10.1023/B:DRUG.0000036687.26604.8c

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  • DOI: https://doi.org/10.1023/B:DRUG.0000036687.26604.8c

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