PHASE I STUDIES

Investigational New Drugs

, Volume 30, Issue 2, pp 604-610

A phase I study of continuous infusion cilengitide in patients with solid tumors

  • Peter H. O’DonnellAffiliated withSection of Hematology/Oncology, Department of Medicine, The University of ChicagoCommittee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago Email author 
  • , Samir D. UndeviaAffiliated withSection of Hematology/Oncology, Department of Medicine, The University of Chicago
  • , Walter M. StadlerAffiliated withSection of Hematology/Oncology, Department of Medicine, The University of ChicagoComprehensive Cancer Center, The University of Chicago
  • , Theodore M. KarrisonAffiliated withComprehensive Cancer Center, The University of ChicagoDepartment of Health Studies, The University of Chicago
  • , M. Kelly NicholasAffiliated withDepartment of Neurology, The University of Chicago
  • , Linda JanischAffiliated withSection of Hematology/Oncology, Department of Medicine, The University of Chicago
  • , Mark J. RatainAffiliated withSection of Hematology/Oncology, Department of Medicine, The University of ChicagoCommittee on Clinical Pharmacology and Pharmacogenomics, The University of ChicagoComprehensive Cancer Center, The University of Chicago

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Summary

Background: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3–5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. Methods: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change. Results: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade ≤2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose. Conclusions: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.

Keywords

Cilengitide EMD121974 Continuous infusion