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’Donnell
  • Samir D. Undevia
  • Walter M. Stadler
  • Theodore M. Karrison
  • M. Kelly Nicholas
  • Linda Janisch
  • Mark J. Ratain
PHASE I STUDIES

DOI: 10.1007/s10637-010-9537-9

Cite this article as:
O’Donnell, P.H., Undevia, S.D., Stadler, W.M. et al. Invest New Drugs (2012) 30: 604. doi:10.1007/s10637-010-9537-9

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

CilengitideEMD121974Continuous infusion

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Peter H. O’Donnell
    • 1
    • 2
  • Samir D. Undevia
    • 1
  • Walter M. Stadler
    • 1
    • 3
  • Theodore M. Karrison
    • 3
    • 4
  • M. Kelly Nicholas
    • 5
  • Linda Janisch
    • 1
  • Mark J. Ratain
    • 1
    • 2
    • 3
  1. 1.Section of Hematology/Oncology, Department of MedicineThe University of ChicagoChicagoUSA
  2. 2.Committee on Clinical Pharmacology and PharmacogenomicsThe University of ChicagoChicagoUSA
  3. 3.Comprehensive Cancer CenterThe University of ChicagoChicagoUSA
  4. 4.Department of Health StudiesThe University of ChicagoChicagoUSA
  5. 5.Department of NeurologyThe University of ChicagoChicagoUSA