Cancer Chemotherapy and Pharmacology

, Volume 57, Issue 4, pp 465–474

Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers

  • Ramesh K. Ramanathan
  • Marwan Fakih
  • Sridhar Mani
  • Melvin Deutsch
  • Raymond P. Perez
  • Mark A. Ritter
  • Julie L. Eiseman
  • S. Percy Ivy
  • Donald L. Trump
  • Chandra P. Belani
  • Robert A. Parise
  • Douglas M. Potter
  • Merrill J. Egorin
Original Article

DOI: 10.1007/s00280-005-0071-y

Cite this article as:
Ramanathan, R.K., Fakih, M., Mani, S. et al. Cancer Chemother Pharmacol (2006) 57: 465. doi:10.1007/s00280-005-0071-y

Abstract

Purpose: To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated. Methods: Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography. Results: Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1–2 μmol/kg occurred between 4 and 6 h after MGd infusion. Conclusion: Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.

Keywords

Phase I studyMotexafin gadoliniumRadiation therapyPancreatic cancer

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Ramesh K. Ramanathan
    • 1
    • 2
    • 10
  • Marwan Fakih
    • 1
    • 2
    • 11
  • Sridhar Mani
    • 3
    • 12
  • Melvin Deutsch
    • 4
  • Raymond P. Perez
    • 5
  • Mark A. Ritter
    • 6
  • Julie L. Eiseman
    • 2
    • 7
  • S. Percy Ivy
    • 8
  • Donald L. Trump
    • 1
    • 2
    • 11
  • Chandra P. Belani
    • 1
    • 2
  • Robert A. Parise
    • 2
  • Douglas M. Potter
    • 9
  • Merrill J. Egorin
    • 1
    • 2
    • 7
  1. 1.Division of Hematology/Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  3. 3.Division of Hematology/Oncology, Department of MedicineUniversity of Chicago School of MedicineChicagoUSA
  4. 4.Department of Radiation OncologyUniversity of Pittsburgh Medical CenterPittsburghUSA
  5. 5.Molecular Therapeutics Research Program, Norris Cotton Cancer CenterDartmouth-Hitchock Medical CenterLebanonUSA
  6. 6.Department of Human OncologyUniversity of Wisconsin School of MedicineMadisonUSA
  7. 7.Department of PharmacologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  8. 8.Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and CentersNational Cancer InstituteBethesdaUSA
  9. 9.Biostatistics Department, Graduate School of Public Health, and Biostatistics FacilityUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  10. 10.UPMC Cancer Pavilion, # 562PittsburghUSA
  11. 11.Department of MedicineRoswell Park Cancer InstituteBuffaloUSA
  12. 12.Montefiore Medical CtrBronxUSA