Original Article

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. RamanathanAffiliated withDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of MedicineMolecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer InstituteUPMC Cancer Pavilion, # 562 Email author 
  • , Marwan FakihAffiliated withDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of MedicineMolecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer InstituteDepartment of Medicine, Roswell Park Cancer Institute
  • , Sridhar ManiAffiliated withDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of MedicineDivision of Hematology/Oncology, Department of Medicine, University of Chicago School of MedicineMontefiore Medical Ctr
  • , Melvin DeutschAffiliated withDepartment of Radiation Oncology, University of Pittsburgh Medical Center
  • , Raymond P. PerezAffiliated withMolecular Therapeutics Research Program, Norris Cotton Cancer Center, Dartmouth-Hitchock Medical Center
  • , Mark A. RitterAffiliated withDepartment of Human Oncology, University of Wisconsin School of Medicine
  • , Julie L. EisemanAffiliated withMolecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer InstituteDepartment of Pharmacology, University of Pittsburgh School of Medicine
  • , S. Percy IvyAffiliated withInvestigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute
  • , Donald L. TrumpAffiliated withDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of MedicineMolecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer InstituteDepartment of Medicine, Roswell Park Cancer Institute
    • , Chandra P. BelaniAffiliated withDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of MedicineMolecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute
    • , Robert A. PariseAffiliated withMolecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute
    • , Douglas M. PotterAffiliated withBiostatistics Department, Graduate School of Public Health, and Biostatistics Facility, University of Pittsburgh Cancer Institute
    • , Merrill J. EgorinAffiliated withDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of MedicineMolecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer InstituteDepartment of Pharmacology, University of Pittsburgh School of Medicine

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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 study Motexafin gadolinium Radiation therapy Pancreatic cancer