title: 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.
abstract: OBJECTIVE
  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 micromol/kg occurred between 4 and 6 h after MGd infusion.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. ramanathanrk@upmc.edu
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Marwan
authors.initials: M
authors.lastname: Fakih
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.forename: Melvin
authors.initials: M
authors.lastname: Deutsch
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Perez
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ritter
authors.forename: Julie L
authors.initials: JL
authors.lastname: Eiseman
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Donald L
authors.initials: DL
authors.lastname: Trump
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
authors.forename: Robert A
authors.initials: RA
authors.lastname: Parise
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Potter
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008665:Metalloporphyrins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; C437683:motexafin gadolinium