title: A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation.
abstract: OBJECTIVE
  To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA, a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR).
  
  
  METHODS
  Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients.
  
  
  RESULTS
  A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132 courses at nine dose levels, ranging from 50 to 700 mg/m(2). The MTD of MTA was 600 mg/m(2), with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of treatment at the 600 mg/m(2) dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve (AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 microg/ml, 40.0 ml/min per m(2), 266 microg. h/ml, and 7.0 l/m(2), respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained in six patients with advanced colorectal cancer.
  
  
  CONCLUSIONS
  The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m(2). MTA is a promising new anticancer agent.
authors.affiliation: Brooke Army Medical Center, Fort Sam Houston, TX, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Rinaldi
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: F A
authors.initials: FA
authors.lastname: Dorr
authors.forename: G
authors.initials: G
authors.lastname: Rodriguez
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: S
authors.initials: S
authors.lastname: Jones
authors.forename: J R
authors.initials: JR
authors.lastname: Woodworth
authors.forename: S
authors.initials: S
authors.lastname: Baker
authors.forename: C
authors.initials: C
authors.lastname: Langley
authors.forename: D
authors.initials: D
authors.lastname: Mascorro
authors.forename: T
authors.initials: T
authors.lastname: Abrahams
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000652:urine; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000652:urine; D000068437:Pemetrexed; D012044:Regression Analysis; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D003404:Creatinine