title: Phase 1 study of weekly polyethylene glycol-camptothecin in patients with advanced solid tumors and lymphomas.
abstract: OBJECTIVE
  To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks.
  
  
  METHODS
  Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of < or =2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m(2). The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables.
  
  
  RESULTS
  Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m(2). Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m(2). Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 +/- 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC(0-infinity)) > 20 ng h/mL and 0 of 10 patients with an AUC(0-infinity) < or = 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer.
  
  
  CONCLUSIONS
  The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m(2). The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m(2)). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, 35294, USA. james.posey@ccc.uab.edu
authors.forename: James A
authors.initials: JA
authors.lastname: Posey
authors.forename: M Wasif
authors.initials: MW
authors.lastname: Saif
authors.forename: Ronda
authors.initials: R
authors.lastname: Carlisle
authors.forename: Andrew
authors.initials: A
authors.lastname: Goetz
authors.forename: Jinee
authors.initials: J
authors.lastname: Rizzo
authors.forename: Suzanne
authors.initials: S
authors.lastname: Stevenson
authors.forename: Marc S
authors.initials: MS
authors.lastname: Rudoltz
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwiatek
authors.forename: Paul
authors.initials: P
authors.lastname: Simmons
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C115093:pegamotecan; D002166:Camptothecin