title: A phase I trial of ISIS 2503, an antisense inhibitor of H-ras, in combination with gemcitabine in patients with advanced cancer.
abstract: OBJECTIVE
  The purpose of this study was to define the toxicity, pharmacokinetics, and clinical activity of the combination of ISIS 2503, an oligodeoxynucleotide antisense inhibitor of H-ras, and gemcitabine in patients with advanced solid tumors.
  
  
  METHODS
  The target dose of ISIS 2503 on this study was 6 mg/kg/day. Twenty-seven patients (16 male, 11 female) received 97 treatment courses (median, 2; range, 1-13). Nineteen patients were treated with a fixed gemcitabine dose of 1000 mg/m(2) on days 1 and 8 and two escalating doses of ISIS 2503 (4 and 6 mg/kg/day) as a 14-day continuous infusion starting on day 1. In addition, 8 patients (5 male, 3 female) received a flat dose of ISIS 2503 based on ideal body weight. Cycles were repeated every 3 weeks. Toxicities, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded as maximum grade/patient for all treatment cycles. Pharmacokinetic analyses were performed to evaluate any interaction between these two agents.
  
  
  RESULTS
  The most common nondose-limiting toxicity was hematological, manifested as neutropenia (5 grade 2, 7 grade 3, and 1 grade 4) and thrombocytopenia (10 grade 1, 5 grade 2, 5 grade 3, and 1 grade 4). Nonhematological toxicities included anorexia (7 grade 1, 3 grade 2, and 1 grade 3), nausea (10 grade 1 and 1 grade 3), fatigue (6 grade 1, 5 grade 2, and 3 grade 3), fever (6 grade 1, 2 grade 2, 1 and grade 3), and thrombosis associated with central lines (5). The plasma concentration of gemcitabine at the end of infusion was altered in the presence of ISIS 2503, leading to alterations on other pharmacokinetic parameters, but the observed differences were not clinically relevant. The plasma disposition of ISIS 2503 was not altered by gemcitabine coadministration. One partial response was documented in a heavily pretreated patient with metastatic breast cancer. Disease stabilization for greater than six cycles of treatment was observed in 5 patients.
  
  
  CONCLUSIONS
  The combination of gemcitabine and ISIS 2503 was well tolerated and clinically active in this group of heavily pretreated patients. The recommended Phase II dose of gemcitabine (1000 mg/m(2)) and ISIS 2503 (6 mg/kg/day) warrants additional evaluation.
authors.affiliation: Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. adjei.alex@mayo.edu
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Sloan
authors.forename: Henry C
authors.initials: HC
authors.lastname: Pitot
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Lorelei J
authors.initials: LJ
authors.lastname: Hanson
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Atherton
authors.forename: Tanya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Jon
authors.initials: J
authors.lastname: Holmlund
authors.forename: F Andrew
authors.initials: FA
authors.lastname: Dorr
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D054735:Phosphorothioate Oligonucleotides; D015398:Signal Transduction; D013997:Time Factors; D018631:ras Proteins / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C122000:ISIS 2503; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D003841:Deoxycytidine; D018631:ras Proteins; D000093542:Gemcitabine