title: Phase I trial of oblimersen (Genasense®) and gemcitabine in refractory and advanced malignancies.
abstract: BACKGROUND
  Overexpression of Bcl-2 is associated with worse prognosis for a number of cancer types. The present study was designed to determine the maximum tolerated dose (MTD) of oblimersen (antisense Bcl-2) and gemcitabine when administered to patients with refractory malignancies.
  
  
  METHODS
  Sixteen patients with advanced solid tumors refractory to standard therapies were treated with escalating doses of oblimersen continuous, 120-h intravenous infusion given every 14 days, with a fixed-dose-rate intravenous infusion of gemcitabine administered on day 5 of each cycle. Serial plasma samples were collected to calculate the pharmacokinetics of oblimersen and gemcitabine, and also to measure the effect of oblimersen on Bcl-2 expression.
  
  
  RESULTS
  7 women and 9 men, median age 55 years (range 35-74 years), received a 5-day infusion of oblimersen at dose levels of 5 mg/kg/day (n = 4) or 7 mg/kg/day (n = 12). On the 5th day of the infusion, gemcitabine was given at 10 mg/m(2)/h for a total dose of 1,000 mg/m(2) (n = 7; cohorts I and II), 1,200 mg/m(2) (n = 3; cohort III), or 1,500 mg/m(2) (n = 6; cohort IV). Edema was the dose-limiting toxicity (DLT), necessitating expansion of cohort IV. No subsequent DLTs were noted. Thus, the maximum planned doses were well tolerated, and a formal MTD was not determined. Most hematologic toxicities were grade 1 or 2. There was low-grade fatigue, nausea/vomiting, and myalgias/arthralgias. Oblimersen C(ss) and AUC increased in relation to the dose escalation, but gemcitabine triphosphate levels did not correlate well with dose. There were no objective responses, though 5 patients had stable disease. A >75% reduction in Bcl-2 expression in peripheral blood mononuclear leucocytes was seen more frequently in patients who achieved stable disease than in progressing patients.
  
  
  CONCLUSIONS
  The maximal planned dose levels of oblimersen and gemcitabine in combination were well tolerated. Only one DLT (edema) occurred. There was a correlation between Bcl-2 reduction and stable disease. The recommended doses of the drugs for future studies are 7 mg/kg/day of oblimersen on days 1-5, and gemcitabine 1,500 mg/m(2) on day 5, every two weeks.
authors.affiliation: Department of Medicine, Oncology, Stanford University School of Medicine, Stanford, CA, USA. peter_galatin@sanjosemed.com
authors.forename: Peter S
authors.initials: PS
authors.lastname: Galatin
authors.forename: Ranjana H
authors.initials: RH
authors.lastname: Advani
authors.forename: George A
authors.initials: GA
authors.lastname: Fisher
authors.forename: Brian
authors.initials: B
authors.lastname: Francisco
authors.forename: Thomas
authors.initials: T
authors.lastname: Julian
authors.forename: Raquel
authors.initials: R
authors.lastname: Losa
authors.forename: Marta I
authors.initials: MI
authors.lastname: Sierra
authors.forename: Branimir I
authors.initials: BI
authors.lastname: Sikic
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013873:Thionucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D003841:Deoxycytidine; C408162:oblimersen; D000093542:Gemcitabine