title: A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer.
abstract: BACKGROUND
  Chemorefractory small-cell lung cancer (SCLC) is defined as disease that progresses during primary therapy or within 3 months of completion of primary therapy. Patients with chemorefractory SCLC have a very poor prognosis, and no treatment has been shown to be of significant clinical benefit. Elevated expression of Bcl-2 is found in the majority of SCLCs and has been associated with therapeutic resistance. Suppression of Bcl-2 levels through the use of G3139, an antisense oligonucleotide complementary to the mRNA encoding Bcl-2, might increase the antitumor efficacy of cytotoxic therapy.
  
  
  METHODS
  Twelve patients with chemorefractory SCLC participated in this pilot trial of paclitaxel combined with G3139. G3139 was given by continuous i.v. infusion over 7 days at a fixed dose of 3 mg/kg/day. Paclitaxel dose was initially 175 mg/m2 on day 6, but was decreased to 150 mg/m2 due to myelosuppression observed in two of the three patients treated in the first dose cohort.
  
  
  RESULTS
  The combination of paclitaxel at 150 mg/m2 and G3139 at 3 mg/kg/day was found to be feasible and well tolerated. No objective responses were observed, but two patients had stable disease, one remaining stable on therapy for >30 weeks. Plasma G3139 levels were determined, and were found to be highest in the patient with prolonged stable disease, suggesting that individual variation in metabolism and clearance of the antisense oligonucleotide may influence activity.
  
  
  CONCLUSIONS
  This study demonstrates that G3139 can be combined with paclitaxel in a cytotoxic dose range, and suggests that a similar combination be tested for activity in the context of chemoresponsive disease.
authors.affiliation: Section of Hematology/Oncology, University of Chicago Medical Center, IL 60637-1470, USA. crudin@medicine.bsd.uchicago.edu
authors.forename: C M
authors.initials: CM
authors.lastname: Rudin
authors.forename: G A
authors.initials: GA
authors.lastname: Otterson
authors.forename: A M
authors.initials: AM
authors.lastname: Mauer
authors.forename: M A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: R
authors.initials: R
authors.lastname: Tomek
authors.forename: B
authors.initials: B
authors.lastname: Prange
authors.forename: C M
authors.initials: CM
authors.lastname: George
authors.forename: L
authors.initials: L
authors.lastname: Szeto
authors.forename: E E
authors.initials: EE
authors.lastname: Vokes
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D019254:Genes, bcl-2; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D013873:Thionucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; C408162:oblimersen; D017239:Paclitaxel