title: A phase I pharmacokinetic and pharmacodynamic correlative study of the antisense Bcl-2 oligonucleotide g3139, in combination with carboplatin and paclitaxel, in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I trial assessed the safety and tolerability of G3139 when given in combination with carboplatin and paclitaxel chemotherapy. The effect of G3139 treatment on Bcl-2 expression in peripheral blood mononuclear cells (PBMC) and paired tumor biopsies was also determined.
  
  
  METHODS
  Patients with advanced solid malignancies received various doses of G3139 (continuous i.v. infusion days 1-7), carboplatin (day 4), and paclitaxel (day 4), repeated in 3-week cycles, in a standard cohort-of-three dose-escalation schema. Changes in Bcl-2/Bax transcription/expression were assessed at baseline and day 4 (prechemotherapy) in both PBMCs and paired tumor biopsies. The pharmacokinetic interactions between G3139 and carboplatin/paclitaxel were measured.
  
  
  RESULTS
  Forty-two patients were evaluable for safety analysis. Primary toxicities were hematologic (myelosuppression and thrombocytopenia). Dose escalation was stopped with G3139 at 7 mg/kg/d, carboplatin at area under the curve of 6, and paclitaxel at 175 mg/m(2) due to significant neutropenia seen in cycle 1 and safety concerns in further escalating chemotherapy in this phase I population. With G3139 at 7 mg/kg/d, 13 patients underwent planned tumor biopsies, of which 12 matched pairs were obtained. Quantitative increases in intratumoral G3139 with decreases in intratumoral Bcl-2 gene expression were seen. This paralleled a decrease in Bcl-2 protein expression observed in PBMCs.
  
  
  CONCLUSIONS
  Although the maximal tolerated dose was not reached, the observed toxicities were consistent with what one would expect from carboplatin and paclitaxel alone. In addition, we show that achievable intratumoral G3139 concentrations can result in Bcl-2 down-regulation in solid tumors and PBMCs.
authors.affiliation: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin 53792, USA. gxl@medicine.wisc.edu
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.forename: Jill
authors.initials: J
authors.lastname: Kolesar
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McNeel
authors.forename: Catherine
authors.initials: C
authors.lastname: Leith
authors.forename: Kathy
authors.initials: K
authors.lastname: Schell
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Fred
authors.initials: F
authors.lastname: Lee
authors.forename: Anne
authors.initials: A
authors.lastname: Traynor
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: James
authors.initials: J
authors.lastname: Zwiebel
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D019254:Genes, bcl-2; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013873:Thionucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; D051028:bcl-2-Associated X Protein; C408162:oblimersen; D016190:Carboplatin; D017239:Paclitaxel