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

Glenn Liu, Jill Kolesar, Douglas G. McNeel, Catherine Leith, Kathy Schell, Jens Eickhoff, Fred Lee, Anne Traynor, Rebecca Marnocha, Dona Alberti, James Zwiebel, George Wilding

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Purpose: 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. Experimental Design: 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/m2 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.

Original languageEnglish
Pages (from-to)2732-2739
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number9
DOIs
StatePublished - May 1 2008

ASJC Scopus subject areas

  • General Medicine

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