Safety and biologic activity of intravenous BCL-2 antisense oligonucleotide (G3139) and taxane chemotherapy in patients with advanced cancer Journal Article
| Authors: | Morris, M. J.; Cordon-Cardo, C.; Kelly, W. K.; Slovin, S. F.; Siedlecki, K.; Regan, K. P.; DiPaola, R. S.; Rafi, M.; Rosen, N.; Scher, H. I. |
| Article Title: | Safety and biologic activity of intravenous BCL-2 antisense oligonucleotide (G3139) and taxane chemotherapy in patients with advanced cancer |
| Abstract: | G3139 is a BCL-2 antisense oligonucleotide whose antitumor effects in preclinical models are enhanced when combined with taxane-based chemotherapy. This trial determined the safety and biologic activity of G3139 given with paclitaxel and docetaxel for the treatment of progressive solid tumors. Three cohorts of patients received weekly paclitaxel 100 mg/m2 on days 1,8, and 15 concurrently with a 21-day continuous infusion of G3139 at 4.1, 5.3, and 6.9 mg/kg/d, depending on the cohort. Two subsequent cohorts received docetaxel (75 mg/m2) on day 5 of a 5-day infusion of G3139 at 5 or 7 mg/kg/d. Bcl-2 protein levels in peripheral blood mononuclear cells (PBMCs) were assayed on an exploratory basis. Fifteen patients were treated. Eight received a total of 14 cycles of G3139 and paclitaxel; seven received a total of 22 cycles of G3139 and docetaxel. Eight patients required dose modifications for either grade 4 neutropenia (6 patients) or grade 1-2 reversible transaminitis (2 patients). No radiographic responses were seen, although two of the six taxane-naive prostate cancer patients exhibited a prostate-specific antigen decline greater than 50%. Bcl-2 protein levels in PBMCs declined with treatment as assessed by immunohistochemistry. The authors conclude that G3139, whether given as a 5- or 21-day infusion, is well tolerated with taxane chemotherapy and is biologically active by immunohistochemistry at doses up to and including 7 mg/kg/d, using weekly paclitaxel (100 mg/m2) or docetaxel every 3 weeks (75 mg/m2). These data support the dose selection of ongoing phase 2 studies of G3139 at 7 mg/kg/d and docetaxel 75 mg/m2. |
| Keywords: | immunohistochemistry; clinical article; protein expression; aged; middle aged; constipation; fatigue; neutropenia; advanced cancer; diarrhea; hypophosphatemia; solid tumor; antineoplastic agents; paclitaxel; chemotherapy; neoplasms; prostate specific antigen; cell cycle; protein bcl 2; apoptosis; anemia; leukopenia; mucosa inflammation; thrombocytopenia; drug administration schedule; creatinine; bone pain; bladder cancer; docetaxel; coughing; dyspnea; fever; hyperglycemia; prostate cancer; mononuclear cell; colon cancer; western blotting; muscle weakness; taxoids; hot flush; taxane derivative; kidney cancer; esophagus cancer; catheter infection; urine retention; infusions, intravenous; oblimersen; heart muscle ischemia; g3139; bcl-2; bridged compounds; antisense oligonucleotide; thionucleotides |
| Journal Title: | Applied Immunohistochemistry & Molecular Morphology |
| Volume: | 13 |
| Issue: | 1 |
| ISSN: | 1541-2016 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2005-03-01 |
| Start Page: | 6 |
| End Page: | 13 |
| Language: | English |
| DOI: | 10.1097/00129039-200503000-00002 |
| PUBMED: | 15722787 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 17" - "Export Date: 24 October 2012" - "CODEN: AIMMF" - "Source: Scopus" |
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