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J Clin Oncol. 2007 Apr 20;25(12):1512-8.

Phase I Trial of G3139, a bcl-2 antisense oligonucleotide, combined with doxorubicin and cyclophosphamide in children with relapsed solid tumors: a Children's Oncology Group Study.

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  • 1Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Abstract

PURPOSE:

To determine the maximum-tolerated dose, toxicity, pharmacokinetics, and biologic effects of G3139 when administered with doxorubicin and cyclophosphamide to children with relapsed solid tumors.

PATIENTS AND METHODS:

Patients received a 7-day continuous infusion of 3, 5, or 7 mg/kg/d of G3139 every 21 days. Doxorubicin, cyclophosphamide, and dexrazoxane were administered on days 5 and 6 of the infusion. Pharmacokinetics and biology studies were performed during the first course.

RESULTS:

Thirty-seven patients, median age 14 years (range, 1 to 19 years), were enrolled, of whom 29 were fully assessable for toxicity. Because of dose-limiting neutropenia, doses of doxorubicin 30 mg/m2/d for 2 days, dexrazoxane 300 mg/m2/d for 2 days, and cyclophosphamide 500 mg/m2/d for 2 days were reduced initially, but with the addition of granulocyte colony-stimulating factor (GCSF), could be re-escalated to starting doses. At the 7 mg/kg/d dose level, only one of six patients experienced DLT (neutropenia > 7 days). At this dose, the average (+/- standard deviation) steady-state G3139 concentration was 2.04 +/- 1 microg/mL, a concentration associated with biologic activity. Eleven of 15 patients had reduced bcl-2 expression in peripheral-blood mononuclear cells at the first assessable time point of G3139 exposure, and in eight of 14 patients with serial specimens this reduction persisted through day 6.

CONCLUSION:

The recommended phase II dose of G3139 is 7 mg/kg/d as a 7-day continuous infusion, with cyclophosphamide 500 mg/m2/d and doxorubicin 30 mg/m2/d on days 5 and 6, followed by GCSF. G3139 may accentuate the myelosuppressive effects of doxorubicin and cyclophosphamide. Evidence for biologic effects of G3139 was demonstrated.

PMID:
17442993
[PubMed - indexed for MEDLINE]
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