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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

Susan R. Rheingold, Michael D. Hogarty, Susan M. Blaney, James A. Zwiebel, Calies Sauk-Schubert, Reddy Chandula, Mark D. Krailo, Peter C. Adamson

From the Children's Hospital of Philadelphia, Philadelphia, PA; Texas Children's Cancer Center at Baylor College of Medicine, Houston, TX; Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD; Genta Inc, Berkeley Heights, NJ; Children's Oncology Group, Arcadia; and University of Southern California Keck School of Medicine, Los Angeles, CA

Address reprint requests to Peter C. Adamson, MD, Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, ARC 916, 34th St & Civic Center Blvd, Philadelphia, PA 19104; e-mail: adamsonp{at}mail.med.upenn.edu

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 µg/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.

Supported by National Cancer Institute Grants No. U01 CA97452, M01 RR00188, M01 RR00084, M01 RR000037, M01 RR00585, and MO1 RR02172. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm.

Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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