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A Phase I Clinical, Pharmacologic, and Biologic Study of Thrombopoietin and Granulocyte Colony-Stimulating Factor in Children Receiving Ifosfamide, Carboplatin, and Etoposide Chemotherapy for Recurrent or Refractory Solid Tumors: A Children's Oncology Group Experience

Authors' Affiliations: ¹ Children's National Medical Center, George Washington University, Washington, District of Columbia; ² Childrens Hospital of New York Presbyterian, Columbia University, New York, New York; ³ Pharmacia Corp., Peapack, New Jersey; and ⁴ Keck School of Medicine, University of Southern California and Children's Oncology Group, Arcadia, California

Requests for reprints: Anne L. Angiolillo, Children's Oncology Group, PO Box 60012, Arcadia, CA 91066-6012. Phone: 626-241-1509; Fax 626-445-4334; E-mail: aangiolillo{at}cnmc.org.

Purpose: Ifosfamide, carboplatin, and etoposide (ICE) are associated with grade III/IV dose-limiting thrombocytopenia. The Children's Oncology Group conducted a phase I dose escalation, pharmacokinetic, and biological study of recombinant human thrombopoietin (rhTPO) after ICE in children with recurrent/refractory solid tumors (CCG-09717) to assess the toxicity and maximum tolerated dose of rhTPO administered at 1.2, 2.4, or 3.6 µg/kg per dose.

Experimental Design: Children received ifosfamide 1,800 mg/m² on days 0 to 4, carboplatin 400 mg/m² on days 0 to 1, and etoposide 100 mg/m² on days 0 to 4. rhTPO was administered i.v. on days +4, +6, +8, +10, and +12 at 1.2, 2.4, or 3.6 µg/kg per dose.

Results: rhTPO was well tolerated and maximum tolerated dose was not reached. Median time to platelet recovery 100,000/µL of rhTPO at 1.2, 2.4, and 3.6 µg/kg/d was 24 days (22-24d), 25 days (23-29d), and 22 days (16-37d), respectively. Patients required a median of 2 days of platelet transfusions (0-7 days). Mean (± SD) rhTPO maximum serum concentrations were 63.3 ± 9.7 and 89.3 ± 15.7 ng/mL and terminal half-lives were 47 ± 13 and 64 ± 42 hours after 2.4 and 3.6 µg/kg/d, respectively. There was a significant increase in colony-forming unit megakaryocyte upon WBC count recovery.

Conclusions: rhTPO was well tolerated. Time to hematologic recovery and median number of platelet transfusions seem to be improved compared with historical controls receiving ICE + granulocyte colony-stimulating factor (CCG-0894).

Key Words: Thrombopoietin • Chemotherapy • Children

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