Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

Authors

  • Adam S. Levy MD,

    Corresponding author
    1. Department of Pediatric Hematology/Oncology, Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, New York
    • Pediatric Neuro-Oncology, Children's Hospital at Montefiore, 3415 Bainbridge Avenue, Bronx, NY 10467===

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    • Fax: (718) 920-6506

  • Paul A. Meyers MD,

    1. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
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  • Leonard H. Wexler MD,

    1. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
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  • Regina Jakacki MD,

    1. Department of Hematology/Oncology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
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  • Anne Angiolillo MD,

    1. Department of Pediatric Hematology-Oncology, Children's National Medical Center, Washington, District of Columbia
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  • Sarah N. Ringuette MPH,

    1. Bristol-Myers Squibb, Wallingford, Connecticut
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  • Marvin B. Cohen PhD,

    1. Bristol-Myers Squibb, Wallingford, Connecticut
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  • Richard Gorlick MD,

    1. Department of Pediatric Hematology/Oncology, Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, New York
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  • Other site principal investigators: Wayne Furman, MD (St. Jude Children's Research Hospital, Memphis, Tennessee); Rochelle Bagatell, MD (University of Arizona Health Sciences Center, Tucson, Arizona); Lori Luchtman-Jones, MD (Washington University School of Medicine, St. Louis, Missouri); Luis Eduardo Garcia, MD (Hospital CIMA, San Jose, Costa Rica); and Eric Sandler, MD (Nemours Children's Clinic, Jacksonville, Florida).


Abstract

BACKGROUND:

Preclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors.

METHODS:

This was a multicenter, open-label, single-arm dose escalation study in which subjects with refractory solid tumors received 21-day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin.

RESULTS:

Twenty-eight patients with a median age of 8.5 years (range, 1-21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m2/dose) experienced dose-limiting gastrointestinal toxicities requiring a dose de-escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m2/dose). Three of 6 subjects at the second dose level experienced dose-limiting gastrointestinal complications and bone marrow suppression. A further dose de-escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m2/dose resulted in dose-limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed.

CONCLUSIONS:

The recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m2/ day × 10 days) given every 21 days. Cancer 2009. © 2008 American Cancer Society.

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