Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: A report from the Children's Oncology Group

Suman Malempati, Brenda Weigel, Ashish M. Ingle, Charlotte H. Ahern, Julie M. Carroll, Charles T. Roberts, Joel M. Reid, Stephen Schmechel, Stephan D. Voss, Steven Y. Cho, Helen X. Chen, Mark D. Krailo, Peter C. Adamson, Susan M. Blaney

Research output: Contribution to journalArticle

Abstract

Purpose: A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). Patients and Methods: Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels - 6 and 9 mg/kg - were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. Results: Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. Conclusion: Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.

Original languageEnglish (US)
Pages (from-to)256-262
Number of pages7
JournalJournal of Clinical Oncology
Volume30
Issue number3
DOIs
StatePublished - Jan 20 2012

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Ewing's Sarcoma
Pharmacokinetics
Pediatrics
Neoplasms
IGF Type 1 Receptor
anti-IGF-1R antibody A12
Insulin-Like Growth Factor I
Dehydration
Heterografts
Intravenous Infusions
Immunohistochemistry
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma : A report from the Children's Oncology Group. / Malempati, Suman; Weigel, Brenda; Ingle, Ashish M.; Ahern, Charlotte H.; Carroll, Julie M.; Roberts, Charles T.; Reid, Joel M.; Schmechel, Stephen; Voss, Stephan D.; Cho, Steven Y.; Chen, Helen X.; Krailo, Mark D.; Adamson, Peter C.; Blaney, Susan M.

In: Journal of Clinical Oncology, Vol. 30, No. 3, 20.01.2012, p. 256-262.

Research output: Contribution to journalArticle

Malempati, S, Weigel, B, Ingle, AM, Ahern, CH, Carroll, JM, Roberts, CT, Reid, JM, Schmechel, S, Voss, SD, Cho, SY, Chen, HX, Krailo, MD, Adamson, PC & Blaney, SM 2012, 'Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: A report from the Children's Oncology Group', Journal of Clinical Oncology, vol. 30, no. 3, pp. 256-262. https://doi.org/10.1200/JCO.2011.37.4355
Malempati, Suman ; Weigel, Brenda ; Ingle, Ashish M. ; Ahern, Charlotte H. ; Carroll, Julie M. ; Roberts, Charles T. ; Reid, Joel M. ; Schmechel, Stephen ; Voss, Stephan D. ; Cho, Steven Y. ; Chen, Helen X. ; Krailo, Mark D. ; Adamson, Peter C. ; Blaney, Susan M. / Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma : A report from the Children's Oncology Group. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. 3. pp. 256-262.
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abstract = "Purpose: A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). Patients and Methods: Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels - 6 and 9 mg/kg - were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. Results: Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. Conclusion: Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.",
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T1 - Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma

T2 - A report from the Children's Oncology Group

AU - Malempati, Suman

AU - Weigel, Brenda

AU - Ingle, Ashish M.

AU - Ahern, Charlotte H.

AU - Carroll, Julie M.

AU - Roberts, Charles T.

AU - Reid, Joel M.

AU - Schmechel, Stephen

AU - Voss, Stephan D.

AU - Cho, Steven Y.

AU - Chen, Helen X.

AU - Krailo, Mark D.

AU - Adamson, Peter C.

AU - Blaney, Susan M.

PY - 2012/1/20

Y1 - 2012/1/20

N2 - Purpose: A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). Patients and Methods: Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels - 6 and 9 mg/kg - were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. Results: Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. Conclusion: Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.

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