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 - PubMed (original) (raw)
Clinical Trial
. 2012 Jan 20;30(3):256-62.
doi: 10.1200/JCO.2011.37.4355. Epub 2011 Dec 19.
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
Affiliations
- PMID: 22184397
- PMCID: PMC3269952
- DOI: 10.1200/JCO.2011.37.4355
Clinical Trial
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 et al. J Clin Oncol. 2012.
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.
Conflict of interest statement
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Figures
Fig 1.
Reduction in [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) activity with cixutumumab. Fused axial PET/computed tomography of chest (A, B) and lower extremities (C,D) showing increased uptake at baseline in metastatic left lower lobe lung nodule (A, arrow) and intense baseline uptake in primary left midthigh mass at baseline (C, arrow) in patient with metastatic fibrosarcoma. After 2 weeks of cixutumumab therapy, although lung nodule had not changed in size, there was no significant residual FDG uptake remaining (B). Similarly, there was significant reduction in FDG uptake at primary left thigh site with no apparent change in size of tumor (D) after 2 weeks of therapy.
Fig 2.
Ewing sarcoma tumor expression of (A) insulin-like growth factor I receptor (IGF-IR), (B) IGF-I, and (C) IGF-II by immunohistochemistry (IHC). Each bar represents the mean IHC score (± standard deviation) calculated from 10 separate representative sections from tumor tissue for a single patient. PD, progressive disease; PR, partial response; SD, stable disease ≥ 3 cycles.
Fig A1.
Insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGF-BP3) increase from baseline after treatment with cixutumumab. Mean percent change (± standard deviation) from baseline in serum levels of IGF-I, IGF-II, IGFBP-2, and IGFBP-3 after one dose of cixutumumab at 6 (n = 16) and 9 mg/kg (n = 6).
Fig A2.
Insulin-like growth factor I receptor (IGF-IR) expression in peripheral blood mononuclear cells decreases with exposure to cixutumumab. Percent change from baseline in degree of IGF-IR expression by peripheral blood mononuclear cells for patients treated at (A) 6 mg/kg intravenously once per week (n = 8) and (B) 9 mg/kg (n = 4).
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