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Clinical Trial
. 2016 Mar 15;22(6):1364-70.
doi: 10.1158/1078-0432.CCR-15-0491. Epub 2015 Nov 3.

Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors

Melinda S Merchant  1 , Matthew Wright  2 , Kristin Baird  2 , Leonard H Wexler  3 , Carlos Rodriguez-Galindo  4 , Donna Bernstein  2 , Cindy Delbrook  2 , Maya Lodish  5 , Rachel Bishop  6 , Jedd D Wolchok  7 , Howard Streicher  8 , Crystal L Mackall  2
Affiliations
Clinical Trial

Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors

Melinda S Merchant et al. Clin Cancer Res. .

Abstract

Purpose: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol.

Experimental design: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity.

Results: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma).

Conclusions: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.

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Figures

Figure 1
Figure 1. Clinical findings
a. Hypophysitis developed in one adolescent with renal cell carcinoma on trial, heralded by vision changes, headache, and polyuria on cycle 4 day 8. MRI revealed pituitary enlargement that resolved within 2 weeks of corticosteroid treatment (cycle 4 day 19). b. Best overall response in an adolescent with unresectable scalp melanoma with visible improvement and 30% decrease in size of this target mass. c. Despite lack of complete or partial responses, overall survival in patients with grade 2 or greater immune related adverse events (irAE) was increased compared to overall survival in patients who only had grade 1 irAE or did not have any irAE.
Figure 2
Figure 2. T cell correlative data
a. Fold change on day 21 (circles) and day 42 (open triangles) in absolute number of T cells (CD3+) and activated T cell subsets expressing HLA-DR. b. Fold change in CD4+HLADR+ cells does not differ between patients who had irAE vs those who did not have any irAE. c. Absolute numbers of CD3+ki67+ cycling T cells are increased at day 21 or day 42 following first dose of ipilimumab compared to baseline in patients receiving 5mg/kg (open squares) and 10mg/kg (diamonds). d. No change was observed in absolute numbers of CD4+CD25+FoxP3+ cells at day 21 or day 42 following first dose of ipilimumab in patients receiving 5mg/kg (open squares) and 10mg/kg (diamonds).
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References

    1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews Cancer. 2012;12:252–64. - PMC - PubMed
    1. Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Annals of surgical oncology. 2005;12:1005–16. - PMC - PubMed
    1. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6. - PubMed
    1. Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26:5275–83. - PubMed
    1. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. The Lancet Oncology. 2010;11:155–64. - PubMed

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