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

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.

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. 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).