To estimate the survival rate at 1 year in adolescent patients (12 to < 18 years) with previously treated
or untreated, unresectable Stage III or Stage IV malignant melanoma at the 3 mg/kg dose level
• To assess safety and tolerability, specifically the frequency of severe (grade 3 - 5) immune-mediated
adverse reactions of ipilimumab in adolescent patients (12 to < 18 years) at the 3 mg/kg dose level.
This is a non randomized, multicenter, open label Phase 2 study in adolescent patients
(12 to < 18 years of age) with previously treated or untreated, unresectable Stage III or Stage IV malignant melanoma. The study will enroll approximately 40 subjects in order to treat at least 30 subjects.approximately 30 subjects with the expectation that 20-25 subjects would be treated at the 3 mg/kg dose level, and the rest of the subjects at the 10 mg/kg dose level. The patient accrual is expected to be completed in approximately 3.5 years with an additional follow up time of 1 year to assess the primary endpoint of overall survival rate at 1 year for patients treated with ipilimumab 3 mg/kg.
Ipilimumab is a fully human monoclonal immunoglobulin (IgG1κ) specific for human cytotoxic T lymphocyte antigen γ 4 (CTLA-4, CD152), which is expressed on a subset of activated T cells. The proposed mechanism of action for ipilimumab is T-cell potentiation through interference of the interaction of CTLA-4 with B7 (CD80 or CD86) molecules on antigen presenting cells, with subsequent blockade of the inhibitory function of CTLA-4. Ipilimumab is approved for use in the US (metastatic melanoma) and in the EU (previously treated metastatic melanoma) in the adult patient population. The current study is designed to determine the efficacy and safety of ipilimumab monotherapy in adolescents (12 to < 18 years) with previously treated or untreated, unresectable Stage III or Stage IV malignant melanoma. Melanoma in children Melanoma in childhood is rare but the incidence is rising rapidly (1.1% per year in children < 20 years). In Australia, where melanoma is most common, the estimated incidence reported in 2008 among children age 0 - 14 years was five cases per million compared to an incidence of 2 cases per million in Western Europe and Northern America. The incidence, as in adults, increases with age and there is a sharp rise following puberty. Fifteen to nineteen year old adolescents account for between 70 and 85% of all melanoma cases diagnosed in individuals under 20 years of age. Risk factors for the development of pediatric melanoma based on the Surveillance, Epidemiology and End Results (SEER) database (1973-2001) include white ethnicity, female gender, increasing age, and environmental UV radiation. The increased incidence of melanoma in children, particularly adolescents, may be attributed to increased UV exposure during childhood and adolescence, as well as an increased awareness of physicians and patients leading to an improvement in the timing of diagnosis. Histologically, melanoma has the same pathologic characteristics in children and in adults, with the most common type being superficial spreading melanoma. Prognostic factors are not as clearly defined for children as for adults. Primary tumor thickness, age and stage at presentation are considered the most important prognostic factors for pediatric melanoma. Studies conducted in children with melanoma have been of small size, from single institutions, and have shown high levels of variability in staging criteria and outcome. Although some reports indicate that pediatric patients may have a higher probability of survival compared to adults, a number of children will develop metastasis and die of their disease, particularly when melanoma is diagnosed after puberty. Some studies which include younger children suggest a more favorable outcome compared to adults. Studies which exclude children younger than 12 years have reported survival similar to that seen among adults. In one series, age greater than 10 years and detection of metastases at the time of diagnosis were significantly related to a higher mortality risk. Another study reported that patients < 20 years of age with regional or distant metastases at diagnosis had 10 year survival rates of approximately 60 and 25% respectively. Livestro et al, when comparing melanomas in children and adults after matching by thickness and year of diagnosis, reported no significant differences in 5 year and 10 year disease free and overall survivals. More recent data show that overall survival for all patients with pediatric melanoma appears similar to that of adults, with no apparent difference in survival between patients < 13 years of age and those 13 to 20 years of age. Treatment of pediatric melanoma There is no established standard treatment for pediatric patients with advanced melanoma. Because of the rarity of pediatric melanoma, accruing adequate numbers of patients for clinical trials to evaluate adjuvant therapy is very difficult. Therefore, treatment of children is often based on information from adult studies. Biologic agents such as interferon α2b (IFNα2b) and interleukin-2 (IL-2) are currently used as adjuvant treatment for high-risk melanoma after surgical resection. The basis of this immunological approach came from the observations that tumors with lymphoid infiltration had a better prognosis than tumors without. In addition, the host response is assumed to be involved in the spontaneous regression of some tumors. There is no approved therapy for metastatic melanoma in children. A few small studies published promising results with the use of chemotherapy. In studies of 10 pediatric patients with metastatic disease treated with cyclophosphamide, vincristine, and dactinomycin, half were in remission for > 5 years. The results of studies with single agent dacarbazine, an agent commonly used in adult melanoma, showed positive activity in 4 children with melanoma treated between 1975 and 1984. In a trial using a combination of vincristine, NCT01519323). In summary, there is a high need for new therapeutic modalities for pediatric melanoma given the limited options and equally poor outcome of treatment in children compared to adults, especially in the advanced disease setting.