Immunotherapies have revolutionized medical oncology following the remarkable and, in some cases, unprecedented outcomes observed in certain groups of patients with cancer. However results in adults and mainly in pediatric cancer are still disappointing. One hypothesis is that the tumor micro-environment (TME) - characterized by hypoxia, a low pH, and a high interstitial fluid pressure - can reduce the effectiveness of virtually all types of anticancer therapies, including immunotherapy. In adults, combination with other therapeutic modalities, including anti-angiogenic agents, is one of the many strategies currently under investigation to improve the response rates and duration of immunotherapies.~Modulators of angiogenesis, such as VEGF, have a broad range of diverse effects on the immune system and the tumor micro-environment that are mainly immunosuppressive. In patients with early-stage disease, anti-VEGF therapy can lead to antitumor effects by modulating immune mechanisms - provided that therapy is maintained for an adequate length and tumors are sufficiently immunogenic. Nevertheless, blocking angiogenic molecules using a strategy based on a single therapeutic approach is likely insufficient to generate a complete or robust immune response against cancer, especially in patients with advanced-stage disease. Therefore, such anti-angiogenic agents will likely need to be used in combination with various immunotherapeutic strategies that boost adaptive immune responses, such as those described in the next sections. For these reasons, the investigators proposed to combine immunotherapy and low dose of pazopanib to enhance the efficacy of immunotherapy in some selected pediatric patients and young adults.~PDR001 (also referred to as spartalizumab) is a humanized monoclonal antibody (mAb) directed against human programmed death-1 (PD-1) that blocks the interaction between PD-1 and its ligands (PD-L1 and PD-L2).~Pazopanib is a potent, selective, oral, ATP competitive multitargeted receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, c-kit, and platelet-derived growth factor receptors. It is approved by the US Food and Drug Administration for the treatment of advanced renal cell carcinoma and soft tissue sarcoma (STS) in adults. Based on the results of previous studies which evaluated the safety profile of spartalizumab, of pazopanib and the combination of antiangiogenic agents with checkpoint inhibitors, a study combining spartalizumab and low-dose pazopanib in refractory or relapsed solid tumors of pediatric and young adults is proposed. This study will include 2 separate cohorts:~the pediatric cohort will consist of a phase I study (dose-finding and expansion phases) combining pazopanib at a fixed dose of 225 mg/m2 and spartalizumab with four potential candidate doses (2, 3, 4 and 6 mg/kg).~the young adult cohort will consist of a phase II study combining pazopanib at a fixed dose of 400 mg and spartalizumab at the RP2D of 400 mg every 4 weeks.
Immunotherapies have revolutionized medical oncology following the remarkable and, in some cases, unprecedented outcomes observed in certain groups of patients with cancer. However results in adults and mainly in pediatric cancer are still disappointing.~Modulators of angiogenesis, such as VEGF, have a broad range of diverse effects on the immune system and the tumor micro-environment that are mainly immunosuppressive. In patients with early-stage disease, anti-VEGF therapy can lead to antitumor effects by modulating immune mechanisms - provided that therapy is maintained for an adequate length and tumors are sufficiently immunogenic. Nevertheless, blocking angiogenic molecules using a strategy based on a single therapeutic approach is likely insufficient to generate a complete or robust immune response against cancer, especially in patients with advanced-stage disease.~Based on the results of previous studies which evaluated the safety profile of spartalizumab, of pazopanib and the combination of antiangiogenic agents with checkpoint inhibitors, a study combining spartalizumab and low-dose pazopanib in refractory or relapsed solid tumors of pediatric and young adults is proposed. This study will include 2 separate cohorts:~the pediatric cohort will consist of a phase I study (dose-finding and expansion phases) combining pazopanib at a fixed dose of 225 mg/m2 and spartalizumab with four potential candidate doses (2, 3, 4 and 6 mg/kg).~the young adult cohort will consist of a phase II study combining pazopanib at a fixed dose of 400 mg and spartalizumab at the RP2D of 400 mg every 4 weeks.