SPARTO: A phase I study of PD-1 inhibitor spartalizumab (PDR001) in combination with low dose of pazopanib in pediatric relapsed/refractory tumors.

10001 Background: The initial results of immunotherapy in children with refractory/relapsed tumors have been disappointing. Modulation of angiogenesis with anti-VEGF may enhance immunotherapy penetration and promote lymphocytes T infiltration. In this context, we propose combining immunotherapy with low doses of pazopanib to enhance therapeutic efficacy in pediatric patients. Methods: Pediatric part of the SPARTO trial (NCT05210413) was a multicenter, open-label, dose-finding phase I clinical trial conducted in France. Pediatric patients with recurrent/refractory solid tumors were eligible to receive pazopanib at a fixed low dose of 225 mg/m²/d combined to anti-PD1 spartalizumab at three candidate doses (2, 3, 4 mg/kg/q4w). Dose-finding was guided by Bayesian Optimal Interval design based on dose-limiting toxicities (DLTs) in cycle 1, with a target toxicity level of 25%. Recommended phase 2 dose (RP2D) was determined on the basis of DLTs and blood exposure of pazopanib and spartalizumab. Toxicities were evaluated using CTCAE v5.0 and responses were evaluated by clinical and radiologic assessment (RECIST1.1 or RANO for brain tumors). Results: From May 2022 to June 2025, 41 patients were enrolled at 8 sites (median age: 13.9y; range: 7-25). Among 39 evaluable patients, 4 DLTs occurred in 1/9 patients at 2 mg/kg of spartalizumab (DL0), 1/6 patients at 3 mg/kg (DL1) and 2/24 patients at 4 mg/kg (DL2). Three patients experienced macrophagic activation syndrome (grade 3 at DL0 and DL2, grade 4 at DL1) and one patient experienced liver enzymes increase grade > 3 at DL2. A total of 58 grade 3–4 adverse events were reported in 26 patients, predominantly hepatic and hematologic toxicities. Median area under the serum concentration-time of spartalizumab from 0 to 28 days post-infusion at cycle 1, were 12.9 g.h/L (IQR 10.7-15.8), 17.2 g.h/L (IQR 15.5-20.0) and 19.5 g.h/L (IQR 16.9-23.6), respectively for DL0, DL1 and DL2. Median trough concentration of pazopanib was 23.1 mg/L (IQR 15.8-32.1). DL2 was identified as the RP2D. Of 40 evaluable patients, one patient with osteosarcoma presented complete response, 4 had partial responses (2 osteosarcoma, 1 chordoma, 1 carcinoma) and 8 had stable disease (including 4 for more than 4 months). The median duration of treatment was 68 days (IQR 57—106); one patient completed 24 cycles and two were still on treatment at data cut-off (at cycle 16 and cycle 23). Conclusions: Spartalizumab combined with low dose pazopanib was well tolerated leading to a RP2D of 4 mg/kg/q4w. The regimen shows evidence of anti-tumor activity in pediatric sarcoma, especially osteosarcoma. Further investigations are ongoing to select the sub-population who could benefit of this combination. Funded by INCa and ARC Foundation (call for project CLIP2 “Novartis Innovative Molecules, INCa-ARC_14820”). Clinical trial information: NCT05210413 .