Background: Anlotinib is an orally available, highly potent, novel multitargeted tyrosine kinase inhibitor, which blocks VEGF signaling by selectively targeting VEGFR-2, -3 as well as FGFR-1, -2, -3, -4 with high affinity. We evaluated the toxicity, and pharmacokinetic profile of anlotinib in children with high-risk, recurrent, or refractory sarcomas. Methods: This was an open-label, single-center, single-arm phase I study, which enrolled pediatric patients with sarcoma. Pediatric patients aged 5-18 years diagnosed with high-risk, recurrent, or refractory sarcomas were enrolled and further categorized into cohort A (＜35 kg) or cohort B (≥ 35kg). Anlotinib was administered orally, once daily, 2-week on off, until disease progression, death, unacceptable toxicity, or withdrawal of consent for any reasons. A fixed anlotinib level of 8 mg was given to cohort A and three dose levels (8mg, 10mg, 12mg) were evaluated using a “3 + 3” design in cohort B. Results: Between December 29, 2020, and September 7, 2022, 34 patients were enrolled to evaluate the safety and 19 (55.9%) were evaluable for efficacy. The median age was 12 (range 5-18) years old. The main subtype eligible was rhabdomyosarcoma (23.5%). Two of fifteen patients in cohort A at a dose level of 8 mg experienced dose-limiting toxicity, including grade 3 hematuria and grade 3 hand-foot syndrome. The grade 3 treatment-related adverse events (AEs) included neutropenia (3 [8.8%]), hand-foot syndrome (2 [5.9%]), headache (1 [2.9%]), hematuria (1 [2.9%]), hypertension (1 [2.9%]), and hyperbilirubinemia (1 [2.9%]). The most common AEs were grade 1 or 2 hypothyroidism (58.8%) and abdominal pain (55.9%). Twelve of 19 (63.2%) patients had a best response of stable disease with seven patients receiving ≥ 6 cycles. Age has no significant effect on the level of body exposure per unit body surface area dose, and patients younger than 12 years old had a faster elimination. Conclusions: Anlotinib in pediatric patients with sarcoma was well tolerated. The RP2D of anlotinib for future studies is 8 mg for patients＜ 35 kg and 12 mg for patients with ≥ 35kg. Clinical trial information: NCT04659733.

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.