Background: Patients with relapsed or refractory pediatric solid tumors have one-year progression-free survival (PFS) <25% even if a remission is achieved [1-9]. Maintenance treatments may extend survival for these patients but have not been tested. Many tyrosine kinase inhibitors (TKIs) target oncogenic pathways active in pediatric cancers and are being evaluated in children with cancer. The multitargeted TKI cabozantinib inhibits MET, VEGFR, AXL, RET, ROS1, KIT, TRKB, FLT3, and TIE2. Preclinical studies and clinical use suggest that cabozantinib may be active against childhood cancers [10-20]. A pediatric Phase 1 study defined a dose of 40 mg/m²/day[21], currently used in an ongoing pediatric Phase 2 study for measurable relapsed/refractory solid tumors, NCT02867592. However, cabozantinib has not been tested as a maintenance agent against cancers in children. We hypothesize that cabozantinib, in patients with ultra-high-risk pediatric solid tumors with minimal disease burden, can prevent recurrent tumor formation or induce a durable remission. Methods: Trial Design: Single arm, open-label, multisite investigator-initiated Phase 2 trial for patients with a “best response,” defined as no progression at least 28 days after end of prior therapy. Primary objective: Evaluate the effect of cabozantinib administered for up to 12 months on 1-year PFS. Statistical design and measure: Bayesian time-to-event optimal phase 2 design with a single interim analysis designed to detect 20% increase in PFS at 1 year with 80% power. Secondary objectives include 2- and 5-year PFS; 1-, 2-, and 5- year OS, duration of response, and safety and tolerability. Exploratory objectives include patient-reported outcomes, predictive biomarkers, PK and PD measurements. Treatment: Patients will take cabozantinib tablets on a continuous dosing schedule, partitioned into 28-day cycles, at an initial dose of 40 mg/m2/day (per dosing nomogram), for up to 365 days. Assessments are defined; radiographic assessment every 3 cycles. Dose modifications will be based on toxicities per protocol. Patients will continue on therapy until progression, toxicities not relieved by dose reduction, or end of planned therapy. Major eligibility criteria: Three strata: Neuroblastoma with residual disease at end of upfront therapy (“Best Response 1”, BR1) or after any relapse, n=36. Pediatric CNS tumors, defined in the protocol, n=30. Other pediatric solid tumors, as defined in the protocol, n=36. Patients must be ≥ 18 months and ≤40 years of age at enrollment, have completed prior therapy ≥ 4 weeks and ≤ 12 weeks prior to enrollment and demonstrate radiographic BR at time of enrollment. Measurable or evaluable disease is not required. Enrollment: Protocol is open to enrollment as of February 12, 2022. At time of abstract submission, we have not yet enrolled the first patient. Clinical trial information: NCT05135975.