Background: Palbociclib is an orally administered, highly selective, reversible, small molecule cyclin-dependent kinases 4/6 (CDK4/6) inhibitor. Inhibition of CDK4/6 reduced growth of neuroblastoma cell lines. The phase 1 portion of the study, conducted and funded by Pfizer in collaboration with the Children's Oncology Group, established the recommended phase 2 dose (RP2D) of palbociclib with topotecan and cyclophosphamide (TOPO/CTX) in children with solid tumors. Per study protocol, if 2 or more patients from the phase 1 study show a confirmed objective response (OR) in a specific tumor type, an open-label, non-randomized tumor-specific cohort (TSC) may be opened. Methods: A neuroblastoma TSC has been opened to evaluate the preliminary antitumor activity of palbociclib with TOPO/CTX in the treatment of patients with recurrent/refractory neuroblastoma using a modified Simon’s 2-stage optimal design. Up to 21 patients will be enrolled and receive palbociclib with TOPO/CTX. The primary endpoint is OR, as assessed by investigator using International Neuroblastoma Response Criteria (INRC). Secondary efficacy endpoints include duration of response, progression-free survival, and overall survival. Key eligibility criteria include: recurrent/refractory neuroblastoma, measurable disease as defined by INRC, aged ≥2 and < 21 years at the time of study entry, adequate blood counts organ function, and performance status. Patients may have received prior TOPO and/or CTX, provided their disease did not progress on this regimen. Prior treatment with a CDK4/6 inhibitor is exclusionary. Patients will receive palbociclib at the RP2D of 75 mg/m² orally once daily on days 1–14 of each 21-day treatment cycle. CTX (250 mg/m²) followed by TOPO (0.75 mg/m²) will be administered intravenously once daily on days 1–5. Concurrent radiotherapy or surgery for local control will be permitted. Treatment will continue until disease progression, patient and/or legal guardian refusal, unacceptable toxicity, or up to 24 months of treatment, whichever occurs first. Enrollment in the neuroblastoma TSC was initiated in December 2022 (NCT03709680). Clinical trial information: NCT03709680.