进行中的临床试验：BCC021——Silmitasertib（CX-4945）联合化疗治疗复发难治性实体瘤儿童和青年患者的I/II期研究

Background: Pediatric patients with recurrent neuroblastoma (NB), Ewing sarcoma (ES), and other rare sarcomas have a poor prognosis with a clear need for more effective therapies. These cancers exhibit high CSNK2A1 expression and Casein Kinase 2 (CK2) activity, which promote oncogenic protein stability. CK2 inhibition reduces the abundance of oncogenic proteins (N-myc, c-myc, EWS-FLI1), thereby suppressing downstream signaling cascades regulated by these transcription factors. CX-4945 treatment significantly decreased tumor progression in patient-derived xenografts. CX-4945, an oral small-molecule CK2 inhibitor, is currently being tested in clinical trials for adult solid tumors and medulloblastoma. Methods: BCC021 is an open-label multicenter Phase I/II trial (NCT06541262) of CX-4945 in combination with chemotherapy in children and young adults with recurrent/refractory (r/r) NB, ES, osteosarcoma, rhabdomyosarcoma, and liposarcoma. Patients with NB receive irinotecan and temozolomide, with vincristine added to this regimen for patients with sarcomas. In Phase I, we aim to evaluate the safety and pharmacokinetics of the combination and determine the recommended Phase II dose. A starting dose of oral CX-4945 is 600 mg/m2/dose twice daily with dose escalation using a novel adaptive Posterior Predictive (PoP) design will be used to evaluate a maximum of 18 subjects. Phase II portion of the study will evaluate the efficacy of the above combination therapy using a Simon two-stage design to estimate the objective response rate. The assessment of treatment response in NB uses the International Neuroblastoma Response Criteria (INRC), while ES uses Response Evaluation Criteria in Solid Tumors (RECIST v1.1). All subjects will receive 21-day cycles of CX-4945 twice a day combined with chemotherapy for up to 24 cycles. Dose-limiting toxicity (DLT) will be assessed during the first cycle. The maximum accrual for Phase II is 78 evaluable subjects (37 NB, 41 ES). Eligibility criteria include age < 30 years at initial presentation with pathologic confirmation of diagnosis. Subjects must have r/r disease following standard upfront therapy with measurable disease at enrollment, and adequate organ function. Subjects with gut malabsorption, uncontrolled diarrhea, gastritis, inflammatory bowel disease, hemorrhagic coloproctitis, or a history of gastric/small bowel resection are excluded. Up to 40 Beat Childhood Cancer (BCC) Research Consortium hospitals in the United States and Canada are expected to participate. Correlative endpoints focus on identifying biomarkers of treatment sensitivity or resistance and evaluating circulating nucleic acid biomarkers as potential indicators of response. Enrollment is ongoing at 18 hospitals, with 15 patients completed the DLT period. We expect to complete enrollment in the Phase 1 study by the end of Q2 2026.