GCT-25. INNOVATIVE, INTENSIVE IRRADIATION-AVOIDING/MINIMIZING CHEMOTHERAPY FOR HIGH-RISK PRIMARY CENTRAL NERVOUS SYSTEM (CNS) MIXED MALIGNANT GERM CELL TUMORS (HR-MMGCT): A PILOT STUDY AND PROPOSED MULTI-NATIONAL PROSPECTIVE TRIAL

BACKGROUND About one-third of children with primary CNS MMGCT experience incomplete responses to initial induction chemotherapy prior to irradiation, many of whom will subsequently relapse. Such high-risk patients are variably defined as having initial alpha-fetoprotein (AFP) elevations exceeding 1,000ng/mL, predominant histopathologies of malignant non-germinomatous GCT and incomplete responses to induction chemotherapy. Drugs targeting GCT-specific molecular markers have been identified for non-germinomatous GCT elements but have yet to be incorporated into prospective clinical trials. Four children with clearly identified HR-MMGCT characteristics have been treated on an innovative pilot regimen incorporating intensified chemotherapy and molecularly targeted agents, with avoidance or minimization of irradiation. METHODS Four children (two with pure suprasellar embryonal carcinoma (EC) - one with Down syndrome and the other with pre-diagnosis cognitive dysfunction; one with initial serum AFP exceeding 7,000ng/mL and yolk sac tumor (YST)+EC+Teratoma pathology; one with initial serum AFP exceeding 1,000ng/mL) were treated with 3 cycles of “standard” induction chemotherapy (ACNS1123), followed by 1–3 transplant cycles (thiotepa/carboplatin) each with complete radiographic and tumor marker responses. Two children with pure EC subsequently received six cycles of brentuximab-vedotin without irradiation and remain disease-free off therapy for 2–4 years. One child with YST+EC+Teratoma has subsequently received reduced dose craniospinal irradiation and pineal region boost, and will receive oral everolimus, erlotinib, palbocyclib and intravenous brentuximab-vedotin. The fourth child with YST+MT will commence everolimus, erlotinib and palbocyclib without irradiation. CONCLUSION This treatment strategy for HR-MMGCT patients provides preliminary tolerance and response data justifying extension to a multi-center trial.