EPCT-18. PHASE 0/I STUDY OF GM-CSF AND INTRATHECAL TRASTUZUMAB IN CHILDREN WITH RECURRENT POSTERIOR FOSSA EPENDYMOMA

BACKGROUND Posterior fossa ependymoma (PF EPN) is a pediatric central nervous system malignancy that has a poor outcome to standard therapeutic approaches. The majority of PF EPN tumors have increased HER2 expression. Trastuzumab is a monoclonal antibody that targets HER2, and sargramostim (GM-CSF) stimulates hematopoietic progenitor cell proliferation. The combination of trastuzumab and GM-CSF has been shown to trigger antibody-dependent cell cytotoxicity in vitro in PF EPN cell lines. METHODS Children aged 1–21 years with relapsed PF EPN and no ventriculoperitoneal shunt or CSF obstruction are eligible for the Phase 0/I institutional trial at Children’s Hospital Colorado. Stratum 1 involves IT trastuzumab and subcutaneous (subQ) GM-CSF prior to standard-of-care surgical resection. Stratum 2 involves a 3 + 3 phase I design with serial IT trastuzumab doses, each preceded by three days of GM-CSF, to establish the MTD for IT trastuzumab. RESULTS Trastuzumab was detected in a sufficient number of tumors after presurgical IT delivery in Stratum 1 to open Stratum 2. Four patients (75% female) have been enrolled in Stratum 2 at trastuzumab Dose Level 1. Median age at enrollment is 9.8 years (range, 3.5–20.2 years). Preliminary CSF pharmacokinetic analysis demonstrated detectable trastuzumab up to 14 days after IT doses. No dose-limiting toxicities have occurred. Two patients progressed on therapy (median, 4 cycles). One patient is progression-free at 18 months off therapy. One patient remains on study therapy. CONCLUSIONS IT trastuzumab penetrates PF EPN tumor tissue. Stratum 2 remains open to accrual at Dose Level 2.