Phase I trial of concurrent weekly paclitaxel and radiation therapy for children with newly diagnosed diffuse intrinsic pontine glioma

PURPOSE: Children diagnosed with diffuse intrinsic pontine glioma (DIPG) have a dismal prognosis with a median overall survival of 8-12 months. Radiation therapy (RT) is considered standard treatment, but is essentially palliative. Paclitaxel inhibits tumor growth by promoting mitotic arrest and the induction of apoptosis. It also acts as a cell-cycle specific radiosensitizer. METHODS: We performed a phase I trial of weekly paclitaxel with concurrent RT in patients with newly diagnosed DIPG. Subjects received intravenous paclitaxel 1-3 hours prior to RT, weekly for six weeks. Paclitaxel starting dose was 175 mg/m2/dose and was escalated using a 3 + 3 design. Radiation was delivered in standard 180cGy fractions to a dose of 54Gy. Response data were obtained six weeks after completion of RT by MRI scan. Subjects could receive an additional 8 courses of post-RT paclitaxel. RESULTS: Eleven patients were enrolled (median age 8.3 years; range, 3-17), and three dose levels explored. All patients were evaluable for dose escalation and response. Two of five patients treated at doselevel 3 (225 mg/m2/dose) experienced grade 4 toxicities. The median time from diagnosis to disease progression was 6.4 months, and the median time from diagnosis to death was 9.9 months. One subject had a partial response following RT and stable disease 106 months from diagnosis. There was subsequent disease progression, but she remains alive 10.9 years from diagnosis. A recommended phase II dose of 200mg/m2/dose during RT was established. CONCLUSION: Delivery of infusional paclitaxel to children with DIPG as a radiosensitizer was feasible and tolerated at 200 mg/ m2/dose weekly during involved-field RT. The study was closed early because of slow accrual due to availability of competing protocols and little evidence of activity. The addition of paclitaxel to radiation did not appear to prolong life in subjects with DIPG beyond that with standard radiation alone.