Combination therapy for children with malignant pontine gliomas.

Children with malignant pontine gliomas have a dismal prognosis. The median overall survival is approximately nine months, the two-year survival rate less than 10%. In the past twenty years the prognosis has remained unchanged, despite several treatment strategies. In this study, the efficacy and feasibility of the radiosensitizer gemcitabine and a new combination of targeted agents will be investigated in three phases. Depending on the maturation of the present study, and on preceding therapy, an individual patient may enrol in phase a, phase a and b, or in phase c. Patients are separately asked informed consent for a biopsy: apart from histological confirmation, the tissue will also be used for retrospective correlation of DNA/RNA amplification or mutation and protein expression and clinical response.

Combination therapy consisting of cytotoxic drugs and multitargeted therapy is needed to improve the dismal prognosis of the multiresistant malignant pontine gliomas.

N/A

At diagnosis: If informed consent is obtained, a biopsy will be performed.



Phase a (after diagnosis):

Cohorts of 3 patients will receive local radiotherapy (54Gy) with 3 escalating dose levels of gemcitabine, or until the MTD has been established. The starting dose (140 mg/m2) is 80% of the MTD in adults with GBM.



Phase b (at disease progression):

Backbone therapy consists of irinotecan 125 mg/m2 IV 2-weekly and bevacizumab 10 mg/kg IV 2-weekly. Cohorts of 3 patients will receive 2 escalating dose levels of erlotinib, or until MTD has been established. If no DLT occurs during the first two courses, patients will be treated in an expanded cohort on the same dose level, until progressive disease or death occurs. The starting dose of erlotinib (65 mg/m2/day) is 80% of the MTD established in combination with temozolomide in children.



After the MTD of erlotinib has been established, everolimus is added to bevacizumab, irinotecan and erlotinib. Cohorts of 3 patients will receive 2 escalating dose levels of everolimus, or until MTD has been established. If no DLT occurs during the first two courses, patients will be treated in an expanded cohort on the same dose level, until progressive disease or death occurs.The starting dose (4 mg/m2) is 80% of the MTD in children.



Phase c (after diagnosis):

If radiosensitizer gemcitabine is feasible in combination with radiotherapy in Phase a, and concurrent treatment with irinotecan, bevacizumab, erlotinib and everolimus is feasible in Phase b, newly diagnosed patients in Phase c will receive both treatments subsequently, with a 2-week interval and drugs dosed at the established MTD’s.