TOPNOC 001 (H-24549), A Phase II Study of Valproic Acid and Radiation, Followed by Maintenance Valproic Acid and Bevacizumab in Children with Newly Diagnosed High-Grade Gliomas or Brainstem Gliomas
- Children’s Medical Center (Dallas, Plano, Southlake)
With the exception of patients with brainstem gliomas, all patients should have maximal surgical resection performed prior to study entry. Submission of frozen tumor is strongly encouraged. after recovery from neurosurgery and signing consent, all patients will start valproic acid and radiation therapy.
Valproic acid (VPa) will be started at 15 mg/kg/day divided tid up to 48 hours prior to the initiation of radiation therapy, but no later than the first day of radiation therapy. Patients may begin VPa and radiation therapy as soon as they have adequately recovered from their definitive surgical resection or biopsy, but no later than 30 days after surgery.
During XRT Phase:
VPa will be continued daily without interruption during radiation therapy. VPa doses will be adjusted in increments of 5 mg/kg/day every 3-5 days to achieve and maintain trough concentrations between 85 to 115 mcg/ml. During this time, patients will receive standard conformal radiation therapy. Radiation should begin within 30 days from surgery or radiographic diagnosis, whichever is the later date.
Post XRT Phase:
Patients will continue to receive VPa as during XRT. For patients that required discontinuation of VPa during radiation, they will not resume VPa until start of maintenance therapy. if necessary, patients who had interruptions in XRT (e.g., secondary to scheduled holidays or the need to have a new mask made) will complete their radiotherapy to the total prescribed protocol dose.
Maintenance therapy will begin 11 weeks after the initiation of radiation therapy. Patients will continue VPa daily during the 4-week break and throughout maintenance therapy. all patients will start bevacizumab, 10 mg/kg iv every two weeks, at the start of maintenance therapy. in the absence of unacceptable toxicity or disease progression, patients will continue to receive protocol treatment for a maximum total duration of two years (including the XRT phase).
Please see section 10.1 of the protocol.
Patients must be >= 3 years and <= 21 years of age at the time of study enrollment. Patients must have histologic verifications of a glioblastoma multiforme, anaplastic astrocytoma, gliomatosis cerebri (WHO grade III or IV glioma with diffuse parenchymal and/or leptomeningeal involvement), or gliosarcoma at the time of study enrollment. Patients with newly diagnosed intrinsic brainstem gliomas are eligible without histologic confirmation. Patients must begin protocol therapy within 30 days of definitive surgery. Patients must have Karnofsky Performance Score (for patients > 16 years of age) or Lansky Performance Score (for patients < 16 years of age) > 50% assessed within two weeks of study enrollment. Patients with intra-tumoral and/or CNS hemorrhage are eligible for study entry if they fulfill the following guideline: patients with an asymptomatic intra-tumoral/intracranial hemorrhage measuring <1 cm in the widest dimension on MRI, at the time of diagnosis, after surgery, and/or any time prior to study enrollment, are eligible; hemorrhage must not have progressed on MRI prior to initiation of protocol therapy; patients must not have developed progressive symptoms thought to be related to the intratumoral/intracranial hemorrhage prior to initiation of protocol therapy, Patients with > 1 asymptomatic intra-tumoral/intracranial hemorrhage but all measuring < 1 cm in the widest dimension on MRI are eligible if they fulfill the guidelines described above. Patients with asymptomatic post-operative hemorrhage in and/or around the surgical cavity are eligible for study entry if they otherwise fulfill the guidelines described above.
Patients with an intra-tumoral hemorrhage > 1 cm at diagnosis but who demonstrates minimal post-operative hemorrhage as described above after tumor resection areis eligible for study. Patients must not have received any prior chemotherapy, radiation therapy, biologic therapy, or bone marrow transplant. For patients who require anticonvulsant prior to study entry, it is permissible to start VPA, but trough VPA concentration must be repeated within 48 hours of study entry. Adequate bone marrow, liver, renal, pancrease, and coagulation function. Protocol therapy is defined as the initiation of valproic acid for antitumor purposes. Valproic acid therapy should be initiated up to 48 hours prior to the initiation of radiotherapy but no later than the first day of radiotherapy. All patients and/or their legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.