Currently, there are few effective treatments for the following aggressive brain tumors: glioblastoma multiforme, anaplastic astrocytoma, gliomatosis cerebri, gliosarcoma, or brainstem glioma. Surgery and radiation can generally slow down these aggressive brain tumors, but in the majority of patients, these tumors will start growing again in 6-12 months. Adding chemotherapy drugs to surgery and radiation does not clearly improve the cure rate of children with malignant gliomas.

The investigators are conducting this study to see if the combination of valproic acid and bevacizumab (also known as AvastinTM) with surgery and radiation will shrink these brain tumors more effectively and improve the chance of cure.

With the exception of patients with diffuse intrinsic pontine glioma (DIPG), all patients should have the maximal surgical resection that can be safely performed prior to study entry. Submission of frozen tumor is strongly encouraged. After recovery from neurosurgery, all patients will start valproic acid (VPA) and radiation therapy.

VPA will be started at 15 mg/kg/day divided into three doses a day, ideally 48 hours prior to first day of radiation therapy, but no later than the first day of radiation therapy. Patients may also begin VPA sooner if they have post-operative seizures and require an anti-convulsant.

Radiation phase (week 1-6): Radiation therapy should begin within 30 days of definitive surgery or radiographic diagnosis, whichever is the later date. Date of surgery or radiographic diagnosis is considered day 1, and radiation should start no later than day 31. 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. All patients will receive standard radiation therapy which will last approximately six week.

Post Radiation Phase (week 7-10): Patients will continue to receive VPA as previously dosed during radiation to maintain a trough concentration of 85-115 mcg/ml.

Maintenance Phase (starting week 11): Maintenance therapy will begin approximately 4 weeks after completion of radiation or week 11, whichever comes first.

Patients will continue VPA daily during maintenance therapy. All patients will start bevacizumab, 10 mg/kg intravenously every two weeks, at the start of maintenance therapy (week 11). Maintenance therapy will continue uninterrupted unless treatment related toxicities requires study drug interruption. In the absence of unacceptable toxicity or disease progression, patients will continue to receive protocol treatment for a maximum duration of two years (including the radiation phase).

Inclusion Criteria:

1. Patient must be greater than or equal to 3 years and less than or equal to 21 years of age at the time of study enrollment.

2. 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, defined as tumors with a pontine epicenter and diffuse rather than focal involvement of th pons, with or without extension to adjacent medulla or midbrain, are eligible without histologic confirmation. Patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be a grade III or IV glioma (anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma).

3. Patients must have Karnofsky Performance Score (for patients greater than 16 years of age) or Lansky Performance Score (for patients less than or equal to 16 years of age) greater than or equal to 50% assessed within two weeks of study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

4. Patients must not have received any prior chemotherapy, radiation therapy, biologic therapy, or bone marrow transplant. Surgery and dexamethasone are permitted prior to study entry. In patients who require anti-convulsant prior to study entry, it is permissible to start VPA, but trough VPA concentration must be repeated within 48 hours of study entry.

5. Patients must have adequate bone marrow function defined as: - Hgb greater than or equal to 8 gm/dL (transfusion independent) - Platelet count greater than or equal to 100,000/mm3 (transfusion independent) - Absolute neutrophil count (ANC) greater than or equal to 1,000/ mm3

6. Patients must have adequate liver function defined as:

   • Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 times institutional upper limit of normal (ULN) for age.
   • SGPT (ALT) less than or equal to 2.5 times institutional ULN for age.
   • Serum albumin greater than or equal to 2 g/dL.

7. Patients must have adequate renal function defined as:

   • Urine protein (albumin)/creatinine ratio of less than 1.0

   • Creatinine clearance or radioisotope GFR greater than or equal to 70 ml/min/1.73m2 OR

   • A serum creatinine based on age and gender as follows:

     • 2 to less than 6 years of age: 0.8 mg/dL for male and female
     • 6 to less than 10 year of age: 1.0 mg/dL for male and female
     • 10 to less than 13 years of age: 1.2 mg/dL for male and female
     • 13 to less than 16 years of age: 1.5 mg/dL for males and 1.4 for females
     • Greater than or equal to 16 years of age: 1.7 mg/dL for males and 1.4 mg/dL for females

   Note: The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

8. Amylase and lipase less than or equal to 2 times institutional ULN for age.

9. Patients must not have a prolonged PT or PTT (greater than 1.2 times the institutional upper limit of normal), and the INR must be less than 1.5.

10. MRI ECHO gradient sequences are required to evaluate for the presence or absence of CNS hemorrhage. Patients with intra-tumoral and/or CNS hemorrhage are eligible for study entry if they fulfill the following guidelines:

    • Patients with an asymptomatic intra-tumoral/intracranial hemorrhage measuring less than 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 mut not have developed progressive symptoms thought to be related to the intra-tumoral/intracranial hemorrhage prior to initiation of protocol therapy.
    • Patients with a greater than 1 asymptomatic intra-tumoral/intracranial hemorrhage but all measuring less than 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 greater than 1 cm at diagnosis but who demonstrate minimal post-operative hemorrhage as described above after tumor resection are eligible for study.

11. Patients must begin radiation therapy within 30 days of surgery or radiographic diagnosis, whichever is the later date.

12. All patients and/or their legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria:

1. Females of reproductive potential must not be pregnant or lactating. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

2. Patients with active or history of cardiac (CHF, myocardial infarction, myocarditis) disease are excluded from this trial.

3. Patients receiving any of the following medications are not eligible for study entry: a. Anti-cancer therapy or investigational agents b.Anti-coagulants (except for heparin to maintain the patency of central venous catheters). c.Growth factors for white blood cell, red blood cell or platelet support d.Aspirin (> 81 mg/day) e.Non-steroidal anti-inflammatory drugs f.Clopidogrel (Plavix), Dypiramidole (Persantine), or any other drug that inhibits platelet function g. Anti-convulsants: patients on any anti-convulsant with the exception of VPA are eligible for study entry. It is strongly recommended that a neurology consult be obtained to enable discontinuation of all anti-convulsant other than VPA, whenever possible.

4. Patients who have an uncontrolled infection are not eligible.

5. Patients with inadequately controlled systemic hypertension (SBP and/or DBP greater than 95th percentile for age and height)

6. Patients with a prior history of hypertensive crisis and/or hypertensive encephalopathy

   If a BP measurement prior to registration is greater than 95th percentile for age and height, it must be rechecked and documented to be less than 95th percentile for age and height prior to registration. If a patient falls between the height or weight percentiles, site should average the value as appropriate. For patients greater than or equal to 18 years, use adult normal ranges for blood pressure. Patients with hypertension are eligible if their blood pressures become less than 95th percentile after anti hypertensive medications.

7. Prior Ischemic Events: Patients with a history of stroke, myocardial infarction, or unstable angina within 6 months prior to registration are not eligible.

8. Vascular Disease: Patients with significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to registration will not be eligible.

9. Patients with a history of hemoptysis, bleeding diathesis, known platelet disorder, or coagulopathy are not eligible.

10. Patients with a history of abdominal fistula or GI perforation within 6 months prior to registration are not eligible.

11. Patients with a known or suspected urea cycle or other metabolic disorder are not eligible.

12. Patients with abnormality of the tibial metaphyseal plate on plain X-ray prior to study entry are not eligible.

13. Patients with a history of a serious non-healing wound, ulcer, or bone fracture are not eligible.

14. Patients with any clinically significant systemic illness, including serious infection, pulmonary, hepatic, or other organ impairment, that would compromise tolerance and/or timely completion of protocol therapy.

16. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements and/or follow-up studies of this trial.

17. Patients with a known hypersensitivity to any component of bevacizumab are not eligible for this trial.

Results of this study has been published (Su JM, et al., Pediatr Blood Cancer 2020: 67:e28283). Additional de-identified information can be provided upon request.

Results of this study has been published (Su JM, et al., Pediatr Blood Cancer 2020: 67:e28283). Additional de-identified information can be provided upon request.

Pediatr Blodd Cancer 2020 Jun;67(6):e28283. doi: 10.1002/pbc.28283. PMID: 32285998.