Valproic Acid, Radiation, and Bevacizumab in Children With High Grade Gliomas or Diffuse Intrinsic Pontine Glioma
Condition: Glial Cell Tumors; Malignant Gliomas; Glioblastoma Multiforme; Anaplastic Astrocytoma; Gliomatosis Cerebri; Gliosarcoma; Brainstem Glioma; Diffuse Intrinsic Pontine Glioma
MeSH terms: Glioblastoma; Glioma; Astrocytoma; Gliosarcoma; Diffuse Intrinsic Pontine Glioma; Neoplasms, Neuroepithelial
Intervention: Valproic acid; Bevacizumab; Radiation therapy
Intervention description: Daily (pre-XRT, During XRT, Post-XRT and Maintenance Therapy) Started at 15 mg/kg/day divided into three doses a day as soon as patients have recovered from surgery but no later than the first day of XRT.
Dosage will be adjusted in increments of 5 mg/kg/day every 3-5 days to achieve and maintain trough concentrations between 85 and 115 mcg/ml; All patients will receive bevacizumab (10 mg/kg iv) during the maintenance phase every two weeks for a maximum duration of therapy of 24 months.; Radiation therapy will start within 30 days of the definitive surgical procedure. Primary brain malignant gliomas will receive a total dose of between 54.0 and 59.4 Gy in 30-33 fractions over 6-7 weeks. Total dose will be 54.0 Gy for completely resected tumors and brainstem gliomas. The total dose will be 59.4 if the tumor is located in the brain but not the brainstem, and the tumor was incompletely resected. Primary spinal cord malignant gliomas will receive a total dose of between 50.4-54 Gy in 28-30 fractions over 5-6 weeks.
Intervention MeSH terms: Bevacizumab; Valproic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 38.0
Sex: All
Minimum age: 3 Years
Maximum age: 21 Years
Healthy volunteers: No
Keywords: brain tumor; bevacizumab; valproic acid; radiation therapy

Summary:

      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.
    

Eligibility criteria:

        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.