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A Phase 2 Study of Valproic Acid and Radiation, Followed by Maintenance Valproic Acid and Bevacizumab in Children With Newly Diagnosed High-grade Gliomas or Brainstem Gliomas

Phase 2
3 Years
21 Years
Open (Enrolling)
Glial Cell Tumors, Malignant Gliomas, Glioblastoma Multiforme, Anaplastic Astrocytoma, Gliomatosis Cerebri, Gliosarcoma, Brainstem Glioma

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Trial Information

A Phase 2 Study of Valproic Acid and Radiation, Followed by Maintenance Valproic Acid and Bevacizumab in Children With Newly Diagnosed High-grade Gliomas or Brainstem Gliomas

With the exception of patients with brainstem gliomas, 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 and radiation therapy.

Valproic Acid (VPA): 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: 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. During this time patients will receive standard radiation therapy.

Post Radiation Phase: Patients will continue to receive VPA as during radiation. If
necessary, patients who had delays in radiation (e.g., secondary to schedule holidays or the
need to have a new mask made) will complete their radiotherapy to the total prescribed
protocol dose.

Maintenance Phase: Maintenance therapy will begin 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 by vein every two weeks, at the start of maintenance therapy.
Maintenance therapy will continue uninterrupted if all laboratory tests continue to meet
on-study criteria. 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 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 not eligible
for study entry except:

- Patients with asymptomatic intra-tumoral hemorrhage of punctate size, at the
time of diagnosis, after surgery, and/or any time during protocol therapy

- Patients with asymptomatic post-operative hemorrhage in and/or around the
surgical cavity are eligible for study entry. Additional imaging studies are not
required, but in the event a repeat MRI is performed for clinical reasons the
post-operative hemorrhage must not have progressed.

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

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

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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event free survival

Outcome Description:

To determine the efficacy of combining valproic acid (VPA) with radiation, followed by maintenance VPA and bevacizumab in children with newly diagnosed high-grade gliomas and brainstem gliomas, as measured by EFS at one-year and two-years.

Outcome Time Frame:

24 months

Safety Issue:



United States: Institutional Review Board

Study ID:




Start Date:

July 2009

Completion Date:

December 2014

Related Keywords:

  • Glial Cell Tumors
  • Malignant Gliomas
  • Glioblastoma Multiforme
  • Anaplastic Astrocytoma
  • Gliomatosis Cerebri
  • Gliosarcoma
  • Brainstem Glioma
  • brain tumor
  • bevacizumab
  • valproic acid
  • radiation therapy
  • Astrocytoma
  • Glioblastoma
  • Glioma
  • Gliosarcoma
  • Neoplasms, Neuroepithelial



University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Driscoll Children's HospitalCorpus Christi, Texas  78466
Texas Children's HospitalHouston, Texas  
Cook Children's Medical CenterFort Worth, Texas  76104
UT Health Science Center - San AntonioSan Antonio, Texas  78229
Children's Medical Center Dallas, Center for Cancer and Blood DisordersDallas, Texas  75235