Valproic Acid, Radiation, and Bevacizumab in Children With High Grade Gliomas or Diffuse Intrinsic Pontine Glioma

• Sponsor: Baylor College of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00879437
• Collaborator: Cook Children's Medical Center (Other), University of Oklahoma (Other), University of Texas, Southwestern Medical Center at Dallas (Other), The University of Texas Health Science Center at San Antonio (Other), M.D. Anderson Cancer Center (Other)
• Enrollment: 38
• Locations: 6
• Arm: 1
• Actual Duration (Months): 97
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Glial Cell Tumors; Malignant Gliomas; Glioblastoma Multiforme; Anaplastic Astrocytoma; Gliomatosis Cerebri; Gliosarcoma; Brainstem Glioma; Diffuse Intrinsic Pontine Glioma	Drug: Valproic acid; Drug: Bevacizumab; Radiation: Radiation therapy	Phase 2

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Aug 30, 2015
• Actual Study Completion Date: Oct 2, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: valproic acid and radiation, followed by valproic acid and bevacizumab radiation phase (week 1-6): daily valproic acid and radiation, for approximately 6 weeks post-radiation phase (week 7-10): valproic acid daily maintenance phase (starting week 11): daily valproic acid, and bevacizumab once every 2 weeks; to continue for a maximum duration of 2 years

Drug: Valproic acid; 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; Other Names: sodium valproate ; Drug: Bevacizumab; 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.; Other Names: Avastin ; Radiation: Radiation therapy; 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.

Outcome Measures

Primary Outcome Measures

1. 1-year Event Free Survival (EFS) [12 months]

   To compare 1-year EFS for this trial versus historical series (ACNS0126 for high-grade gliomas; CCG-9941 for DIPG)

2. Percentage of Participants With Grade 3 Thrombocytopenia Assessed by CTCAE v3.0 During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

   document frequency of grade 3 thrombocytopenia, graded according to CTCAE v3.0, during concurrent valproic acid and radiation treatment for week 1-10

3. Percentage of Participants With Grade 3 Neutropenia Assessed by CTCAE v3.0 During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

   document frequency of grade 3 neutropenia, graded by CTCAE v3.0, during concurrent valproic acid and radiation treatment for the first 10 weeks

4. Percentage of Participants With Grade 3 Lymphopenia Assessed by CTCAE v3.0 During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

   document frequency of grade 3 lymphopenia, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

5. Percentage of Participants With Grade 3 Leukopenia, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

   document frequency of grade 3 leukopenia, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

6. Percentage of Participants With Grade 2 Somnolence, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

   document frequency of grade 2 somnolence, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

7. Percentage of Participants With Grade 2 Fatigue, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

   document frequency of grade 2 fatigue, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

8. Percentage of Participants With Grade 3 Weight Gain, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

   document frequency of grade 3 weight gain, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment during week 1-10

9. Percentage of Participants With Grade 2 Weight Gain, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

   document frequency of grade 2 weight gain, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

10. Percentage of Participants With Grade 2 Hypoglycemia, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

    document frequency of grade 2 hypoglycemia, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

11. Percentage of Participants With Grade 3 Lipase and Amylase Elevation, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of therapy]

    document frequency of grade 3 lipase and amylase elevation, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

12. Percentage of Participants With Grade 2 Pancreatitis, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of study]

    document frequency of grade 2 pancreatitis, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

13. Percentage of Participants With Grade 3 Dehydration, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of therapy]

    document frequency of grade 3 dehydration, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

14. Percentage of Participants With Grade 4 Radiation Necrosis, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of therapy]

    document frequency of grade 4 radiation necrosis, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

15. Percentage of Participants With Grade 2 Abdominal Pain, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of therapy]

    document frequency of grade 2 abdominal pain, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment, week 1-10

16. Percentage of Participants With Grade 2 AST Elevation, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of therapy]

    document frequency of grade 2 AST elevation, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

17. Percentage of Participants With Grade 1 Cystitis, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment [first 10 weeks of therapy]

    document frequency of grade 2 cystitis, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10

18. Percentage of Participants With Grade 3 Thrombocytopenia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 3 thrombocytopenia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to 24 months

19. Percentage of Participants With Grade 3 Neutropenia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 3 neutropenia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

20. Percentage of Participants With Grade 3 Lymphopenia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 3 lymphopenia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

21. Percentage of Participants With Grade 2 Intratumoral/Intracranial Hemorrhage, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 intratumoral/intracranial hemorrhage, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

22. Percentage of Participants With Grade 3 Fatigue, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    Document frequency of grade 3 fatigue, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

23. Percentage of Participants With Grade 2 Fatigue, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 or higher fatigue, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

24. Percentage of Participants With Grade 3 Somonolence, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    Document frequency of grade 3 somonolence, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

25. Percentage of Participants With Grade 2 Somonolence, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 somnolence, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

26. Percentage of Participants With Grade 3 Weight Gain, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    Document frequency of grade 3 weight gain, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

27. Percentage of Participants With Grade 2 Weight Gain, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of 2 weight gain, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

28. Percentage of Participants With Grade 3 Hypertension, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 3 hypertension, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

29. Percentage of Grade 2 Hypertension, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    Document frequency of grade 2 hypertension, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab

30. Percentage of Participants With Grade 2 Hypoglycemia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 hypoglycemia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

31. Percentage of Participants With Grade 3 Subacute Bone Infarction, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 3 subacute bone infarction, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

32. Percentage of Participants With Grade 3 Cellulitis, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 3 cellulitis, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

33. Percentage of Participants With Grade 2 Proteinuria, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 proteinuria, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

34. Percentage of Participants With Grade 4 Deep Vein Thrombosis, Pulmonary Embolism, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 4 deep vein thrombosis, pulmonary embolism, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

35. Percentage of Participants With Grade 2 Ocular Keratitis, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 ocular keratitis, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

36. Percentage Participants With Grade 2 Urinary Tract Infection, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 urinary tract infection, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

37. Percentage of Participants With Grade 2 Cough, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 cough, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

38. Percentage of Participants With Grade 2 Anorexia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 anorexia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

39. Percentage of Participants With Grade 2 Hypoalbuminemia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 hypoalbuminemia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

40. Percentage of Participants With Grade 2 Abdominal Pain, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab [from week 11 to up to 24 months]

    document frequency of grade 2 abdominal pain, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months

Secondary Outcome Measures

1. Median Event Free Survival (EFS) [24 months]

   estimate the median event free survival of patients receiving protocol therapy

2. Median Overall Survival (OS) [24 months]

   median OS of patients receiving protocol therapy

3. Partial Response in Diffuse Intrinsic Pontine Glioma [up to 24 months]

   partial response defined as 51% to 99% reduction in tumor size,determined using WHO bi-dimensional criteria (product of the greatest tumor diameter and its perpendicular diameter)

4. Partial Response in High-grade Gliomas [up to 24 months]

   partial response defined as 51% to 99% reduction in tumor size,determined using WHO bi-dimensional criteria (product of the greatest tumor diameter and its perpendicular diameter)

5. Complete Response in High-grade Gliomas [up to 24 months]

   complete response defined as complete disappearance of all measurable lesions,determined using WHO bi-dimensional criteria (product of the greatest tumor diameter and its perpendicular diameter)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. 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.

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

2. 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.

3. 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.

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

2. 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:

1. 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.

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

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

3. 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.

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

2. 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.

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

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

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

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

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

8. 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.

9. 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.

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73126
2	Children's Medical Center Dallas, Center for Cancer and Blood Disorders	Dallas	Texas	United States	75235
3	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
4	MD Anderson Cancer Center	Houston	Texas	United States	77030
5	Texas Children's Hospital	Houston	Texas	United States	77030
6	University of Texas Health Science Center	San Antonio	Texas	United States	78207

Sponsors and Collaborators

• Baylor College of Medicine
• Cook Children's Medical Center
• University of Oklahoma
• University of Texas, Southwestern Medical Center at Dallas
• The University of Texas Health Science Center at San Antonio
• M.D. Anderson Cancer Center

Investigators

• Study Chair: Jack Su, MD, Baylor College of Medicine

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Sep 27, 2013

More Information

Additional Information:

• Results of this trial has been peer-reviewed and published

Publications

None provided.

• Responsible Party: Jack Su, MD, Study Chair, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT00879437
• Other Study ID Numbers: 24549
• First Posted: Apr 10, 2009
• Last Update Posted: Jul 21, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Jack Su, MD, Study Chair, Baylor College of Medicine: brain tumor; bevacizumab; valproic acid; radiation therapy
• Additional relevant MeSH terms: Glioblastoma; Glioma; Astrocytoma; Gliosarcoma; Diffuse Intrinsic Pontine Glioma; Neoplasms, Neuroepithelial; Bevacizumab; Valproic Acid

Study Results

Participant Flow

Recruitment Details	Participants enrolled between September 2009 through August 2015, from five participating sites.
Pre-assignment Detail	A total of 38 eligible patients, 20 diffuse intrinsic pontine glioma (DIPG), and 18 high-grade glioma (HGG), were enrolled from five institutions.

Arm/Group Title	Diffuse Intrinsic Pontine Gliomas (DIPG)	High-grade Gliomas (HGG)
Arm/Group Description	Newly diagnosed diffuse intrinsic pontine gliomas; a total of 20 patients enrolled treatment description: radiation phase (week 1-6): daily valproic acid and radiation, for approximately 6 weeks post-radiation phase (week 7-10): valproic acid daily maintenance phase (starting week 11): daily valproic acid, and bevacizumab once every 2 weeks; to continue for a maximum duration of 2 years Valproic acid: 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 Bevacizumab: 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: 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.	Newly diagnosed high grade gliomas; a total of 18 patients enrolled treatment description: radiation phase (week 1-6): daily valproic acid and radiation, for approximately 6 weeks post-radiation phase (week 7-10): valproic acid daily maintenance phase (starting week 11): daily valproic acid, and bevacizumab once every 2 weeks; to continue for a maximum duration of 2 years Valproic acid: 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 Bevacizumab: 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: 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.
Period Title: Overall Study
STARTED	20	18
COMPLETED	19	17
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Valproic Acid and Radiation, Followed by Valproic Acid and Bevacizumab
Arm/Group Description	radiation phase (week 1-6): daily valproic acid and radiation, for approximately 6 weeks post-radiation phase (week 7-10): valproic acid daily maintenance phase (starting week 11): daily valproic acid, and bevacizumab once every 2 weeks; to continue for a maximum duration of 2 years Valproic acid: 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 Bevacizumab: 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: 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.
Overall Participants	38
Age (Count of Participants)
<=18 years	37 97.4%
Between 18 and 65 years	1 2.6%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	18 47.4%
Male	20 52.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 26.3%
Not Hispanic or Latino	28 73.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 5.3%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 13.2%
White	29 76.3%
More than one race	2 5.3%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	38 100%

Outcome Measures

1. Primary Outcome

Title	1-year Event Free Survival (EFS)
Description	To compare 1-year EFS for this trial versus historical series (ACNS0126 for high-grade gliomas; CCG-9941 for DIPG)
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

1 patient with DIPG not evaluable due to early death (did not complete valproic acid and radiation) related to a surgical complication (unrelated to protocol therapy) 1 patient with HGG not evaluable due to non-compliance with protocol therapy

Arm/Group Title	Diffuse Intrinsic Pontine Glioma	High-grade Gliomas
Arm/Group Description	20 eligible patients, 19 evaluable patients	18 eligible patients, 17 evaluable patients
Measure Participants	19	17
Number (95% Confidence Interval) [percentage of participants]	12 31.6%	24 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diffuse Intrinsic Pontine Glioma, High-grade Gliomas
	Comments	comparing 1-year EFS of DIPG on this trial versus historical control (1-year EFS of 17% from CCG-9941; PMID 12177103) comparing 1-year EFS of HGG on this trial versus historical control (1-year EFS of 36% from ACNS0126; PMID 21339192)
	Type of Statistical Test	Non-Inferiority
	Comments	if 19 evaluable patients enrolled for DIPG, study is powered at 80% to detect a 20% improvement in 1-year EFS compared to historical control if 21 evaluable patients enrolled for HGG, study is powered at 80% to detect a 20% improvement in 1-year EFS compared to historical control
Statistical Test of Hypothesis	p-Value	< 0.05
	Comments
	Method	Log Rank
	Comments	one sample log-rank

2. Primary Outcome

Title	Percentage of Participants With Grade 3 Thrombocytopenia Assessed by CTCAE v3.0 During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 3 thrombocytopenia, graded according to CTCAE v3.0, during concurrent valproic acid and radiation treatment for week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

3. Primary Outcome

Title	Percentage of Participants With Grade 3 Neutropenia Assessed by CTCAE v3.0 During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 3 neutropenia, graded by CTCAE v3.0, during concurrent valproic acid and radiation treatment for the first 10 weeks
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	3 7.9%

4. Primary Outcome

Title	Percentage of Participants With Grade 3 Lymphopenia Assessed by CTCAE v3.0 During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 3 lymphopenia, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	5 13.2%

5. Primary Outcome

Title	Percentage of Participants With Grade 3 Leukopenia, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 3 leukopenia, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

6. Primary Outcome

Title	Percentage of Participants With Grade 2 Somnolence, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 2 somnolence, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

7. Primary Outcome

Title	Percentage of Participants With Grade 2 Fatigue, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 2 fatigue, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	3 7.9%

8. Primary Outcome

Title	Percentage of Participants With Grade 3 Weight Gain, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 3 weight gain, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment during week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

9. Primary Outcome

Title	Percentage of Participants With Grade 2 Weight Gain, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 2 weight gain, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	4 10.5%

10. Primary Outcome

Title	Percentage of Participants With Grade 2 Hypoglycemia, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 2 hypoglycemia, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

11. Primary Outcome

Title	Percentage of Participants With Grade 3 Lipase and Amylase Elevation, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 3 lipase and amylase elevation, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

12. Primary Outcome

Title	Percentage of Participants With Grade 2 Pancreatitis, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 2 pancreatitis, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

13. Primary Outcome

Title	Percentage of Participants With Grade 3 Dehydration, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 3 dehydration, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

14. Primary Outcome

Title	Percentage of Participants With Grade 4 Radiation Necrosis, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 4 radiation necrosis, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

15. Primary Outcome

Title	Percentage of Participants With Grade 2 Abdominal Pain, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 2 abdominal pain, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment, week 1-10
Time Frame	first 10 weeks of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

16. Primary Outcome

Title	Percentage of Participants With Grade 2 AST Elevation, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 2 AST elevation, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

17. Primary Outcome

Title	Percentage of Participants With Grade 1 Cystitis, Assessed by CTCAE v3.0, During Concurrent Valproic Acid and Radiation Treatment
Description	document frequency of grade 2 cystitis, assessed by CTCAE v3.0, during concurrent valproic acid and radiation treatment from week 1-10
Time Frame	first 10 weeks of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

18. Primary Outcome

Title	Percentage of Participants With Grade 3 Thrombocytopenia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 3 thrombocytopenia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	3 7.9%

19. Primary Outcome

Title	Percentage of Participants With Grade 3 Neutropenia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 3 neutropenia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	3 7.9%

20. Primary Outcome

Title	Percentage of Participants With Grade 3 Lymphopenia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 3 lymphopenia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	3 7.9%

21. Primary Outcome

Title	Percentage of Participants With Grade 2 Intratumoral/Intracranial Hemorrhage, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 intratumoral/intracranial hemorrhage, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

22. Primary Outcome

Title	Percentage of Participants With Grade 3 Fatigue, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	Document frequency of grade 3 fatigue, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	3 7.9%

23. Primary Outcome

Title	Percentage of Participants With Grade 2 Fatigue, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 or higher fatigue, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	7 18.4%

24. Primary Outcome

Title	Percentage of Participants With Grade 3 Somonolence, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	Document frequency of grade 3 somonolence, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

25. Primary Outcome

Title	Percentage of Participants With Grade 2 Somonolence, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 somnolence, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	2 5.3%

26. Primary Outcome

Title	Percentage of Participants With Grade 3 Weight Gain, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	Document frequency of grade 3 weight gain, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	2 5.3%

27. Primary Outcome

Title	Percentage of Participants With Grade 2 Weight Gain, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of 2 weight gain, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

28. Primary Outcome

Title	Percentage of Participants With Grade 3 Hypertension, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 3 hypertension, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	4 10.5%

29. Primary Outcome

Title	Percentage of Grade 2 Hypertension, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	Document frequency of grade 2 hypertension, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	8 21.1%

30. Primary Outcome

Title	Percentage of Participants With Grade 2 Hypoglycemia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 hypoglycemia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

31. Primary Outcome

Title	Percentage of Participants With Grade 3 Subacute Bone Infarction, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 3 subacute bone infarction, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

32. Primary Outcome

Title	Percentage of Participants With Grade 3 Cellulitis, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 3 cellulitis, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

33. Primary Outcome

Title	Percentage of Participants With Grade 2 Proteinuria, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 proteinuria, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	2 5.3%

34. Primary Outcome

Title	Percentage of Participants With Grade 4 Deep Vein Thrombosis, Pulmonary Embolism, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 4 deep vein thrombosis, pulmonary embolism, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

35. Primary Outcome

Title	Percentage of Participants With Grade 2 Ocular Keratitis, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 ocular keratitis, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

36. Primary Outcome

Title	Percentage Participants With Grade 2 Urinary Tract Infection, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 urinary tract infection, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

37. Primary Outcome

Title	Percentage of Participants With Grade 2 Cough, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 cough, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

38. Primary Outcome

Title	Percentage of Participants With Grade 2 Anorexia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 anorexia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	3 7.9%

39. Primary Outcome

Title	Percentage of Participants With Grade 2 Hypoalbuminemia, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 hypoalbuminemia, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	3 7.9%

40. Primary Outcome

Title	Percentage of Participants With Grade 2 Abdominal Pain, Assessed by CTCAE v3.0, During Maintenance Therapy of Valproic Acid and Bevacizumab
Description	document frequency of grade 2 abdominal pain, assessed by CTCAE v3.0, during maintenance therapy of valproic acid and bevacizumab, from week 11 to up to 24 months
Time Frame	from week 11 to up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
Measure Participants	38
Count of Participants [Participants]	1 2.6%

41. Secondary Outcome

Title	Median Event Free Survival (EFS)
Description	estimate the median event free survival of patients receiving protocol therapy
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Diffuse Intrinsic Pontine Glioma	High-grade Gliomas
Arm/Group Description	20 eligible patients, 19 evaluable patients	18 eligible patients, 17 evaluable patients
Measure Participants	19	17
Median (95% Confidence Interval) [months]	7.8	9.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diffuse Intrinsic Pontine Glioma
	Comments
	Type of Statistical Test	Other
	Comments	The Kaplan-Meier method was used to estimate the median EFS for each cohort with 95% confidence intervals. All analyses were performed in SAS version 9.4 statistical software (SAS Institute Inc) and R (https://cran.r-project.org/).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		The Kaplan-Meier method was used to estimate the median EFS for each cohort with 95% confidence intervals.

42. Secondary Outcome

Title	Median Overall Survival (OS)
Description	median OS of patients receiving protocol therapy
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Diffuse Intrinsic Pontine Glioma	High-grade Gliomas
Arm/Group Description	20 eligible patients, 19 evaluable patients	18 eligible patients, 17 evaluable patients
Measure Participants	19	17
Median (95% Confidence Interval) [months]	10.3	12.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diffuse Intrinsic Pontine Glioma, High-grade Gliomas
	Comments
	Type of Statistical Test	Other
	Comments	The Kaplan-Meier method was used to estimate the one-year EFS for each cohort with 95% confidence intervals. All analyses were performed in SAS version 9.4 statistical software (SAS Institute Inc) and R (https://cran.r-project.org/).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		The Kaplan-Meier method was used to estimate the one-year EFS for each cohort with 95% confidence intervals.

43. Secondary Outcome

Title	Partial Response in Diffuse Intrinsic Pontine Glioma
Description	partial response defined as 51% to 99% reduction in tumor size,determined using WHO bi-dimensional criteria (product of the greatest tumor diameter and its perpendicular diameter)
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Diffuse Intrinsic Pontine Glioma
Arm/Group Description	20 eligible patients, 16 evaluable patients
Measure Participants	16
Count of Participants [Participants]	8 21.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Diffuse Intrinsic Pontine Glioma
	Comments	partial response defined as 51% to 99% reduction in tumor size,determined using WHO bi-dimensional criteria (product of the greatest tumor diameter and its perpendicular diameter)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Not applicable (8 partial responses in 16 patients = 50%)

44. Secondary Outcome

Title	Partial Response in High-grade Gliomas
Description	partial response defined as 51% to 99% reduction in tumor size,determined using WHO bi-dimensional criteria (product of the greatest tumor diameter and its perpendicular diameter)
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-grade Gliomas
Arm/Group Description	18 eligible patients, 14 evaluable patients
Measure Participants	14
Count of Participants [Participants]	5 13.2%

45. Secondary Outcome

Title	Complete Response in High-grade Gliomas
Description	complete response defined as complete disappearance of all measurable lesions,determined using WHO bi-dimensional criteria (product of the greatest tumor diameter and its perpendicular diameter)
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-grade Gliomas
Arm/Group Description	18 eligible patients, 14 evaluable patients
Measure Participants	14
Count of Participants [Participants]	1 2.6%

Adverse Events

Time Frame	up to 24 months
Arm/Group Title	38 Eligible Patients
Arm/Group Description	38 eligible patients, regardless of tumor type
All Cause Mortality
	38 Eligible Patients
	Affected / at Risk (%)	# Events
Total	37/38 (97.4%)
Serious Adverse Events
	38 Eligible Patients
	Affected / at Risk (%)	# Events
Total	4/38 (10.5%)
Gastrointestinal disorders
amylase and lipase elevation	1/38 (2.6%)	1
Musculoskeletal and connective tissue disorders
subacute bone infarction	1/38 (2.6%)	1
Nervous system disorders
radiation necrosis	1/38 (2.6%)	1
intratumoral hemorrhage	1/38 (2.6%)	1
Other (Not Including Serious) Adverse Events
	38 Eligible Patients
	Affected / at Risk (%)	# Events
Total	33/38 (86.8%)
Blood and lymphatic system disorders
thormbocytopenia	3/38 (7.9%)	5
neutropenia	3/38 (7.9%)	4
lymphopenia	3/38 (7.9%)	3
Cardiac disorders
hypertension	12/38 (31.6%)	18
Metabolism and nutrition disorders
weight gain	3/38 (7.9%)	5
anorexia	3/38 (7.9%)	3
hypoalbuminemia	3/38 (7.9%)	3
Nervous system disorders
somnolence	3/38 (7.9%)	4
fatigue	10/38 (26.3%)	11
Renal and urinary disorders
proteinuria	2/38 (5.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.