Valproic Acid and Radiation Followed by Maintenance Valproic Acid and Bevacizumab in Children With High Grade Gliomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Baylor College of Medicine
Sponsor:
Information provided by (Responsible Party):
Jack Su, MD, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT00879437
First received: April 9, 2009
Last updated: March 18, 2014
Last verified: March 2014
  Purpose

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 Intervention Phase
Glial Cell Tumors
Malignant Gliomas
Glioblastoma Multiforme
Anaplastic Astrocytoma
Gliomatosis Cerebri
Gliosarcoma
Brainstem Glioma
Drug: Valproic acid
Drug: Bevacizumab
Radiation: Radiation therapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Event free survival [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    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.

  • To determine toxicities of VPA when combined with radiation and when combined with bevacizumab in the post-radiotherapy phase. [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 56
Study Start Date: July 2009
Estimated Study Completion Date: May 2019
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 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

Drug: Bevacizumab
All patients will receive bevacizumab (10mg/kg iv) during the maintenance phase every two weeks for a maximum duration of therapy of 24 months.
Other Name: 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.

Detailed Description:

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).

  Eligibility

Ages Eligible for Study:   3 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00879437

Contacts
Contact: Jack Su, MD 832-822-4306 jmsu@txch.org
Contact: Susan Blaney, MD 832-822-4586 smblaney@txch.org

Locations
United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73126
Contact: Renee McNall-Knapp, MD       rene-mcnall@ouhsc.edu   
United States, Texas
Driscoll Children's Hospital Recruiting
Corpus Christi, Texas, United States, 78411
Contact: Chris Johnson, MD       cris.johnson@dchstx.org   
Children's Medical Center Dallas, Center for Cancer and Blood Disorders Recruiting
Dallas, Texas, United States, 75235
Contact: Daniel C Bowers, MD       Daniel.Bowers@utsouthwestern.edu   
Cook Children's Medical Center Recruiting
Fort Worth, Texas, United States, 76104
Contact: Jefferey Murray, MD       jmurray@cookchildrens.org   
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Jack M Su, MD    832-822-4306    jmsu@txch.org   
Contact: Susan Blaney, MD    832-822-4586    smblaney@txch.org   
UT Health Science Center - San Antonio Recruiting
San Antonio, Texas, United States, 78284
Contact: Shafqat Shah, MD    210-567-7462    ShahS2@uthscsa.edu   
Sponsors and Collaborators
Baylor College of Medicine
  More Information

No publications provided

Responsible Party: Jack Su, MD, Study Chair, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00879437     History of Changes
Other Study ID Numbers: 24549
Study First Received: April 9, 2009
Last Updated: March 18, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Baylor College of Medicine:
brain tumor
bevacizumab
valproic acid
radiation therapy

Additional relevant MeSH terms:
Astrocytoma
Glioblastoma
Glioma
Gliosarcoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Valproic Acid
Bevacizumab
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on August 21, 2014