Official Title: “Valproate (Valproic Acid) and Etoposide for Patients With Progressive, Relapsed or Refractory Neuronal Tumors and Brain Metastases”

Primary Objective:

1. Determine the interindividual range and median of individual maximum tolerated doses of valproic acid administered as one time evening dose in conjunction with a fixed (standard) dose oral etoposide of 50mg/m2 for four different age groups.

Secondary Objectives:

1. Determine the qualitative and quantitative toxicity and reversibility of toxicity of valproic acid in conjunction with oral etoposide,

2. To investigate the clinical pharmacokinetics of valproic acid when given in conjunction with oral etoposide,

3. To describe quality of life of patients with relapsed, or progressive central and peripheral nervous system tumors when treated with oral valproic acid and etoposide

4. To observe and describe the response pattern of progressive central nervous system tumors treated with oral valproic acid and etoposide,

5. To observe and describe event free survival time and overall survival time of patients with relapsed, or progressive central nervous system tumors when treated with oral valproic acid and etoposide,

6. To determine if histone deacetylase activity and topoisomerase expression in lymphocytes of patients is related to valproic acid levels, and

7. To determine, if the individual maximal tolerated dose (iMTD) depends on the initial performance status of the patient in the beginning of the treatment.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Study Primary Completion Date: January 2010

STUDY DRUGS:

ETOPOSIDE is designed to block cell growth by breaking the DNA, which may cause the cells to die.

VALPROIC ACID was first designed as an anti-seizure medication. It was also found to change cancer cells and make them more sensitive to etoposide.

SCREENING TESTS:

Before you start treatment on this study, you will have "screening tests". These tests help your doctor decide if you are eligible to take part in this study: - Your medical history will be reviewed. - You will have a physical exam. - You will be asked how well you are able to perform the normal activities of daily living (performance status evaluation). - You will complete a questionnaire about your activities or daily living. The questionnaire will take about 5 to 10 minutes to complete. - Blood (about 2-3 tablespoons) will be drawn for routine tests. This routine blood draw may include a pregnancy test for women who are able to have children. To be eligible to take part in this study, the pregnancy test must be negative. - Urine will be collected to check for metabolic disease. This urine sample may include a pregnancy test for women who are able to have children. To be eligible to take part in this study, the pregnancy test must be negative. - You will have a magnetic resonance imaging (MRI) or computed tomography (CT) scan. - If your doctor thinks it is necessary, you may have additional blood and/or urine tests.

DOSE ESCALATION:

When you begin the study, you will begin receiving the lowest dose level of valproic acid.

Every week, the dose will be increased. This will continue until the maximum tolerated dose (MTD) is found. Once the MTD is found, you will continue to receive that dose level of valproic acid while you are on study. However, if your doctor thinks it is necessary, this dose level could be lowered.

The amount of etoposide that you take while on study will not change.

STUDY DRUG ADMINISTRATION:

You will receive valproic acid and etoposide every evening in pill form.

If you have difficulty swallowing the pills, etoposide can be given in the evening in liquid form. Valproic acid can be given in liquid form, divided in 2 doses per day, 1 in the morning and 1 in the evening.

STUDY VISITS DURING DOSE ESCALATION:

While your valproic acid medication is being increased, every week you will have a physical exam and blood (about 2-3 tablespoons)and urine will be collected for routine tests.

Every other month, you will have CT or MRI scans to check the status of the disease. You may have these tests and procedures more often if your doctor thinks it is necessary.

STUDY VISITS AFTER MAXIMUM TOLERATED DOSE (MTD):

Every month, you will have a physical exam, and blood (about 2-3 tablespoons) and urine will be collected for routine tests.

Every other month, you will have CT or MRI scans to check the status of the disease.

Every 6 months, a portion of the blood or urine collected for routine tests will be used for a pregnancy test for women who are able to have children.

You may have these tests and procedures more often if your doctor thinks it is necessary.

LENGTH OF STUDY:

You may remain on study for up to 2 years. You will be taken off study if the disease gets worse or intolerable side effects occur.

END-OF-STUDY VISIT:

Once you are off study, you will have an end-of-study visit. At this visit, the following tests and procedures will be performed: - You will have a physical exam. - Blood (about 2-3 tablespoons) and urine will be collected for routine tests. - If your doctor thinks it is necessary, you will have a CT or MRI to check the status of the disease.

FOLLOW-UP:

Once you are off study, you will be contacted by telephone once a year to check the status of the disease. The phone call will take 2-3 minutes.

This is an investigational study. Etoposide is FDA approved and commercially available.

Valproic acid is FDA approved and commercially available for the treatment of seizures. The use of these drugs together is investigational. Up to 120 patients will take part in this multicenter study. Up to 100 will be enrolled at M. D. Anderson.

Intervention(s) in this Clinical Trial

• Drug: Valproate
  • 10 mg/kg PO Daily
• Drug: Etoposide
  • 50 mg/m^2 PO Daily

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Valproate + Etoposide

Primary Measures

• To find the highest tolerated dose of valproate (valproic acid) that can be given in combination with etoposide.
  • Time Frame: 2.5 Years
    Safety Issue?: No

Secondary Measures

• To learn about the side effects that may occur and the affect that the drugs may have on the tumor.
  • Time Frame: 2.5 Years
    Safety Issue?: Yes

Inclusion Criteria:

• 1. Diagnosis of a neuroectodermal tumor of the central or peripheral nervous system including but not limited to glioma, astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma, medulloblastoma, pineoblastoma, pineocytoma, ependymoma, choroid plexus papilloma, atypical choroid plexus papilloma, choroid plexus carcinoma, teratoma, teratocarcinoma, germinoma, marker positive malignant germ cell tumors of the central nervous system, embryonal cell carcinoma, 2. (continued from #1): yolk sac carcinoma of the central nervous system, neurocytoma, atypical rhabdoid tumor (ATRT), retinoblastoma, neuroblastoma, neurosarcoma, ganglioglioma, gliofibroma, primary neuroectodermal tumor (PNET), optic glioma, and diffuse intrinsic pontine glioma. Eligible are also brain metastases of malignant non-CNS tumors such as lung, prostate, or ovarian cancer.
• 3. Disease confirmation: Diagnosis has to be confirmed with original histology for each diagnosis, except for (a) diffuse intrinsic pontine glioma, (b) optic glioma, (c) marker positive malignant germ cell tumors, and (d) catecholamine positive neuroblastoma. For those diagnoses, the need for histology may be substituted with: (a) MRI diagnosis-neuroimaging is sufficient for diffuse intrinsic pontine glioma; (b)
• MRI diagnosis-neuroimaging is sufficient for diagnosis of optic glioma;
• 4. (continued from #3): (c) Contrast-enhancing tumor located either in pineal or suprasellar region in conjunction with elevation of alpha feto-protein of 5x the normal values is sufficient for the diagnosis of a marker positive germ cell tumor;
• (d) Homovanillic acid (HVA) and Vanillylmandelic acid (VMA) elevation above 5x normal in urin, in combination with measurable peripheral tumor is sufficient for the diagnosis of neuroblastoma. No exception are: retinoblastomas, which are frequently treated first without histology but operated later.
• 5. (continued from #4): Those tumors still require one histological or cytological result confirming the diagnosis. Diagnosis confirmation is only necessary once, typically during front-line treatment. Recurrent disease or metastatic disease does not require repeated histological confirmation for the purpose of this study.
• 6. Disease progression and treatment failure: Patient must have failed standard front-line treatment and must not be eligible for any higher-priority therapy. Failure is defined by clear evidence of tumor progression, recurrence or metastases during or after completion of standard front-line treatment. Standard treatment is defined as the most frequently used treatment or alternatives of similar intensity.
• 7. (continued from #6): For infant brain tumors this includes chemotherapy following one of the infant brain tumor protocols of the collaborative groups such as COG, SIOP or GPOH, and previous radiation is not required in this age group.For older children with medulloblastoma and malignant germ cell tumors this includes intensive chemotherapy and radiation. For patients with high grade glioma or pontine glioma this includes radiation with or without chemotherapy. For patients with low grade glioma, older than 3 years of age this includes both chemotherapy and radiation.
• 8. Negative pregnancy test for female patients between menarche and menopause is required.
• 9. Patients must sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of the hospital.
• 10. Measurable tumor is not mandatory. Patients with recurrent tumors that have been resected and are now without any evidence of disease but known to be yet incompletely treated because the tumor is expected to recur, are eligible.
• 11. Life expectancy of more than eight weeks is not mandatory for enrollment. However, patients, who expire on study earlier than six weeks after enrolment, will be considered non-eligible for the analysis of response.
• 12. Age limit: There is no age limit on the study. It is primarily targeted to the pediatric population, but adult patients are welcome.
• 13. Functional Status: There is no limit for functional status on this study. It is a secondary objective of this study to find out if the frequently assumed higher toxicity in patients with low performance status is correct.
• 14. Patients may have measurable or non-measurable disease.
• 15. Patients may be on or may not be on dexamethasone treatment.
• 16. Patients with previous treatment with intravenous etoposide are not excluded.
• 17. Approval for the use of this treatment regimen by the individual's Human Rights
• Committee or Institutional Review Board (IRB) must be obtained in accordance with the individual institutional policies and the local, state, and national rules, regulations and laws, is mandatory for an enrolling institution. The documentation of this approval must be on file at the MDAnderson Cancer Center Pediatric Oncology
• Trials Office prior to enrollment of any patient on study.

Exclusion Criteria:

• 1. Neurofibromatosis type I
• 2. Known or suspected inborn errors of metabolism, such as ornithine transcarbamylase deficiency or having a parent or sibling with an inborn error of metabolism has been linked to a higher incidence of acute liver failure on valproic acid. Abnormal laboratory values coming up with the first screening such as too low carnitine, or abnormal organic acid levels in urine screening, need to be explored, identified as being not due to inborn errors of metabolism, treated, and normalized before the patient can receive valproic acid on this study.
• 3. (continued from #2): Once the laboratory values are explained, treated and normalized, and do not indicate an inborn error the patient is not excluded any more.
• 4. Patients who require any of the following medications are excluded from enrollment:
• Carbamazepine, Oxcarbazepine, Primidone, Phenobarbital, Topiramate, Carbapenem antibiotics (ertaenenm, imipenem, meropenem), Felbamate, Isoniazid, Lamotrigine, Acrolid antibiotics (clarithromycin, erythromycin, troleandomycin, azithromycin), Zidovudine, Risperidone, Salicylates, as these medications have a known interaction with valproic acid. However, ther is no "wash out period" if patients can be taken off these medications (different from what is otherwise common for previous chemotherapy).
• 5. (continued from #4): Patients may be enrolled as soon as they are taken off the not allowed drug from the list above. If an indication for these prohibited drugs occurs during treatment (such as infections to be treated with carbapenem antibiotics) while a patient is on study with valproic acid and etoposide, the patient has to be taken off study formally. Valproic acid dose levels and toxicity are to be closely monitored. Continuing or not continuing valproic acid during the carbapenem treatment is at the discretion of the treating physician while the patient is off study.
• 6. Patients who take antiviral medications usually targeted to treat HIV infections or have clinical signs for acquired immunodeficiency syndrome (AIDS) are excluded. HIV testing is not mandatory.
• 7. Patients who had previous chemotherapy less than three weeks (21 days) ago cannot be enrolled: Patients must have been off all previous chemotherapy or radiotherapy for the 3 weeks prior to initiation of study treatment and recovered from toxic effects of that therapy.
• 8. Patients which are on a stable dose for valproic acid prior to enrolment are not eligible
• 9. Patients which have been treated with valproic acid or other histone deacetylase inhibitors such as SAHAa or MS275 and the treatment has failed to control the tumor are not eligible
• 10. Patient which have been treated with oral continuous etoposide previously and the treatment has failed to control the tumor are not eligible
• 11. White blood cell count below 2,000/µL excludes patient from enrollment
• 12. Absolute neutrophil count below 700/uL excludes patient from enrolment
• 13. Platelet count below 80,000 excludes patient from enrolment
• 14. Pancreatitis with amylase above two times the upper normal limit excludes patient from enrolment, (even in the absence of clinical signs of pancreatitis)
• 15. Somnolence at daytime for more than 6 hours excludes patient from enrollment
• 16. Bilirubin total > 1.5 mg/dL excludes patient from enrollment
• 17. ALT > 2.5 times upper normal value excludes patient from enrolment
• 18. AST >2.5 x upper normal value excludes patients from enrolment
• 19. NH3 (ammonia) elevation above 50 mM suggests a metabolic inborn error of metabolism with increased risk for liver failure on valproate and excludes patient from enrollment.
• 20. Frequent vomiting or medical condition that could interfere with oral medication intake (e.g., partial bowel obstruction) excludes patient from enrollment
• 21. Pregnant or nursing women cannot be enrolled.
• 22. Women of childbearing potential who are not using an effective method of contraception cannot be enrolled.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: M.D. Anderson Cancer Center

Overall Clinical Trial Officials and Contacts

Johannes Wolff, MD Principal Investigator U.T.M.D. Anderson Cancer Center  

Overall Contact: Johannes Wolff, MD 713-794-4963 

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00513162

Study ID Number: 2007-0370

ClinicalTrials.gov Identifier: NCT00513162

Health Authority: United States: Institutional Review Board

The University of Texas M.D.Anderson Cancer Center