Vorinostat and Temozolomide in Treating Young Patients With Relapsed or Refractory Primary Brain Tumors or Spinal Cord Tumors

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of vorinostat when given together with temozolomide in treating young patients with relapsed or refractory primary brain tumors or spinal cord tumors. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may help temozolomide work better by making tumor cells more sensitive to the drug.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose and/or recommended phase II dose of vorinostat in combination with temozolomide in pediatric patients with relapsed or refractory primary CNS tumors. II. To define and describe the toxicities of this regimen in these patients. SECONDARY OBJECTIVES: I. To preliminarily define the antitumor activity of this regimen within the confines of a phase I study. II. To characterize the pharmacokinetic parameters of vorinostat in these patients. III. To determine whether acetylated histones in peripheral blood mononuclear cells can be identified as a surrogate marker of the biologic effect of vorinostat at various treatment doses. IV. To assess the feasibility of collecting and analyzing serum DNA for methylation of the MGMT promoter and describe the relationship between promoter methylation and clinical responses within the confines of this phase I study. OUTLINE: This is a multicenter, dose-escalation study of vorinostat. Patients receive oral vorinostat and oral temozolomide once daily on days 1-5. Courses repeat every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients may undergo blood sample collection periodically for pharmacokinetic and correlative laboratory studies by western blotting and MGMT promoter methylation assays. After completion of study therapy, patients are followed up for 30 days.

Official Title
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A Phase I Study of SAHA and Temozolomide in Children With Relapsed or Refractory Primary Brain or Spinal Cord Tumors

Conditions
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Childhood Atypical Teratoid/Rhabdoid Tumor, Childhood Central Nervous System Choriocarcinoma, Childhood Central Nervous System Embryonal Tumor, Childhood Central Nervous System Germinoma, Childhood Central Nervous System Mixed Germ Cell Tumor, Childhood Central Nervous System Teratoma, Childhood Central Nervous System Yolk Sac Tumor, Childhood Choroid Plexus Tumor, Childhood Craniopharyngioma, Childhood Ependymoblastoma, Childhood Grade I Meningioma, Childhood Grade II Meningioma, Childhood Grade III Meningioma, Childhood High-grade Cerebellar Astrocytoma, Childhood High-grade Cerebral Astrocytoma, Childhood Infratentorial Ependymoma, Childhood Low-grade Cerebellar Astrocytoma, Childhood Low-grade Cerebral Astrocytoma, Childhood Medulloepithelioma, Childhood Mixed Glioma, Childhood Oligodendroglioma, Childhood Supratentorial Ependymoma, Extra-adrenal Paraganglioma, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Central Nervous System Embryonal Tumor, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Ependymoma, Recurrent Childhood Medulloblastoma, Recurrent Childhood Pineoblastoma, Recurrent Childhood Spinal Cord Neoplasm, Recurrent Childhood Subependymal Giant Cell Astrocytoma, Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor, Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Intervention / Treatment
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* Drug: vorinostat
* Drug: temozolomide
* Other: diagnostic laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed CNS malignancy at original diagnosis or relapse Histologic confirmation not required for patients with intrinsic brain stem tumors, optic pathway gliomas, or pineal tumors provided CSF or serum tumor markers, including alpha-fetoprotein orbeta-HCG, are elevated Recurrent or refractory spinal cord tumors allowed Measurable or evaluable disease No known curative therapy or therapy proven to prolong survival with an acceptable quality of life Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) OR Lansky PS 50-100% (for patients ≤ 16 years of age) Neurological deficits must have been relatively stable for ≥ 1 week before study entry Patients unable to walk due to paralysis, but who are up in a wheelchair, are considered ambulatory for the purpose of assessing performance status ANC ≥ 1,000/μL Platelet count ≥ 100,000/μL (transfusion independent, defined as no platelet transfusion within the past 7 days) Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed) Creatinine clearance or radioisotope GFR ≥ 70mL/min OR maximum serum creatinine based on age and/or gender as follows: 0.6 mg/dL (1 year of age) 0.8 mg/dL (2 to 5 years of age) 1.0 mg/dL (6 to 9 years of age) 1.2 mg/dL (10 to 12 years of age) 1.5 mg/dL (males) or 1.4 mg/dL (females) (13 to 15 years of age) 1.7 mg/dL (males) or 1.4 mg/dL (females) (≥ 16 years of age) Bilirubin ≤ 1.5 times upper limit of normal ALT ≤ 110 U/L Serum albumin ≥ 2 g/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able to swallow capsules or liquid Seizure disorder allowed provided it is well controlled with nonenzyme-inducing anticonvulsants No pre-existing QTc ≥ 450 msec No uncontrolled infection No patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of study Fully recovered from prior chemotherapy, immunotherapy, or radiotherapy More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea) At least 7 days since prior hematopoietic growth factors At least 7 days since prior biologic agent (antineoplastic agent) At least 7 days or 3 half-lives, whichever is longer, since prior monoclonal antibodies More than 2 weeks since prior local palliative radiotherapy (small port) At least 6 months since prior total-body radiotherapy (TBI), craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis At least 6 weeks since other prior substantial bone marrow radiotherapy At least 3 months since prior stem cell transplantation or rescue (without TBI) No evidence of active graft-vs-host disease At least 2 weeks since prior valproic acid No prior vorinostat Prior temozolomide allowed provided there was no progressive disease during or within 1 month after completion of treatment Concurrent corticosteroids allowed provided patient has been on a stable or decreasing dose for ≥ 7 days before study entry No other concurrent investigational drugs No other concurrent anticancer agents, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy No concurrent enzyme-inducing anticonvulsants

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral vorinostat and oral temozolomide once daily on days 1-5. Courses repeat every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br> <br> * Other names: Zolinza;Drug: temozolomide<br> <br> * Other names: TMZ;Other: diagnostic laboratory biomarker analysis<br> <br> Other: pharmacological study<br> <br> * Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose defined as the maximum dose at which fewer than one-third of patients experience DLT using NCI CTCAE version 4.0 | In addition to determination of the MTD, a descriptive summary of all toxicities will be reported. | 28 days | 
| Pharmacokinetic parameters of vorinostat in combination with temozolomide | The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). | Pre-dose, 15 and 30 minutes, 1, 2, 4, 6, 8, and 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response assessed according to RECIST criteria | Will be reported descriptively. | Up to 30 days |