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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01076530
Recruitment Status : Completed
First Posted : February 26, 2010
Last Update Posted : May 3, 2013
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: vorinostat Drug: temozolomide Other: diagnostic laboratory biomarker analysis Other: pharmacological study Phase 1

Detailed Description:


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.


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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of SAHA and Temozolomide in Children With Relapsed or Refractory Primary Brain or Spinal Cord Tumors
Study Start Date : February 2010
Actual Primary Completion Date : October 2012

Arm Intervention/treatment
Experimental: Arm I
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
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza

Drug: temozolomide
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ

Other: diagnostic laboratory biomarker analysis
Other: pharmacological study
Other Name: pharmacological studies

Primary Outcome Measures :
  1. Maximum tolerated dose defined as the maximum dose at which fewer than one-third of patients experience DLT using NCI CTCAE version 4.0 [ Time Frame: 28 days ]
    In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.

  2. Pharmacokinetic parameters of vorinostat in combination with temozolomide [ Time Frame: Pre-dose, 15 and 30 minutes, 1, 2, 4, 6, 8, and 24 hours ]
    The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

Secondary Outcome Measures :
  1. Response assessed according to RECIST criteria [ Time Frame: Up to 30 days ]
    Will be reported descriptively.

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01076530

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United States, Illinois
Childrens Memorial Hospital
Chicago, Illinois, United States, 60614
United States, Michigan
C S Mott Children's Hospital
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
University of Minnesota Medical Center-Fairview
Minneapolis, Minnesota, United States, 55455
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Hospital Sainte-Justine
Montreal, Quebec, Canada, H3T 1C5
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Trent Hummel COG Phase I Consortium
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: National Cancer Institute (NCI) Identifier: NCT01076530    
Other Study ID Numbers: NCI-2011-02011
U01CA097452 ( U.S. NIH Grant/Contract )
First Posted: February 26, 2010    Key Record Dates
Last Update Posted: May 3, 2013
Last Verified: May 2013
Additional relevant MeSH terms:
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Neoplasms, Germ Cell and Embryonal
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Endodermal Sinus Tumor
Rhabdoid Tumor
Choroid Plexus Neoplasms
Spinal Cord Neoplasms
Paraganglioma, Extra-Adrenal
Neoplasms, Neuroepithelial
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Vascular Tissue
Meningeal Neoplasms
Central Nervous System Neoplasms