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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01076530
First received: February 25, 2010
Last updated: May 1, 2013
Last verified: May 2013
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.

  • Pharmacokinetic parameters of vorinostat in combination with temozolomide [ Time Frame: Pre-dose, 15 and 30 minutes, 1, 2, 4, 6, 8, and 24 hours ] [ Designated as safety issue: No ]
    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:
  • Response assessed according to RECIST criteria [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    Will be reported descriptively.


Enrollment: 27
Study Start Date: February 2010
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT01076530

Locations
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
Investigators
Principal Investigator: Trent Hummel COG Phase I Consortium
  More Information

No publications provided by National Cancer Institute (NCI)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01076530     History of Changes
Other Study ID Numbers: NCI-2011-02011, ADVL0819, CDR0000664388, COG-ADVL0819, U01CA097452
Study First Received: February 25, 2010
Last Updated: May 1, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Paraganglioma
Paraganglioma, Extra-Adrenal
Neoplasms
Glioma
Astrocytoma
Ependymoma
Oligodendroglioma
Meningioma
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Endodermal Sinus Tumor
Choriocarcinoma
Medulloblastoma
Craniopharyngioma
Adamantinoma
Choroid Plexus Neoplasms
Rhabdoid Tumor
Optic Nerve Glioma
Neoplasms, Germ Cell and Embryonal
Spinal Cord Neoplasms
Neoplasms, Neuroepithelial
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Vascular Tissue
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases

ClinicalTrials.gov processed this record on September 18, 2014