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

Primary Purpose

Childhood Atypical Teratoid/Rhabdoid Tumor, Childhood Central Nervous System Choriocarcinoma, Childhood Central Nervous System Embryonal Tumor

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
vorinostat
temozolomide
diagnostic laboratory biomarker analysis
pharmacological study
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Childhood Atypical Teratoid/Rhabdoid Tumor

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Childrens Memorial Hospital
  • C S Mott Children's Hospital
  • University of Minnesota Medical Center-Fairview
  • Oregon Health and Science University
  • St. Jude Children's Research Hospital
  • Baylor College of Medicine
  • Seattle Children's Hospital
  • Hospital for Sick Children
  • Hospital Sainte-Justine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm I

Arm Description

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.

Outcomes

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
In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.
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).

Secondary Outcome Measures

Response assessed according to RECIST criteria
Will be reported descriptively.

Full Information

First Posted
February 25, 2010
Last Updated
May 1, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01076530
Brief Title
Vorinostat and Temozolomide in Treating Young Patients With Relapsed or Refractory Primary Brain Tumors or Spinal Cord Tumors
Official Title
A Phase I Study of SAHA and Temozolomide in Children With Relapsed or Refractory Primary Brain or Spinal Cord Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
May 2013
Overall Recruitment Status
Completed
Study Start Date
February 2010 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
27 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
vorinostat
Other Intervention Name(s)
L-001079038, SAHA, suberoylanilide hydroxamic acid, Zolinza
Intervention Type
Drug
Intervention Name(s)
temozolomide
Other Intervention Name(s)
SCH 52365, Temodal, Temodar, TMZ
Intervention Type
Other
Intervention Name(s)
diagnostic laboratory biomarker analysis
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Primary Outcome Measure Information:
Title
Maximum tolerated dose defined as the maximum dose at which fewer than one-third of patients experience DLT using NCI CTCAE version 4.0
Description
In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.
Time Frame
28 days
Title
Pharmacokinetic parameters of vorinostat in combination with temozolomide
Description
The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
Time Frame
Pre-dose, 15 and 30 minutes, 1, 2, 4, 6, 8, and 24 hours
Secondary Outcome Measure Information:
Title
Response assessed according to RECIST criteria
Description
Will be reported descriptively.
Time Frame
Up to 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Trent Hummel
Organizational Affiliation
COG Phase I Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Childrens Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
C S Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
University of Minnesota Medical Center-Fairview
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Hospital Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
23554030
Citation
Hummel TR, Wagner L, Ahern C, Fouladi M, Reid JM, McGovern RM, Ames MM, Gilbertson RJ, Horton T, Ingle AM, Weigel B, Blaney SM. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children's Oncology Group phase 1 consortium study. Pediatr Blood Cancer. 2013 Sep;60(9):1452-7. doi: 10.1002/pbc.24541. Epub 2013 Mar 28.
Results Reference
derived

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

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