A Phase I Study of SAHA and Temozolomide in Children With Relapsed or Refractory Primary Brain or Spinal Cord Tumors
1 Year
21 Years
Both
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
Trial Information
A Phase I Study of SAHA and Temozolomide in Children With Relapsed or Refractory Primary Brain or Spinal Cord Tumors
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.
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
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose defined as the maximum dose at which fewer than one-third of patients experience DLT using NCI CTCAE version 4.0
Outcome Description:
In addition to determination of the MTD, a descriptive summary of all toxicities will be reported.
Outcome Time Frame:
28 days
Safety Issue:
Yes
Principal Investigator
Trent Hummel
Investigator Role:
Principal Investigator
Investigator Affiliation:
COG Phase I Consortium
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2011-02011
NCT ID:
NCT01076530
Start Date:
February 2010
Completion Date:
Related Keywords:
- 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
- Astrocytoma
- Neoplasms
- Choriocarcinoma
- Craniopharyngioma
- Adamantinoma
- Endodermal Sinus Tumor
- Ependymoma
- Glioma
- Medulloblastoma
- Meningioma
- Carcinoma, Embryonal
- Neoplasms, Germ Cell and Embryonal
- Oligodendroglioma
- Paraganglioma
- Paraganglioma, Extra-Adrenal
- Spinal Cord Neoplasms
- Teratoma
- Choroid Plexus Neoplasms
- Pinealoma
- Neuroectodermal Tumors
- Neuroectodermal Tumors, Primitive
- Germinoma
- Rhabdoid Tumor
- Optic Nerve Glioma
- Brain Neoplasms
Name | Location |
|---|---|
| Baylor College of Medicine | Houston, Texas 77030 |
| St. Jude Children's Research Hospital | Memphis, Tennessee 38105-2794 |
| Oregon Health and Science University | Portland, Oregon 97201 |
| Seattle Children's Hospital | Seattle, Washington 98105 |
| Childrens Memorial Hospital | Chicago, Illinois 60614 |
| University of Minnesota Medical Center-Fairview | Minneapolis, Minnesota 55455 |
| C S Mott Children's Hospital | Ann Arbor, Michigan 48109 |
