Clinical trial NCT01076530: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-02-26
Enrollment: 27
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
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
timeFrame: 28 days
measure: Pharmacokinetic parameters of vorinostat in combination with temozolomide
timeFrame: Pre-dose, 15 and 30 minutes, 1, 2, 4, 6, 8, and 24 hours
Secondary outcomes:
measure: Response assessed according to RECIST criteria
timeFrame: Up to 30 days
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Childrens Memorial Hospital
state: Illinois
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center-Fairview
state: Minnesota
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Hospital Sainte-Justine
state: Quebec
Study officials:
affiliation: COG Phase I Consortium
name: Trent Hummel
role: PRINCIPAL_INVESTIGATOR
References:
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.