Valproic Acid in Treating Young Patients With Recurrent or Refractory Solid Tumors or CNS Tumors

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00107458
First received: April 5, 2005
Last updated: August 6, 2014
Last verified: August 2014
  Purpose

RATIONALE: Drugs used in chemotherapy, such as valproic acid, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Valproic acid may also stop the growth of solid tumors or CNS tumors by blocking blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and best dose of valproic acid in treating patients with recurrent or refractory solid tumors or CNS tumors.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Unspecified Childhood Solid Tumor, Protocol Specific
Drug: valproic acid
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: A Phase I Study of Valproic Acid in Children With Recurrent/Progressive Solid Tumors Including CNS Tumors

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Efficacy of oral etoposide at 50 mg/m2/day given concurrently with radiotherapy [ Designated as safety issue: Yes ]

Enrollment: 26
Study Start Date: May 2005
Study Completion Date: March 2012
Primary Completion Date: October 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment 1
VPA Target Trough Concentration 75-100 mcg/mL, week 1 VPA dose: 15 mg/kg/day, divided tid
Drug: valproic acid
Experimental: Treatment 10
VPA Target Trough Concentration 100-150 mcg/mL, week 1 VPA dose: 15 mg/kg/day, divided tid
Drug: valproic acid
Experimental: Treatment 20
VPA Target Trough Concentration 150-200 mcg/mL
Drug: valproic acid

Detailed Description:

OBJECTIVES:

Primary

  • Determine the toxic effects of valproic acid (VPA) administered at doses required to maintain serum trough VPA concentrations of 100-150 mcg/mL or 150-200 mcg/mL in young patients with recurrent or refractory solid tumors or CNS tumors.

Secondary

  • Determine the steady-state serum trough concentration of free and total VPA at the targeted total trough VPA concentration in these patients.
  • Determine the steady state histone acetylation status of peripheral blood monocytes at the targeted trough VPA concentration in these patients.
  • Determine the pharmacokinetic profile of this drug in these patients.
  • Correlate histone acetylation with free or total trough VPA concentration in these patients.
  • Determine, preliminarily, the antitumor activity of this drug in these patients.

OUTLINE: This is a dose-escalation, multicenter study.

For course 1, patients receive escalating doses of oral valproic acid (VPA) twice daily until a target serum trough VPA concentration range is maintained for 28 days. Patients who achieve the target serum trough VPA concentration range receive subsequent courses of oral VPA twice daily (at the dose found to maintain the target serum trough VPA concentration range) on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

The first cohort of 6 patients receives VPA to achieve an initial target trough serum VPA concentration. If fewer than 2 of 6 patients in the first cohort experience dose-limiting toxicity (DLT), then a second cohort of 6 patients receives VPA to achieve the next higher target trough serum VPA concentration. If fewer than 2 patients from the second cohort experience DTL, then 6 additional patients are enrolled in this cohort to better define pharmacokinetics and DLT at this VPA concentration range.

After completion of study treatment, patients are followed annually.

PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   2 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed* malignant solid tumor, including CNS tumors, at original diagnosis or relapse

    • Recurrent or refractory disease NOTE: *Histologic confirmation not required for intrinsic brain stem or optic pathway tumors
  • Measurable or evaluable disease, defined by 1 of the following criteria:

    • Any unidimensionally measurable lesion ≥ 10 mm by standard MRI or CT scan for either solid or CNS tumors
    • At least 1 nonmeasurable lesion that is evaluable by nuclear medicine, immunocytochemistry, tumor markers, cerebrospinal fluid cytology, or other reliable measures
  • No known curative therapy exists
  • No documented tumor involvement in the bone marrow

PATIENT CHARACTERISTICS:

Age

  • 2 to 21

Performance status*

  • Lansky 50-100% (for patients ≤ 10 years of age)
  • Karnofsky 50-100% (for patients > 10 years of age)

Life expectancy

  • Not specified

Hematopoietic

  • Absolute neutrophil count ≥ 1,000/mm^3
  • Platelet count ≥ 100,000/mm^3 (transfusion independent)
  • Hemoglobin ≥ 8.0 g/dL (transfusions allowed)

Hepatic

  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • ALT ≤ 110 (ULN for this study is 45 U/L)
  • Albumin ≥ 2 g/dL

Renal

  • Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR
  • Creatinine based on age as follows:

    • No greater than 0.8 mg/dL (for patients ≤ 5 years of age)
    • No greater than 1.0 mg/dL (for patients 6 to 10 years of age)
    • No greater than 1.2 mg/dL (for patients 11 to 15 years of age)
    • No greater than 1.5 mg/dL (for patients over 15 years of age)

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Neurologic deficits in patients with CNS tumors must be stable for ≥ 1 week before study entry
  • No uncontrolled infection
  • No known urea cycle disorders or other metabolic disorders
  • No other condition that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • Recovered from prior immunotherapy
  • At least 7 days since prior hematopoietic growth factors that support platelet or WBC number or function
  • At least 7 days since prior antineoplastic biologic agents
  • At least 3 months since prior stem cell transplantation or rescue without total body irradiation

    • No evidence of active graft vs host disease
  • No other concurrent anticancer biologic therapy or immunotherapy

Chemotherapy

  • More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered
  • No other concurrent anticancer chemotherapy

Endocrine therapy

  • Patients with CNS tumors must be on a stable or decreasing dose of dexamethasone for the past 7 days

Radiotherapy

  • See Biologic therapy
  • Recovered from prior radiotherapy
  • At least 6 months since prior total body irradiation, craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis
  • At least 6 weeks since other prior substantial bone marrow radiotherapy
  • At least 2 weeks since prior local palliative small port radiotherapy
  • No concurrent anticancer radiotherapy

Surgery

  • Not specified

Other

  • No other concurrent investigational agents
  • No other concurrent anticancer agents
  • No other concurrent anticonvulsants

    • Patients receiving valproic acid (VPA) before study entry must have a total trough VPA concentration < 100 mcg/mL within the past 7 days
  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: NCT00107458

Locations
United States, California
Children's Hospital of Orange County
Orange, California, United States, 92868
Stanford Comprehensive Cancer Center - Stanford
Stanford, California, United States, 94305
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, Indiana
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States, 46202-5289
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Minnesota
University of Minnesota Children's Hospital - Fairview
Minneapolis, Minnesota, United States, 55455
Mayo Clinic Cancer Center
Rochester, Minnesota, United States, 55905
United States, New York
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
New York, New York, United States, 10032
SUNY Upstate Medical University Hospital
Syracuse, New York, United States, 13210
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
United States, Oregon
Oregon Health & Science University Cancer Institute
Portland, Oregon, United States, 97239-3098
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-9786
United States, Texas
Baylor University Medical Center - Houston
Houston, Texas, United States, 77030-2399
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Hopital Sainte Justine
Montreal, Quebec, Canada, H3T 1C5
Sponsors and Collaborators
Children's Oncology Group
Investigators
Study Chair: Jack M. Su, MD Texas Children's Cancer Center
Study Chair: Heidi V. Russell, MD Texas Children's Cancer Center
  More Information

Additional Information:
Publications:
Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00107458     History of Changes
Other Study ID Numbers: ADVL0419, COG-ADVL0419, NCI-05-C-0235, NCI-P6631, CDR0000417845
Study First Received: April 5, 2005
Last Updated: August 6, 2014
Health Authority: United States: Federal Government

Keywords provided by Children's Oncology Group:
recurrent childhood brain stem glioma
recurrent childhood brain tumor
recurrent childhood cerebellar astrocytoma
recurrent childhood cerebral astrocytoma
recurrent childhood ependymoma
recurrent childhood medulloblastoma
recurrent childhood supratentorial primitive neuroectodermal tumor
unspecified childhood solid tumor, protocol specific
recurrent childhood visual pathway and hypothalamic glioma
childhood high-grade cerebral astrocytoma
childhood low-grade cerebral astrocytoma
childhood infratentorial ependymoma
childhood supratentorial ependymoma
childhood spinal cord neoplasm
childhood grade I meningioma
childhood grade II meningioma
childhood grade III meningioma
childhood craniopharyngioma
childhood central nervous system germ cell tumor

Additional relevant MeSH terms:
Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Valproic Acid
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs

ClinicalTrials.gov processed this record on September 18, 2014