Capecitabine and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Nonmetastatic Brain Stem Glioma or High-Grade Glioma

A Phase I Trial of Capecitabine Rapidly Disintegrating Tablets and Concomitant Radiation Therapy in Children With Newly Diagnosed Brainstem Gliomas and High Grade Gliomas

RATIONALE: Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Capecitabine may make tumor cells more sensitive to radiation therapy. Giving capecitabine together with radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of capecitabine when given together with radiation therapy in treating young patients with newly diagnosed, nonmetastatic brain stem glioma or high-grade glioma.

Study Overview

• Status: Completed
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: capecitabine; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

Primary

• Estimate the maximum tolerated dose of capecitabine rapidly disintegrating tablets (RDT) administered concurrently with radiotherapy in young patients with newly diagnosed, nondisseminated intrinsic brain stem glioma or high-grade glioma.
• Describe the dose-limiting toxicity in patients treated with this regimen.

Secondary

• Describe the safety profile of this regimen.
• Characterize the pharmacokinetics of capecitabine RDT in these patients.
• Explore the exposure-response relationship for measures of safety and effectiveness using pharmacokinetic and pharmacodynamic models.
• Describe the antitumor activity of this regimen observed in these patients.
• Estimate distributions of progression-free survival and survival in patients treated with this regimen.
• Characterize radiographic changes in tumor, using MRI, perfusion and diffusion MRI, and positron emission tomography (PET) scans, in patients treated with this regimen.

OUTLINE: This a multicenter, dose-escalation study of capecitabine rapidly disintegrating tablets (RDT).

Patients undergo radiotherapy once daily, 5 days a week, for approximately 6 weeks. Beginning within 24 hours of starting radiotherapy, patients also receive oral capecitabine RDT twice daily on days 1-21. Treatment with capecitabine RDT repeats every 21 days for 3 courses.

Cohorts of 3-6 patients receive escalating doses of capecitabine RDT until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Beginning in week 12, patients receive capecitabine RDT at a fixed dose twice daily on days 1-14. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically during course 1 for pharmacokinetic correlative studies. Patients also undergo MRI, and rapid perfusion/diffusion MRI at baseline and periodically during study for radiographic correlative studies.

After completion of study treatment, patients are followed periodically for 2 years.

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

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
  • Maryland
    • Bethesda, Maryland, United States, 20892-1182
      • Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4318
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Houston, Texas, United States, 77030-2399
      • Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
    • Houston, Texas, United States, 77030
      • Dan L. Duncan Cancer Center at Baylor College of Medicine
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• One of the following newly diagnosed, nondisseminated brain tumors:

  • Intrinsic infiltrating brain stem glioma

    • Histopathologic diagnosis not required

  • Histopathologically confirmed high-grade glioma, meeting all of the following criteria:

    • Underwent prior definitive surgery ≤ 28 days ago with incompletely resected disease

    • Any of the following subtypes allowed:

      • Anaplastic astrocytoma
      • Glioblastoma multiforme
      • Other high-grade glioma
• No anaplastic oligodendroglioma

PATIENT CHARACTERISTICS:

• Karnofsky performance scale (PS) 50-100% (if > 16 years of age) or Lansky PS 50-100% (if ≤ 16 years of age)
• Absolute neutrophil count ≥ 1,000/mm³
• Platelet count ≥ 100,000/mm³ (transfusion independent)
• Hemoglobin ≥ 8 g/dL (transfusion independent)

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

  • No more than 0.8 mg/dL (for patients 5 years of age and under)
  • No more than 1 mg/dL (for patients 6-10 years of age)
  • No more than 1.2 mg/dL (for patients 11-15 years of age)
  • No more than 1.5 mg/dL (for patients over 15 years of age)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT ≤ 5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled infection
• No significant cardiac, hepatic, gastrointestinal, renal, pulmonary, or other systemic disease
• No known hypersensitivity to capecitabine or any of its components
• No known dihydropyrimidine dehydrogenase (DPD) deficiency

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior dexamethasone and/or surgery allowed
• No prior chemotherapy, radiotherapy, immunotherapy, or bone marrow transplantation
• No other concurrent anticancer or experimental drug therapies or agents
• No concurrent warfarin or sorivudine or its chemically related analogues (e.g., brivudine)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose of capecitabine rapidly disintegrating tablets (RDT) in combination with radiotherapy	First 11 weeks of therapy
Dose-limiting toxicity	First 11 weeks of therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of capecitabine RDT measured periodically during course 1		Day 1 and Day 14 of therapy
Tumor response	Brain imaging to assess tumor response to the treatment is performed at baseline, week 11, end of course 6, and then every 3 months for two years.	From day 1 of treatment until off study
Survival		From initiation of treatment until death or off study
Radiographic changes in gliomas as measured by MRI, magnetic resonance spectroscopy (MRS), perfusion and diffusion MRI		Baseline, week 11, then every 3 months for 2 years or until off study

Collaborators and Investigators

• Sponsor: Pediatric Brain Tumor Consortium
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Susan M. Blaney, MD, Texas Children's Cancer Center

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: July 26, 2006
• First Submitted That Met QC Criteria: July 26, 2006
• First Posted (Estimate): July 27, 2006

Study Record Updates

• Last Update Posted (Estimate): January 10, 2013
• Last Update Submitted That Met QC Criteria: January 8, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: untreated childhood brain stem glioma; childhood high-grade cerebral astrocytoma; untreated childhood cerebellar astrocytoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine
• Other Study ID Numbers: CDR0000484429; U01CA081457 (U.S. NIH Grant/Contract); PBTC-021