RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs such as pentoxifylline and hydroxyurea may make tumor cells more sensitive to radiation therapy. PURPOSE: Phase I trial to study the effectiveness of radiation therapy plus pentoxifylline and hydroxyurea in treating patients who have high-grade astrocytoma or glioblastoma.

Condition	Treatment or Intervention	Phase
adult glioblastoma multiforme	Drug: hydroxyurea  Drug: pentoxifylline	Phase I

Further Study Details: 

OBJECTIVES: I. Determine the maximum tolerated dose of pentoxifylline administered with hydroxyurea during a course of cranial radiotherapy in patients with glioblastoma multiforme. II. Determine the toxicity of this regimen in these patients. III. Measure PTX levels in plasma and CSF in order to assess whether therapeutic drug exposures (e.g., 0.4-2.0 mM/24 hours) can be achieved with an acceptable level of toxicity. IV. Assess the local control of glioblastoma in patients treated with this regimen. V. Determine the response of surrounding normal brain in patients treated with this regimen. VI. Determine the survival of patients treated with this regimen.

PROTOCOL OUTLINE: This is a dose escalation study of pentoxifylline (PTX). Patients receive hydroxyurea (HU) and PTX IV continuously 5 days a week concurrently with cranial radiotherapy twice daily, 5 days a week, for 4 weeks in the absence of disease progression or unacceptable toxicity. The first cohort of 3 patients is treated with radiotherapy and HU alone. Subsequent cohorts of 3-6 patients receive HU and radiotherapy plus escalating doses of PTX until the maximum tolerated dose of PTX is determined or serum or CSF drug concentrations reach 0.4-2.0 mM in 6 consecutive patients with acceptable toxicity. The MTD is defined as the dose immediately preceding that at which 2 of 6 patients experience dose-limiting toxicity. Patients are followed at 1 week, at 1 and 3 months, every 3 months for 2 years, and then every 4 months for 5 years.

PROJECTED ACCRUAL: A maximum of 24-34 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically proven grade IV astrocytoma or glioblastoma multiforme confined to 1 or both hemispheres of the brain; Confirmation of histology by NIH neuropathology review required; MRI or CT completed within 3 weeks of initial evaluation
• No clinically apparent leptomeningeal metastases
• No uncontrolled seizures despite standard anticonvulsant therapy
• No history of epilepsy diagnosed a year or more before glioblastoma

--Prior/Concurrent Therapy--

• Biologic therapy: Not specified
• Chemotherapy: No prior chemotherapy
• Endocrine therapy: Not specified
• Radiotherapy: No prior radiotherapy
• Surgery: Prior biopsy or subtotal or near-total resection allowed; At least 7-10 days but no more than 3 months since prior surgery and/or biopsy
• Other: No recent methylxanthine-containing medications; No concurrent anticoagulants or methylxanthines (e.g., aspirin, nonsteroidal antiinflammatory drugs, warfarin, heparin, theophylline, aminophylline, theobromine) for preexisting medical conditions

--Patient Characteristics--

• Age: Over 18
• Performance status: Karnofsky 80-100% OR ECOG 0-1
• Life expectancy: More than 3 months
• Hematopoietic: WBC at least 3,500/mm3; Absolute granulocyte count at least 900/mm3; Platelet count at least 100,000/mm3; Hemoglobin at least 10 g/dL; No hematologic disease requiring treatment
• Hepatic: Liver function tests no greater than 2.5 times upper limit of normal; No hepatic disease requiring treatment
• Renal: Creatinine no greater than 1.3 mg/dL OR Creatinine clearance at least 95 mL/min; No renal disease requiring treatment
• Cardiovascular: No history of hospitalization or medication for: Cardiovascular disease with LVEF 45% or less; Myocardial infarction; Arrhythmia Coronary artery disease; Angina; Congestive heart failure; Stroke; No thromboembolic disease requiring treatment
• Pulmonary: No history of hospitalization or medication for chronic obstructive pulmonary disease or asthma
• Other: No peptic ulcer disease or inflammatory bowel disease within the past 2 years; No documented history of intolerance to methylxanthines (e.g., allergic or serious adverse reactions); No history of psychiatric or medical illness that would preclude therapy; No other malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix; No contraindication to serial CT or MRI (e.g., logistical problems, noncompliance, contrast allergies); Not pregnant or nursing; Negative pregnancy test

Maryland
      Radiation Oncology Branch, Bethesda,  Maryland,  20892,  United States

Study chairs or principal investigators

Brian G. Fuller,  Study Chair,  National Cancer Institute (NCI)   

Study ID Numbers:  CDR0000064077; NCI-95-C-0069; NCI-95-C-0069A; NCI-95-C-0069D
Record last reviewed:  April 2004
Last Updated:  October 13, 2004
Record first received:  July 11, 2001
ClinicalTrials.gov Identifier:  NCT00019058
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08