Brain and Central Nervous System Tumors
Conditions
Keywords
adult tumors metastatic to brain
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as cytochlor and tetrahydrouridine, may make tumor cells more sensitive to radiation therapy. PURPOSE: This phase I trial is studying the side effects and best dose of cytochlor when given together with tetrahydrouridine and external-beam radiation therapy in treating patients with cancer that has spread to the brain.
Detailed description
OBJECTIVES: Primary * Establish the safety and toxicity profile of cytochlor and H4U when given in combination with external-beam radiotherapy for 2 weeks after treatment with the drugs alone in the previous week. Secondary * Determine the effectiveness of H4U to inhibit systemic cytidine deaminase (CD) during the course of treatment with cytochlor and H4U. * Perform detailed pharmacokinetic studies to determine the levels of cytochlor and its metabolites in serum and in urine in weeks 1, 2, and 3 during treatment. OUTLINE: This is a dose-escalation study of cytochlor. Patients receive cytochlor IV and tetrahydrouridine (H4U) IV over 5 minutes on 3 days in week 1 and on days 1-5 in weeks 2 and 3. Patients also undergo external-beam radiotherapy 5 days a week in weeks 2 and 3 initiated 3-4 hours after infusions of cytochlor and H4U. Treatment may repeat in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed monthly for 3 months, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then yearly thereafter.
Interventions
DRUGCytochlor
The study's starting dose of CldC is 50 mg/m2/day. The dose of CldC will be escalated / de-escalated for patients. Patients will receive CldC+H4U on 3 days (Wed, Thr, Fri) in week 1, which precedes the initiation of radiation therapy. Patients will receive H4U and CldC IV by bolus infusion. Treatment with CldC+H4U will then continue for 5 days (Mon-Fri) during each of weeks 2 and 3, and will be accompanied by radiation therapy at 3 Gy/fraction initiated 3-4 h after bolus infusion of CldC+H4U. Treatment with CldC+H4U and radiation will then stop at the end of week 3.
A fixed dose of H4U at 720 mg/m2/day will be used, regardless of the dose of CldC administered. H4U will be delivered by an IV bolus infusion over a period of 5 minutes, followed 5 minutes later by an IV bolus infusion of CldC. Patients will receive CldC+H4U on 3 days (Wed, Thr, Fri) in week 1, which precedes the initiation of radiation therapy. Patients will receive H4U and CldC IV by bolus infusion. Treatment with CldC+H4U will then continue for 5 days (Mon-Fri) during each of weeks 2 and 3, and will be accompanied by radiation therapy at 3 Gy/fraction initiated 3-4 h after bolus infusion of CldC+H4U. Treatment with CldC+H4U and radiation will then stop at the end of week 3.
RADIATIONRadiation Therapy
One treatment of 3 Gy will be given daily 5 days per week (10 fractions) for a total of 30 Gy over two weeks.
Sponsors
Brian Lally
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of metastatic cancer to the brain by contrast-enhanced MRI or CT scan * Eligible for whole-brain radiotherapy (WBRT) * Patients treated with prior surgery are eligible if WBRT is to be used post operatively * Not planning to be treated with stereotactic radiosurgery * No leptomeningeal metastasis documented by contrast-enhanced MRI/CT scan or cerebrospinal fluid evaluation PATIENT CHARACTERISTICS: Inclusion criteria: * Karnofsky performance status (PS) 70-100% or ECOG PS 0-1 * Leukocytes ≥ 3,000/µL * Absolute neutrophil count \> 1,500/µL * Platelet count \> 100,000/µL * Total bilirubin normal * AST and ALT \< 2.5 times upper limit of normal * Creatinine normal OR creatinine clearance \> 60 mL/min * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation
Exclusion criteria
* Uncontrolled intercurrent illness including, but not limited to, any of the following: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness/social situations that would limit compliance with study requirements * Pregnant or lactating * Alcohol dependence PRIOR CONCURRENT THERAPY: * No prior radiotherapy to the brain * No concurrent combination antiretroviral therapy for HIV-positive patients * No other concurrent chemotherapy, immunotherapy, hormonal therapy (excluding contraceptives and replacement steroids), or other experimental medication * No other concurrent anticancer therapy outside the protocol * Systemic therapy one month before or after brain radiotherapy is allowed * No concurrent heparin or coumadin
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To establish a dose range of CldC for further clinical studies (Phase II clinical trials) based on safety and toxicity. | 2 Years |
| b) Establish the safety and toxicity profile of CldC+ H4U when given in combination with RT for 2 weeks following treatment with the drug alone for 3 days in the week prior to the combined treatment. | Duration of study treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| a) Determine the effectiveness of H4U to inhibit systemic cytidine deaminase (CD) during the course of treatment with CldC + H4U. | At protocol specified timepoints during treatment | Baseline Levels of CD will be obtained by assaying CD in serum prior to initiation of treatment on Wednesday of week 1. Follow-up assays of CD in serum will be made on the Fridays of weeks 1 to 3 after each day's treatment with CldC + H4U. In weeks 2 and 3 this will take place prior to RT |
| Cytochlor and metabolite levels in serum at weeks 1, 2, and 3 | Pharmacokinetic sampling at protocol-specified timepoints during duration of treatment | — |
| Cytochlor and metabolite levels in urine at weeks 1, 2, and 3 | Pharmacokinetic sampling at protocol-specified timepoints during duration of treatment | — |
Countries
United States
Outcome results
None listed