Ph I Study of Lithium During Whole Brain Radiotherapy For Patients With Brain Metastases

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as lithium, may protect normal cells from the side effects of radiation therapy. Giving lithium together with radiation therapy may allow a higher dose of radiation therapy to be given so that more tumor cells are killed. PURPOSE: This phase I trial is studying the side effects and best dose of lithium when given together with whole-brain radiation therapy in treating patients with brain metastases from primary cancer outside the brain.

Detailed Description
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OBJECTIVES: Determine the feasibility of concurrent lithium carbonate and whole-brain radiotherapy, as measured by safety and compliance, in patients with primary extracranial malignancy and brain metastases. OUTLINE: This is an open-label, dose-escalation study of lithium carbonate. Patients receive oral lithium carbonate twice daily on days 1-7 and 2-4 times daily on days 8-21. Patients undergo whole-brain radiotherapy once daily on days 8-12 and 15-19. Cohorts of 3-6 patients receive escalating doses of lithium carbonate 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. Quality of life and mental status are assessed at baseline, on days 1, 8, and 15, at 1-month post-treatment, and then periodically thereafter. After completion of study treatment, patients are followed at 1 month and then periodically thereafter. PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study.

Official Title
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A Phase I Study of Lithium During Whole Brain Radiotherapy for Patients With Brain Metastases

Conditions
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Brain and Central Nervous System Tumors, Cognitive/Functional Effects, Neurotoxicity, Solid Tumor

Intervention / Treatment
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* Drug: lithium carbonate
* Procedure: cognitive assessment
* Procedure: quality-of-life assessment
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed extracranial primary malignancy Multiple (i.e., > 3) brain metastases OR < 3 metastases with at least 1 metastasis > 4.0 cm in diameter Not eligible for radiosurgery No requirement for immediate whole-brain radiotherapy No metastases to the midbrain or brainstem Exclusion Criteria: Zubrod performance status 0-2 Life expectancy ≥ 8 weeks Platelet count > 100,000/mm^3 ANC > 1,500/mm^3 Hemoglobin ≥ 10 g/dL BUN < 25 mg/dL Creatinine < 1.5 mg/dL Bilirubin < 1.5 mg/dL ALT ≤ 2 times normal Sodium > 136 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Neurologically stable No seizure disorders or seizures due to brain metastases No medical illnesses or psychiatric conditions that would preclude completion of study treatment No sensory neuropathy ≥ grade 2 No bipolar disorder No thyroid disease No QTc interval prolongation PRIOR CONCURRENT THERAPY: More than 2 weeks since prior and no concurrent chemotherapy At least 2 weeks since prior and no concurrent NSAIDs, angiotensin-converting enzyme inhibitors (e.g., enalapril or captopril), calcium channel blockers, diuretics, selective cyclooxygenase-2 inhibitors, acetazolamide, urea, xanthine, or alkalinizing agents (e.g., sodium bicarbonate) No prior radiotherapy to the head and neck area No prior radiosurgery No concurrent radiotherapy to other sites No concurrent anticonvulsants due to brain metastases No concurrent psychoactive drugs No concurrent thyroid medications No concurrent amifostine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic Intervention<br> | Drug: lithium carbonate<br>* Dose levels Neoadjuvant lithium Concurrent lithium Dose level -1 300mg po QD 300mg po QD Dose level (starting dose) 300mg po BID 300mg po BID Dose level 2 300mg po TID 300mg po TID Dose level 3 300mg po QID 300mg po QID<br>* Other names: lithium;Procedure: cognitive assessment<br>* cognitive assessment<br>Procedure: quality-of-life assessment<br>* quality-of-life assessment<br>Radiation: radiation therapy<br>* Protocol radiotherapy must begin within seven days following initiation of Lithium therapy if day seven falls on a holiday or weekend; it is acceptable to begin treatment the next business day. One treatment of 3Gy will be given daily with the exception of weekends and holidays for a total of (10 fractions) for a total of 30 Gy over 2 to 3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of concurrent lithium carbonate and whole-brain radiotherapy as measured by safety and compliance |  | Safety is measured by the rate of grade 3 or worse | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiation toxicity, neurotoxicity, cognitive/functional effects, unspecified adult solid tumor, protocol specific, adult tumors metastatic to brain