Neuroprotective Effects of Lithium in Patients With Small Cell Lung Cancer Undergoing Radiation Therapy to the Brain

Study Overview
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Brief Summary
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This phase I/II trial studies the effects and safety of giving lithium carbonate (lithium) to patients with small cell lung cancer (SCLC) undergoing radiation therapy to the brain (PCI; prophylactic cranial irradiation). PCI is used to prevent cancer metastases from returning in the brain. This treatment can cause short-term memory problems by damaging the hippocampus. Lithium may help prevent or lessen memory problems caused by PCI by protecting the hippocampus.

Official Title
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Phase I/II Trial of Lithium as a Neuroprotective Agent for Patients With Small Cell Lung Cancer (SCLC) Treated With Prophylactic Cranial Irradiation (PCI)

Conditions
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Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: Lithium Carbonate
* Radiation: Prophylactic cranial irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have histologically or cytologically confirmed small cell lung cancer. Patients with either limited or extensive stage disease are eligible. Patient must have completed 4-6 cycles of platinum-based chemotherapy (+/- thoracic radiotherapy). Patient must have no evidence of progressive disease on restaging imaging within 3 months of enrollment For patients taking medications known to have a significant interaction with lithium carbonate, these medications should be discontinued at least 1 week prior to and during lithium treatment Patient must be > or = 18 years old. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 Leukocytes >= 3,000/mcL Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 3.0 x IULN Creatinine within normal institutional limits OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Patient must have an electrocardiogram without evidence of arrhythmia, QT prolongation (QTc > 450 ms in males and > 470 ms in females), or other severe dysfunction within 2 weeks of initiation of lithium Women of childbearing potential (women with regular menses, women with amenorrhea, women with irregular cycles, women using a contraceptive method that precludes withdrawal bleeding, and women who have had a tubal ligation) are required to have a negative urine pregnancy test within 14 days prior to the first dose of lithium. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately Patient (or legally authorized representative if applicable) must be able to understand and willing to sign an Internal Review Board (IRB) approved written informed consent document Exclusion Criteria: Patient must not have history of prior cranial radiotherapy Patient must not have brain metastases present prior to initiation of initial therapy or PCI Patient must not have evidence of progressive disease Patient must not have received chemotherapy within 3 weeks of initiation of PCI Patient must not have a history of other malignancy =< 2 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix Patient must not be actively receiving any other investigational agents Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to lithium carbonate Patient must not have any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Patient must not have any uncontrolled thyroid disease Patient must not have a seizure disorder Patient must not be pregnant and/or breastfeeding

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: Arm 1: Lithium carbonate + prophylactic cranial irradiation<br>Lithium carbonate 300 mg PO BID for 7 days prior to the start of prophylactic cranial irradiation (PCI) and will be continued during PCI. PCI will be given at 2.5 Gy per fraction, 5 days per week, for 2 weeks to a total dose of 25 Gy, starting on Day 8 after 7 days of lithium. | Drug: Lithium Carbonate<br> <br> * Other names: Eskalith, Lithane, Lithium, Lithobid, Lithonate, Lithotabs;Radiation: Prophylactic cranial irradiation<br> <br> * Other names: PCI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immediate Recall Memory Deterioration as Measured by the Hopkins Verbal Learning Test - Immediate Recall (HVLT-IR) Total Score | The HVLT is a word learning test measuring episodic visual memory The immediate recall memory deterioration test portion consists of 36 words split into 3 sections (animals, gemstones, places of shelter, types of birds, tools, items of clothing, kitchen utensils,weapons, and alcoholic beverages) The words were read aloud and the participants was asked to freely recall them immediately. The list was read a second time followed by a second free recall trial. This was followed by a third reading and third free recall. The words recalled for each trial were recorded and a total recall score tallied (range: 0-36). The higher the score the better the recall | 3 months | 
| Safety of Lithium Carbonate as Measured by Number of Patients in the Safety lead-in Who Experienced a Dose-limiting Toxicity (DLT) | -Graded and described using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4. Safety will be defined as < 2 patients experiencing DLTs of the first 6 treated. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immediate Recall Memory Deterioration as Measured by the Hopkins Verbal Learning Test - Immediate Recall (HVLT-IR) Total Score | The HVLT is a word learning test measuring episodic visual memory The immediate recall memory deterioration test portion consists of 36 words split into 3 sections (animals, gemstones, places of shelter, types of birds, tools, items of clothing, kitchen utensils,weapons, and alcoholic beverages) The words were read aloud and the participants was asked to freely recall them immediately. The list was read a second time followed by a second free recall trial. This was followed by a third reading and third free recall. The words recalled for each trial were recorded and a total recall score tallied (range: 0-36). The higher the score the better the recall | 6 months | 
| Immediate Recall Memory Deterioration as Measured by the Hopkins Verbal Learning Test - Immediate Recall (HVLT-IR) Total Score | The HVLT is a word learning test measuring episodic visual memory The immediate recall memory deterioration test portion consists of 36 words split into 3 sections (animals, gemstones, places of shelter, types of birds, tools, items of clothing, kitchen utensils,weapons, and alcoholic beverages) The words were read aloud and the participants was asked to freely recall them immediately. The list was read a second time followed by a second free recall trial. This was followed by a third reading and third free recall. The words recalled for each trial were recorded and a total recall score tallied (range: 0-36). The higher the score the better the recall | 12 months | 
| Delayed Recall Memory Deterioration as Measured by the Hopkins Verbal Learning Test - Delayed Recall (HVLT-DR) Total Score | The HVLT is a word learning test measuring episodic visual memory The delayed recall memory deterioration test portion consists of 36 words split into 3 sections (animals, gemstones, places of shelter, types of birds, tools, items of clothing, kitchen utensils,weapons, and alcoholic beverages) The words were read aloud and the participants was asked to freely recall them 20-25 minutes later. The words recalled were recorded and a total recall score tallied (range: 0-36). The higher the score the better the recall | 3 months | 
| Delayed Recall Memory Deterioration as Measured by the Hopkins Verbal Learning Test - Delayed Recall (HVLT-DR) Total Score | The HVLT is a word learning test measuring episodic visual memory The delayed recall memory deterioration test portion consists of 36 words split into 3 sections (animals, gemstones, places of shelter, types of birds, tools, items of clothing, kitchen utensils,weapons, and alcoholic beverages) The words were read aloud and the participants was asked to freely recall them 20-25 minutes later. The words recalled were recorded and a total recall score tallied (range: 0-36). The higher the score the better the recall | 6 months | 
| Delayed Recall Memory Deterioration as Measured by the Hopkins Verbal Learning Test - Delayed Recall (HVLT-DR) Total Score | The HVLT is a word learning test measuring episodic visual memory The delayed recall memory deterioration test portion consists of 36 words split into 3 sections (animals, gemstones, places of shelter, types of birds, tools, items of clothing, kitchen utensils,weapons, and alcoholic beverages) The words were read aloud and the participants was asked to freely recall them 20-25 minutes later. The words recalled were recorded and a total recall score tallied (range: 0-36). The higher the score the better the recall | 12 months | 
| Changes in Quality-of-life as Measured by Overall Quality of Life Using the EORTC QLQ30 | Assessed by comparing questionnaire test scores to baseline; European Organization for Research and Treatment of Cancer (EORTC) QLQ30 (global health/QOL, cognitive functioning, and fatigue scales) 30 total questions with 28 questions having answers ranging from 1-4 with 1=not at all and 4= very much and 2 questions ranging from 0-7 with 1-very poor and 7=excellent Raw scores will be transformed to a 100-point scale (0=lowest score, 100=highest score) The higher the score the lower the quality of life | 3 months | 
| Changes in Quality-of-life as Measured by Overall Quality of Life Using the Total Score of the EORTC QLQ-BN20 | Assessed by comparing questionnaire test scores to baseline; BN20 (future uncertainty and communications deficit scales) 20 questions with answers ranging from 1-4 with 1=not at all and 4=very much Raw scores will be transformed to a 100-point scale (0=lowest score, 100=highest score) The higher the score the lower quality of life | 12 months | 
| Feasibility of Performing Serial Neurocognitive Testing and Quality of Life Exams as Measured by Number of Patients Who Complete the Neurocognitive Testing and Quality of Life Exams | -Defined as at least 4 of 6 patients successfully completing pre-treatment and 3 month post-treatment testing | 3 months | 
| Change in Hippocampal Morphology Following Lithium + PCI as Measured by Total Hippocampal Volume |  | Baseline through 12 months | 
| Number of Participants With Brain Metastases | 1-year rate of brain metastases | 12 months | 
| Number of Central Nervous System (CNS) Adverse Events | Adverse events will be tabulated by type and grade using NCI CTCAE v 4. | Through 12 months | 
| Rate of Overall Survival | -Overall survival is defined as the time between date of on study and date of death due to any cause | 12 months |