Cisplatin Disposition and Kidney Injury

Study Overview
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Brief Summary
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This study is being done to determine 1) whether drugs to treat cisplatin-related nausea can influence harm to the kidneys, 2) whether cisplatin levels in the body can influence the risk of harm to the kidneys, and 3) whether a person's genetic make-up can increase or decrease the likelihood of kidney injury due to cisplatin therapy.

Detailed Description
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Cisplatin (cis-diamminedichloroplatinum, Platinol®) is commonly utilized in chemotherapy regimens for the treatment of solid cancers including lung, head and neck, and cervix. Its main mechanism of action is through binding of DNA to form cross-links, leading to arrest of DNA synthesis and replication. A major adverse consequence of cisplatin therapy is acute kidney injury (AKI). It is reported that between 30 and 38 percent of patients develop signs of nephrotoxicity (toxicity in the kidneys) after a single cisplatin dose, despite strategies such as hydration to limit renal exposure. This is problematic for patients as kidney injury can delay further treatment and limit the total number of chemotherapy cycles received, thereby reducing the overall efficacy of cisplatin-containing regimens. Furthermore, it is apparent that cisplatin will remain a central component to the treatment of solid tumors in the foreseeable future. New approaches to identify patients at risk of acute kidney injury (AKI) and prevent its development and progression are urgently needed. Cisplatin causes nausea and vomiting, which requires treatment with 5-HT3 antagonists (5-HT3A) to control. Associations between the clinical use of the 5-HT3A antiemetic drugs and the risk of cisplatin AKI have recently been discovered. This study will interrogate relationships between 5-HT3A drugs (granisetron, ondansetron, and palonosetron) and cisplatin AKI.

Official Title
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Drug Disposition and Nephrotoxicity

Conditions
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Nephrotoxicity

Intervention / Treatment
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* Drug: Granisetron
* Drug: Ondansetron
* Drug: Palonosetron


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient prescribed cisplatin at a dose of >25 mg/m^2 Age 18-80 years Hemoglobin >/=10 g/dl No consumption of grapefruit juice or alcohol within 7 days No history of alcohol consumption of >14 drinks/week No history of organ transplantation or kidney dialysis Willingness to comply with study Not pregnant or lactating No changes in chronic medications within 2 weeks Estimated glomerular filtration rate (eGFR) > 60 ml/min^2 Normal liver function (ALT and AST <2x ULN) Exclusion Criteria: Diagnosis of kidney cancer Previous exposure to platinum-based chemotherapy Herbal supplement use beyond marijuana Exposure to other known nephrotoxins (including contrast agents) within the previous 2 weeks Concurrent use of competitive inhibitors of transport proteins (metformin, cimetidine, ranitidine, antiviral drugs, cephalosporins, topotecan, methotrexate, vinblastine) Severe gastrointestinal disease with fluid losses Diagnosis of a rapidly progressive glomerulonephritis Allergy or contraindication to 5-HT3 Antagonists

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Granisetron<br>Participants randomized to an antiemetic regimen containing granisetron 2 mg oral or IV and evaluated for cisplatin toxicity after the first dose of cisplatin. | Drug: Granisetron<br>* An antiemetic regimen containing granisetron 2 mg oral or IV.<br>* Other names: Kytril;|
| Experimental: Ondansetron<br>Participants randomized to an antiemetic regimen containing ondansetron 8 mg oral or IV and evaluated for cisplatin toxicity after the first dose of cisplatin. | Drug: Ondansetron<br>* An antiemetic regimen containing ondansetron 8 mg oral or IV.<br>* Other names: Zofran;|
| Experimental: Palonosetron<br>Participants randomized to an antiemetic regimen containing palonosetron 0.25 mg IV and evaluated for cisplatin toxicity after the first dose of cisplatin. | Drug: Palonosetron<br>* An antiemetic regimen containing palonosetron 0.25 mg IV.<br>* Other names: Aloxi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kidney Injury with Cisplatin and 5-HT3 Antagonist Antiemetic Regimen as Assessed by a 1.5 fold increase in a Biomarker Panel | The effects of 5-HT3 antagonist antiemetic drugs on cisplatin kidney injury as indicated by a 1.5 fold increase in the urinary biomarker panel values at 3 days after treatment | 3 days | 
| The Effects of 5-HT3 Antagonist Antiemetic Drugs on Cisplatin Secretion | The changes to cisplatin secretion in the urine (as an early biomarker for the detection of kidney injury) as indicated by a 6 mg difference between 5-HT3 Antagonist Antiemetic Drugs at 3 days after treatment | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Targeted Genetic Polymorphisms are Associated with Risk of Kidney Injury Due to Cisplatin and 5-HT3 Antagonist Antiemetic Regimen as Assessed by a 1.5 fold increase in a Biomarker Panel | The influence of targeted genetic polymorphisms on risk of kidney injury due to cisplatin and 5-HT3 Antagonist Antiemetic Drugs as indicated by a 1.5 fold increase in a urinary biomarker panel values at 3 days after treatment | 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nephrotoxicity, Cisplatin, Kidney Injury, anti-emetics