Cisplatin Disposition and Kidney Injury

Phase 3

Active, not recruiting

• Conditions: Nephrotoxicity
• Interventions: Drug: Granisetron; Drug: Ondansetron; Drug: Palonosetron

• Registration Number: NCT03817970
• Lead Sponsor: University of Colorado, Denver

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2018-11-27
• Study First Submitted QC: 2019-01-22
• Study First Posted: 2019-01-28
• Study Start: 2019-11-15
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-18
• Last Update Posted: 2024-11-21
• Primary Completion: 2025-09-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 72

Inclusion Criteria

• Male or female patient prescribed cisplatin at a dose of >25mg/m^2
• Age 18-80 years
• Hemoglobin >/=9 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 with the exception of one previous dose as part of the current course
• Herbal supplement use beyond marijuana
• Exposure to other known nephrotoxins (including contrast agents) within the previous 2 weeks
• Severe gastrointestinal disease with fluid losses
• Diagnosis of a rapidly progressive glomerulonephritis
• Allergy or contraindication to 5-HT3 Antagonists

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Granisetron	Granisetron	Participants randomized to an antiemetic regimen containing granisetron 2 mg oral or IV and evaluated for cisplatin toxicity after the first dose of cisplatin.
Ondansetron	Ondansetron	Participants randomized to an antiemetic regimen containing ondansetron 8 mg oral or IV and evaluated for cisplatin toxicity after the first dose of cisplatin.
Palonosetron	Palonosetron	Participants randomized to an antiemetic regimen containing palonosetron 0.25 mg IV and evaluated for cisplatin toxicity after the first dose of cisplatin.

Primary Outcome Measures

Name	Time	Method
The Effects of 5-HT3 Antagonist Antiemetic Drugs on Cisplatin Secretion	3 days	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
Kidney Injury with Cisplatin and 5-HT3 Antagonist Antiemetic Regimen as Assessed by a 1.5 fold increase in a Biomarker Panel	3 days	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

Secondary Outcome Measures

Name	Time	Method
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	3 days	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

Trial Locations

Locations (2)

UCHealth-Metro Denver; 🇺🇸 Denver, Colorado, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States