Cisplatin Disposition and Kidney Injury

Nephrotoxicity Clinical Trial

Official title:

Drug Disposition and Nephrotoxicity

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03817970
• Other study ID #: 18-1752.cc
• Secondary ID: 1R01GM123330-01A
• Status: Recruiting
• Phase: Phase 3
• Start date: November 15, 2019
• Est. completion date: December 31, 2026

Study information

• Verified date: November 2023
• Source: University of Colorado, Denver
• Contact: Melanie Joy, PharmD, PhD
• Phone: 303-724-7416
• Email: Melanie.Joy[@]ucdenver.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: December 31, 2026
• Est. primary completion date: September 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Nephrotoxicity

Intervention

Drug:
• Granisetron
An antiemetic regimen containing granisetron 2 mg oral or IV.
• Ondansetron
An antiemetic regimen containing ondansetron 8 mg oral or IV.
• Palonosetron
An antiemetic regimen containing palonosetron 0.25 mg IV.

Locations

Country	Name	City	State
United States	UCHealth-Metro Denver	Denver	Colorado
United States	Memorial Sloan Kettering Cancer Center	New York	New York

Sponsors (4)

Lead Sponsor	Collaborator
University of Colorado, Denver	Memorial Sloan Kettering Cancer Center, National Institute of General Medical Sciences (NIGMS), Rutgers University

Country where clinical trial is conducted

United States, 

References & Publications (4)

Chang C, Hu Y, Hogan SL, Mercke N, Gomez M, O'Bryant C, Bowles DW, George B, Wen X, Aleksunes LM, Joy MS. Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin. Int J Mol Sci. 2017 Jun 22;18(7):1333. doi: 10.3390/ijms18071333. — View Citation

George B, Joy MS, Aleksunes LM. Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy. Exp Biol Med (Maywood). 2018 Feb;243(3):272-282. doi: 10.1177/1535370217745302. Epub 2017 Dec 12. — View Citation

George B, Wen X, Mercke N, Gomez M, O'Bryant C, Bowles DW, Hu Y, Hogan SL, Joy MS, Aleksunes LM. Profiling of Kidney Injury Biomarkers in Patients Receiving Cisplatin: Time-dependent Changes in the Absence of Clinical Nephrotoxicity. Clin Pharmacol Ther. 2017 Apr;101(4):510-518. doi: 10.1002/cpt.606. Epub 2017 Feb 14. — View Citation

George B, You D, Joy MS, Aleksunes LM. Xenobiotic transporters and kidney injury. Adv Drug Deliv Rev. 2017 Jul 1;116:73-91. doi: 10.1016/j.addr.2017.01.005. Epub 2017 Jan 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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