Evaluation of the Effect of Genetic Polymorphisms in ERCC1 and OCT2 on the Occurrence and Severity of Cisplatin-induced Nephrotoxicity

Cisplatin Adverse Reaction Clinical Trial

Official title:

Evaluation of the Effect of Genetic Polymorphisms in ERCC1 and OCT2 on the Occurrence and Severity of Cisplatin-induced Nephrotoxicity

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05247671
• Other study ID #: PG study on cisplatin
• Status: Not yet recruiting
• Start date: February 15, 2022
• Est. completion date: December 15, 2022

Study information

• Verified date: November 2021
• Source: Ain Shams University
• Contact: Israa Abdelbar, BSc
• Phone: 00201013138111
• Email: israa.aly[@]bue.edu.eg
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Approximately one-third of all patients treated with cisplatin develop renal dysfunction after a single dosage of cisplatin. Germline genetic polymorphisms may cause variations in cisplatin pharmacokinetics and in the ability of epithelial kidney cells to take up cisplatin and repair cisplatin-induced Deoxyribonucleic Acid (DNA) damage. Knowledge concerning which genotypes are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, to prevent Acute Kidney Injury (AKI).

Description:

Approximately one-third of all patients treated with cisplatin develop renal dysfunction after a single dosage of cisplatin. Germline genetic polymorphisms may cause variations in cisplatin pharmacokinetics and in the ability of epithelial kidney cells to take up cisplatin and repair cisplatin-induced DNA damage. Knowledge concerning which genotypes are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, to prevent AKI. Patient written informed consent will be taken prior to study conductance 1. Full laboratory evaluation before and after cisplatin administration including: (Complete Blood Count) CBC, liver and renal functions. glomerular filtration rate (GFR), and estimated glomerular filtration rate (eGFR) Serum electrolytes. Marker of nephrotoxicity: Cystatin C. 2. Sample Collection and single nucleotide polymorphism (SNP) Genotyping: Venous blood (2 mL) will be collected from each subject into tubes containing 50 mmol of Ethylenediamine tetraacetic acid (EDTA) per liter and genomic DNA will be isolated with the GeneJET Whole Blood Genomic DNA purification Mini kit, according to manufacturer's instructions. Polymorphisms will be assessed using the TaqMan based real-time polymerase chain reaction (PCR) assay. This study aims to assess the influence of single nucleotide polymorphisms in the DNA repair gene Excision Repair Cross Complementation group 1 (ERCC1) and Cisplatin uptake transporter gene Organic Cation Transporter 2 (OCT2) on cisplatin-induced nephrotoxicity by assessment of the following: 1. Occurrence of nephrotoxicity. 2. Degree of renal impairment. 3. Changes in traditional and novel protein biomarkers for AKI.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 89
• Est. completion date: December 15, 2022
• Est. primary completion date: August 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Males or females aged >18 years receiving cisplatin-containing chemotherapy.
• A Cisplatin dose starting from 75 mg/m2
• Various cancer types
• No history of organ transplantation or kidney dialysis.
• Patients with normal renal function

Exclusion Criteria:

• Co-administration of ifosfamide with cisplatin, because of the known risk of nephrotoxicity.
• Pregnant or lactation.
• Infection with the human immunodeficiency virus (HIV).
• Prior administration of cisplatin.
• Intraperitoneal chemotherapy.
• Inadequate liver function (bilirubin > 1.5 times upper normal limit (UNL) and alanine transaminase (ALT) or aspartate transaminase (AST) > 3.0 UNL or up to 5.0 UNL in the presence of hepatic metastases).
• Inadequate renal function (creatinine > 1.25 times UNL, creatinine clearance < 50 mL/min).
• Serious comorbid systemic disorder incompatible with the study (uncontrolled diabetes mellitus (DM) or hypertension (HTN), myocardial infarction within the last 6 months).
• Patients diagnosed with kidney cancer.
• Exposure to any nephrotoxic drugs or agents.

Related Conditions & MeSH terms

• Cisplatin Adverse Reaction

Intervention

Genetic:
• ERCC1
ERCC1 is a rate-limiting enzyme in the nucleotide excision repair pathway that is known to repair cisplatin-induced DNA damage. Polymorphisms in ERCC1 are known to affect response to cisplatin treatment. A mechanism explaining the effect of the ERCC1 polymorphism on the kidney may be that the homozygous carriers of this rs3212986 allele might have a greater capacity to repair cisplatin-induced DNA damage in their kidney epithelia, and thus would be more resistant to cisplatin-induced nephrotoxicity
• OCT2
OCT2 is expressed on the basolateral membrane of Proximal Tubular Epithelial Cell (PTEC) and plays a central role in cisplatin uptake into tubular cells. Genetic variants in the cisplatin uptake transporter OCT2 showed association with the preservation of kidney function. Patients with the CT genotype in OCT2 polymorphism rs596881 exhibited positive changes in eGFR compared to individuals with the wild type CC genotype

Locations

Country	Name	City	State
Egypt	Faculty of medicine, Ain Shams University	Cairo

Sponsors (1)

Lead Sponsor	Collaborator
Ain Shams University

Country where clinical trial is conducted

Egypt, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum Creatinine	available in patient profile	Change from baseline at the end of cycle 1 (each cycle is 28 days)
Primary	Serum Creatinine	available in patient profile	Change from baseline at the end of cycle 2 (each cycle is 28 days)
Secondary	cystatin c	measured by Human cystatin C ELISA kit	Change from baseline at the end of cycle 2 (each cycle is 28 days)

External Links

•   Pharmacogenetic analyses of cisplatin-induced nephrotoxicity indicate a renoprotective effect of ERCC1 polymorphisms. Pharmacogenomics, 12(10), 1417-1427.
•   Pharmacogenomic variants may influence the urinary excretion of novel kidney injury biomarkers in patients rec