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

February 9, 2022 updated by: Ain Shams University
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).

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Observational

Enrollment (Anticipated)

89

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Egypt
      • Cairo, Egypt
        • Faculty of Medicine, Ain Shams University
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Males or females aged >18 years receiving cisplatin-containing chemotherapy presenting to the Department of Oncology, faculty of medicine, Ain Shams University will be assessed for eligibility according to the inclusion & exclusion criteria.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Case
All eligible patients will be recruited to the study and will be assessed for SNPs in both ERCC1 and OCT2 and their association with cisplatin-induced nephrotoxicity through the measurement of cystatin C before taking cisplatin and after receiving the second cycle of cisplatin.
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
Genetic: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum Creatinine
Time Frame: Change from baseline at the end of cycle 1 (each cycle is 28 days)
available in patient profile
Change from baseline at the end of cycle 1 (each cycle is 28 days)
Serum Creatinine
Time Frame: Change from baseline at the end of cycle 2 (each cycle is 28 days)
available in patient profile
Change from baseline at the end of cycle 2 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
cystatin c
Time Frame: Change from baseline at the end of cycle 2 (each cycle is 28 days)
measured by Human cystatin C ELISA kit
Change from baseline at the end of cycle 2 (each cycle is 28 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ain Shams University

Investigators

  • Study Director: Lamia Elwakeel, Head of Clinical Department, Faculty of Pharmacy, Ain Shams University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

February 15, 2022

Primary Completion (Anticipated)

August 15, 2022

Study Completion (Anticipated)

December 15, 2022

Study Registration Dates

First Submitted

December 10, 2021

First Submitted That Met QC Criteria

February 9, 2022

First Posted (Actual)

February 21, 2022

Study Record Updates

Last Update Posted (Actual)

February 21, 2022

Last Update Submitted That Met QC Criteria

February 9, 2022

Last Verified

November 1, 2021

More Information

Terms related to this study

Other Study ID Numbers

  • PG study on cisplatin

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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