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Cisplatin Disposition and Kidney Injury

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ClinicalTrials.gov Identifier: NCT03817970
Recruitment Status : Not yet recruiting
First Posted : January 28, 2019
Last Update Posted : June 24, 2019
Sponsor:
Collaborators:
Memorial Sloan Kettering Cancer Center
Rutgers University
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Nephrotoxicity Drug: Granisetron Drug: Ondansetron Drug: Palonosetron Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Drug Disposition and Nephrotoxicity
Estimated Study Start Date : August 1, 2019
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Granisetron
An antiemetic regimen containing granisetron 2 mg oral or IV.
Other Name: Kytril

Experimental: 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.
Drug: Ondansetron
An antiemetic regimen containing ondansetron 8 mg oral or IV.
Other Name: Zofran

Experimental: Palonosetron
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
An antiemetic regimen containing palonosetron 0.25 mg IV.
Other Name: Aloxi




Primary Outcome Measures :
  1. Kidney Injury with Cisplatin and 5-HT3 Antagonist Antiemetic Regimen as Assessed by a 1.5 fold increase in a Biomarker Panel [ Time Frame: 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

  2. The Effects of 5-HT3 Antagonist Antiemetic Drugs on Cisplatin Secretion [ Time Frame: 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


Secondary Outcome Measures :
  1. 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 [ Time Frame: 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



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03817970


Contacts
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Contact: Melanie Joy, PharmD, PhD 303-724-7416 Melanie.Joy@ucdenver.edu
Contact: Cindy O'Bryant, PharmD 303-724-2625 Cindy.Obryant@ucdenver.edu

Sponsors and Collaborators
University of Colorado, Denver
Memorial Sloan Kettering Cancer Center
Rutgers University
National Institute of General Medical Sciences (NIGMS)
Investigators
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Principal Investigator: Lauren Aleksunes, PharmD, PhD Rutgers University
Principal Investigator: Melanie Joy, PharmD, PhD University of Colorado, Denver

Publications:
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Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT03817970     History of Changes
Other Study ID Numbers: 18-1752.cc
1R01GM123330-01A1 ( U.S. NIH Grant/Contract )
First Posted: January 28, 2019    Key Record Dates
Last Update Posted: June 24, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by University of Colorado, Denver:
Nephrotoxicity
Cisplatin
Kidney Injury
anti-emetics

Additional relevant MeSH terms:
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Cisplatin
Ondansetron
Palonosetron
Granisetron
Antiemetics
Antineoplastic Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Antipruritics
Dermatologic Agents
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Anti-Anxiety Agents
Serotonin 5-HT3 Receptor Antagonists