TDM for Optimized Outcome in Patients With mRCC.

Therapeutic Drug Monitoring for Optimized Outcome in Patients With Metastatic Renal Cell Carcinoma

The purpose of this observational study is to assess the role of plasma concentration monitoring of treatment drugs for patients with metastatic renal cell carcinoma (mRCC) in terms of efficacy and side effects.

Furthermore, the investigators examines the role of anti-drug antibodies and receptor polymorphisms in CTLA-4 and PD-1 receptors in treatment failure among patients with mRCC treated with check point immunotherapy. Moreover, polymorphisms in the UGT1A1 gene will be correlated with the pazopanib treatment dose.

Study Overview

• Status: Recruiting
• Conditions: Kidney Cancer; Renal Cell Carcinoma Metastatic; Drug Toxicity; Drug Side Effect; Drug Mechanism
• Intervention / Treatment: Other: Measurement of concentration of active metabolite in cancer treatment.

Detailed Description

BACKGROUND:

Treatment of metastatic renal cell carcinoma (mRCC) is ineffective among 25 % of patients. However, treatment still reduces patients' quality of life.

From clinical experience, interindividual dose requirements vary greatly among patients with mRCC treated with tyrosine kinase inhibitors.

The investigators expect this to partly be explained by great variation in the plasma concentration of treatment drugs. Furthermore, treatment failure among patients with mRCC treated with check point immunotherapy has not been fully investigated.

RATIONALE:

The few studies concerning plasma concentration measurement of tyrosine kinase inhibitors in patients with mRCC have found that a certain level of drug concentration is necessary for treatment efficacy. The role of plasma concentration in side effects is yet unknown.

Anti drug antibodies against the check point inhibitor ipilimumab has been shown to reduce efficacy and lead to treatment failure among patients with malignant melanoma. Receptor polymorphism in CTLA-4 and PD-1 receptors in terms of efficacy have not yet been studied.

A therapeutic drug interval for TKI treatment will allow for quicker and more precise dosing, and early signs of treatment failure of checkpoint immunotherapy will allow for quicker change of therapy, or define a subgroup of patients who will not benefit from checkpoint immunotherapy and therefore should be offered another effective treatment instead.

HYPOTHESIS:

1. Patients treated with TKIs for more than 6 months have an optimal plasma trough concentration. Objective response rate, progression free survival (PFS), overall survival (OS), and toxicity in these patients are favorable compared with pivotal phase III study results.
2. Patients treated with CPI obtaining response have a higher plasma trough concentration value of ipilimumab and nivolumab than patients with progressive disease (PD). Patients treated with CPI who develop PD have a higher amount of ADA than patients with response to treatment.
3. Certain polymorphisms in CTLA-4 and PD-1 are associated with poor outcome.
4. UGT1A1 polymorphism is associated with improved survival despite dose reductions in patients treated with pazopanib.

MATERIALS AND METHODS:

All eligible TKI-patients will have blood samples drawn at each clinical visit during a 6-months period.

The plasma concentration of TKIs will be measured with liquid chromatography-mass spectrometry at the Department of Clinical Biochemistry at Aarhus University Hospital.

All eligible CPI-patients will have blood samples drawn from start CPI-treatment and during treatment until treatment failure or full treatment (2 years).

Analysis of checkpoint immunotherapy will be be done using in-house bead-based assays, anti-human IgG detection antibody and in-house developed flow cytometry-based assay at the Institute for Inflammation Research at Rigshospitalet.

Overall survival, progression free survival and quality of life using FKSI-19 questionnaire will be recorded for each patient.

This is an observational study among Danish patients treated for mRCC over a 6 year year period.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Jakob N Henriksen, MD; Phone Number: +4540438804; Email: jakob.n.henriksen@oncology.au.dk
• Study Contact Backup: Name: Niels Fristrup, MD, PhD; Phone Number: +4520914161; Email: niels.fristrup@rm.dk

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Not yet recruiting
    • Department of Oncology, Herlev Hospital
    • Contact: Anne Kirstine H Moller, MD, PhD
    • Principal Investigator: Anne Kirstine H Moller, MD, PhD
  • Danmark
    • Aarhus, Danmark, Denmark, 8200
      • Recruiting
      • Department of Oncology, Aarhus University Hospital
      • Contact: Niels Fristrup, MD, PhD; Phone Number: +4520914161; Email: niels.fristrup@rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Adult patients in Denmark with medically treated metastatic renal cell carcinoma. Patients are treated in three different oncology departments in Denmark, Aarhus, Odense and Herlev, all of whom are recruiting and participating in this study.

Description

Inclusion Criteria:

• Patients in Denmark with medically treated metastatic renal cell carcinoma.

Exclusion Criteria:

• No written informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort 1; Patients treated for metastatic renal cell carcinoma in Denmark over a 6-year period.	Other: Measurement of concentration of active metabolite in cancer treatment.; Medical treatment for metastatic renal cell carcinoma with axitinib, cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, ipilimumab and nivolumab.; Other Names: Measurement of autoantibodies and receptor polymorfia for CTLA-4 and PD-1 inhibition.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Calculated from the date of inclusion, to the date of death of any cause or censored at the date at last follow-up.	6 months follow-up for each patient.
Progression free survival (PFS)	According to the RECIST v1.1	6 months follow-up for each patient.
Quality of life according to NCCN-FACT FKSI-19.	National Comprehensive Cancer Network/ Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19 (NCCN-FACT FKSI-19). 19 items, each item scored on a 5 point Likert-scale, covering cancer quality of life.	6 months follow-up for each patient.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In pts treated with pazopanib: UGT1A1 genetic polymorphism	TA6/TA6, TA6/TA7 or TA7/TA7	At baseline
Amount of antidrug antibodies (ADAs) developed.	In patients treated with ipilimumab/nivolumab	6 months follow-up for each patient.
SNP-genotype of PD-1 and CTLA-4 receptors reported as proportion of patients with pp-, pq- and qq-genotype respectively.	In pts treated with ipilimumab/nivolumab	6 months follow-up for each patient.

Collaborators and Investigators

• Sponsor: Aarhus University Hospital
• Collaborators: Rigshospitalet, Denmark; Herlev Hospital
• Investigators: Principal Investigator: Niels Fristrup, MD, PhD, University of Aarhus

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2020
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: November 20, 2020
• First Submitted That Met QC Criteria: December 2, 2020
• First Posted (Actual): December 9, 2020

Study Record Updates

• Last Update Posted (Estimated): February 5, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Drug-Related Side Effects and Adverse Reactions; Physiological Effects of Drugs; Immunologic Factors; Autoantibodies
• Other Study ID Numbers: 1-10-72-277-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No