Observational Study Evaluating The Efficacy And Effects On Quality Of Life Of Targeted Treatments Following TKIs In mRCC

OBSERVATIONAL STUDY EVALUATING THE EFFICACY OF TARGETED TREATMENTS FOLLOWING TYROSINE KINASE INHIBITORS IN METASTATIC RENAL CELL CARCINOMA PATIENTS AND EFFECTS ON QUALITY OF LIFE: A NATIONAL, MULTICENTER STUDY

Metastatic renal cell carcinoma (mRCC) is the most common malignant tumour of the kidneys. Targeted therapies, which were recently introduced in the treatment of mRCC, have become the standard treatment in these patients. With improved survival rate and a tolerable side effect profile, Tyrosine Kinase Inhibitors (TKIs) have largely replaced conventional immunotherapies worldwide.

In Turkey, due to reimbursement conditions, cytokine (interferon alpha) treatment is the standard treatment as first-line therapy.

Therefore, the data on quality of life (QoL) from the pivotal studies with standard TKI treatment does not reflect the QoL status of patients treated with TKIs as second or third line treatment in Turkey. In this study, the clinical outcomes and the impact on quality of life of targeted treatments following TKIs will be explored. To our knowledge, since there is no similar reimbursement condition in the world placing IFN as the first line standard treatment, this will be the first study evaluating the QoL status with targeted therapies used as 3rd line treatment in mRCC patients.

Background:

Metastatic renal cell carcinoma (mRCC) is the most common malignant tumour of the kidneys. Targeted therapies, which were recently introduced in the treatment of mRCC, have become the standard treatment in these patients [1]. With improved survival rate and a tolerable side effect profile, Tyrosine Kinase Inhibitors (TKIs) have largely replaced conventional immunotherapies worldwide. [2-3] In Turkey, due to reimbursement conditions defined by the authority, cytokine (interferon alpha) treatment is the standard treatment as first-line therapy [4].

Rationale:

TKI therapy is used after interferon alpha in Turkey due to current reimbursement status. Therefore, the data on quality of life (QoL) from the pivotal studies with standard TKI treatment does not reflect the QoL status of patients treated with TKIs as second or third line treatment in Turkey. In this study, the clinical outcomes and the impact on quality of life of targeted treatments following TKIs will be explored. To our knowledge, since there is no similar reimbursement condition in the world placing IFN as the first line standard treatment, this will be the first study evaluating the QoL status with targeted therapies used as 3rd line treatment in mRCC patients.

Research Question and Objectives

Research Question:

There is no data available in the literature explaining the effect of targeted therapies used as 3rd line treatment following IFN and TKIs in metastatic renal cell carcinoma patients. Therefore, it is essential to understand health-related quality of life and efficacy of targeted therapies used as 3rd line treatment due to current reimbursement conditions in Turkey.

Primary Objective:

• Measurement of health-related quality of life with targeted therapy used as 3rd line treatment
• Overall response rate at the end of follow up
• Median progression free survival according to RECIST version 1.1

Secondary Objectives:

• Overall survival rate
• Effect of quality of life on prognosis.
• Adverse events during 3rd line targeted treatment according to CTCAE.4.03
• Dose modifications due to adverse events
• Correlation between efficacy (overall response rate at month 12 and median PFS) and dose modifications due to adverse events
• Correlation between efficacy (overall response rate at month 12 and median PFS) and blood pressure Study Design: This is a multi-center, national, non-interventional/observational study. It has been defined according to the NUTS (Nomenclature of Territorial Units for Statistics: Nomenclature d'unites Territoriales Statistiques, French) criteria, which is a regional classification, created in order to reduce interregional disparities in socio-economic analysis of the regions, and to produce data comparable to that of the European Union (EU). Turkey has been divided into 12 NUTS regions depending on the economic, social, cultural, and geographical aspects, and the population size. In this study, patients with metastatic renal cell carcinoma from centers in 12 NUTS regions of Turkey will be included, who meet the inclusion criteria. In this study, approximately 152 patients planned to be recruited in 12 months and followed-up for 12 months. Additionally, every patient will be followed-up once for survival follow-up in order to assess the overall survival before the site close out visit. Survival follow-up will be performed via telephone visit or site visit if exist.

Study Population:

Metastatic renal cell carcinoma patients under 3rd line targeted therapy following 1st line interferon alpha and 2nd line TKI. All patients will be ≥ 18 years old and have signed the informed consent document.

Variables:

Age, gender, height, weight, and vital signs such as blood pressure Socio-demographic characteristics ECOG performance status Concomitant diseases and medication Medical history Histopathological findings Type of the surgical procedure Treatment history and current treatment information Metastatic features MSKCC risk factors Laboratory findings The quality of life questionnaire (FKSI-15, EQ5D-3L, FKSI-DRS) on each visit. Blood pressure diary Other treatment during follow-up, if any, the dose and the duration Side effects (treatment of the side effects, interruption of the treatment, dose reduction, dose-elevation) PFS, OS and ORR evaluation during 3rd, 6th, 9th and 12th months performed according to RECIST version 1.1, additionally, every patient will be followed-up once for survival follow-up in order to assess the overall survival before the site close out visit. Survival follow-up will be performed via telephone visit or site visit if exist.

ORR: The best overall response is the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. The patient's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may also require confirmatory measurement.

PFS: The length of time during and after the treatment of a disease, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works.

OS: 1 year Overall Survival (OS), defined as the time from the start of 3rd line treatment until death or 1 year due to any cause (measured at the end of follow-up).

Data Sources: The source of the data will be the electronic or the written patient records of the participating centers. The patient's data can be accessed through a patient file. In the centers, both systems can be used in conjunction. The data can be accessed using both systems.

Sample Size: This is a multi-center, national, non-interventional/observational study. In this study, patients with metastatic renal cell carcinoma who meet the inclusion criteria will be included from centers in 12 NUTS regions of Turkey. Since this is a non-interventional observational study, there is no specific follow-up protocol. In this study, approximately 152 patients will be evaluated.

According to Turkish Statistical Institute data at the end of 2013 population of Turkey is approximately 80 million [5]. In the project of Turkey Association of Cancer Research Control which was named Cancer Record and Incidence shows that cancer incidence is 100-150 in 100.000 [6] and 2% of all new cancers are renal cell carcinoma [7]. There would be 1800 new RCC patients in 1 year, and according to the OS of the disease, there would be 4000 RCC patients in Turkey. 15% of these are metastatic at the time of diagnosis and 30-40% of these are metastatic after a period of a time [8]. Presuming that there are 1800 patients with metastatic renal carcinoma in Turkey, the minimum sample size with 7,6 confidence interval, 95% confidence level and 80% power was calculated as 152.

Data Analysis:

Statistical analyses will be primarily of explorative and descriptive nature. Patients who received at least one dose of 3rd line therapy and have sufficient information whether they had an adverse event or not will be valid for safety analysis. Patients who received at least one dose of 3rd line therapy and have any information regarding efficacy of therapy will be valid for intent-to-treat efficacy analysis.

Demographic data, baseline characteristics, diagnosis and prior treatment of RCC, concomitant diseases, and concomitant medication will be described with summary statistics such as mean, SD, minimum, 1, 5, 25, 75, 95, 99 percent quartiles, median, maximum for continuous variables, and category counts and frequencies (percentages) for categorical variables. Concomitant diseases on the case report form correspond to MedDRA terms. Concomitant medication will be coded using WHO's drug dictionary.

Descriptive summaries of Kaplan-Meier (KM) estimates (including number of failed, number censored, 25th and 75th percentiles with respective 95% confidence level and median with 95%Confidence level) and KM curves will be presented for time-to-event efficacy variables (PFS, TTP, time to treatment failure). Mean, SD, minimum, 1, 5, 25, 75, 95, 99 percent quartiles, median, maximum will be produced for duration of treatment. Category counts and frequencies (percentages) will be calculated for tumor status at different visits and general subjective rating of efficacy of 3rd line therapy from the treating physician.

Adverse events will be summarized using the CTCAE.4.03 coding system. Event rates for single adverse events will be calculated based on the total number of patients valid for safety. Adverse events will be categorized according to relation, seriousness, CTCAE grade (version 4.03), and discontinuation of therapy, action taken and outcome. Special attention will be paid to serious adverse events and unexpected or unlisted ADRs.

Category counts and frequencies (percentages) will be calculated for overall tolerability.

Since the enrollment is after the initiation of the treatment, some information will be collected and analyzed retrospectively.

The best overall response is the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation.

Inclusion criteria:

Patients must meet all of the following inclusion criteria to be eligible for inclusion in the study:

• Histologically confirmed metastatic renal cell cancer patients who have already been using targeted therapies for up to 3 months as 3rd line treatment
• Patients older than 18 years
• Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.

Exclusion criteria:

Patients meeting any of the following criteria will not be included in the study:

• Patients with contraindications for the use of the study medications
• Patients with (suspected) pregnancy or in lactation period
• Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.
• Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks before included in the current study.