Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients With Metastatic Renal Cell Carcinoma

Study Overview
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Brief Summary
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This study assessed the efficacy and safety of first-line RAD001 followed by second-line sunitinib versus the opposite sequence: first-line sunitinib followed by second-line RAD001 for the treatment of patients with MRCC.

Official Title
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An Open-label, Multicenter Phase II Study to Compare the Efficacy and Safety of RAD001 as First-line Followed by Second-line Sunitinib Versus Sunitinib as First-line Followed by Second-line RAD001 in the Treatment of Patients With Metastatic Renal Cell Carcinoma.

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: everolimus
* Drug: sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with advanced renal cell carcinoma. Patients with at least one measurable lesion. Patients with a Karnofsky Performance Status ≥70%. Adequate bone marrow function. Adequate liver function. Adequate renal function. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) Women of childbearing potential must have had a negative serum pregnancy test within 14 days prior to the administration of the study medication. Adequate contraception must be used while on study. Exclusion Criteria: Less than 4 weeks post-major surgery Patients who had radiation therapy within 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed within 2 weeks prior to study treatment start). Patients in need for major surgical procedure during the course of the study Patients with a serious non-healing wound, ulcer, or bone fracture Patients with a history of seizure(s) not controlled with standard medical therapy Patients who have received prior systemic treatment for their metastatic RCC Patients who have previously received systemic mTOR inhibitors (sirolimus, temsirolimus, everolimus) or VEGF inhibitors. Note: History of adjuvant immunotherapy, vaccines or adjuvant sorafenib following localized surgical nephrectomy is acceptable. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins or to its excipients Patients with a known hypersensitivity to sunitinib or its excipients History or clinical evidence of central nervous system (CNS) metastases. Note: Subjects who have previously-treated CNS metastases (surgery plus or minus radiotherapy, radiosurgery, or gamma knife) and meet all 3 of the following criteria are eligible: Are asymptomatic and, have had no evidence of active CNS metastases for ≥ 6 months prior to enrollment and, have no requirement for steroids or enzyme-inducing anticonvulsants (EIAC) Clinically significant gastrointestinal abnormalities including, but not limited to: Malabsorption syndrome Major resection of the stomach or small bowel that could affect the absorption of study drug Active peptic ulcer disease Inflammatory bowel disease Ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥160mmHg or diastolic blood pressure (DBP) of ≥ 95mmHg] Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent Patients with a known history of HIV seropositivity. Patients with active bleeding. Patients who have any severe and/or uncontrolled medical conditions or other conditions within the past 12 months that could affect their participation in the study such as: Cardiac angioplasty or stenting, unstable angina pectoris, symptomatic peripheral vascular disease, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ≤ 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents ≤ 6 months before study treatment start. Prolongation of corrected QT interval (QTc) > 500 milliseconds (msecs). Severally impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 0^2 saturation that is 88% or less at rest on room air. Poorly controlled diabetes as defined by fasting serum glucose >2.0 x ULN. Any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study. Liver disease such as chronic active hepatitis or chronic persistent hepatitis. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA). History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible. Patients who have a history of another primary malignancy and off treatment for ≤ 3 years Female patients of child-bearing potential who are not using adequate birth control methods, or who are pregnant or breast feeding. Patients who are using other investigational agents or who had received investigational drugs ≤ 2 weeks prior to study treatment start. Patients unwilling or unable to comply with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: everolimus 1L/sunitinib 2L<br>everolimus First Line: 10 mg orally, once daily, (two 5 mg tablets), continuous treatment. sunitinib Second Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) | Drug: everolimus<br>* Everolimus was administered orally at 10 mg/day. Everolimus is formulated as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets.<br>* Other names: RAD001;Drug: sunitinib<br>* Sunitinib was administered orally 50 mg daily, on a schedule of 4 weeks on/2 weeks off. Sunitinib was supplied as hard gelatin capsules of 12.5 mg, 25 mg, or 50 mg strength according to local practice.<br>|
| Active Comparator: sunitinib 1L/everolimus 2L<br>sunitinib First Line: 50 mg orally, once daily, 4 weeks on treatment followed by 2 weeks off (4/2) everolimus Second Line: 10 mg orally, once daily (two 5 mg tablets), continuous treatment | Drug: everolimus<br>* Everolimus was administered orally at 10 mg/day. Everolimus is formulated as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets.<br>* Other names: RAD001;Drug: sunitinib<br>* Sunitinib was administered orally 50 mg daily, on a schedule of 4 weeks on/2 weeks off. Sunitinib was supplied as hard gelatin capsules of 12.5 mg, 25 mg, or 50 mg strength according to local practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival First-Line (PFS 1-L) | PFS_1L based on investigator assessment of radiology data by RECIST 1.0, was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause during or after first-line treatment with everolimus or sunitinib. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Combined (PFS-C) | PFS-C (1L and 2L study drugs combined) was a composite endpoint which combined both lines of study treatment. It was defined as the time from the date of randomization to the first of the following: date of death due to any cause, or date of the first radiologically documented progression disease during or after the second-line treatment period for patients with a radiologically documented progression disease in the first-line treatment period and who had crossed-over to second-line treatment no more than 6 weeks after progression. | based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to about 56 months | 
| Overall Survival (OS) | Overall survival was defined as the time from date of randomization to date of death due to any cause. The analysis of OS included all deaths in the FAS regardless of when they were observed. | Every 2 months from randomization up to 3 years after last patient randomized | 
| Overall Response Rate (ORR) - First -Line (1-L) | ORR was defined as the number of participants with best overall response (BOR) of complete response (CR) or partial response (PR) and was based on investigator assessment of radiology data per RECIST. Participants with best overall response of 'Unknown' were treated as non-responders in the calculation of the ORR. Confirmed CR = at least two determinations of CR at least 4 weeks apart before progression. Confirmed PR = at least two determinations of PR or better at least 4 weeks apart before progression. CR required a disappearance of all target and non-target lesions. PR required at least a 30% decrease in the sum of the longest diameters of all target lesions, taking as a reference the baseline sum of the longest diameters. Radiological assessments : every 12 weeks until disease progression, the start of another antineoplastic therapy or for any other reason. | based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months | 
| Duration of Response (DoR) - First-Line (1-L) | Duration of overall response (CR or PR) applies only to patients whose Best Overall Response (BOR) was Complete Response (CR) or Partial Response (PR) during the first-line treatment period. The start date was the date of first documented response (CR or PR) during the first-line treatment and the end date was the date of the event defined as the first documented progression or death due to underlying cancer during or after the same treatment line. | based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months | 
| Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First-line Drug | The Functional Assessment of Cancer Therapy - Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) is a set of items to assess symptoms experienced by patients with advanced kidney cancer. These symptoms include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration was defined as a decrease by at least 3 units compared to baseline, with no later increase above this threshold observed during the 1-L of treatment. A single measure reporting a decrease of at least 3 units was considered definitive only if it was the last one available for the patient. | <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months | 
| Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First and Second-line Drugs Combined | The Functional Assessment of Cancer Therapy - Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) is a set of items to assess symptoms experienced by patients with advanced kidney cancer. These symptoms include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration was defined as a decrease by at least 3 units compared to baseline, with no later increase above this threshold observed during the 1-L or 2-L treatment. A single measure reporting a decrease of at least 3 units was considered definitive only if it was the last one available for the patient. | <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months | 
| Time to Definitive Deterioration of the Physical Functioning (PF) Scale of the EORTC QLQ-C30 - by First-Line (1L) Drug | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant. | <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months | 
| Time to Definitive Deterioration of the Physical Functioning Scale of the EORTC QLQ-C30 - by First and Second-Line Drugs Combined | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant. | <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months | 
| Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First-Line Drug | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant. | <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months | 
| Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First and Second-Line Drugs Combined | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant. | <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months | 
| Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First-Line Drug | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items.The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line of treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant. | <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months | 
| Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First and Second-Line Drugs Combined | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. The standardized score for the PF, fatigue subscales and global health status ranges from 0 to 100, with a higher score representing a high level of functioning/high level of symptom/high quality of life. Definitive deterioration by at least 10% was defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the first line or second line treatment. A single measure reporting a decrease of at least 10% was considered definitive only if it was the last one available for the participant. | <=14 days prior to the first dose of study medication, on day 1, day 28 of every cycle, at the end of treatment visit, at the 28 day FUP visit and monthly thereafter for up to 3 months or until initiation of another anticancer therapy up to 35 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RAD001, everolimus, sunitinib, renal cell carcinoma, kidney cancer, metastatic renal cell cancer, advanced kidney cancer