RECORD-3: Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients With Metastatic Renal Cell Carcinoma

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00903175
• Collaborator: (none)
• Enrollment: 471
• Locations: 84
• Arms: 2
• Duration (Months): 67
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: everolimus; Drug: sunitinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 471 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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.
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: everolimus 1L/sunitinib 2L 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; 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.; Other Names: RAD001 ; Drug: sunitinib; 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.
Active Comparator: sunitinib 1L/everolimus 2L 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; 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.; Other Names: RAD001 ; Drug: sunitinib; 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.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival First-Line (PFS 1-L) [based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months]

   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.

Secondary Outcome Measures

1. Progression-free Survival Combined (PFS-C) [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]

   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.

2. Overall Survival (OS) [Every 2 months from randomization up to 3 years after last patient randomized]

   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.

3. Overall Response Rate (ORR) - First -Line (1-L) [based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months]

   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.

4. Duration of Response (DoR) - First-Line (1-L) [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 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.

5. Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First-line Drug [<=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]

   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.

6. Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First and Second-line Drugs Combined [<=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]

   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.

7. Time to Definitive Deterioration of the Physical Functioning (PF) Scale of the EORTC QLQ-C30 - by First-Line (1L) Drug [<=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]

   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.

8. Time to Definitive Deterioration of the Physical Functioning Scale of the EORTC QLQ-C30 - by First and Second-Line Drugs Combined [<=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]

   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.

9. Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First-Line Drug [<=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]

   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.

10. Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First and Second-Line Drugs Combined [<=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]

    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.

11. Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First-Line Drug [<=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]

    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.

12. Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First and Second-Line Drugs Combined [<=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]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients with advanced renal cell carcinoma.

2. Patients with at least one measurable lesion.

3. Patients with a Karnofsky Performance Status ≥70%.

4. Adequate bone marrow function.

5. Adequate liver function.

6. Adequate renal function.

7. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN)

8. 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:

1. Less than 4 weeks post-major surgery

2. 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).

3. Patients in need for major surgical procedure during the course of the study

4. Patients with a serious non-healing wound, ulcer, or bone fracture

5. Patients with a history of seizure(s) not controlled with standard medical therapy

6. Patients who have received prior systemic treatment for their metastatic RCC

7. 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.

8. 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

9. Patients with a known hypersensitivity to sunitinib or its excipients

10. 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)

1. 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.

1. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥160mmHg or diastolic blood pressure (DBP) of ≥ 95mmHg]

2. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent

3. Patients with a known history of HIV seropositivity.

4. Patients with active bleeding.

5. 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.

1. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA).

2. 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.

3. Patients who have a history of another primary malignancy and off treatment for ≤ 3 years

4. Female patients of child-bearing potential who are not using adequate birth control methods, or who are pregnant or breast feeding.

5. Patients who are using other investigational agents or who had received investigational drugs ≤ 2 weeks prior to study treatment start.

6. Patients unwilling or unable to comply with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham/ Kirklin Clinic Comprehensive CancerCenter (1)	Birmingham	Alabama	United States	35294-0006
2	University of South Alabama / Mitchell Cancer Institute Dept. of Mitchell Cancer Inst.	Mobile	Alabama	United States	36688
3	Highlands Oncology Group HighlandsOncGrp-Bentonville(2)	Fayetteville	Arkansas	United States	72703
4	University of California San Diego - Moores Cancer Center Dept of Moores Cancer Ctr (5)	La Jolla	California	United States	92093-0658
5	University of California at Los Angeles Dept. of UCLA (3)	Los Angeles	California	United States	90095
6	University of Colorado Dept. of Anschutz Cancer (2)	Aurora	Colorado	United States	80045
7	Norwalk Hospital Norwlak SC	Norwalk	Connecticut	United States	06856
8	Georgetown University/Lombardi Cancer Center Dept.of Lombardi Cancer Ctr (2	Washington	District of Columbia	United States	20007-2197
9	Lynn Cancer Institute	Boca Raton	Florida	United States	33486
10	University of Miami SC	Miami	Florida	United States	33136
11	MD Anderson Cancer Center - Orlando Dept.ofMDACC-Orlando	Orlando	Florida	United States	32806
12	University Cancer & Blood Center, LLC Dept of NE GCC (2)	Athens	Georgia	United States	30607
13	Georgia Health Sciences University Dept. of MCG	Augusta	Georgia	United States	30912
14	Summit Cancer Care	Savannah	Georgia	United States	31405
15	NorthwesternUniv.Med.School/Robert H. Lurie Comp.Cancer Ctr Dept.ofNorthwesternMemHospital	Chicago	Illinois	United States	60611
16	Loyola University Medical Center /Cardinal Bernardin Cancer Cardinal Bernardin Cancer (3)	Maywood	Illinois	United States	60153
17	Crescent City Research Consortium, LLC SC	Metairie	Louisiana	United States	70006
18	VA Maryland Health Care Dept.of GreenbaumCancerCent(7)	Baltimore	Maryland	United States	21201
19	Weinberg Cancer Institute at Franklin Square Hospital	Baltimore	Maryland	United States	21237-3998
20	Billings Clinic Dept of Billings Clinic(2)	Billings	Montana	United States	59107
21	Hackensack University Medical Center DeptofHackensackUniv.MedCtr.	Hackensack	New Jersey	United States	07601
22	Cooper Cancer Center	Voorhees	New Jersey	United States	08043
23	Clinical Research Alliance	Lake Success	New York	United States	11042
24	Memorial Sloan Kettering Cancer Center Dept. of MSKCC	NY	New York	United States	10065
25	SUNY - Upstate Medical University Div. of Hematology-Oncology	Syracuse	New York	United States	13210
26	University of North Carolina Dept. of LinbergerCancerCtr(3)	Chapel Hill	North Carolina	United States	27599-7295
27	Levine Cancer Institute Oncology	Charlotte	North Carolina	United States	28203
28	Duke University Medical Center Duke	Durham	North Carolina	United States	27710
29	University of Oklahoma Health Sciences Center Dept of OHSC	Oklahoma City	Oklahoma	United States	73104
30	St. Luke's Hospital and Health Network St Luke's Hospital (2)	Bethlehem	Pennsylvania	United States	18015
31	The West Clinic Dept. of the West Clinic	Memphis	Tennessee	United States	38120
32	The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD(2)	Fort Worth	Texas	United States	76104
33	East Texas Medical Center Cancer Institute	Tyler	Texas	United States	75701
34	Utah Cancer Specialists Dept.of Utah Cancer Spec. (3)	Salt Lake City	Utah	United States	84106
35	Aurora Advanced Healthcare SC	Milwaukee	Wisconsin	United States	53215
36	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1405BCH
37	Novartis Investigative Site	La Plata	Buenos Aires	Argentina	B1902CMK
38	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2002KDS
39	Novartis Investigative Site	Tucuman		Argentina	T4000IAK
40	Novartis Investigative Site	Woodville	South Australia	Australia	5011
41	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	20230-130
42	Novartis Investigative Site	Porto Alegre	RS	Brazil	90610-000
43	Novartis Investigative Site	Sao Paulo	SP	Brazil	05403-000
44	Novartis Investigative Site	Calgary	Alberta	Canada	T2N 4N2
45	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 1Z2
46	Novartis Investigative Site	Vancouver	British Columbia	Canada	V5Z 4E6
47	Novartis Investigative Site	Victoria	British Columbia	Canada	V8R 6V5
48	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
49	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
50	Novartis Investigative Site	Greenfield Park	Quebec	Canada	J4V 2H1
51	Novartis Investigative Site	Montreal	Quebec	Canada	H2X 3J4
52	Novartis Investigative Site	Saskatoon	Saskatchewan	Canada	S7N 4H4
53	Novartis Investigative Site	Herlev		Denmark	DK-2730
54	Novartis Investigative Site	Angers cedex 02		France	49055
55	Novartis Investigative Site	Lille Cedex		France	59020
56	Novartis Investigative Site	Paris		France	75015
57	Novartis Investigative Site	Vandoeuvre-Les-Nancy Cede		France	54511
58	Novartis Investigative Site	Aschaffenburg		Germany	63739
59	Novartis Investigative Site	Berlin		Germany	10098
60	Novartis Investigative Site	Weiden		Germany	92637
61	Novartis Investigative Site	Hongkong		Hong Kong
62	Novartis Investigative Site	Shatin, New Territories		Hong Kong
63	Novartis Investigative Site	Arezzo	AR	Italy	52100
64	Novartis Investigative Site	Modena	MO	Italy	41100
65	Novartis Investigative Site	Napoli		Italy	80132
66	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	03080
67	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	03722
68	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
69	Novartis Investigative Site	Daejeon		Korea, Republic of	301-747
70	Novartis Investigative Site	Chihuahua		Mexico	31000
71	Novartis Investigative Site	Den Haag		Netherlands	2545 CH
72	Novartis Investigative Site	Maastricht		Netherlands	6229 HX
73	Novartis Investigative Site	Jesus Maria	Lima	Peru	11
74	Novartis Investigative Site	Elche	Alicante	Spain	03203
75	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
76	Novartis Investigative Site	Sabadell	Barcelona	Spain	08208
77	Novartis Investigative Site	Lleida	Cataluna	Spain	25198
78	Novartis Investigative Site	Taipei	Taiwan, ROC	Taiwan	112
79	Novartis Investigative Site	Niaosong Township		Taiwan	83301
80	Novartis Investigative Site	Bangkok		Thailand	10700
81	Novartis Investigative Site	Istanbul		Turkey	34093
82	Novartis Investigative Site	Bristol	Avon	United Kingdom	BS2 8ED
83	Novartis Investigative Site	London		United Kingdom	SW3 6JJ
84	Novartis Investigative Site	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00903175
• Other Study ID Numbers: CRAD001L2202; 2009-011056-21
• First Posted: May 18, 2009
• Last Update Posted: Nov 8, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Novartis Pharmaceuticals: RAD001; everolimus; sunitinib; renal cell carcinoma; kidney cancer; metastatic renal cell cancer; advanced kidney cancer
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Everolimus; Sunitinib

Study Results

Participant Flow

Recruitment Details	238 patients were randomized to everolimus as 1st line followed by 2nd line sunitinib. All patients in this group were treated. 233 patients were randomized to the sunitinib as 1st line followed by 2nd line everolimus. However 2 of the 233 patients were not treated in this group.
Pre-assignment Detail	The trial had a crossover design: first-line therapy until disease progression followed by second-line therapy until disease progression.Patients were randomized 1:1 to either everolimus-sunitinib or sunitinib-everolimus treatment sequence and were stratified by MSKCC risk criteria

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Period Title: Period 1 - First Line
STARTED	238	231
COMPLETED	161	142
NOT COMPLETED	77	89
Period Title: Period 1 - First Line
STARTED	128	116
COMPLETED	79	80
NOT COMPLETED	49	36

Baseline Characteristics

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L	Total
Arm/Group Description	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)	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	Total of all reporting groups
Overall Participants	238	233	471
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.36 (12.102)	60.84 (11.627)	61.10 (11.860)
Sex/Gender, Customized (Number) [Number]
Female	72 30.3%	57 24.5%	129 27.4%
Male	166 69.7%	176 75.5%	342 72.6%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival First-Line (PFS 1-L)
Description	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.
Time Frame	based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	7.85	10.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus 1L/Sunitinib 2L, Sunitinib 1L/Everolimus 2L
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Primary objective was to assess the non-inferiority of everolimus as compared to Sunitinib in terms of PFS-1L & was based on Bayesian methodology. If the estimated HR for PFS-1L had a value ≤ 1.1, non-inferiority of everolimus to Sunitinib would be declared. Non-inferiority of everolimus compared with Sunitinib as a first-line therapy was not achieved. The estimated HR for PFS-1L was 1.43 which did not satisfy the protocol-defined non-inferiority margin of a HR ≤ 1.1.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; 1.15 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival Combined (PFS-C)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	21.68	22.18

3. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	Every 2 months from randomization up to 3 years after last patient randomized

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	22.41	29.47

4. Secondary Outcome

Title	Overall Response Rate (ORR) - First -Line (1-L)
Description	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.
Time Frame	based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Complete Response (CR)	1 0.4%	3 1.3%
Partial Response (PR)	18 7.6%	59 25.3%
Overall Response Rate (CR + PR)	19 8%	62 26.6%

5. Secondary Outcome

Title	Duration of Response (DoR) - First-Line (1-L)
Description	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.
Time Frame	based on radiological assessments every 3 months until disease progression, start of another antineoplastic therapy or for any other reason up to 35 months

Outcome Measure Data

Analysis Population Description

The analysis population corresponds to the patients included in the Full analysis set (i.e. randomized patients analyzed according to the treatment and stratum they were assigned to at randomization) and who achieved a best overall response of CR or PR during the first-line treatment period.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	19	62
Median (95% Confidence Interval) [Months]	13.37	17.25

6. Secondary Outcome

Title	Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First-line Drug
Description	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.
Time Frame	<=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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	12.65	16.66

7. Secondary Outcome

Title	Time to Definitive Deterioration of the FKSI-DRS Risk Score by at Least 3 Score Units by First and Second-line Drugs Combined
Description	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.
Time Frame	<=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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	14.23	15.97

8. Secondary Outcome

Title	Time to Definitive Deterioration of the Physical Functioning (PF) Scale of the EORTC QLQ-C30 - by First-Line (1L) Drug
Description	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.
Time Frame	<=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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	13.47	14.03

9. Secondary Outcome

Title	Time to Definitive Deterioration of the Physical Functioning Scale of the EORTC QLQ-C30 - by First and Second-Line Drugs Combined
Description	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.
Time Frame	<=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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	12.25	14.03

10. Secondary Outcome

Title	Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First-Line Drug
Description	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.
Time Frame	<=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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	7.92	12.25

11. Secondary Outcome

Title	Time to Definitive Deterioration of the Global Health Status/QoL Scores of the EORTC QLQ-C30 by First and Second-Line Drugs Combined
Description	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.
Time Frame	<=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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	10.84	12.71

12. Secondary Outcome

Title	Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First-Line Drug
Description	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.
Time Frame	<=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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Median (95% Confidence Interval) [Months]	9.20	11.37

13. Secondary Outcome

Title	Time to Definitive Deterioration of the Fatigue Scale of the EORTC QLQ-C30 by First and Second-Line Drugs Combined
Description	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.
Time Frame	<=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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consists of all randomized patients analyzed according to the treatment and stratum they were assigned to at randomization.

Arm/Group Title	Everolimus 1L/Sunitinib 2L	Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)	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
Measure Participants	238	233
Mean (95% Confidence Interval) [Months]	11.56	13.34

Adverse Events

Arm/Group Title	Everolimus 1L/Sunitinib 2L		Sunitinib 1L/Everolimus 2L
Arm/Group Description	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)		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
All Cause Mortality
	Everolimus 1L/Sunitinib 2L		Sunitinib 1L/Everolimus 2L
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Everolimus 1L/Sunitinib 2L		Sunitinib 1L/Everolimus 2L
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	139/238 (58.4%)		131/231 (56.7%)
Blood and lymphatic system disorders
Anaemia	16/238 (6.7%)		9/231 (3.9%)
Coagulopathy	1/238 (0.4%)		0/231 (0%)
Disseminated intravascular coagulation	0/238 (0%)		1/231 (0.4%)
Febrile neutropenia	0/238 (0%)		1/231 (0.4%)
Lymph node pain	0/238 (0%)		1/231 (0.4%)
Lymphopenia	0/238 (0%)		1/231 (0.4%)
Thrombocytopenia	2/238 (0.8%)		9/231 (3.9%)
Cardiac disorders
Acute myocardial infarction	1/238 (0.4%)		2/231 (0.9%)
Arrhythmia supraventricular	0/238 (0%)		1/231 (0.4%)
Atrial fibrillation	7/238 (2.9%)		0/231 (0%)
Atrial flutter	1/238 (0.4%)		0/231 (0%)
Atrioventricular block second degree	1/238 (0.4%)		0/231 (0%)
Bradycardia	0/238 (0%)		1/231 (0.4%)
Cardiac arrest	1/238 (0.4%)		0/231 (0%)
Cardiac failure	0/238 (0%)		2/231 (0.9%)
Cardiac failure congestive	3/238 (1.3%)		0/231 (0%)
Cardio-respiratory arrest	2/238 (0.8%)		0/231 (0%)
Cardiomyopathy	0/238 (0%)		1/231 (0.4%)
Cardiopulmonary failure	0/238 (0%)		2/231 (0.9%)
Myocardial infarction	3/238 (1.3%)		3/231 (1.3%)
Myocardial ischaemia	1/238 (0.4%)		1/231 (0.4%)
Pericardial effusion	2/238 (0.8%)		0/231 (0%)
Sinus bradycardia	0/238 (0%)		1/231 (0.4%)
Sinus tachycardia	0/238 (0%)		1/231 (0.4%)
Stress cardiomyopathy	1/238 (0.4%)		0/231 (0%)
Supraventricular tachycardia	1/238 (0.4%)		0/231 (0%)
Ventricular dysfunction	1/238 (0.4%)		0/231 (0%)
Ear and labyrinth disorders
Vertigo	0/238 (0%)		1/231 (0.4%)
Endocrine disorders
Hypothyroidism	0/238 (0%)		2/231 (0.9%)
Eye disorders
Corneal disorder	0/238 (0%)		1/231 (0.4%)
Diplopia	0/238 (0%)		1/231 (0.4%)
Optic ischaemic neuropathy	1/238 (0.4%)		0/231 (0%)
Visual impairment	0/238 (0%)		1/231 (0.4%)
Gastrointestinal disorders
Abdominal distension	2/238 (0.8%)		1/231 (0.4%)
Abdominal pain	6/238 (2.5%)		8/231 (3.5%)
Abdominal pain lower	0/238 (0%)		1/231 (0.4%)
Abdominal pain upper	3/238 (1.3%)		1/231 (0.4%)
Anal fissure	2/238 (0.8%)		0/231 (0%)
Anal fistula	1/238 (0.4%)		1/231 (0.4%)
Ascites	2/238 (0.8%)		2/231 (0.9%)
Colitis	1/238 (0.4%)		3/231 (1.3%)
Constipation	1/238 (0.4%)		3/231 (1.3%)
Diarrhoea	6/238 (2.5%)		5/231 (2.2%)
Diverticulum	1/238 (0.4%)		0/231 (0%)
Duodenal obstruction	1/238 (0.4%)		0/231 (0%)
Dyspepsia	0/238 (0%)		1/231 (0.4%)
Dysphagia	0/238 (0%)		1/231 (0.4%)
Enteritis	1/238 (0.4%)		0/231 (0%)
Enterocolitis	1/238 (0.4%)		0/231 (0%)
Gastritis	1/238 (0.4%)		0/231 (0%)
Gastrointestinal erosion	1/238 (0.4%)		0/231 (0%)
Gastrointestinal haemorrhage	3/238 (1.3%)		2/231 (0.9%)
Gastrointestinal inflammation	0/238 (0%)		1/231 (0.4%)
Gingival bleeding	1/238 (0.4%)		0/231 (0%)
Haematemesis	1/238 (0.4%)		1/231 (0.4%)
Haematochezia	3/238 (1.3%)		0/231 (0%)
Haemorrhoids	0/238 (0%)		1/231 (0.4%)
Ileus	0/238 (0%)		1/231 (0.4%)
Intestinal ischaemia	0/238 (0%)		1/231 (0.4%)
Intestinal obstruction	3/238 (1.3%)		0/231 (0%)
Localised intraabdominal fluid collection	0/238 (0%)		1/231 (0.4%)
Melaena	1/238 (0.4%)		1/231 (0.4%)
Nausea	4/238 (1.7%)		5/231 (2.2%)
Oesophageal ulcer	0/238 (0%)		1/231 (0.4%)
Oral pain	1/238 (0.4%)		0/231 (0%)
Pancreatitis	3/238 (1.3%)		0/231 (0%)
Peritoneal adhesions	1/238 (0.4%)		0/231 (0%)
Rectal haemorrhage	1/238 (0.4%)		1/231 (0.4%)
Small intestinal obstruction	0/238 (0%)		1/231 (0.4%)
Stomatitis	6/238 (2.5%)		0/231 (0%)
Upper gastrointestinal haemorrhage	1/238 (0.4%)		0/231 (0%)
Vomiting	5/238 (2.1%)		8/231 (3.5%)
General disorders
Asthenia	6/238 (2.5%)		6/231 (2.6%)
Fatigue	6/238 (2.5%)		5/231 (2.2%)
General physical health deterioration	3/238 (1.3%)		4/231 (1.7%)
Generalised oedema	1/238 (0.4%)		0/231 (0%)
Impaired healing	1/238 (0.4%)		1/231 (0.4%)
Influenza like illness	1/238 (0.4%)		1/231 (0.4%)
Localised oedema	0/238 (0%)		1/231 (0.4%)
Malaise	3/238 (1.3%)		1/231 (0.4%)
Mucous membrane disorder	1/238 (0.4%)		0/231 (0%)
Multi-organ failure	1/238 (0.4%)		1/231 (0.4%)
Non-cardiac chest pain	2/238 (0.8%)		3/231 (1.3%)
Oedema peripheral	2/238 (0.8%)		3/231 (1.3%)
Pelvic mass	0/238 (0%)		1/231 (0.4%)
Performance status decreased	1/238 (0.4%)		1/231 (0.4%)
Peripheral swelling	1/238 (0.4%)		2/231 (0.9%)
Pyrexia	10/238 (4.2%)		7/231 (3%)
Sudden death	0/238 (0%)		1/231 (0.4%)
Hepatobiliary disorders
Cholangitis	0/238 (0%)		1/231 (0.4%)
Cholecystitis	2/238 (0.8%)		4/231 (1.7%)
Cholecystitis acute	2/238 (0.8%)		0/231 (0%)
Cholelithiasis	1/238 (0.4%)		1/231 (0.4%)
Haemobilia	0/238 (0%)		1/231 (0.4%)
Hepatic function abnormal	0/238 (0%)		1/231 (0.4%)
Hepatic haemorrhage	0/238 (0%)		1/231 (0.4%)
Hyperbilirubinaemia	0/238 (0%)		1/231 (0.4%)
Jaundice	0/238 (0%)		1/231 (0.4%)
Jaundice cholestatic	1/238 (0.4%)		1/231 (0.4%)
Immune system disorders
Drug hypersensitivity	1/238 (0.4%)		0/231 (0%)
Hypersensitivity	1/238 (0.4%)		0/231 (0%)
Infections and infestations
Abdominal abscess	0/238 (0%)		1/231 (0.4%)
Abscess oral	0/238 (0%)		1/231 (0.4%)
Anal abscess	0/238 (0%)		1/231 (0.4%)
Aspergillus infection	0/238 (0%)		1/231 (0.4%)
Bacteraemia	0/238 (0%)		1/231 (0.4%)
Bacterial prostatitis	0/238 (0%)		1/231 (0.4%)
Bacterial sepsis	1/238 (0.4%)		0/231 (0%)
Bronchitis	1/238 (0.4%)		1/231 (0.4%)
Bronchopneumonia	1/238 (0.4%)		0/231 (0%)
Cellulitis	3/238 (1.3%)		3/231 (1.3%)
Clostridium difficile infection	1/238 (0.4%)		0/231 (0%)
Diverticulitis	1/238 (0.4%)		2/231 (0.9%)
Empyema	1/238 (0.4%)		0/231 (0%)
Endocarditis	1/238 (0.4%)		1/231 (0.4%)
Escherichia sepsis	1/238 (0.4%)		0/231 (0%)
Gastrointestinal viral infection	0/238 (0%)		1/231 (0.4%)
Hepatitis A	1/238 (0.4%)		0/231 (0%)
Herpes zoster	1/238 (0.4%)		0/231 (0%)
Infected bites	0/238 (0%)		1/231 (0.4%)
Kidney infection	0/238 (0%)		1/231 (0.4%)
Localised infection	0/238 (0%)		1/231 (0.4%)
Lower respiratory tract infection	2/238 (0.8%)		0/231 (0%)
Lung infection	2/238 (0.8%)		1/231 (0.4%)
Pneumonia	18/238 (7.6%)		15/231 (6.5%)
Respiratory tract infection	2/238 (0.8%)		0/231 (0%)
Salmonella sepsis	0/238 (0%)		1/231 (0.4%)
Sepsis	3/238 (1.3%)		4/231 (1.7%)
Septic shock	4/238 (1.7%)		2/231 (0.9%)
Urinary tract infection	3/238 (1.3%)		5/231 (2.2%)
Wound infection	1/238 (0.4%)		0/231 (0%)
Wound sepsis	0/238 (0%)		1/231 (0.4%)
Injury, poisoning and procedural complications
Femoral neck fracture	1/238 (0.4%)		0/231 (0%)
Femur fracture	1/238 (0.4%)		2/231 (0.9%)
Head injury	1/238 (0.4%)		0/231 (0%)
Heat stroke	1/238 (0.4%)		0/231 (0%)
Hip fracture	1/238 (0.4%)		0/231 (0%)
Humerus fracture	3/238 (1.3%)		0/231 (0%)
Pneumothorax traumatic	1/238 (0.4%)		0/231 (0%)
Post procedural haematoma	0/238 (0%)		1/231 (0.4%)
Post-traumatic pain	0/238 (0%)		1/231 (0.4%)
Rib fracture	2/238 (0.8%)		0/231 (0%)
Road traffic accident	0/238 (0%)		1/231 (0.4%)
Scar	1/238 (0.4%)		0/231 (0%)
Subdural haematoma	1/238 (0.4%)		1/231 (0.4%)
Subdural haemorrhage	1/238 (0.4%)		0/231 (0%)
Investigations
Blood creatinine increased	3/238 (1.3%)		3/231 (1.3%)
Body temperature increased	1/238 (0.4%)		0/231 (0%)
C-reactive protein increased	1/238 (0.4%)		0/231 (0%)
Creatinine renal clearance decreased	0/238 (0%)		1/231 (0.4%)
Eastern cooperative oncology group performance status worsened	1/238 (0.4%)		0/231 (0%)
Electrocardiogram T wave abnormal	0/238 (0%)		1/231 (0.4%)
Gamma-glutamyltransferase increased	0/238 (0%)		1/231 (0.4%)
Haemoglobin decreased	1/238 (0.4%)		2/231 (0.9%)
Hepatic enzyme increased	0/238 (0%)		1/231 (0.4%)
Troponin	0/238 (0%)		1/231 (0.4%)
Troponin I increased	1/238 (0.4%)		0/231 (0%)
Troponin increased	1/238 (0.4%)		0/231 (0%)
Metabolism and nutrition disorders
Decreased appetite	3/238 (1.3%)		0/231 (0%)
Dehydration	13/238 (5.5%)		6/231 (2.6%)
Diabetes mellitus	1/238 (0.4%)		1/231 (0.4%)
Electrolyte imbalance	1/238 (0.4%)		0/231 (0%)
Failure to thrive	1/238 (0.4%)		1/231 (0.4%)
Feeding disorder	1/238 (0.4%)		0/231 (0%)
Food intolerance	1/238 (0.4%)		0/231 (0%)
Gout	1/238 (0.4%)		0/231 (0%)
Hypercalcaemia	2/238 (0.8%)		5/231 (2.2%)
Hyperglycaemia	4/238 (1.7%)		5/231 (2.2%)
Hyperkalaemia	1/238 (0.4%)		1/231 (0.4%)
Hypoalbuminaemia	1/238 (0.4%)		1/231 (0.4%)
Hypocalcaemia	1/238 (0.4%)		0/231 (0%)
Hypoglycaemia	2/238 (0.8%)		1/231 (0.4%)
Hypokalaemia	1/238 (0.4%)		1/231 (0.4%)
Hypomagnesaemia	1/238 (0.4%)		0/231 (0%)
Hyponatraemia	0/238 (0%)		1/231 (0.4%)
Hypovolaemia	0/238 (0%)		1/231 (0.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/238 (0.4%)		2/231 (0.9%)
Back pain	5/238 (2.1%)		3/231 (1.3%)
Bone pain	2/238 (0.8%)		1/231 (0.4%)
Flank pain	3/238 (1.3%)		0/231 (0%)
Fracture pain	0/238 (0%)		1/231 (0.4%)
Muscular weakness	0/238 (0%)		1/231 (0.4%)
Musculoskeletal chest pain	1/238 (0.4%)		0/231 (0%)
Myalgia	1/238 (0.4%)		0/231 (0%)
Osteonecrosis of jaw	0/238 (0%)		1/231 (0.4%)
Pain in extremity	0/238 (0%)		2/231 (0.9%)
Pathological fracture	4/238 (1.7%)		3/231 (1.3%)
Spinal column stenosis	1/238 (0.4%)		0/231 (0%)
Spinal pain	0/238 (0%)		1/231 (0.4%)
Vertebral lesion	0/238 (0%)		1/231 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/238 (0%)		1/231 (0.4%)
Endometrial adenocarcinoma	0/238 (0%)		1/231 (0.4%)
Gastrointestinal stromal tumour	1/238 (0.4%)		0/231 (0%)
Lung neoplasm malignant	1/238 (0.4%)		0/231 (0%)
Lymphangiosis carcinomatosa	1/238 (0.4%)		0/231 (0%)
Malignant ascites	1/238 (0.4%)		0/231 (0%)
Malignant neoplasm progression	1/238 (0.4%)		0/231 (0%)
Metastases to bone	2/238 (0.8%)		0/231 (0%)
Metastases to central nervous system	1/238 (0.4%)		1/231 (0.4%)
Renal cell carcinoma	0/238 (0%)		1/231 (0.4%)
Squamous cell carcinoma	0/238 (0%)		1/231 (0.4%)
Tumour associated fever	0/238 (0%)		1/231 (0.4%)
Tumour pain	0/238 (0%)		1/231 (0.4%)
Waldenstrom's macroglobulinaemia	1/238 (0.4%)		0/231 (0%)
Nervous system disorders
Balance disorder	0/238 (0%)		1/231 (0.4%)
Brain oedema	0/238 (0%)		1/231 (0.4%)
Cerebral haemorrhage	3/238 (1.3%)		1/231 (0.4%)
Cerebrovascular accident	2/238 (0.8%)		1/231 (0.4%)
Coma	0/238 (0%)		1/231 (0.4%)
Dizziness	1/238 (0.4%)		1/231 (0.4%)
Dysgeusia	1/238 (0.4%)		0/231 (0%)
Generalised tonic-clonic seizure	0/238 (0%)		1/231 (0.4%)
Haemorrhagic stroke	0/238 (0%)		1/231 (0.4%)
Headache	2/238 (0.8%)		0/231 (0%)
Hemiparesis	2/238 (0.8%)		0/231 (0%)
Hypoaesthesia	0/238 (0%)		1/231 (0.4%)
Intracranial pressure increased	0/238 (0%)		1/231 (0.4%)
Lethargy	1/238 (0.4%)		0/231 (0%)
Loss of consciousness	0/238 (0%)		2/231 (0.9%)
Meningorrhagia	0/238 (0%)		1/231 (0.4%)
Neuralgia	0/238 (0%)		1/231 (0.4%)
Seizure	0/238 (0%)		2/231 (0.9%)
Somnolence	0/238 (0%)		1/231 (0.4%)
Spinal cord compression	4/238 (1.7%)		3/231 (1.3%)
Status epilepticus	0/238 (0%)		1/231 (0.4%)
Syncope	1/238 (0.4%)		2/231 (0.9%)
Transient ischaemic attack	1/238 (0.4%)		1/231 (0.4%)
Visual field defect	1/238 (0.4%)		0/231 (0%)
Psychiatric disorders
Anxiety	1/238 (0.4%)		0/231 (0%)
Completed suicide	1/238 (0.4%)		0/231 (0%)
Confusional state	1/238 (0.4%)		2/231 (0.9%)
Disorientation	0/238 (0%)		1/231 (0.4%)
Mental status changes	1/238 (0.4%)		0/231 (0%)
Panic attack	1/238 (0.4%)		0/231 (0%)
Renal and urinary disorders
Acute kidney injury	11/238 (4.6%)		10/231 (4.3%)
Anuria	0/238 (0%)		1/231 (0.4%)
Azotaemia	2/238 (0.8%)		3/231 (1.3%)
Calculus ureteric	0/238 (0%)		1/231 (0.4%)
Chronic kidney disease	0/238 (0%)		1/231 (0.4%)
Dysuria	1/238 (0.4%)		1/231 (0.4%)
Haematuria	4/238 (1.7%)		0/231 (0%)
Hydronephrosis	0/238 (0%)		1/231 (0.4%)
Nephrotic syndrome	1/238 (0.4%)		0/231 (0%)
Proteinuria	0/238 (0%)		1/231 (0.4%)
Renal failure	5/238 (2.1%)		3/231 (1.3%)
Renal vein thrombosis	0/238 (0%)		1/231 (0.4%)
Tubulointerstitial nephritis	1/238 (0.4%)		0/231 (0%)
Urinary retention	2/238 (0.8%)		0/231 (0%)
Urinary tract obstruction	1/238 (0.4%)		0/231 (0%)
Reproductive system and breast disorders
Oedema genital	0/238 (0%)		1/231 (0.4%)
Pelvic pain	0/238 (0%)		1/231 (0.4%)
Uterine haemorrhage	0/238 (0%)		1/231 (0.4%)
Uterine polyp	0/238 (0%)		1/231 (0.4%)
Vaginal haemorrhage	0/238 (0%)		1/231 (0.4%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/238 (0%)		1/231 (0.4%)
Acute respiratory failure	0/238 (0%)		1/231 (0.4%)
Bronchial disorder	0/238 (0%)		1/231 (0.4%)
Chronic obstructive pulmonary disease	2/238 (0.8%)		1/231 (0.4%)
Cough	2/238 (0.8%)		1/231 (0.4%)
Dyspnoea	12/238 (5%)		13/231 (5.6%)
Dyspnoea exertional	2/238 (0.8%)		0/231 (0%)
Epistaxis	2/238 (0.8%)		3/231 (1.3%)
Haemoptysis	4/238 (1.7%)		0/231 (0%)
Hypoxia	2/238 (0.8%)		1/231 (0.4%)
Interstitial lung disease	3/238 (1.3%)		0/231 (0%)
Obstructive airways disorder	1/238 (0.4%)		0/231 (0%)
Pleural effusion	10/238 (4.2%)		12/231 (5.2%)
Pneumonia aspiration	1/238 (0.4%)		1/231 (0.4%)
Pneumonitis	4/238 (1.7%)		0/231 (0%)
Pneumothorax	1/238 (0.4%)		2/231 (0.9%)
Pulmonary embolism	0/238 (0%)		3/231 (1.3%)
Pulmonary granuloma	0/238 (0%)		1/231 (0.4%)
Pulmonary haemorrhage	0/238 (0%)		1/231 (0.4%)
Pulmonary oedema	1/238 (0.4%)		3/231 (1.3%)
Respiratory failure	6/238 (2.5%)		1/231 (0.4%)
Skin and subcutaneous tissue disorders
Angioedema	2/238 (0.8%)		0/231 (0%)
Dermatitis	1/238 (0.4%)		0/231 (0%)
Generalised erythema	1/238 (0.4%)		0/231 (0%)
Skin ulcer	0/238 (0%)		1/231 (0.4%)
Vascular disorders
Aortic aneurysm	0/238 (0%)		1/231 (0.4%)
Aortic dissection	0/238 (0%)		1/231 (0.4%)
Hypertension	0/238 (0%)		4/231 (1.7%)
Hypertensive crisis	0/238 (0%)		2/231 (0.9%)
Hypotension	3/238 (1.3%)		1/231 (0.4%)
Other (Not Including Serious) Adverse Events
	Everolimus 1L/Sunitinib 2L		Sunitinib 1L/Everolimus 2L
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	231/238 (97.1%)		228/231 (98.7%)
Blood and lymphatic system disorders
Anaemia	75/238 (31.5%)		70/231 (30.3%)
Leukopenia	11/238 (4.6%)		14/231 (6.1%)
Neutropenia	21/238 (8.8%)		45/231 (19.5%)
Thrombocytopenia	37/238 (15.5%)		58/231 (25.1%)
Endocrine disorders
Hyperthyroidism	4/238 (1.7%)		14/231 (6.1%)
Hypothyroidism	30/238 (12.6%)		57/231 (24.7%)
Eye disorders
Periorbital oedema	9/238 (3.8%)		12/231 (5.2%)
Gastrointestinal disorders
Abdominal discomfort	13/238 (5.5%)		8/231 (3.5%)
Abdominal distension	19/238 (8%)		16/231 (6.9%)
Abdominal pain	49/238 (20.6%)		41/231 (17.7%)
Abdominal pain upper	32/238 (13.4%)		38/231 (16.5%)
Aphthous stomatitis	14/238 (5.9%)		2/231 (0.9%)
Constipation	66/238 (27.7%)		68/231 (29.4%)
Diarrhoea	131/238 (55%)		140/231 (60.6%)
Dry mouth	16/238 (6.7%)		22/231 (9.5%)
Dyspepsia	37/238 (15.5%)		59/231 (25.5%)
Dysphagia	16/238 (6.7%)		12/231 (5.2%)
Gastritis	8/238 (3.4%)		13/231 (5.6%)
Gastrooesophageal reflux disease	14/238 (5.9%)		28/231 (12.1%)
Mouth ulceration	18/238 (7.6%)		14/231 (6.1%)
Nausea	114/238 (47.9%)		125/231 (54.1%)
Oral pain	12/238 (5%)		12/231 (5.2%)
Stomatitis	134/238 (56.3%)		146/231 (63.2%)
Toothache	15/238 (6.3%)		8/231 (3.5%)
Vomiting	73/238 (30.7%)		76/231 (32.9%)
General disorders
Asthenia	44/238 (18.5%)		63/231 (27.3%)
Chills	29/238 (12.2%)		20/231 (8.7%)
Face oedema	16/238 (6.7%)		19/231 (8.2%)
Fatigue	124/238 (52.1%)		131/231 (56.7%)
Non-cardiac chest pain	33/238 (13.9%)		30/231 (13%)
Oedema peripheral	79/238 (33.2%)		58/231 (25.1%)
Pain	14/238 (5.9%)		11/231 (4.8%)
Peripheral swelling	15/238 (6.3%)		10/231 (4.3%)
Pyrexia	66/238 (27.7%)		48/231 (20.8%)
Infections and infestations
Bronchitis	12/238 (5%)		6/231 (2.6%)
Influenza	16/238 (6.7%)		8/231 (3.5%)
Nasopharyngitis	26/238 (10.9%)		18/231 (7.8%)
Pneumonia	16/238 (6.7%)		10/231 (4.3%)
Upper respiratory tract infection	25/238 (10.5%)		38/231 (16.5%)
Urinary tract infection	21/238 (8.8%)		23/231 (10%)
Investigations
Alanine aminotransferase increased	16/238 (6.7%)		18/231 (7.8%)
Aspartate aminotransferase increased	14/238 (5.9%)		12/231 (5.2%)
Blood alkaline phosphatase increased	4/238 (1.7%)		12/231 (5.2%)
Blood creatinine increased	34/238 (14.3%)		39/231 (16.9%)
Gamma-glutamyltransferase increased	12/238 (5%)		16/231 (6.9%)
Haemoglobin decreased	21/238 (8.8%)		26/231 (11.3%)
Neutrophil count decreased	7/238 (2.9%)		15/231 (6.5%)
Platelet count decreased	6/238 (2.5%)		17/231 (7.4%)
Weight decreased	63/238 (26.5%)		49/231 (21.2%)
Metabolism and nutrition disorders
Decreased appetite	93/238 (39.1%)		101/231 (43.7%)
Dehydration	19/238 (8%)		23/231 (10%)
Hypercholesterolaemia	19/238 (8%)		12/231 (5.2%)
Hyperglycaemia	41/238 (17.2%)		30/231 (13%)
Hyperkalaemia	12/238 (5%)		14/231 (6.1%)
Hypertriglyceridaemia	21/238 (8.8%)		15/231 (6.5%)
Hypoalbuminaemia	13/238 (5.5%)		10/231 (4.3%)
Hypokalaemia	14/238 (5.9%)		13/231 (5.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	50/238 (21%)		46/231 (19.9%)
Back pain	60/238 (25.2%)		66/231 (28.6%)
Bone pain	8/238 (3.4%)		15/231 (6.5%)
Flank pain	23/238 (9.7%)		17/231 (7.4%)
Muscle spasms	17/238 (7.1%)		11/231 (4.8%)
Muscular weakness	15/238 (6.3%)		13/231 (5.6%)
Musculoskeletal chest pain	15/238 (6.3%)		11/231 (4.8%)
Musculoskeletal pain	29/238 (12.2%)		20/231 (8.7%)
Myalgia	19/238 (8%)		22/231 (9.5%)
Neck pain	10/238 (4.2%)		15/231 (6.5%)
Pain in extremity	47/238 (19.7%)		44/231 (19%)
Nervous system disorders
Dizziness	40/238 (16.8%)		30/231 (13%)
Dysgeusia	73/238 (30.7%)		75/231 (32.5%)
Headache	58/238 (24.4%)		50/231 (21.6%)
Hypoaesthesia	16/238 (6.7%)		10/231 (4.3%)
Neuropathy peripheral	12/238 (5%)		14/231 (6.1%)
Paraesthesia	12/238 (5%)		12/231 (5.2%)
Psychiatric disorders
Anxiety	21/238 (8.8%)		19/231 (8.2%)
Depression	22/238 (9.2%)		13/231 (5.6%)
Insomnia	41/238 (17.2%)		41/231 (17.7%)
Renal and urinary disorders
Dysuria	19/238 (8%)		15/231 (6.5%)
Haematuria	12/238 (5%)		17/231 (7.4%)
Proteinuria	6/238 (2.5%)		13/231 (5.6%)
Respiratory, thoracic and mediastinal disorders
Cough	96/238 (40.3%)		76/231 (32.9%)
Dysphonia	13/238 (5.5%)		6/231 (2.6%)
Dyspnoea	68/238 (28.6%)		57/231 (24.7%)
Dyspnoea exertional	18/238 (7.6%)		14/231 (6.1%)
Epistaxis	53/238 (22.3%)		54/231 (23.4%)
Nasal congestion	12/238 (5%)		5/231 (2.2%)
Oropharyngeal pain	28/238 (11.8%)		22/231 (9.5%)
Pleural effusion	14/238 (5.9%)		11/231 (4.8%)
Pneumonitis	16/238 (6.7%)		7/231 (3%)
Productive cough	24/238 (10.1%)		19/231 (8.2%)
Rhinorrhoea	26/238 (10.9%)		17/231 (7.4%)
Skin and subcutaneous tissue disorders
Alopecia	15/238 (6.3%)		15/231 (6.5%)
Dermatitis	4/238 (1.7%)		12/231 (5.2%)
Dermatitis acneiform	20/238 (8.4%)		9/231 (3.9%)
Dry skin	34/238 (14.3%)		38/231 (16.5%)
Erythema	11/238 (4.6%)		18/231 (7.8%)
Hair colour changes	6/238 (2.5%)		16/231 (6.9%)
Nail disorder	13/238 (5.5%)		10/231 (4.3%)
Night sweats	9/238 (3.8%)		13/231 (5.6%)
Palmar-plantar erythrodysaesthesia syndrome	46/238 (19.3%)		92/231 (39.8%)
Pruritus	43/238 (18.1%)		38/231 (16.5%)
Rash	95/238 (39.9%)		67/231 (29%)
Swelling face	12/238 (5%)		6/231 (2.6%)
Yellow skin	12/238 (5%)		28/231 (12.1%)
Vascular disorders
Hypertension	61/238 (25.6%)		84/231 (36.4%)

Limitations/Caveats

PRO Tools - completed on Days 1 & 28 of a cycle. Assessments on D1 coincided with end of a 14-day break for patients on sunitinib but not everolimus. So D1 assessments of patients in sunitinib arm may be less impacted by potential toxicity effects.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.