A Study of E7080 Alone, and in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic Renal Cell Carcinoma Following One Prior Vascular Endothelial Growth Factor (VEGF)-Targeted Treatment

• ClinicalTrials.gov Identifier: NCT01136733
• Recruitment Status: Completed
• First Posted: June 3, 2010
• Results First Posted: February 27, 2019
• Last Update Posted: February 27, 2019
• Sponsor: Eisai Inc.
• Information provided by (Responsible Party): Eisai Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Renal Cell Carcinoma
• Interventions: Drug: Lenvatinib; Drug: Everolimus
• Enrollment: 173

Participant Flow

Recruitment Details
Pre-assignment Details	A total of 173 participants were enrolled into the study and treated.

Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18mg) and everolimus (5 mg) was once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Period Title: Phase 1b
Started	7 [1]	11 [1]	2 [1]	0 [1]	0	0	0
Completed	6	6	0	0	0	0	0
Not Completed	1	5	2	0	0	0	0
Reason Not Completed
Adverse Event	0	3	1	0	0	0	0
Participant Choice	0	0	1	0	0	0	0
Administrative-Withdrew Consent	0	1	0	0	0	0	0
Clinical Progression	1	1	0	0	0	0	0
[1] Participants in Phase 1b did not advance to Phase 2.
Period Title: Phase 2
Started	0	0	0	0	51 [1]	52 [1]	50 [1]
Completed	0	0	0	0	0	0	0
Not Completed	0	0	0	0	51	52	50
Reason Not Completed
Disease Progression	0	0	0	0	30	32	38
Adverse Event	0	0	0	0	11	13	5
Participant Choice	0	0	0	0	3	0	1
Administrative-Withdrew Consent	0	0	0	0	1	0	0
Other	0	0	0	0	6	7	6
[1] Participants in Phase 2 did not participate in Phase 1b.

Baseline Characteristics

Arm/Group Title		Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus	Total
Arm/Group Description		Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18 mg) and everolimus (5 mg) was once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.	Total of all reporting groups
Overall Number of Baseline Participants		7	11	2	0	51	52	50	173
Baseline Analysis Population Description		Full analysis set included all randomized participants.
Age, Customized; Geometric Mean (Standard Deviation); Unit of measure: Years	Number Analyzed	7 participants	11 participants	2 participants	0 participants	51 participants	52 participants	50 participants	173 participants
Phase 1b		58.0 (3.92)	58.1 (7.97)	61.0 (2.83)		0 (0)	0 (0)	0 (0)	58.4 (6.29)
Phase 2		0 (0)	0 (0)	0 (0)		61.7 (8.2)	63.3 (8.6)	58.9 (9.2)	61.3 (8.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	7 participants	11 participants	2 participants	0 participants	51 participants	52 participants	50 participants	173 participants
	Female	3 42.9%	2 18.2%	1 50.0%		16 31.4%	13 25.0%	12 24.0%	47 27.2%
	Male	4 57.1%	9 81.8%	1 50.0%		35 68.6%	39 75.0%	38 76.0%	126 72.8%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: Number of Participants With Dose-limiting Toxicity (DLT)
Description	A DLT was defined as either a treatment-related failure to administer greater than or equal to (>=) 75% of the planned dosage of lenvatinib/everolimus or a specific National Cancer Institute Common Toxicity Criteria (NCI CTC) >= Grade 3 (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care daily living activities) hematologic or nonhematologic toxicities considered to be possibly related to lenvatinib and/or everolimus therapy assessed during the first treatment cycle of each dose level. Higher grade indicates more severe toxicity.
Time Frame	First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least one dose of study treatment.

Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	7	11	2	0	0	0	0
Measure Type: Number; Unit of Measure: Participants
Grade 3 abdominal pain	1	0	0
Grade 2 fatigue with Grade 1 GI reflux & anorexia	0	1	0
Grade 3 nausea	0	0	1
Grade 2 stomatitis	0	0	1

2. Primary Outcome

Title	Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose
Description	The highest dose level resulting in 0 or 1 DLT in 6 participants was to be considered the MTD of Phase 1b. Once the MTD was established, the participant cohort was expanded to a minimum of 10 participants. The MTD was confirmed by assessing DLTs during Cycle 1 and intolerable toxicities (i.e., not manageable with dose interruption and/or reduction) during Cycle 2 of therapy. Once the dose of lenvatinib/everolimus combination to be used in the succeeding Phase 2 part of the study was established, enrollment into Phase 2 was started. The RP2 dose was the same as the confirmed MTD and was used for the Phase 2 Treatment Arm A of this study.
Time Frame	First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least one dose of study treatment.

Arm/Group Title	Phase 1b: Dose Escalation and MTD Expansion Cohorts
Arm/Group Description:	Oral everolimus (18 mg) and lenvatinib (5 mg) were taken once daily in the morning (consistently with or without food) with water. Any dietary habits around the time of study medication intake had to be kept as consistent as possible throughout the study.
Overall Number of Participants Analyzed	11
Measure Type: Number; Unit of Measure: mg/day
	18.0

3. Primary Outcome

Title	Phase 2: Progression-Free Survival (PFS)
Description	PFS was defined as the time (in months) from the date of first dose of study drug to the first documentation of disease progression or death, whichever occurred first. Kaplan-Meier (K-M) estimates were used to estimate median PFS, presented with 2-sided 95% confidence intervals (CIs). Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease using computed tomography (CT) or magnetic resonance imaging (MRI) and scan acquisition techniques (including use or nonuse of intravenous (IV) contrast). Tumor response was determined at the site by the investigator and radiologist using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 in the evaluation of the tumor assessment scans. The date of objective disease progression was defined as the earliest date of radiological disease progression. Participants removed from therapy due to clinical progression with no radiologic confirmation were censored at their last radiologic assessment date.
Time Frame	Date of randomization into Phase 2 (Cycle 1 Day 1) to the date of first documentation of disease progression or death (whichever occurred first), assessed up to data cutoff date (13 Jun 2014), up to approximately 2 years and 3 months

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants.

Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	0	0	0	0	51	52	50
Median (95% Confidence Interval); Unit of Measure: Months
					14.6; (5.9 to 20.1)	7.4; (5.6 to 10.2)	5.5; (3.5 to 7.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm C): 10 mg Everolimus
	Comments	Null hypothesis of no difference in PFS was analyzed using the stratified log-rank test with hemoglobin (less than or equal to 13 g/dL vs greater than 13 g/dL for males; and less than or equal to 11.5 g/dL vs greater than 11.5 g/dL for females) and corrected serum calcium (greater than or equal to 10 mg/dL vs less than 10 mg/dL) as stratification factors. Each null hypothesis was tested at a nominal alpha=0.05.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0005
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.24 to 0.68
	Estimation Comments	Hazard ratio between treatment groups and corresponding 95% CI was estimated using the stratified Cox regression model (stratified by hemoglobin and corrected serum calcium) with treatment as a factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm B): 24 mg Lenvatinib, Phase 2 (Arm C): 10 mg Everolimus
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0479
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.38 to 0.98
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1209
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.39 to 1.10
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Phase 2: Overall Survival (OS)
Description	OS was defined as the time (in months) from the date of randomization until date of death from any cause. Median survival time was calculated using K-M estimate for each treatment arm and presented with 2-sided 95% CIs. Participants who were lost to follow-up or alive at the data cutoff date (10 Dec 2014) were censored at the date the participants were last known to be alive.
Time Frame	Randomization (Cycle 1 Day 1) until date of death from any cause, assessed up to the data cutoff date (10 Dec 2014), up to approximately 2 years and 9 months

Outcome Measure Data

Analysis Population Description

Full analysis set which included all randomized participants.

Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	0	0	0	0	51	52	50
Median (95% Confidence Interval); Unit of Measure: Months
					25.5 [1]; (16.4 to NA)	19.1; (13.6 to 26.2)	15.4; (11.8 to 19.6)

[1]

NA = not estimable

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm C): 10 mg Everolimus
	Comments	Planned analyses were performed to test null hypothesis of treatment difference in OS at a nominal significance level of 0.05 (2-sided) using the stratified log-rank test using stratification factors.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0242
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.514
	Confidence Interval	(2-Sided) 95%; 0.299 to 0.884
	Estimation Comments	Hazard ratio between treatment groups and corresponding 95% CI was estimated using the stratified Cox regression model (stratified by hemoglobin and corrected serum calcium) with treatment as a factor.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm B): 24 mg Lenvatinib, Phase 2 (Arm C): 10 mg Everolimus
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.1181
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.684
	Confidence Interval	(2-Sided) 95%; 0.411 to 1.138
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.3157
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.751
	Confidence Interval	(2-Sided) 95%; 0.433 to 1.301
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Phase 2: Objective Response Rate (ORR)
Description	The ORR was defined as the percentage of participants who had the best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator, using RECIST 1.1 in the evaluation of MRI or CT scans of targeted lesions. Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease). The BOR was defined as the best response recorded from the start of the study treatment until discontinuation from the study. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR was calculated with exact 95% CIs using the method of Clopper and Pearson.
Time Frame	Randomization (Cycle 1 Day 1) until first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months

Outcome Measure Data

Analysis Population Description

Full analysis set which included all randomized participants.

Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	0	0	0	0	51	52	50
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
					43.1; (29.3 to 57.8)	26.9; (15.6 to 41.0)	6.0; (1.3 to 16.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm C): 10 mg Everolimus
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	7.2
	Confidence Interval	(2-Sided) 95%; 2.3 to 22.5
	Estimation Comments	Rate ratio was based on the normal approximation.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm B): 24 mg Lenvatinib, Phase 2 (Arm C): 10 mg Everolimus
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0067
	Comments	Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	4.5
	Confidence Interval	(2-Sided) 95%; 1.4 to 14.7
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.1007
	Comments	Analysis performed after database lock. P-value was based on the 2-sided Fisher's exact P-value.
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; 0.9 to 2.8
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	The DCR was defined as the percentage of participants who had a BOR of CR or PR or SD (minimum duration from randomization to SD greater than or equal to 7 weeks). Assessments were performed every 8 weeks and were based on investigator review data using RECIST 1.1. The 95% CI was constructed using the method of Clopper and Pearson. DCR = CR + PR + SD greater than or equal to 7 weeks.
Time Frame	Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months

Outcome Measure Data

Analysis Population Description

Full analysis set which included all randomized participants.

Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day withwater, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	0	0	0	0	51	52	50
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
					84.3; (71.4 to 93.0)	78.8; (65.3 to 88.9)	68.0; (53.3 to 80.5)

7. Secondary Outcome

Title	Durable Stable Disease (SD) Rate
Description	The durable SD rate was defined as the percentage of participants whose BOR was SD and the duration of SD was greater than or equal to 23 weeks. The durable SD was based on investigator review data using RECIST 1.1. The 95% CI was constructed using the method of Clopper and Pearson.
Time Frame	Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months

Outcome Measure Data

Analysis Population Description

Full analysis set which included all randomized participants.

Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	0	0	0	0	51	52	50
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
					25.5; (14.3 to 39.6)	38.5; (25.3 to 53.0)	36.0; (22.9 to 50.8)

8. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	The CBR was defined as the percentage of participants who had BOR of CR, PR, or durable SD (duration of SD was greater than or equal to 23 weeks) and was based on investigator review data using RECIST 1.1. The BOR was defined as the best response recorded from the start of study treatment until discontinuation from the study. There was no requirement for confirmatory measurement of PR or CR to deem either one the BOR. The 95% CI was constructed using the method of Clopper and Pearson. CBR = CR + PR + SD greater than or equal to 23 weeks.
Time Frame	Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months

Outcome Measure Data

Analysis Population Description

Full analysis set which included all randomized participants.

Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4 week) cycles.
Overall Number of Participants Analyzed	0	0	0	0	51	52	50
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
					68.6; (54.1 to 80.9)	65.4; (50.9 to 78.0)	42.0; (28.2 to 56.8)

9. Secondary Outcome

Title	Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2
Description	Blood samples were collected during the Randomization Phase. Most participants had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose). Plasma concentrations of lenvatinib were measured and concentration data were summarized. The summary statistics at time points with one or more below the limit of quantitation (BLQ) values were calculated by assigning zero for each BLQ value.
Time Frame	Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set included all participants who have received at least one dose of study drug (lenvatinib or everolimus) and have evaluable concentration data.

Arm/Group Title	Cycle 1, Day 1 (0 Hours)	Cycle 1, Day 1 (2-8 Hours)	Cycle 2, Day 1 (0 Hours)	Cycle 2, Day 1 (2-8 Hours)	Cycle 3, Day 1 (0 Hours)	Cycle 3, Day 1 (2-8 Hours)
Arm/Group Description:	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.
Overall Number of Participants Analyzed	57	55	45	41	42	40
Geometric Mean (Standard Deviation); Unit of Measure: ng/mL
	5.6 (29.8)	197 (140)	66.9 (52.7)	237 (154)	37.0 (35.5)	180 (118)

10. Secondary Outcome

Title	Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2
Description	Blood samples were collected during the Randomization Phase. Most participants had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose). Whole blood concentrations of everolimus were measured and concentration data were summarized. The summary statistics at time points with one or more BLQ values were calculated by assigning zero for each BLQ value.
Time Frame	Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set included all participants who received at least one dose of study drug (lenvatinib or everolimus) and had evaluable concentration data.

Arm/Group Title	Cycle 1, Day 1 (0 Hours)	Cycle 1, Day 1 (2-8 Hours)	Cycle 2, Day 1 (0 Hours)	Cycle 2, Day 1 (2-8 Hours)	Cycle 3, Day 1 (0 Hours)	Cycle 3, Day 1 (2-8 Hours)
Arm/Group Description:	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration.	Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.
Overall Number of Participants Analyzed	37	35	29	28	27	25
Geometric Mean (Standard Deviation); Unit of Measure: ng/mL
	0.0 (0.00)	19.4 (9.16)	10.0 (7.28)	24.3 (14.2)	6.8 (6.06)	26.4 (14.8)

11. Secondary Outcome

Title	Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC(0-24)) for Lenvatinib When Administered Alone or in Combination With Everolimus
Description	Between 9 and 12 participants in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling. Blood samples were analyzed for study drug using standardized methods. PK parameters for lenvatinib were derived from lenvatinib concentration data using non-compartmental methods. Data were compared via descriptive statistics between single agent and combination therapy.
Time Frame	Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic sub analysis set consisted of all participants who agreed to participate in the intensive PK sampling portion of Phase 2 of the study, had received at least 1 dose of study drug (lenvatinib or everolimus), and had evaluable concentration data.

Arm/Group Title	Phase 2: 18 mg Lenvatinib + 5 mg Everolimus	Phase 2: 24 mg Lenvatinib
Arm/Group Description:	Oral lenvatinib (18mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	8	9
Mean (Standard Deviation); Unit of Measure: ng·hr/mL
	3185 (1030)	5252 (2717)

12. Secondary Outcome

Title	Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus
Description	Cmax for lenvatinib was defined as the maximum observed concentration of lenvatinib in plasma following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured plasma concentration-time curves.
Time Frame	Phase 2: Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

PK sub analysis set

Arm/Group Title	Phase 2: 18 mg Lenvatinib + 5 mg Everolimus	Phase 2: 24 mg Lenvatinib
Arm/Group Description:	Oral lenvatinib (18mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	8	9
Mean (Standard Deviation); Unit of Measure: ng/mL
	327 (179)	403 (165)

13. Secondary Outcome

Title	Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus
Description	Tmax for lenvatinib was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach maximum concentration (Cmax) of lenvatinib in plasma.
Time Frame	Phase 2: Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

PK sub analysis set

Arm/Group Title	Phase 2: 18 mg Lenvatinib + 5 mg Everolimus	Phase 2: 24 mg Lenvatinib
Arm/Group Description:	Oral lenvatinib (18mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	8	9
Median (Full Range); Unit of Measure: Hours
	2.0; (2.0 to 8.2)	4.0; (0.5 to 8.0)

14. Secondary Outcome

Title	Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib
Description	Between 9 and 12 participants in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling. Blood samples were analyzed for study drug using standardized methods. PK parameters for everolimus were derived from everolimus concentration data using non-compartmental methods. Data were compared via descriptive statistics between single agent and combination therapy.
Time Frame	Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)

Outcome Measure Data

Analysis Population Description

PK sub analysis set. n=8 for AUC(0-24)

Arm/Group Title	Phase 2: 18 mg Lenvatinib + 5 mg Everolimus	Phase 2: 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	4	8
Mean (Standard Deviation); Unit of Measure: ng·hr/mL
	378 (88.1)	463 (263)

15. Secondary Outcome

Title	Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib
Description	Cmax for everolimus was defined as the maximum observed concentration of everolimus in blood following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured blood concentration-time curves.
Time Frame	Phase 2: Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

PK sub analysis set

Arm/Group Title	Phase 2: 18 mg Lenvatinib + 5 mg Everolimus	Phase 2: 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	4	11
Mean (Standard Deviation); Unit of Measure: ng/mL
	38 (14.5)	54 (24.9)

16. Secondary Outcome

Title	Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib
Description	Tmax for everolimus was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach the maximum concentration (Cmax) of everolimus in blood.
Time Frame	Phase 2: Cycle 1 Day 15

Outcome Measure Data

Analysis Population Description

PK sub analysis set

Arm/Group Title	Phase 2: 18 mg Lenvatinib + 5 mg Everolimus	Phase 2: 10 mg Everolimus
Arm/Group Description:	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
Overall Number of Participants Analyzed	4	11
Median (Full Range); Unit of Measure: Hours
	1.0; (0.5 to 8.0)	1.0; (0.5 to 25.9)

Adverse Events

Time Frame	Treatment-emergent adverse events (AEs) were collected and defined as those AEs that occurred after the first dose of study medication and up to 30 days after the last dose of study medication. AEs were collected for approximately 4 years.
Adverse Event Reporting Description	Safety analysis set included all participants who received at least one dose of study drug/s and had at least one postbaseline safety evaluation. AE severity was assessed using Common Terminology for Adverse Events (CTCAE). Serious AEs were followed until the event resolved or the event or sequelae stabilized.
Arm/Group Title	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
Arm/Group Description	Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 1. If 1 or none of the 6 participants had a DLT, then enrollment proceeded to Cohort 2. If 2 or more participants had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.	Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 participant had a DLT, 3 more participants were enrolled in Cohort 2. If 1 or none of the 6 participants exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 participants in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 participant had a DLT, 3 more participants were enrolled Cohort 3. If 1 or none of the 6 participants exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more participants had a DLT during Cycle 1, dose escalation ceased and additional participants were enrolled to the next lower dose to achieve a total of 6 participants in that cohort.	The DLT was achieved and no participants were enrolled into this cohort.	Oral lenvatinib (18mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.	Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.	Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4 week) cycles.
All-Cause Mortality
	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	6/7 (85.71%)	9/11 (81.82%)	0/2 (0.00%)	0/0	43/51 (84.31%)	40/52 (76.92%)	45/50 (90.00%)
Serious Adverse Events
	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	6/7 (85.71%)	8/11 (72.73%)	0/2 (0.00%)	0/0	30/51 (58.82%)	28/52 (53.85%)	21/50 (42.00%)
Blood and lymphatic system disorders
Anaemia * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	4/51 (7.84%)	1/52 (1.92%)	4/50 (8.00%)
Sideroblastic Anaemia * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Thrombocytopenia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	0/52 (0.00%)	0/50 (0.00%)
Cardiac disorders
Cardiomyopathy † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Myocardial Infarction † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	0/50 (0.00%)
Acute Myocardial Infarction † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	3/52 (5.77%)	1/50 (2.00%)
Cardiac Failure † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Cardiac Failure Congestive † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Tachycardia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Ear and labyrinth disorders
Vertigo Positional * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Endocrine disorders
Inappropriate Antidiuretic Hormone Secretion † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Gastrointestinal disorders
Abdominal Pain † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	0/50 (0.00%)
Gastritis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Vomiting † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	0/50 (0.00%)
Diarrhoea † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	0/52 (0.00%)	0/50 (0.00%)
Dysphagia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Gastric Haemorrhage * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Ileus † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Haemorrhoids † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
General disorders
Fatigue † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	0/50 (0.00%)
General Physical Health Deterioration † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	0/50 (0.00%)
Non-Cardiac Chest Pain † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Asthenia * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	1/50 (2.00%)
Chest Discomfort † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Pain * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	1/50 (2.00%)
Pyrexia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	1/50 (2.00%)
Hepatobiliary disorders
Cholangitis * 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Cholecystitis * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	0/50 (0.00%)
Cholecystitis Acute * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Immune system disorders
Drug Hypersensitivity * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Infections and infestations
Cellulitis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Lung Infection † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Appendicitis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Appendicitis Perforated * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Bronchopneumonia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Diabetic Foot Infection † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Escherichia Sepsis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	1/50 (2.00%)
Infection † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Infectious Pleural Effusion † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Lower Respiratory Tract Infection † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	2/50 (4.00%)
Osteomyelitis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	1/50 (2.00%)
Parotitis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Pneumonia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	1/50 (2.00%)
Rectal Abscess † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Sepsis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	1/50 (2.00%)
Upper Respiratory Tract Infection * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Injury, poisoning and procedural complications
Joint Dislocation † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Spinal Compression Fracture † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Toxicity to Various Agents † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Investigations
Ejection Fraction Decreased * 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
White Blood Cell Count Decreased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Blood Bilirubin Increased † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Blood Creatinine Phosphokinase Increased † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Body Temperature Increased † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Electrocardiogram Repolarisation Abnormality † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Fibrin D Dimer Increased † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Transaminases Increased † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Lipase Increased † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Metabolism and nutrition disorders
Dehydration † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	4/51 (7.84%)	0/52 (0.00%)	0/50 (0.00%)
Hypercholesterolaemia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Hyponatraemia † 1	2/7 (28.57%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Decreased Appetite * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Failure to Thrive * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Glucose Tolerance Impaired † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Hyperkalaemia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	0/50 (0.00%)
Hypomagnesaemia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Malnutrition † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Hypokalaemia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	0/50 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Back Pain † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	0/50 (0.00%)
Flank Pain † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	0/50 (0.00%)
Haemarthrosis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Musculoskeletal Chest Pain † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	0/50 (0.00%)
Psoriatic Arthropathy † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Pathological Fracture † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Spinal Pain † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic Pain † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Malignant Pleural Effusion † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Nervous system disorders
Cerebral Haemorrhage * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Convulsion † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	1/50 (2.00%)
Haemorrhage Intracranial * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Headache † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	3/52 (5.77%)	1/50 (2.00%)
Ischaemic Stroke † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Paresis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Posterior Reversible Encephalopathy Syndrome † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Somnolence † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Spinal Cord Compression † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Trigeminal Neuralgia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Carotid Artery Occlusion † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Psychiatric disorders
Anxiety † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Confusional State * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	0/50 (0.00%)
Renal and urinary disorders
Proteinuria † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Renal Failure Acute † 1	1/7 (14.29%)	2/11 (18.18%)	0/2 (0.00%)	0/0	3/51 (5.88%)	4/52 (7.69%)	0/50 (0.00%)
Haematuria * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Renal Impairment † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	0/50 (0.00%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	2/50 (4.00%)
Pleural Effusion † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Acute Respiratory Failure † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	1/50 (2.00%)
Haemoptysis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Pneumonitis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	3/50 (6.00%)
Pulmonary Embolism † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	1/50 (2.00%)
Vascular disorders
Deep Vein Thrombosis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Hot Flush † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Subclavian Vein Thrombosis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Venous Thrombosis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
1 Term from vocabulary, MedDRA 19.1; * Indicates events were collected by non-systematic assessment; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus	Phase 1b (Cohort 4): 24 mg Lenvatinib Plus 10 mg Everolimus	Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus	Phase 2 (Arm B): 24 mg Lenvatinib	Phase 2 (Arm C): 10 mg Everolimus
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	7/7 (100.00%)	11/11 (100.00%)	2/2 (100.00%)	0/0	51/51 (100.00%)	51/52 (98.08%)	50/50 (100.00%)
Blood and lymphatic system disorders
Anaemia * 1	2/7 (28.57%)	2/11 (18.18%)	0/2 (0.00%)	0/0	7/51 (13.73%)	3/52 (5.77%)	11/50 (22.00%)
Haemorrhagic Disorder † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Lymphadenopathy † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Neutropenia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Thrombocytopenia † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	5/51 (9.80%)	1/52 (1.92%)	4/50 (8.00%)
Cardiac disorders
Angina Pectoris † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Aortic Valve Incompetence † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Coronary Artery Disease † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Coronary Artery Occlusion † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Mitral Valve Incompetence † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Palpitations † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	2/50 (4.00%)
Tachycardia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	0/50 (0.00%)
Ventricular Hypokinesia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Left ventricular dysfunction † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Ear and labyrinth disorders
Ear Pain * 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Vertigo † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	3/52 (5.77%)	0/50 (0.00%)
Endocrine disorders
Hypothyroidism † 1	1/7 (14.29%)	3/11 (27.27%)	0/2 (0.00%)	0/0	12/51 (23.53%)	19/52 (36.54%)	1/50 (2.00%)
Inappropriate Antidiuretic Hormone Secretion † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Eye disorders
Diplopia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Eye Swelling † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Ocular Hyperaemia † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Vision Blurred † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Gastrointestinal disorders
Abdominal Pain † 1	1/7 (14.29%)	3/11 (27.27%)	0/2 (0.00%)	0/0	12/51 (23.53%)	11/52 (21.15%)	1/50 (2.00%)
Abdominal Pain Upper † 1	2/7 (28.57%)	1/11 (9.09%)	0/2 (0.00%)	0/0	8/51 (15.69%)	7/52 (13.46%)	3/50 (6.00%)
Anal Pruritus † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Anorectal Discomfort † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Aphthous Stomatitis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	0/50 (0.00%)
Constipation † 1	3/7 (42.86%)	4/11 (36.36%)	1/2 (50.00%)	0/0	6/51 (11.76%)	19/52 (36.54%)	9/50 (18.00%)
Diarrhoea † 1	3/7 (42.86%)	7/11 (63.64%)	1/2 (50.00%)	0/0	43/51 (84.31%)	37/52 (71.15%)	17/50 (34.00%)
Dry Mouth † 1	1/7 (14.29%)	0/11 (0.00%)	1/2 (50.00%)	0/0	2/51 (3.92%)	6/52 (11.54%)	3/50 (6.00%)
Dyspepsia † 1	0/7 (0.00%)	4/11 (36.36%)	0/2 (0.00%)	0/0	6/51 (11.76%)	6/52 (11.54%)	6/50 (12.00%)
Flatulence † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	4/51 (7.84%)	3/52 (5.77%)	0/50 (0.00%)
Gastric Haemorrhage † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Gastritis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	0/52 (0.00%)	0/50 (0.00%)
Gastrooesophageal Reflux Disease † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	2/52 (3.85%)	0/50 (0.00%)
Gingival Bleeding † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	0/50 (0.00%)
Glossitis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Glossodynia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	0/50 (0.00%)
Haemorrhoidal Haemorrhage † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Haemorrhoids * 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	0/50 (0.00%)
Lip Discolouration † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Nausea † 1	6/7 (85.71%)	6/11 (54.55%)	1/2 (50.00%)	0/0	22/51 (43.14%)	32/52 (61.54%)	8/50 (16.00%)
Oral Mucosal Blistering † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Oral Pain † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	6/51 (11.76%)	5/52 (9.62%)	1/50 (2.00%)
Paraesthesia Oral † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Stomatitis † 1	4/7 (57.14%)	7/11 (63.64%)	2/2 (100.00%)	0/0	15/51 (29.41%)	13/52 (25.00%)	21/50 (42.00%)
Vomiting † 1	5/7 (71.43%)	5/11 (45.45%)	1/2 (50.00%)	0/0	24/51 (47.06%)	20/52 (38.46%)	6/50 (12.00%)
Abdominal Pain Lower * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	1/52 (1.92%)	0/50 (0.00%)
Anal Fissure † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	1/52 (1.92%)	0/50 (0.00%)
Cheilitis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	1/52 (1.92%)	1/50 (2.00%)
Toothache † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	5/51 (9.80%)	3/52 (5.77%)	1/50 (2.00%)
Mouth Ulceration † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	5/51 (9.80%)	0/52 (0.00%)	5/50 (10.00%)
Abdominal Discomfort † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	1/52 (1.92%)	0/50 (0.00%)
Abdominal Distension † 1	0/7 (0.00%)	1/11 (9.09%)	1/2 (50.00%)	0/0	4/51 (7.84%)	2/52 (3.85%)	0/50 (0.00%)
General disorders
Asthenia † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	13/51 (25.49%)	8/52 (15.38%)	3/50 (6.00%)
Chills † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	2/51 (3.92%)	3/52 (5.77%)	1/50 (2.00%)
Fatigue † 1	4/7 (57.14%)	11/11 (100.00%)	2/2 (100.00%)	0/0	26/51 (50.98%)	21/52 (40.38%)	16/50 (32.00%)
Gait Disturbance † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	1/50 (2.00%)
Localised Oedema † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Non-Cardiac Chest Pain † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	1/50 (2.00%)
Oedema Peripheral † 1	1/7 (14.29%)	6/11 (54.55%)	0/2 (0.00%)	0/0	15/51 (29.41%)	9/52 (17.31%)	9/50 (18.00%)
Pyrexia † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	9/51 (17.65%)	5/52 (9.62%)	5/50 (10.00%)
Influenza Like Illness † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	4/51 (7.84%)	2/52 (3.85%)	0/50 (0.00%)
Pain † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	2/52 (3.85%)	1/50 (2.00%)
Malaise † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	3/52 (5.77%)	1/50 (2.00%)
Peripheral Swelling † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	5/51 (9.80%)	1/52 (1.92%)	2/50 (4.00%)
Hepatobiliary disorders
Dilatation Intrahepatic Duct Acquired † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Infections and infestations
Bronchitis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	4/52 (7.69%)	1/50 (2.00%)
Cellulitis † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Infectious Pleural Effusion † 1	0/7 (0.00%)	3/11 (27.27%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Influenza † 1	2/7 (28.57%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	0/50 (0.00%)
Lymph Gland Infection † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Nasopharyngitis † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	7/51 (13.73%)	4/52 (7.69%)	7/50 (14.00%)
Oral Herpes † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	3/50 (6.00%)
Osteomyelitis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Paronychia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Pneumonia † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	1/50 (2.00%)
Sinusitis † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	0/50 (0.00%)
Skin Infection † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Upper Respiratory Tract Infection † 1	2/7 (28.57%)	0/11 (0.00%)	0/2 (0.00%)	0/0	4/51 (7.84%)	7/52 (13.46%)	7/50 (14.00%)
Urinary Tract Infection † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	4/52 (7.69%)	3/50 (6.00%)
Lower Respiratory Tract Infection † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	4/52 (7.69%)	4/50 (8.00%)
Respiratory Tract Infection * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	4/51 (7.84%)	4/52 (7.69%)	1/50 (2.00%)
Gingivitis * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	0/52 (0.00%)	0/50 (0.00%)
Injury, poisoning and procedural complications
Arthropod Bite * 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Contusion † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	0/50 (0.00%)
Fall † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	1/50 (2.00%)
Periorbital Contusion † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Toxicity to Various Agents * 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Investigations
Alanine Aminotransferase Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	5/51 (9.80%)	3/52 (5.77%)	3/50 (6.00%)
Amylase Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	0/50 (0.00%)
Aspartate Aminotransferase Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	2/52 (3.85%)	3/50 (6.00%)
Blood Alkaline Phosphatase Increased † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	2/50 (4.00%)
Blood Bilirubin Increased † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	0/50 (0.00%)
Blood Cholesterol Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	4/51 (7.84%)	2/52 (3.85%)	3/50 (6.00%)
Blood Creatine Phosphokinase Increased † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	4/51 (7.84%)	0/52 (0.00%)	1/50 (2.00%)
Blood Glucose Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	1/50 (2.00%)
Blood Phosphorus Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	0/50 (0.00%)
Blood Potassium Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Blood Triglycerides Increased † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	1/50 (2.00%)
Cardiac Murmur † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Computerised Tomogram Thorax Abnormal † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Ejection Fraction Decreased † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	4/52 (7.69%)	0/50 (0.00%)
Electrocardiogram QT Prolonged † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	0/50 (0.00%)
Haemoglobin Decreased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	5/50 (10.00%)
Lipase Increased † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	4/51 (7.84%)	5/52 (9.62%)	3/50 (6.00%)
Liver Function Test Abnormal † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Murphy's Sign Positive † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Platelet Count Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Protein Urine Present † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Transaminases Increased † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Weight Decreased † 1	2/7 (28.57%)	5/11 (45.45%)	0/2 (0.00%)	0/0	16/51 (31.37%)	26/52 (50.00%)	4/50 (8.00%)
White Blood Cell Count Decreased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
White Blood Cell Count Increased † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Blood Thyroid Stimulating Hormone Increased * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	7/51 (13.73%)	2/52 (3.85%)	1/50 (2.00%)
Blood Creatinine Increased * 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	2/52 (3.85%)	4/50 (8.00%)
Metabolism and nutrition disorders
Decreased Appetite † 1	3/7 (42.86%)	6/11 (54.55%)	1/2 (50.00%)	0/0	27/51 (52.94%)	30/52 (57.69%)	10/50 (20.00%)
Dehydration † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	1/50 (2.00%)
Failure to Thrive † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Hypercalcaemia † 1	2/7 (28.57%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Hypercholesterolaemia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	18/51 (35.29%)	6/52 (11.54%)	8/50 (16.00%)
Hyperglycaemia † 1	2/7 (28.57%)	3/11 (27.27%)	0/2 (0.00%)	0/0	8/51 (15.69%)	3/52 (5.77%)	12/50 (24.00%)
Hyperkalaemia † 1	1/7 (14.29%)	2/11 (18.18%)	0/2 (0.00%)	0/0	1/51 (1.96%)	3/52 (5.77%)	1/50 (2.00%)
Hyperlipidaemia † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Hypernatraemia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Hypertriglyceridaemia † 1	1/7 (14.29%)	7/11 (63.64%)	0/2 (0.00%)	0/0	18/51 (35.29%)	7/52 (13.46%)	12/50 (24.00%)
Hypophagia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Hypophosphataemia * 1	3/7 (42.86%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	1/50 (2.00%)
Hypovolaemia † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Malnutrition † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Metabolic Acidosis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Hypomagnesaemia † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	4/52 (7.69%)	0/50 (0.00%)
Hypocalcaemia * 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	4/51 (7.84%)	3/52 (5.77%)	2/50 (4.00%)
Hypokalaemia † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	7/51 (13.73%)	0/52 (0.00%)	1/50 (2.00%)
Hyponatraemia * 1	1/7 (14.29%)	2/11 (18.18%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	4/7 (57.14%)	2/11 (18.18%)	0/2 (0.00%)	0/0	14/51 (27.45%)	13/52 (25.00%)	7/50 (14.00%)
Back Pain † 1	3/7 (42.86%)	4/11 (36.36%)	0/2 (0.00%)	0/0	11/51 (21.57%)	11/52 (21.15%)	7/50 (14.00%)
Flank Pain † 1	0/7 (0.00%)	3/11 (27.27%)	0/2 (0.00%)	0/0	2/51 (3.92%)	2/52 (3.85%)	2/50 (4.00%)
Intervertebral Disc Protrusion † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Muscle Spasms * 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	2/50 (4.00%)
Muscular Weakness † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	2/51 (3.92%)	3/52 (5.77%)	0/50 (0.00%)
Musculoskeletal Chest Pain † 1	1/7 (14.29%)	2/11 (18.18%)	0/2 (0.00%)	0/0	8/51 (15.69%)	7/52 (13.46%)	2/50 (4.00%)
Musculoskeletal Pain † 1	3/7 (42.86%)	2/11 (18.18%)	0/2 (0.00%)	0/0	4/51 (7.84%)	8/52 (15.38%)	1/50 (2.00%)
Myalgia † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	4/51 (7.84%)	7/52 (13.46%)	1/50 (2.00%)
Neck Pain † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	1/50 (2.00%)
Pain in Extremity † 1	2/7 (28.57%)	4/11 (36.36%)	0/2 (0.00%)	0/0	6/51 (11.76%)	6/52 (11.54%)	3/50 (6.00%)
Spinal Osteoarthritis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Bone Pain † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	4/52 (7.69%)	2/50 (4.00%)
Groin Pain † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	4/51 (7.84%)	1/52 (1.92%)	0/50 (0.00%)
Pain In Jaw † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	1/52 (1.92%)	0/50 (0.00%)
Nervous system disorders
Disturbance In Attention † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Dizziness † 1	1/7 (14.29%)	5/11 (45.45%)	1/2 (50.00%)	0/0	2/51 (3.92%)	4/52 (7.69%)	2/50 (4.00%)
Dysgeusia † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	4/51 (7.84%)	4/52 (7.69%)	1/50 (2.00%)
Headache † 1	4/7 (57.14%)	3/11 (27.27%)	0/2 (0.00%)	0/0	10/51 (19.61%)	13/52 (25.00%)	4/50 (8.00%)
Hyperaesthesia † 1	0/7 (0.00%)	0/11 (0.00%)	1/2 (50.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Hypoaesthesia † 1	1/7 (14.29%)	2/11 (18.18%)	0/2 (0.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	1/50 (2.00%)
Paraesthesia † 1	1/7 (14.29%)	1/11 (9.09%)	1/2 (50.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	1/50 (2.00%)
Peripheral Sensory Neuropathy † 1	2/7 (28.57%)	2/11 (18.18%)	0/2 (0.00%)	0/0	0/51 (0.00%)	4/52 (7.69%)	0/50 (0.00%)
Sensory Disturbance † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Sinus Headache † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Tremor † 1	0/7 (0.00%)	2/11 (18.18%)	1/2 (50.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Lethargy † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	4/51 (7.84%)	7/52 (13.46%)	2/50 (4.00%)
Psychiatric disorders
Anxiety † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	3/52 (5.77%)	1/50 (2.00%)
Confusional State † 1	2/7 (28.57%)	0/11 (0.00%)	1/2 (50.00%)	0/0	1/51 (1.96%)	1/52 (1.92%)	0/50 (0.00%)
Depression † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	3/51 (5.88%)	1/52 (1.92%)	2/50 (4.00%)
Insomnia † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	10/51 (19.61%)	8/52 (15.38%)	1/50 (2.00%)
Renal and urinary disorders
Haematuria † 1	0/7 (0.00%)	1/11 (9.09%)	1/2 (50.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	0/50 (0.00%)
Nocturia † 1	0/7 (0.00%)	3/11 (27.27%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	3/50 (6.00%)
Proteinuria † 1	5/7 (71.43%)	6/11 (54.55%)	0/2 (0.00%)	0/0	13/51 (25.49%)	16/52 (30.77%)	7/50 (14.00%)
Renal Failure Acute † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Renal Failure Chronic † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Renal Mass † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Pollakiuria † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	4/50 (8.00%)
Reproductive system and breast disorders
Vaginal Haemorrhage † 1	0/7 (0.00%)	0/11 (0.00%)	1/2 (50.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	6/7 (85.71%)	3/11 (27.27%)	0/2 (0.00%)	0/0	20/51 (39.22%)	9/52 (17.31%)	16/50 (32.00%)
Dysphonia * 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	10/51 (19.61%)	19/52 (36.54%)	2/50 (4.00%)
Dyspnoea † 1	1/7 (14.29%)	7/11 (63.64%)	1/2 (50.00%)	0/0	11/51 (21.57%)	11/52 (21.15%)	11/50 (22.00%)
Dyspnoea Exertional † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	4/51 (7.84%)	1/52 (1.92%)	5/50 (10.00%)
Epistaxis † 1	2/7 (28.57%)	5/11 (45.45%)	1/2 (50.00%)	0/0	9/51 (17.65%)	4/52 (7.69%)	12/50 (24.00%)
Haemoptysis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	3/52 (5.77%)	2/50 (4.00%)
Lung Infiltration † 1	0/7 (0.00%)	1/11 (9.09%)	1/2 (50.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Nasal Congestion † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	2/51 (3.92%)	1/52 (1.92%)	1/50 (2.00%)
Oropharyngeal Pain † 1	1/7 (14.29%)	3/11 (27.27%)	0/2 (0.00%)	0/0	4/51 (7.84%)	2/52 (3.85%)	2/50 (4.00%)
Pleural Effusion † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	3/50 (6.00%)
Pneumonitis † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	4/50 (8.00%)
Productive Cough † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	2/50 (4.00%)
Rhinorrhoea † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	2/50 (4.00%)
Sinus Congestion † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Sputum Discoloured † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Upper-Airway Cough Syndrome † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Wheezing † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	2/50 (4.00%)
Paranasal sinus discomfort † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	/0	1/51 (1.96%)	0/52 (0.00%)	0/50 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis Acneiform † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	1/50 (2.00%)
Dry Skin † 1	3/7 (42.86%)	2/11 (18.18%)	0/2 (0.00%)	0/0	5/51 (9.80%)	3/52 (5.77%)	3/50 (6.00%)
Ecchymosis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Erythema † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	2/50 (4.00%)
Erythema Multiforme † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Hyperhidrosis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	1/50 (2.00%)
Hyperkeratosis † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	2/51 (3.92%)	0/52 (0.00%)	1/50 (2.00%)
Night Sweats † 1	1/7 (14.29%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	2/52 (3.85%)	2/50 (4.00%)
Palmar-Plantar Erythrodysaesthesia Syndrome † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	4/51 (7.84%)	8/52 (15.38%)	2/50 (4.00%)
Petechiae † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Pruritus † 1	2/7 (28.57%)	1/11 (9.09%)	0/2 (0.00%)	0/0	7/51 (13.73%)	3/52 (5.77%)	7/50 (14.00%)
Rash † 1	3/7 (42.86%)	5/11 (45.45%)	1/2 (50.00%)	0/0	9/51 (17.65%)	8/52 (15.38%)	11/50 (22.00%)
Rash Erythematous † 1	0/7 (0.00%)	2/11 (18.18%)	0/2 (0.00%)	0/0	2/51 (3.92%)	3/52 (5.77%)	4/50 (8.00%)
Rash Macular † 1	1/7 (14.29%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	5/50 (10.00%)
Skin Mass † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	1/52 (1.92%)	0/50 (0.00%)
Skin Ulcer † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	1/51 (1.96%)	2/52 (3.85%)	1/50 (2.00%)
Onychoclasis † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	3/50 (6.00%)
Acne † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	3/51 (5.88%)	1/52 (1.92%)	3/50 (6.00%)
Vascular disorders
Aortic Dilatation † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	0/52 (0.00%)	0/50 (0.00%)
Deep Vein Thrombosis † 1	0/7 (0.00%)	1/11 (9.09%)	0/2 (0.00%)	0/0	0/51 (0.00%)	3/52 (5.77%)	0/50 (0.00%)
Hypertension † 1	5/7 (71.43%)	4/11 (36.36%)	0/2 (0.00%)	0/0	21/51 (41.18%)	26/52 (50.00%)	5/50 (10.00%)
Hypotension † 1	1/7 (14.29%)	3/11 (27.27%)	0/2 (0.00%)	0/0	3/51 (5.88%)	1/52 (1.92%)	0/50 (0.00%)
Hot Flush † 1	0/7 (0.00%)	0/11 (0.00%)	0/2 (0.00%)	0/0	1/51 (1.96%)	3/52 (5.77%)	0/50 (0.00%)
1 Term from vocabulary, MedDRA 19.1; * Indicates events were collected by non-systematic assessment; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Eisai Medical Services
• Organization: Eisai Medical Inc.
• Phone: 1-888-422-4743

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lee CH, Motzer RJ, Glen H, Michaelson MD, Larkin J, Minoshima Y, Kanekiyo M, Ikezawa H, Sachdev P, Dutcus CE, Funahashi Y, Voss MH. Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma. Br J Cancer. 2021 Jan;124(1):237-246. doi: 10.1038/s41416-020-01092-0. Epub 2020 Oct 7.

Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015 Nov;16(15):1473-1482. doi: 10.1016/S1470-2045(15)00290-9. Epub 2015 Oct 22. Erratum In: Lancet Oncol. 2016 Jul;17 (7):e270. Lancet Oncol. 2018 Oct;19(10):e509.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT01136733
• Other Study ID Numbers: E7080-G000-205
• First Submitted: May 26, 2010
• First Posted: June 3, 2010
• Results First Submitted: November 23, 2016
• Results First Posted: February 27, 2019
• Last Update Posted: February 27, 2019