Study of Lenvatinib in Subjects With Advanced Endometrial Cancer and Disease Progression

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01111461
• Collaborator: (none)
• Enrollment: 133
• Locations: 79
• Arm: 1
• Duration (Months): 67
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To assess the objective response rate (ORR: complete response + partial response [CR+ PR]) of E7080 in subjects with unresectable endometrial cancer and disease progression following platinum-based, first-line chemotherapy. .

Condition or Disease	Intervention/Treatment	Phase
Endometrial Cancer	Drug: Lenvatinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 133 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Single-Arm, Multicenter Phase II Study of E7080 (Lenvatinib) in Subjects With Advanced Endometrial Cancer and Disease Progression Following First-Line Chemotherapy
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lenvatinib 24 mg Participants with advanced endometrial cancer and disease progression following platinum-based, first line chemotherapy.

Drug: Lenvatinib; Lenvatinib 24 mg administered orally, once daily continuously in 28-day cycles to participants with advanced endometrial cancer and disease progression following first-line chemotherapy. Participants continued to receive study drug until disease progression, development of unacceptable toxicity or withdrawal of consent. 'Treatment interruption and subsequent dose reduction' was allowed for participants who experienced lenvatinib-related toxicity.; Other Names: E7080, Lenvima

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) [From the date of first administration of study treatment until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to the end of Cycle 6 (as of 21 May 2012 data cut-off)]

   ORR was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans, as determined by independent radiologic review. BOR of CR was confirmed by a subsequent CR assessment at least 4 weeks later. BOR of PR was confirmed by a subsequent CR or PR assessment at least 4 weeks later. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. The null hypothesis ORR was ≤10% was tested using 1-sided exact test of a single proportion, at 1-sided 0.05 level. ORR was presented with corresponding 2-sided, 95% confidence interval (CI). ORR=CR+PR

Secondary Outcome Measures

1. Progression Free Survival (PFS) [From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression or up to approximately 26 months (as of 21 May 2012 data cut-off)]

   PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death (whichever occurred first), as determined by independent radiologic review (IRR) and Investigator based on RECIST 1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.

2. Overall Survival (OS) [From date of first administration of study treatment until the date of death, or up to approximately 32 months (as of 26 Nov 2012 data cut-off)]

   OS was the length time in months from the date of first treatment until the date of death from any cause. If death was not observed, OS was censored at the last known alive date or data cut-off. Additional survival follow-up data was collected for all participants who had not withdrawn consent and were alive at the time of the initial survival follow-up as of 26 Nov 2012 data cut-off. Participants who were lost to follow-up at the time of the initial assessment may have been contacted again at the investigator's discretion. Updated survival (based on 26 Nov 2012 cut-off) was derived for these participants if the contact was made successfully.

3. Disease Control Rate (DCR) [From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, or up to approximately 26 months (as of 21 May 2012 data cut-off)]

   DCR was defined as the percentage of participants with BOR of CR or PR or stable disease (SD) based on RECIST 1.1 and SD lasting greater than or equal to 7 weeks, as determined by IRR and Investigator.

4. Clinical Benefit Rate (CBR) [From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, or up to approximately 26 months (as of 21 May 2012 data cut-off)]

   CBR was defined as the percentage of participants with BOR of CR or PR or durable stable disease (dSD) [CR + PR + dSD] based on RECIST 1.1. The dSD rate was defined as the percentage of participants with dSD (based on RECIST 1.1 and defined as SD lasting greater than or equal to 23 weeks), as determined by the IRR and Investigator.

5. Number of Participants With Adverse Events (AEs) /Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib Tolerability of Lenvatinib [From the administration of first dose up to 30 days after the last dose, or up to data cut-off (21 May 2012), or up to approximately 26 months.]

   Safety was assessed by monitoring and recording all AEs and SAEs, regular monitoring of hematology, clinical chemistry, and urine values, regular measurement of vital signs, electrocardiograms (ECGs), and echocardiograms.

Other Outcome Measures

1. Summary of Plasma Concentration of Lenvatinib [Predose and 2 hours postdose on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1]

   A total of 6 blood samples for pharmacokinetic (PK) analysis were collected from each participant who received lenvatinib once daily.

2. Percentage Change From Baseline for the Imaging Biomarker Parameter of the Area Under the Plasma Concentration Curve Blood Normalized (90) (AUCBN (90)) Median for Total Volume [Cycle 1 Day 5]

   The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of 2 dynamic contrast-enhanced magnetic resonance imaging/diffusion-weighted magnetic resonance imaging (DCE-MRI/DWI MRI) scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included percentage change in initial area under the gadolinium contrast agent time-concentration curve (first 90 seconds, blood normalized) from baseline.

3. Percentage Change From Baseline in the Contrast Volume Transfer Coefficient (Ktrans) Median [Cycle 1 Day 5]

   The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of two DCE-MRI/DWI MRI scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included the percentage change in Ktrans for gadolinium chelate movement from the vasculature into the tissue extracellular space from baseline.

4. Percentage Change From Baseline in the Apparent Diffusion Coefficient (ADC) Median [Cycle 1 Day 5]

   The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of two DCE-MRI/DWI MRI scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included the percentage change in ADC for gadolinium chelate movement from the vasculature into the tissue extracellular space from baseline.

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Histologically confirmed diagnosis of endometrial carcinoma.

2. Radiographic evidence of disease progression according to modified RECIST 1.1 after 1 prior systemic, platinum-based chemotherapy regimen for recurrent metastatic or primary unresectable endometrial carcinoma for which no surgical or radiotherapy treatment option exists.

3. Measureable disease meeting the following criteria:

• At least 1 lesion of greater than 1.0 cm in the longest diameter for a non-lymph node or greater than 1.5 cm in the short-axis diameter for a lymph node which is serially measureable according to modified RECIST 1.1 using computerized tomography / magnetic resonance imaging.

• Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency ablation must show evidence of progressive disease based on modified RECIST 1.1 to be deemed a target lesion.

1. Eastern Cooperative Oncology Group (ECOG) performance status less than 2.

2. Adequate controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Screening Visit.

3. Adequate renal function defined as calculated creatinine clearance greater than 30 mL/min per the Cockcroft and Gault formula.

4. Adequate bone marrow, blood coagulation, and liver functions, as defined in the study protocol.

5. Negative serum or urine pregnancy test for women of reproductive potential.

Exclusion criteria:

1. Brain or leptomeningeal metastases, including stable metastases.

2. More than 1 prior systemic chemotherapy regimen for recurrent metastatic or primary unresectable endometrial carcinoma or any treatment targeting vascular endothelial growth factor (VEGF)-directed angiogenesis. No restriction regarding prior adjuvant chemotherapy or hormonal therapy.

3. Prior systemic anti-tumor therapy within 3 weeks.

4. Not fully recovered from prior radiotherapy based on investigator judgement.

5. Participants with greater than 1+ proteinuria on urine dipstick testing to undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with greater than 1 gm will be ineligible.

6. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association Class II; unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug; cardiac arrhythmia requiring medical treatment.

7. Prolongation of QTc interval greater than 480 msec.

8. Bleeding disorder or thrombotic disorders requiring anticoagulant therapy, such as warfarin, or similar agents requiring therapeutic INR monitoring (treatment with low molecular weight heparin [LMWH] allowed).

9. Active hemoptysis within 3 weeks prior to the first dose of study drug.

10. Females who are pregnant or breast feeding.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States
2		Scottsdale	Arizona	United States
3		Tucson	Arizona	United States
4		Los Angeles	California	United States
5		Honolulu	Hawaii	United States
6		Arlington Heights	Illinois	United States
7		Niles	Illinois	United States
8		Boston	Massachusetts	United States
9		Detroit	Michigan	United States
10		Burnsville	Minnesota	United States
11		Edina	Minnesota	United States
12		Maplewood	Minnesota	United States
13		Minneapolis	Minnesota	United States
14		Saint Paul	Minnesota	United States
15		Woodbury	Minnesota	United States
16		St. Louis	Missouri	United States
17		Morristown	New Jersey	United States
18		New York	New York	United States
19		Chapel Hill	North Carolina	United States
20		Cleveland	North Carolina	United States
21		Durham	North Carolina	United States
22		Winston-Salem	North Carolina	United States
23		Eugene	Oregon	United States
24		Portland	Oregon	United States
25		Springfield	Oregon	United States
26		Tualatin	Oregon	United States
27		Charleston	South Carolina	United States
28		Austin	Texas	United States
29		Bedford	Texas	United States
30		Dallas	Texas	United States
31		Fort Worth	Texas	United States
32		Tyler	Texas	United States
33		Newport News	Virginia	United States
34		Norfolk	Virginia	United States
35		Virginia Beach	Virginia	United States
36		Vancouver	Washington	United States
37		Arlon		Belgium
38		Charleroi		Belgium
39		Duffel		Belgium
40		Ghent		Belgium
41		Kortrijk		Belgium
42		Leuven		Belgium
43		Liege		Belgium
44		Namur		Belgium
45		Oostende		Belgium
46		Roeselare		Belgium
47		Yvoir		Belgium
48		Pleven		Bulgaria
49		Plovdiv		Bulgaria
50		Sofia		Bulgaria
51		Varna		Bulgaria
52		Veliko Tarnovo		Bulgaria
53		Budapest		Hungary
54		Gyor		Hungary
55		Lublin		Poland
56		Poznan		Poland
57		Warsaw		Poland
58		Brasov County		Romania
59		Bucharest		Romania
60		Cluj County		Romania
61		Dolj County		Romania
62		Kazan		Russian Federation
63		Nizhny Novgorod		Russian Federation
64		Orenburg		Russian Federation
65		Petersburg		Russian Federation
66		Pyatigorsk		Russian Federation
67		Sochi,		Russian Federation
68		St. Petersburg		Russian Federation
69		Stavropol		Russian Federation
70		Syktyvkar		Russian Federation
71		Tomsk		Russian Federation
72		Tula		Russian Federation
73		Ufa		Russian Federation
74		Vladivostok		Russian Federation
75		Chernihiv		Ukraine
76		Donetsk		Ukraine
77		Kharkiv		Ukraine
78		Kyiv		Ukraine
79		Zaporizhia		Ukraine

Sponsors and Collaborators

• Eisai Inc.

Investigators

• Study Director: Eisai Medical Services, Eisai Limited

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT01111461
• Other Study ID Numbers: E7080-G000-204
• First Posted: Apr 27, 2010
• Last Update Posted: Jan 20, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by Eisai Inc.: Advanced Endometrial Cancer
• Additional relevant MeSH terms: Endometrial Neoplasms; Disease Progression; Lenvatinib

Study Results

Participant Flow

Pre-assignment Detail	A total of 167 participants were screened for entry into the study. Of these 167 participants, 133 participants met inclusion/exclusion criteria and were treated with at least 1 dose of lenvatinib 24 mg.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib hard capsules, 24 mg (two 10-mg capsules and one 4-mg capsule) were self-administered orally once a day in the morning (without regard to food intake) in 28-day cycles. Dose reduction or interruption was allowed for participants who experienced lenvatinib-related toxicity.
Period Title: Overall Study
STARTED	133
COMPLETED	82
NOT COMPLETED	51

Baseline Characteristics

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Overall Participants	133
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.7 (8.75)
Gender (Count of Participants)
Female	133 100%
Male	0 0%
Prior Platinum-based Chemotherapy Regimen (Number) [Number]
Carboplatin	80 60.2%
Cisplatin	47 35.3%
Cisplatin w/Doxorubicin	4 3%
Taxol [Paclitaxel] w/Carboplatin	10 7.5%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	ORR was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans, as determined by independent radiologic review. BOR of CR was confirmed by a subsequent CR assessment at least 4 weeks later. BOR of PR was confirmed by a subsequent CR or PR assessment at least 4 weeks later. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. The null hypothesis ORR was ≤10% was tested using 1-sided exact test of a single proportion, at 1-sided 0.05 level. ORR was presented with corresponding 2-sided, 95% confidence interval (CI). ORR=CR+PR
Time Frame	From the date of first administration of study treatment until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to the end of Cycle 6 (as of 21 May 2012 data cut-off)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (Intent-to-Treat [ITT] Analysis Set) was used and included all participants who received at least 1 dose lenvatinib.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	133
Number (95% Confidence Interval) [Percentage of participants]	14.3 10.8%

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death (whichever occurred first), as determined by independent radiologic review (IRR) and Investigator based on RECIST 1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.
Time Frame	From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression or up to approximately 26 months (as of 21 May 2012 data cut-off)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (ITT Population) included all participants who received at least 1 dose of lenvatinib.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	133
Determined by IRR	5.6
Determined by Investigator	5.4

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was the length time in months from the date of first treatment until the date of death from any cause. If death was not observed, OS was censored at the last known alive date or data cut-off. Additional survival follow-up data was collected for all participants who had not withdrawn consent and were alive at the time of the initial survival follow-up as of 26 Nov 2012 data cut-off. Participants who were lost to follow-up at the time of the initial assessment may have been contacted again at the investigator's discretion. Updated survival (based on 26 Nov 2012 cut-off) was derived for these participants if the contact was made successfully.
Time Frame	From date of first administration of study treatment until the date of death, or up to approximately 32 months (as of 26 Nov 2012 data cut-off)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (ITT Population) included all participants who received at least 1 dose of lenvatinib.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	133
Median (95% Confidence Interval) [Months]	10.6

4. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR was defined as the percentage of participants with BOR of CR or PR or stable disease (SD) based on RECIST 1.1 and SD lasting greater than or equal to 7 weeks, as determined by IRR and Investigator.
Time Frame	From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, or up to approximately 26 months (as of 21 May 2012 data cut-off)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (ITT Population) included all participants who received at least 1 dose of lenvatinib.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	133
Determined by IRR	60.9 45.8%
Determined by Investigator	66.2 49.8%

5. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	CBR was defined as the percentage of participants with BOR of CR or PR or durable stable disease (dSD) [CR + PR + dSD] based on RECIST 1.1. The dSD rate was defined as the percentage of participants with dSD (based on RECIST 1.1 and defined as SD lasting greater than or equal to 23 weeks), as determined by the IRR and Investigator.
Time Frame	From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, or up to approximately 26 months (as of 21 May 2012 data cut-off)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (ITT Population) included all participants who received at least 1 dose of lenvatinib.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	133
Determined by IRR	37.6 28.3%
Determined by Investigator	44.4 33.4%

6. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) /Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib Tolerability of Lenvatinib
Description	Safety was assessed by monitoring and recording all AEs and SAEs, regular monitoring of hematology, clinical chemistry, and urine values, regular measurement of vital signs, electrocardiograms (ECGs), and echocardiograms.
Time Frame	From the administration of first dose up to 30 days after the last dose, or up to data cut-off (21 May 2012), or up to approximately 26 months.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set included all participants who received at least 1 dose of lenvatinib and had at least 1 postbaseline safety evaluation. This was the analysis set for all safety evaluations.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	133
AEs	126 94.7%
SAEs	62 46.6%

7. Other Pre-specified Outcome

Title	Summary of Plasma Concentration of Lenvatinib
Description	A total of 6 blood samples for pharmacokinetic (PK) analysis were collected from each participant who received lenvatinib once daily.
Time Frame	Predose and 2 hours postdose on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK analysis set was used and included all participants with an evaluable plasma concentration.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	133
Cycle 1, Day 1 (Pre-dose) n=132	0 (0)
Cycle 1, Day 1 (2-hour Post-dose) n=132	318.9 (242.16)
Cycle 1, Day 8 (Pre-dose) n=122	105.6 (121.66)
Cycle 1, Day 8 (2-hour Post-dose) n=123	352.6 (243.88)
Cycle 2, Day 1 (Pre-dose) n=107	88.63 (78.768)
Cycle 2, Day 1 (2-hour Post-dose) n=102	336.8 (222.56)

8. Other Pre-specified Outcome

Title	Percentage Change From Baseline for the Imaging Biomarker Parameter of the Area Under the Plasma Concentration Curve Blood Normalized (90) (AUCBN (90)) Median for Total Volume
Description	The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of 2 dynamic contrast-enhanced magnetic resonance imaging/diffusion-weighted magnetic resonance imaging (DCE-MRI/DWI MRI) scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included percentage change in initial area under the gadolinium contrast agent time-concentration curve (first 90 seconds, blood normalized) from baseline.
Time Frame	Cycle 1 Day 5

Outcome Measure Data

Analysis Population Description

Imaging biomarker analysis set included those participants who received at least 1 dose of lenvatinib and had, at minimum, a baseline and 1 postbaseline evaluable imaging assessment. n = 4 participants with evaluable data.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	4
Mean (Standard Deviation) [Percentage change]	-34.0 (18.98)

9. Other Pre-specified Outcome

Title	Percentage Change From Baseline in the Contrast Volume Transfer Coefficient (Ktrans) Median
Description	The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of two DCE-MRI/DWI MRI scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included the percentage change in Ktrans for gadolinium chelate movement from the vasculature into the tissue extracellular space from baseline.
Time Frame	Cycle 1 Day 5

Outcome Measure Data

Analysis Population Description

Imaging biomarker analysis set included those participants who received at least 1 dose of lenvatinib and had, at a minimum, a baseline and 1 postbaseline evaluable imaging assessment. n = 4 participants with evaluable data.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	4
Mean (Standard Deviation) [Percentage change]	-41.5 (22.02)

10. Other Pre-specified Outcome

Title	Percentage Change From Baseline in the Apparent Diffusion Coefficient (ADC) Median
Description	The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of two DCE-MRI/DWI MRI scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included the percentage change in ADC for gadolinium chelate movement from the vasculature into the tissue extracellular space from baseline.
Time Frame	Cycle 1 Day 5

Outcome Measure Data

Analysis Population Description

Imaging biomarker analysis set included those participants who received at least 1 dose of lenvatinib and had, at a minimum, a baseline and 1 postbaseline evaluable imaging assessment. n = 2 participants with evaluable data.

Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
Measure Participants	2
Mean (Standard Deviation) [Percentage change]	2.1 (2.27)

Adverse Events

Time Frame	From date of administration of first dose up to 30 days after the last dose, or up to data cut-off (21 May 2012), or up to approximately 26 months.
Adverse Event Reporting Description	Treatment-emergent adverse events (TEAEs) and serious TEAEs were collected and reported. Safety analysis set included all participants who received at least one dose of study drug. AEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Arm/Group Title	Lenvatinib 24 mg
Arm/Group Description	Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles
All Cause Mortality
	Lenvatinib 24 mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lenvatinib 24 mg
	Affected / at Risk (%)	# Events
Total	62/133 (46.6%)
Cardiac disorders
Angina pectoris	1/133 (0.8%)
Atrial fibrillation	1/133 (0.8%)
Bradycardia	1/133 (0.8%)
Cardiac failure	1/133 (0.8%)
Cardiac failure congestive	1/133 (0.8%)
Cardiopulmonary failure	1/133 (0.8%)
Tachycardia	1/133 (0.8%)
Ear and labyrinth disorders
Deafness	1/133 (0.8%)
Gastrointestinal disorders
Abdominal pain	7/133 (5.3%)
Vomiting	5/133 (3.8%)
Diarrhoea	4/133 (3%)
Nausea	3/133 (2.3%)
Colitis	2/133 (1.5%)
Constipation	2/133 (1.5%)
Intestinal obstruction	2/133 (1.5%)
Small intestinal obstruction	2/133 (1.5%)
Abdominal pain upper	1/133 (0.8%)
Gastrointestinal fistula	1/133 (0.8%)
Ileitis	1/133 (0.8%)
Ileus	1/133 (0.8%)
Intestinal perforation	1/133 (0.8%)
Rectal haemorrhage	1/133 (0.8%)
Rectal perforation	1/133 (0.8%)
General disorders
Asthenia	6/133 (4.5%)
General physical health deterioration	3/133 (2.3%)
Device leakage	1/133 (0.8%)
Impaired healing	1/133 (0.8%)
Multi-organ failure	1/133 (0.8%)
Pyrexia	1/133 (0.8%)
Hepatobiliary disorders
Cholecystitis	1/133 (0.8%)
Cholecystitis chronic	1/133 (0.8%)
Hepatic failure	1/133 (0.8%)
Infections and infestations
Urinary tract infection	2/133 (1.5%)
Gastroenteritis	1/133 (0.8%)
Peridiverticular abscess	1/133 (0.8%)
Proctitis infectious	1/133 (0.8%)
Sepsis	1/133 (0.8%)
Urosepsis	1/133 (0.8%)
Wound infection	1/133 (0.8%)
Injury, poisoning and procedural complications
Rib fracture	1/133 (0.8%)
Investigations
Ejection fraction decreased	1/133 (0.8%)
Metabolism and nutrition disorders
Dehydration	6/133 (4.5%)
Hypocalcaemia	2/133 (1.5%)
Hypokalaemia	2/133 (1.5%)
Decreased appetite	1/133 (0.8%)
Metabolic disorder	1/133 (0.8%)
Tumour lysis syndrome	1/133 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/133 (0.8%)
Neoplasm malignant	1/133 (0.8%)
Tumour necrosis	1/133 (0.8%)
Nervous system disorders
Cerebrovascular accident	1/133 (0.8%)
Headache	1/133 (0.8%)
Syncope	1/133 (0.8%)
Transient ischaemic attack	1/133 (0.8%)
Psychiatric disorders
Mental status changes	2/133 (1.5%)
Confusional state	1/133 (0.8%)
Renal and urinary disorders
Renal failure acute	6/133 (4.5%)
Azotaemia	1/133 (0.8%)
Proteinuria	1/133 (0.8%)
Renal disorder	1/133 (0.8%)
Renal failure	1/133 (0.8%)
Reproductive system and breast disorders
Female genital tract fistula	2/133 (1.5%)
Vaginal haemorrhage	1/133 (0.8%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	5/133 (3.8%)
Dyspnoea	2/133 (1.5%)
Pleural effusion	2/133 (1.5%)
Pneumonitis	1/133 (0.8%)
Tachypnoea	1/133 (0.8%)
Vascular disorders
Hypertension	6/133 (4.5%)
Hypotension	4/133 (3%)
Deep vein thrombosis	1/133 (0.8%)
Haematoma	1/133 (0.8%)
Other (Not Including Serious) Adverse Events
	Lenvatinib 24 mg
	Affected / at Risk (%)	# Events
Total	125/133 (94%)
Blood and lymphatic system disorders
Anaemia	14/133 (10.5%)
Thrombocytopenia	11/133 (8.3%)
Endocrine disorders
Hypothyroidism	23/133 (17.3%)
Eye disorders
Vision blurred	7/133 (5.3%)
Gastrointestinal disorders
Abdominal distension	9/133 (6.8%)
Abdominal pain	33/133 (24.8%)
Abdominal pain upper	17/133 (12.8%)
Constipation	25/133 (18.8%)
Diarrhoea	46/133 (34.6%)
Dry mouth	15/133 (11.3%)
Dyspepsia	7/133 (5.3%)
Flatulence	7/133 (5.3%)
Nausea	41/133 (30.8%)
Stomatitis	30/133 (22.6%)
Vomiting	32/133 (24.1%)
General disorders
Asthenia	30/133 (22.6%)
Fatigue	55/133 (41.4%)
Oedema peripheral	20/133 (15%)
Infections and infestations
Urinary tract infection	17/133 (12.8%)
Investigations
Blood thyroid stimulating hormone increased	8/133 (6%)
Weight decreased	27/133 (20.3%)
Metabolism and nutrition disorders
Decreased appetite	45/133 (33.8%)
Dehydration	8/133 (6%)
Hypokalaemia	17/133 (12.8%)
Hypomagnesaemia	11/133 (8.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/133 (6.8%)
Back pain	16/133 (12%)
Pain in extremity	8/133 (6%)
Nervous system disorders
Dizziness	20/133 (15%)
Dysgeusia	16/133 (12%)
Headache	35/133 (26.3%)
Psychiatric disorders
Insomnia	7/133 (5.3%)
Renal and urinary disorders
Dysuria	9/133 (6.8%)
Proteinuria	28/133 (21.1%)
Reproductive system and breast disorders
Vaginal haemorrhage	8/133 (6%)
Respiratory, thoracic and mediastinal disorders
Cough	19/133 (14.3%)
Dysphonia	27/133 (20.3%)
Dyspnoea	17/133 (12.8%)
Epistaxis	13/133 (9.8%)
Skin and subcutaneous tissue disorders
Alopecia	7/133 (5.3%)
Palmar-plantar erythrodysaesthesia syndrome	10/133 (7.5%)
Rash	9/133 (6.8%)
Vascular disorders
Hypertension	71/133 (53.4%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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