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SELECT: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer (DTC)

Sponsor
Eisai Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01321554
Collaborator
(none)
392
Enrollment
155
Locations
4
Arms
96.1
Actual Duration (Months)
2.5
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study to compare the progression free survival, overall response rate (ORR) and safety of participants treated with lenvatinib 24 mg by continuous once daily oral dosing versus placebo. The study is conducted in 3 phases: a Prerandomization Phase (screening and baseline period), a Randomization Phase (double-blind treatment period), and an Extension Phase (Optional Open Label (OOL) Lenvatinib Treatment Period and a follow-up period).

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Randomization Phase: Participants will receive blinded study drug (lenvatinib/placebo) in 2:1 ratio until documentation of disease progression (confirmed by independent imaging review), development of unacceptable toxicity, or withdrawal of consent. After having completed the primary analysis, subjects treated with lenvatinib who have not experienced disease progression may request to continue open label lenvatinib at the same dose, according to the clinical judgment of the investigator. Participants who discontinue treatment for any reason other than disease progression will be followed in the Randomization Phase until disease progression or start of another anticancer treatment; these participants then enter the Extension Phase for survival follow-up. Extension Phase: Participants in the placebo arm who have disease progression confirmed by IIR could request to enter the OOL Lenvatinib Treatment Period and receive lenvatinib treatment. Participants will receive lenvatinib treatment until disease progression (investigator's assessment), development of intolerable toxicity, or withdrawal of consent. Participants who had disease progression during the Randomization Phase and did not enter the OOL Lenvatinib Treatment Period and all participants who discontinued lenvatinib treatment in the OOL Lenvatinib Treatment Period will enter the follow-up period. Participants will be followed for survival, and all anticancer treatments will be recorded until the time of death.

Study Design

Study Type:
Interventional
Actual Enrollment :
392 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer
Actual Study Start Date :
Mar 17, 2011
Actual Primary Completion Date :
Nov 15, 2013
Actual Study Completion Date :
Mar 19, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Lenvatinib (Randomization Phase)

Participants randomly assigned in a 2:1 ratio to receive blinded study drug (lenvatinib or matching placebo) until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

Drug: Lenvatinib
Lenvatinib 24 mg (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity.
Other Names:
  • Lenvatinib (Lenvima, E7080)

    		•
    Placebo Comparator: Placebo (Randomization Phase)

    Participants randomly assigned in a 2:1 ratio to receive blinded study drug (lenvatinib or matching placebo) until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

    Drug: Placebo
    Matching placebo (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously.
    Experimental: Lenvatinib 24 mg (OOL Lenvatinib Treatment Period)

    Participants will receive lenvatinib 24 mg, orally once daily until documentation of disease progression (confirmed by investigator's assessment), development of unacceptable toxicity, or withdrawal of consent. Placebo treated participants in the Randomization Phase who have progressive disease confirmed by IIR could request to receive lenvatinib treatment in the OOL Treatment Period.

    Drug: Lenvatinib
    Lenvatinib 24 mg (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity.
    Other Names:
  • Lenvatinib (Lenvima, E7080)

    		•
    Experimental: Lenvatinib 20 mg (OOL Lenvatinib Treatment Period)

    Participants will receive lenvatinib 20 mg, orally once daily until documentation of disease progression (confirmed by investigator's assessment), development of unacceptable toxicity, or withdrawal of consent. Placebo treated participants in the Randomization Phase who have progressive disease confirmed by IIR could request to receive lenvatinib treatment in the OOL Treatment Period.

    Drug: Lenvatinib
    Lenvatinib 20 mg (two 10-mg capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity. The dose of lenvatinib during the OOL Lenvatinib Treatment Period was 24 mg once daily from 03 Oct 2011 until 15 Feb 2013. The dose was lowered at the request of the Data Monitoring Committee to 20 mg on 16 Feb 2013. Thus, more subjects were treated with 24 mg starting dose and the treatment duration was longer for these participants than those whose starting dose was 20 mg.
    Other Names:
  • Lenvatinib (Lenvima, E7080)

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Progression Free Survival (PFS) [Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years]

      PFS was defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurred first), as determined by blinded IIR using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for the double-blind treatment period (Randomization Phase). Disease progression per RECIST v1.1 was defined as at least a 20 percent (%) relative increase and 5 millimeter (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.

    Secondary Outcome Measures

    1. Overall Response Rate (ORR) [Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years]

      ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by blinded IIR using RECIST 1.1 for target lesions and assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans (for double blind treatment period i.e. Randomization Phase). 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.

    2. Overall Survival (OS) [Date of randomization until date of death from any cause, assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years]

      Overall survival measured from the date of randomization until date of death from any cause. Overall survival is adjusted with rank preserving structural failure time.

    3. Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve [Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose]

    Eligibility Criteria

    Criteria

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

    1. Histologically or cytologically confirmed diagnosis of one of the following DTC subtypes: Papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC).

    2. Measurable disease according to (RECIST 1.1) and confirmed by central radiographic review.

    3. 131 I-refractory/resistant disease.

    4. Evidence of disease progression within 12 months prior to signing informed consent (+1 month screening window).

    5. Prior treatment with 0 or 1 vascular endothelial growth-factor (VEGF) or vascular endothelial growth-factor receptors (VEGFR) targeted therapy.

    6. Adequate renal, liver, bone marrow, and blood coagulation function, as defined in the protocol.

    Exclusion criteria:

    1. Anaplastic or medullary carcinoma of the thyroid

    2. 2 or more prior VEGF/ VEGFR-targeted therapies

    3. Received any anticancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug.

    Inclusion criteria for OOL Lenvatinib Treatment Period :

    Participants were eligible for lenvatinib treatment in the OOL Lenvatinib Treatment Period if the met the following criteria:

    1. Placebo-treated participants in the Randomization Phase who had progressive disease (PD) confirmed by IIR, and who requested treatment with lenvatinib.

    2. Participants who continued to satisfy specified inclusion and exclusion criteria as presented in the study protocol.

    3. Participants with maximum interval between the day of confirmation of PD by IIR and Cycle 1/Day 1 of the OOL Lenvatinib Treatment Period of less than or equal to 3 months.

    4. No systemic anticancer treatment during the interval between the day of confirmation of PD by the IIR and Cycle 1/Day 1 of the OOL Lenvatinib Treatment Period.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Facility 1 Little Rock Arkansas United States
    2 Facility 1 La Jolla California United States
    3 Facility 1 Los Gatos California United States
    4 Facility 1 Mission Viejo California United States
    5 Facility 1 Orange California United States
    6 Facility 2 Orange California United States
    7 Facility 1 Sacramento California United States
    8 Facility 1 Torrance California United States
    9 Facility 1 Aurora Colorado United States
    10 Facility 1 Washington District of Columbia United States
    11 Facility 1 Orlando Florida United States
    12 Facility 1 Weston Florida United States
    13 Facility 1 Chicago Illinois United States
    14 Facility 2 Chicago Illinois United States
    15 Facility 1 Indianapolis Indiana United States
    16 Facility 1 Lexington Kentucky United States
    17 Facility 1 Baltimore Maryland United States
    18 Facility 1 Boston Michigan United States
    19 Facility 2 Boston Michigan United States
    20 Facility 1 Detroit Michigan United States
    21 Facility 1 Lansing Michigan United States
    22 Facility 1 Minneapolis Minnesota United States
    23 Facility 1 Columbia Missouri United States
    24 Facility 1 Omaha Nebraska United States
    25 Facility 1 Lebanon New Hampshire United States
    26 Facility 1 Morristown New Jersey United States
    27 Facility 1 Neptune New Jersey United States
    28 Facility 1 Bronx New York United States
    29 Facility 1 New York New York United States
    30 Facility 2 New York New York United States
    31 Facility 1 Columbus Ohio United States
    32 Facility 1 Portland Oregon United States
    33 Facility 1 Philadelphia Pennsylvania United States
    34 Facility 2 Philadelphia Pennsylvania United States
    35 Facility 1 Houston Texas United States
    36 Facility 1 Seattle Washington United States
    37 Facility 1 Morgantown West Virginia United States
    38 Facility 1 Milwaukee Wisconsin United States
    39 Facility 1 Rosario Argentina
    40 Facility 1 San Salvador de Jujuy Argentina
    41 Facility 1 Tucuman Argentina
    42 Facility 1 Saint Leonards New South Wales Australia
    43 Facility 1 Herston Queensland Australia
    44 Facility 1 Hobart Tasmania Australia
    45 Facility 1 Melbourne Victoria Australia
    46 Facility 1 Heidelberg Australia
    47 Facility 1 Wien Austria
    48 Facility 1 Bruxelles Belgium
    49 Facility 1 Edegem Belgium
    50 Facility 1 Namur Belgium
    51 Facility 1 Brasilia Brazil
    52 Facility 1 Joinville Brazil
    53 Facility 1 Novo Hamburgo Brazil
    54 Facility 1 Rio de Janeiro Brazil
    55 Facility 1 Salvador Brazil
    56 Facility 1 Sao Paulo Brazil
    57 Facility 2 Sao Paulo Brazil
    58 Facility 1 London Ontario Canada
    59 Facility 1 Toronto Ontario Canada
    60 Facility 1 Montreal Quebec Canada
    61 Facility 1 Quebec Canada
    62 Facility 1 Santiago Chile
    63 Facility 2 Santiago Chile
    64 Facility 3 Santiago Chile
    65 Facility 1 Temuco Chile
    66 Facility 1 Vina del Mar Chile
    67 Facility 1 Olomouc Czechia
    68 Facility 1 Odense Denmark
    69 Facility 1 Angers France
    70 Facility 1 Bordeaux France
    71 Facility 1 Caen France
    72 Facility 1 Clermont-Ferrand France
    73 Facility 1 Dijon France
    74 Facility 1 Lille France
    75 Facility 1 Lyon France
    76 Facility 1 Marseille France
    77 Facility 1 Nice France
    78 Facility 1 Paris France
    79 Facility 2 Paris France
    80 Facility 1 Strasbourg France
    81 Facility 1 Vandoeuvre Les Nancy France
    82 Facility 1 Villejuif France
    83 Facility 1 Essen Germany
    84 Facility 1 Hannover Germany
    85 Facility 1 Leipzig Germany
    86 Facility 1 Mainz Germany
    87 Facility 1 Munchen Germany
    88 Facility 1 Tubingen Germany
    89 Facility 1 Wurzburg Germany
    90 Facility 1 Catania Italy
    91 Facility 1 Livorno Italy
    92 Facility 1 Milano Italy
    93 Facility 2 Milano Italy
    94 Facility 3 Milano Italy
    95 Facility 4 Milano Italy
    96 Facility 5 Milano Italy
    97 Facility 1 Monserrato Italy
    98 Facility 1 Napoli Italy
    99 Facility 1 Padova Italy
    100 Facility 1 Pisa Italy
    101 Facility 1 Roma Italy
    102 Facility 2 Roma Italy
    103 Facility 1 Rozzano Italy
    104 Facility 1 Torino Italy
    105 Facility 1 Viagrande Italy
    106 Eisai Trial Site 1 Nagoya Aichi Japan
    107 Eisai Trial Site 2 Nagoya Aichi Japan
    108 Eisai Trial Site 1 Kashiwa Chiba Japan
    109 Eisai Trial Site 1 Fukui-city Fukui Japan
    110 Eisai Trial Site 1 Kobe-city Hyogo Japan
    111 Eisai Trial Site 1 Koto-ku Tokyo Japan
    112 Facility 1 Daejeon Korea, Republic of
    113 Facility 1 Gyeonggi-do Korea, Republic of
    114 Facility 1 Seoul Korea, Republic of
    115 Facility 2 Seoul Korea, Republic of
    116 Facility 3 Seoul Korea, Republic of
    117 Facility 1 Uijeongbu Korea, Republic of
    118 Facility 1 Gliwice Poland
    119 Facility 1 Kielce Poland
    120 Facility 1 Poznan Poland
    121 Facility 1 Lisbon Portugal
    122 Facility 1 Porto Portugal
    123 Facility 1 Bucharest Romania
    124 Facility 2 Bucharest Romania
    125 Facility 1 Cluj-Napoca Romania
    126 Facility 1 Krasnodar Russian Federation
    127 Facility 1 Kursk Russian Federation
    128 Facility 1 Obninsk Russian Federation
    129 Facility 1 Ufa Russian Federation
    130 Facility 2 Malaga Andalucia Spain
    131 Facility 1 Barcelona Cataluna Spain
    132 Facility 1 La Coruna Galicia Spain
    133 Facility 2 Barcelona Spain
    134 Facility 1 L'Hospitalet de Llobregat Spain
    135 Facility 1 Madrid Spain
    136 Facility 2 Madrid Spain
    137 Facility 3 Madrid Spain
    138 Facility 4 Madrid Spain
    139 Facility 5 Madrid Spain
    140 Facility 1 Goteborg Sweden
    141 Facility 1 Lund Sweden
    142 Facility 1 Stockholm Sweden
    143 Facility 1 Bangkok Thailand
    144 Facility 2 Bangkok Thailand
    145 Facility 1 Chiang Mai Thailand
    146 Facility 1 Khon Kaen Thailand
    147 Facility 1 Pathumwan Thailand
    148 Facility 1 Aberdeen United Kingdom
    149 Facility 1 Glasgow United Kingdom
    150 Facility 2 London United Kingdom
    151 Facility 3 London United Kingdom
    152 Facility 1 Manchester United Kingdom
    153 Facility 2 Manchester United Kingdom
    154 Facility 1 Sheffield United Kingdom
    155 Facility 1 Sutton United Kingdom

    Sponsors and Collaborators

    • Eisai Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Eisai Inc.
    ClinicalTrials.gov Identifier:
    NCT01321554
    Other Study ID Numbers:
    • E7080-G000-303
    • 2010-023783-41
    First Posted:
    Mar 23, 2011
    Last Update Posted:
    Apr 2, 2020
    Last Verified:
    Mar 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Additional relevant MeSH terms:
    Thyroid Neoplasms
    Thyroid Diseases
    Lenvatinib

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 117 investigative sites in Europe, North America, Asia Pacific, Japan, and Latin America from 17 March 2011 to 19 March 2019.
    Pre-assignment Detail A total of 612 participants were screened for entry into the study. Of these 612 participants, 220 participants were screening failures and 392 participants were randomly assigned to receive either lenvatinib or placebo in a 2:1 ratio.
    Arm/Group Title Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo OOL, Treatment Period: Lenvatinib 24 mg OOL, Treatment Period: Lenvatinib 20 mg
    Arm/Group Description Participants received lenvatinib 24 milligram (mg), hard capsule, orally, once daily, until documentation of disease progression (confirmed by Investigator-Initiated Research [IIR]), development of unacceptable toxicity, or withdrawal of consent. Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. Participants received lenvatinib 24 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib. OOL refers to Optional Open-Label. Participants received lenvatinib 20 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.
    Period Title: Randomization Phase
    STARTED 261 131 0 0
    COMPLETED 261 131 0 0
    NOT COMPLETED 0 0 0 0
    Period Title: Randomization Phase
    STARTED 0 0 85 30
    COMPLETED 0 0 85 30
    NOT COMPLETED 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo Total
    Arm/Group Description Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. Total of all reporting groups
    Overall Participants 261 131 392
    Age (years) [Geometric Mean (Standard Deviation) ]
    Geometric Mean (Standard Deviation) [years]
    62.1
    (10.57)
    61.5
    (10.09)
    61.9
    (10.40)
    Sex: Female, Male (Count of Participants)
    Female
    136
    52.1%
    56
    42.7%
    192
    49%
    Male
    125
    47.9%
    75
    57.3%
    200
    51%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival (PFS)
    Description PFS was defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurred first), as determined by blinded IIR using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for the double-blind treatment period (Randomization Phase). Disease progression per RECIST v1.1 was defined as at least a 20 percent (%) relative increase and 5 millimeter (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 Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

    Outcome Measure Data

    Analysis Population Description
    The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.
    Arm/Group Title Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo
    Arm/Group Description Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
    Measure Participants 261 131
    Median (95% Confidence Interval) [months]
    18.3
    3.6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Randomization Phase: Lenvatinib 24 mg, Randomization Phase: Placebo
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Cox Proportional Hazard
    Estimated Value 0.21
    Confidence Interval (2-Sided) 99%
    0.14 to 0.31
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Overall Response Rate (ORR)
    Description ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by blinded IIR using RECIST 1.1 for target lesions and assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans (for double blind treatment period i.e. Randomization Phase). 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.
    Time Frame Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

    Outcome Measure Data

    Analysis Population Description
    The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.
    Arm/Group Title Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo
    Arm/Group Description Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
    Measure Participants 261 131
    Number (95% Confidence Interval) [percentage of participants]
    64.8
    24.8%
    1.5
    1.1%
    3. Secondary Outcome
    Title Overall Survival (OS)
    Description Overall survival measured from the date of randomization until date of death from any cause. Overall survival is adjusted with rank preserving structural failure time.
    Time Frame Date of randomization until date of death from any cause, assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years

    Outcome Measure Data

    Analysis Population Description
    The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.
    Arm/Group Title Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo
    Arm/Group Description Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
    Measure Participants 261 131
    Median (95% Confidence Interval) [months]
    NA
    NA
    4. Secondary Outcome
    Title Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve
    Description
    Time Frame Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose

    Outcome Measure Data

    Analysis Population Description
    The PK analysis set included all the participants who received at least one dose of study drug and had evaluable PK data.
    Arm/Group Title Randomization Phase: Lenvatinib 24 mg
    Arm/Group Description Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
    Measure Participants 260
    Median (Full Range) [nanogram*hour per milliliter (ng*h/mL)]
    3490

    Adverse Events

    Time Frame For each participant, from the first dose till 30 days after the last dose up to approximately 8 years
    Adverse Event Reporting Description Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
    Arm/Group Title Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo OOL, Treatment Period: Lenvatinib 24 mg OOL, Treatment Period: Lenvatinib 20 mg
    Arm/Group Description Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. Participants received lenvatinib 24 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib. Participants received lenvatinib 20 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated participants in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.
    All Cause Mortality
    Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo OOL, Treatment Period: Lenvatinib 24 mg OOL, Treatment Period: Lenvatinib 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 161/261 (61.7%) 13/16 (81.3%) 62/85 (72.9%) 15/30 (50%)
    Serious Adverse Events
    Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo OOL, Treatment Period: Lenvatinib 24 mg OOL, Treatment Period: Lenvatinib 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 171/261 (65.5%) 31/131 (23.7%) 62/85 (72.9%) 16/30 (53.3%)
    Blood and lymphatic system disorders
    Anaemia 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 1/30 (3.3%) 1
    Neutropenia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Thrombocytopenia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Febrile neutropenia 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Splenic haemorrhage 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Cardiac disorders
    Acute myocardial infarction 5/261 (1.9%) 7 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Angina pectoris 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Bundle branch block right 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Cardio-respiratory arrest 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Coronary artery stenosis 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Myocardial infarction 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Pericardial effusion 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Right ventricular hypertrophy 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Sinus tachycardia 0/261 (0%) 0 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Atrial fibrillation 4/261 (1.5%) 6 0/131 (0%) 0 3/85 (3.5%) 4 0/30 (0%) 0
    Atrial flutter 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Cardiac arrest 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Cardiac failure 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 2 0/30 (0%) 0
    Acute coronary syndrome 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Angina unstable 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Atrioventricular block complete 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Cardiac failure congestive 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Coronary artery insufficiency 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Coronary artery occlusion 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 1/30 (3.3%) 1
    Tachycardia 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Ventricular hypokinesia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Ventricular tachycardia 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Palpitations 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Acute left ventricular failure 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Eye disorders
    Retinal vein thrombosis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Retinal detachment 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Diplopia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 3/261 (1.1%) 3 0/131 (0%) 0 4/85 (4.7%) 5 0/30 (0%) 0
    Anal fistula 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Abdominal pain upper 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Colitis 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Colitis ischaemic 0/261 (0%) 0 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Constipation 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 2/30 (6.7%) 2
    Diarrhoea 2/261 (0.8%) 4 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Functional gastrointestinal disorder 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Gastrooesophageal reflux disease 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Intestinal obstruction 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Nausea 0/261 (0%) 0 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Oesophageal stenosis 0/261 (0%) 0 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Pneumatosis intestinalis 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Stomatitis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Vomiting 5/261 (1.9%) 5 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Diverticular perforation 0/261 (0%) 0 0/131 (0%) 0 2/85 (2.4%) 2 0/30 (0%) 0
    Dysphagia 3/261 (1.1%) 3 3/131 (2.3%) 3 1/85 (1.2%) 1 0/30 (0%) 0
    Inguinal hernia 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Mesenteric artery thrombosis 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Pancreatitis 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Abdominal mass 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Gastrointestinal inflammation 1/261 (0.4%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pneumoperitoneum 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Small intestinal obstruction 2/261 (0.8%) 4 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Dental cyst 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Intestinal perforation 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Gastroenteritis viral 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 2 0/30 (0%) 0
    General disorders
    Asthenia 3/261 (1.1%) 4 0/131 (0%) 0 2/85 (2.4%) 3 0/30 (0%) 0
    Chest pain 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Device failure 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Impaired healing 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Multi-organ failure 1/261 (0.4%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Non-cardiac chest pain 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 3 0/30 (0%) 0
    Pyrexia 3/261 (1.1%) 3 1/131 (0.8%) 1 0/85 (0%) 0 1/30 (3.3%) 1
    Sudden death 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Death 2/261 (0.8%) 2 1/131 (0.8%) 1 3/85 (3.5%) 3 0/30 (0%) 0
    Device breakage 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Fatigue 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    General physical health deterioration 7/261 (2.7%) 9 0/131 (0%) 0 1/85 (1.2%) 2 0/30 (0%) 0
    Pain 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Hepatobiliary disorders
    Cholecystitis acute 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Cholelithiasis 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Cholecystitis 4/261 (1.5%) 5 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Gallbladder mucocoele 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Gallbladder perforation 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Hepatic failure 2/261 (0.8%) 4 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Hepatic function abnormal 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Liver injury 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Hepatocellular injury 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Hydrocholecystis 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Immune system disorders
    Anaphylactic reaction 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Contrast media allergy 0/261 (0%) 0 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Infections and infestations
    Abscess intestinal 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Anal abscess 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Bronchitis 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Cellulitis 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Colonic abscess 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Diverticulitis 2/261 (0.8%) 3 0/131 (0%) 0 1/85 (1.2%) 2 0/30 (0%) 0
    Empyema 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Abscess limb 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Abscess soft tissue 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Appendicitis 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Bacteraemia 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Chest wall abscess 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Chronic sinusitis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Fungal skin infection 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Erysipelas 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Infection 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Gastroenteritis 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 1 1/30 (3.3%) 1
    Intervertebral discitis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Lower respiratory tract infection 4/261 (1.5%) 7 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Perineal abscess 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pyelonephritis 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Sepsis 6/261 (2.3%) 6 2/131 (1.5%) 3 1/85 (1.2%) 1 0/30 (0%) 0
    Testicular abscess 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Urinary tract infection 4/261 (1.5%) 4 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Urosepsis 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Wound infection 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Implant site infection 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Lobar pneumonia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Lung infection 4/261 (1.5%) 6 0/131 (0%) 0 1/85 (1.2%) 3 2/30 (6.7%) 2
    Lymph gland infection 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Osteomyelitis 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Pneumonia 12/261 (4.6%) 14 3/131 (2.3%) 3 5/85 (5.9%) 5 2/30 (6.7%) 3
    Pneumonia necrotising 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 2 0/30 (0%) 0
    Pneumonia staphylococcal 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Bartholin's abscess 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Biliary tract infection 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Candida sepsis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Cholecystitis infective 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Laryngitis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Meningitis viral 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Subcutaneous abscess 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Tracheitis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Appendicitis perforated 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Phlebitis infective 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Upper respiratory tract infection 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Injury, poisoning and procedural complications
    Eschar 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Femur fracture 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Hip fracture 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Renal haematoma 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Vascular pseudoaneurysm 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Wound dehiscence 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Wound secretion 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Post procedural haemorrhage 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Splenic rupture 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Incisional hernia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Lumbar vertebral fracture 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Subdural haematoma 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Traumatic fracture 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Thermal burn 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Investigations
    Blood uric acid increased 2/261 (0.8%) 3 1/131 (0.8%) 2 1/85 (1.2%) 1 0/30 (0%) 0
    Electrocardiogram T wave inversion 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Alanine aminotransferase increased 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Aspartate aminotransferase increased 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Blood alkaline phosphatase increased 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Blood creatine phosphokinase increased 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Lipase increased 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Platelet count decreased 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Weight decreased 2/261 (0.8%) 2 1/131 (0.8%) 2 0/85 (0%) 0 0/30 (0%) 0
    Blood creatinine increased 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Blood calcium increased 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Metabolism and nutrition disorders
    Decreased appetite 1/261 (0.4%) 1 0/131 (0%) 0 2/85 (2.4%) 2 1/30 (3.3%) 1
    Dehydration 9/261 (3.4%) 9 0/131 (0%) 0 2/85 (2.4%) 3 1/30 (3.3%) 1
    Hypercalcaemia 2/261 (0.8%) 2 1/131 (0.8%) 1 1/85 (1.2%) 1 0/30 (0%) 0
    Hypocalcaemia 4/261 (1.5%) 8 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Hyponatraemia 2/261 (0.8%) 2 1/131 (0.8%) 1 1/85 (1.2%) 2 0/30 (0%) 0
    Hypovolaemia 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Hypokalaemia 3/261 (1.1%) 3 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Hypomagnesaemia 1/261 (0.4%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 3/261 (1.1%) 3 1/131 (0.8%) 1 1/85 (1.2%) 1 1/30 (3.3%) 1
    Back pain 3/261 (1.1%) 3 0/131 (0%) 0 3/85 (3.5%) 3 0/30 (0%) 0
    Flank pain 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Bone pain 2/261 (0.8%) 3 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Musculoskeletal chest pain 1/261 (0.4%) 1 1/131 (0.8%) 1 2/85 (2.4%) 3 0/30 (0%) 0
    Muscular weakness 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Musculoskeletal pain 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Myalgia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Neck pain 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Osteoarthritis 3/261 (1.1%) 3 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pain in extremity 1/261 (0.4%) 1 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Rhabdomyolysis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pathological fracture 1/261 (0.4%) 1 0/131 (0%) 0 2/85 (2.4%) 2 1/30 (3.3%) 1
    Soft tissue necrosis 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Foot deformity 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Osteonecrosis of jaw 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Mobility decreased 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intracranial tumour haemorrhage 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Malignant neoplasm progression 2/261 (0.8%) 2 0/131 (0%) 0 3/85 (3.5%) 4 0/30 (0%) 0
    Malignant pleural effusion 5/261 (1.9%) 5 1/131 (0.8%) 2 1/85 (1.2%) 2 0/30 (0%) 0
    Metastases to bone 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Metastatic pain 1/261 (0.4%) 1 0/131 (0%) 0 3/85 (3.5%) 3 1/30 (3.3%) 1
    Adenocarcinoma gastric 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Cancer pain 3/261 (1.1%) 3 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Metastases to spine 0/261 (0%) 0 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Plasmacytoma 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Tumour pain 0/261 (0%) 0 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Lymphocytic leukaemia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Malignant melanoma 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Spindle cell sarcoma 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Squamous cell carcinoma of skin 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Metastatic pulmonary embolism 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Nervous system disorders
    Cauda equina syndrome 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Cerebrovascular accident 2/261 (0.8%) 2 0/131 (0%) 0 3/85 (3.5%) 3 1/30 (3.3%) 1
    Coma 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Diabetic encephalopathy 0/261 (0%) 0 1/131 (0.8%) 1 1/85 (1.2%) 1 0/30 (0%) 0
    Osmotic demyelination syndrome 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Cerebral ischaemia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Dizziness 2/261 (0.8%) 4 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Epilepsy 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Haemorrhagic stroke 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Headache 4/261 (1.5%) 4 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Ischaemic stroke 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Loss of consciousness 1/261 (0.4%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Metabolic encephalopathy 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Monoparesis 3/261 (1.1%) 6 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Parkinson's disease 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Posterior reversible encephalopathy syndrome 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Postictal paralysis 1/261 (0.4%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Spinal cord compression 4/261 (1.5%) 4 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Syncope 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 1 1/30 (3.3%) 1
    Transient ischaemic attack 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Vocal cord paralysis 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Spinal cord ischaemia 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Subarachnoid haemorrhage 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    seizure 4/261 (1.5%) 5 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Dementia 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Facial paresis 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Psychiatric disorders
    Confusional state 3/261 (1.1%) 4 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Anxiety 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Depression 0/261 (0%) 0 1/131 (0.8%) 1 1/85 (1.2%) 3 0/30 (0%) 0
    Suicidal ideation 0/261 (0%) 0 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Delirium 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Renal and urinary disorders
    Acute prerenal failure 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Dysuria 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Nephrotic syndrome 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Renal failure 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Renal impairment 1/261 (0.4%) 3 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Renal tubular necrosis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Urinary retention 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Acute kidney injury 6/261 (2.3%) 6 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Chronic kidney disease 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Haematuria 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Proteinuria 2/261 (0.8%) 2 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Urinary incontinence 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Cystocele 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Rectocele 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Uterine prolapse 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Genital prolapse 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Chronic obstructive pulmonary disease 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 2 0/30 (0%) 0
    Dyspnoea 6/261 (2.3%) 12 5/131 (3.8%) 7 3/85 (3.5%) 5 1/30 (3.3%) 1
    Dyspnoea exertional 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Haemoptysis 0/261 (0%) 0 0/131 (0%) 0 2/85 (2.4%) 2 1/30 (3.3%) 1
    Laryngeal necrosis 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Laryngeal obstruction 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Laryngeal oedema 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Lung disorder 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 2 0/30 (0%) 0
    Pneumothorax 1/261 (0.4%) 1 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Pulmonary haemorrhage 1/261 (0.4%) 1 1/131 (0.8%) 1 1/85 (1.2%) 1 0/30 (0%) 0
    Respiratory distress 1/261 (0.4%) 1 0/131 (0%) 0 2/85 (2.4%) 4 0/30 (0%) 0
    Respiratory failure 2/261 (0.8%) 2 2/131 (1.5%) 3 2/85 (2.4%) 3 0/30 (0%) 0
    Acute respiratory failure 2/261 (0.8%) 2 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Aspiration 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Bronchospasm 1/261 (0.4%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Epistaxis 2/261 (0.8%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Haemothorax 1/261 (0.4%) 1 1/131 (0.8%) 2 0/85 (0%) 0 0/30 (0%) 0
    Hypoxia 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Laryngeal haemorrhage 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pleural effusion 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pneumonia aspiration 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pneumonitis 1/261 (0.4%) 2 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Productive cough 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pulmonary embolism 6/261 (2.3%) 8 2/131 (1.5%) 2 0/85 (0%) 0 0/30 (0%) 0
    Atelectasis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Bronchial secretion retention 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Hydrothorax 1/261 (0.4%) 5 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Oropharyngeal pain 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pneumothorax spontaneous 1/261 (0.4%) 5 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pulmonary mass 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Pleuritic pain 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Respiratory depression 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Skin and subcutaneous tissue disorders
    Angioedema 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Erythema 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Rash 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Skin ulcer 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Drug eruption 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Dermatitis contact 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Vascular disorders
    Aneurysm ruptured 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Hypertension 10/261 (3.8%) 11 0/131 (0%) 0 1/85 (1.2%) 1 1/30 (3.3%) 2
    Hypertensive crisis 0/261 (0%) 0 0/131 (0%) 0 2/85 (2.4%) 2 0/30 (0%) 0
    Hypotension 5/261 (1.9%) 5 0/131 (0%) 0 2/85 (2.4%) 2 0/30 (0%) 0
    Varicose vein 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 1
    Deep vein thrombosis 1/261 (0.4%) 1 0/131 (0%) 0 0/85 (0%) 0 0/30 (0%) 0
    Vasculitis 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 1/30 (3.3%) 3
    Thrombophlebitis 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 0/30 (0%) 0
    Other (Not Including Serious) Adverse Events
    Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo OOL, Treatment Period: Lenvatinib 24 mg OOL, Treatment Period: Lenvatinib 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 259/261 (99.2%) 118/131 (90.1%) 84/85 (98.8%) 29/30 (96.7%)
    Blood and lymphatic system disorders
    Lymphopenia 20/261 (7.7%) 60 2/131 (1.5%) 2 0/85 (0%) 0 0/30 (0%) 0
    Anaemia 31/261 (11.9%) 60 6/131 (4.6%) 13 7/85 (8.2%) 11 3/30 (10%) 11
    Thrombocytopenia 25/261 (9.6%) 83 3/131 (2.3%) 4 7/85 (8.2%) 84 1/30 (3.3%) 1
    Leukopenia 15/261 (5.7%) 47 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Endocrine disorders
    Hypothyroidism 14/261 (5.4%) 26 0/131 (0%) 0 7/85 (8.2%) 7 2/30 (6.7%) 2
    Gastrointestinal disorders
    Oral pain 26/261 (10%) 44 1/131 (0.8%) 3 5/85 (5.9%) 9 0/30 (0%) 0
    Cheilitis 0/261 (0%) 0 0/131 (0%) 0 5/85 (5.9%) 5 0/30 (0%) 0
    Toothache 18/261 (6.9%) 22 5/131 (3.8%) 5 7/85 (8.2%) 8 2/30 (6.7%) 3
    Haemorrhoids 0/261 (0%) 0 0/131 (0%) 0 6/85 (7.1%) 6 1/30 (3.3%) 1
    Glossodynia 18/261 (6.9%) 32 0/131 (0%) 0 9/85 (10.6%) 12 0/30 (0%) 0
    Abdominal pain upper 46/261 (17.6%) 85 11/131 (8.4%) 11 11/85 (12.9%) 13 9/30 (30%) 11
    Dry mouth 46/261 (17.6%) 58 11/131 (8.4%) 13 11/85 (12.9%) 12 1/30 (3.3%) 1
    Dyspepsia 38/261 (14.6%) 66 6/131 (4.6%) 6 11/85 (12.9%) 14 3/30 (10%) 10
    Dysphagia 34/261 (13%) 47 9/131 (6.9%) 10 15/85 (17.6%) 15 3/30 (10%) 5
    Abdominal pain 50/261 (19.2%) 109 5/131 (3.8%) 10 20/85 (23.5%) 34 8/30 (26.7%) 15
    Constipation 83/261 (31.8%) 113 20/131 (15.3%) 26 25/85 (29.4%) 32 5/30 (16.7%) 8
    Stomatitis 100/261 (38.3%) 246 9/131 (6.9%) 10 28/85 (32.9%) 50 13/30 (43.3%) 22
    Vomiting 100/261 (38.3%) 217 19/131 (14.5%) 24 36/85 (42.4%) 67 9/30 (30%) 19
    Nausea 127/261 (48.7%) 295 34/131 (26%) 48 34/85 (40%) 67 12/30 (40%) 31
    Diarrhoea 182/261 (69.7%) 740 22/131 (16.8%) 27 55/85 (64.7%) 263 21/30 (70%) 66
    Flatulence 15/261 (5.7%) 18 1/131 (0.8%) 1 3/85 (3.5%) 4 2/30 (6.7%) 6
    Abdominal distension 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 2/30 (6.7%) 2
    Gastrooesophageal reflux disease 0/261 (0%) 0 0/131 (0%) 0 2/85 (2.4%) 2 2/30 (6.7%) 2
    Gingival pain 0/261 (0%) 0 0/131 (0%) 0 2/85 (2.4%) 3 2/30 (6.7%) 2
    General disorders
    General physical health deterioration 0/261 (0%) 0 0/131 (0%) 0 6/85 (7.1%) 7 1/30 (3.3%) 1
    Pyrexia 41/261 (15.7%) 58 15/131 (11.5%) 17 10/85 (11.8%) 20 5/30 (16.7%) 8
    Oedema peripheral 65/261 (24.9%) 124 10/131 (7.6%) 12 18/85 (21.2%) 20 3/30 (10%) 8
    Asthenia 69/261 (26.4%) 209 18/131 (13.7%) 29 21/85 (24.7%) 43 10/30 (33.3%) 26
    Fatigue 116/261 (44.4%) 298 33/131 (25.2%) 45 35/85 (41.2%) 64 13/30 (43.3%) 28
    Malaise 17/261 (6.5%) 29 0/131 (0%) 0 5/85 (5.9%) 8 1/30 (3.3%) 1
    Influenza like illness 20/261 (7.7%) 25 4/131 (3.1%) 4 0/85 (0%) 0 0/30 (0%) 0
    Non-cardiac chest pain 14/261 (5.4%) 16 4/131 (3.1%) 5 3/85 (3.5%) 3 2/30 (6.7%) 2
    Pain 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 2/30 (6.7%) 2
    Infections and infestations
    Urinary tract infection 30/261 (11.5%) 54 7/131 (5.3%) 9 6/85 (7.1%) 8 3/30 (10%) 4
    Pneumonia 0/261 (0%) 0 0/131 (0%) 0 6/85 (7.1%) 11 0/30 (0%) 0
    Upper respiratory tract infection 26/261 (10%) 40 7/131 (5.3%) 9 5/85 (5.9%) 10 3/30 (10%) 4
    Nasopharyngitis 28/261 (10.7%) 54 8/131 (6.1%) 8 6/85 (7.1%) 7 6/30 (20%) 6
    Bronchitis 17/261 (6.5%) 24 2/131 (1.5%) 2 5/85 (5.9%) 13 2/30 (6.7%) 3
    Influenza 16/261 (6.1%) 17 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Gastrointestinal infection 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 2/30 (6.7%) 2
    Sinusitis 0/261 (0%) 0 0/131 (0%) 0 6/85 (7.1%) 11 3/30 (10%) 5
    Investigations
    Platelet count decreased 17/261 (6.5%) 108 0/131 (0%) 0 2/85 (2.4%) 2 5/30 (16.7%) 7
    Aspartate aminotransferase increased 17/261 (6.5%) 30 2/131 (1.5%) 2 6/85 (7.1%) 7 0/30 (0%) 0
    Blood thyroid stimulating hormone increased 18/261 (6.9%) 20 0/131 (0%) 0 5/85 (5.9%) 5 0/30 (0%) 0
    Alanine aminotransferase increased 21/261 (8%) 33 0/131 (0%) 0 8/85 (9.4%) 9 2/30 (6.7%) 2
    Electrocardiogram QT prolonged 27/261 (10.3%) 53 2/131 (1.5%) 3 9/85 (10.6%) 26 1/30 (3.3%) 5
    Weight decreased 142/261 (54.4%) 450 20/131 (15.3%) 22 44/85 (51.8%) 101 18/30 (60%) 49
    Blood alkaline phosphatase increased 18/261 (6.9%) 29 3/131 (2.3%) 3 5/85 (5.9%) 5 0/30 (0%) 0
    Blood creatinine increased 25/261 (9.6%) 54 2/131 (1.5%) 2 6/85 (7.1%) 8 1/30 (3.3%) 2
    Ejection fraction decreased 18/261 (6.9%) 31 1/131 (0.8%) 1 7/85 (8.2%) 9 2/30 (6.7%) 2
    White blood cell count decreased 14/261 (5.4%) 47 4/131 (3.1%) 4 0/85 (0%) 0 0/30 (0%) 0
    Blood cholesterol increased 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 2/30 (6.7%) 2
    Lipase increased 0/261 (0%) 0 0/131 (0%) 0 4/85 (4.7%) 7 2/30 (6.7%) 5
    Metabolism and nutrition disorders
    Hyperglycaemia 15/261 (5.7%) 22 6/131 (4.6%) 7 5/85 (5.9%) 5 1/30 (3.3%) 3
    Hypocalcaemia 38/261 (14.6%) 74 0/131 (0%) 0 11/85 (12.9%) 23 3/30 (10%) 6
    Hypoalbuminaemia 27/261 (10.3%) 50 2/131 (1.5%) 2 12/85 (14.1%) 17 1/30 (3.3%) 3
    Decreased appetite 148/261 (56.7%) 352 24/131 (18.3%) 31 43/85 (50.6%) 86 11/30 (36.7%) 24
    Dehydration 24/261 (9.2%) 29 3/131 (2.3%) 3 0/85 (0%) 0 0/30 (0%) 0
    Hypokalaemia 41/261 (15.7%) 78 5/131 (3.8%) 5 0/85 (0%) 0 0/30 (0%) 0
    Hypomagnesaemia 20/261 (7.7%) 28 2/131 (1.5%) 2 6/85 (7.1%) 13 2/30 (6.7%) 2
    Hyponatraemia 17/261 (6.5%) 25 3/131 (2.3%) 6 5/85 (5.9%) 11 1/30 (3.3%) 1
    Vitamin D deficiency 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 2/30 (6.7%) 2
    Musculoskeletal and connective tissue disorders
    Neck pain 23/261 (8.8%) 33 15/131 (11.5%) 19 6/85 (7.1%) 8 1/30 (3.3%) 1
    Muscle spasms 22/261 (8.4%) 31 5/131 (3.8%) 5 11/85 (12.9%) 15 5/30 (16.7%) 13
    Musculoskeletal chest pain 32/261 (12.3%) 40 13/131 (9.9%) 14 11/85 (12.9%) 14 3/30 (10%) 5
    Myalgia 51/261 (19.5%) 95 6/131 (4.6%) 9 12/85 (14.1%) 16 9/30 (30%) 16
    Pain in extremity 48/261 (18.4%) 73 9/131 (6.9%) 13 12/85 (14.1%) 27 7/30 (23.3%) 9
    Back pain 52/261 (19.9%) 81 12/131 (9.2%) 14 18/85 (21.2%) 29 6/30 (20%) 7
    Musculoskeletal pain 46/261 (17.6%) 60 11/131 (8.4%) 13 14/85 (16.5%) 27 4/30 (13.3%) 6
    Arthralgia 85/261 (32.6%) 148 9/131 (6.9%) 15 19/85 (22.4%) 39 12/30 (40%) 25
    Muscular weakness 20/261 (7.7%) 23 3/131 (2.3%) 3 5/85 (5.9%) 8 0/30 (0%) 0
    Flank pain 0/261 (0%) 0 0/131 (0%) 0 3/85 (3.5%) 3 3/30 (10%) 3
    Joint swelling 0/261 (0%) 0 0/131 (0%) 0 2/85 (2.4%) 2 2/30 (6.7%) 2
    Nervous system disorders
    Dysgeusia 48/261 (18.4%) 70 4/131 (3.1%) 4 10/85 (11.8%) 13 6/30 (20%) 9
    Dizziness 45/261 (17.2%) 77 13/131 (9.9%) 14 15/85 (17.6%) 19 8/30 (26.7%) 12
    Headache 105/261 (40.2%) 223 15/131 (11.5%) 21 19/85 (22.4%) 28 10/30 (33.3%) 35
    Paraesthesia 14/261 (5.4%) 18 4/131 (3.1%) 8 2/85 (2.4%) 2 3/30 (10%) 4
    Hyperaesthesia 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 2/30 (6.7%) 2
    Sciatica 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 2 2/30 (6.7%) 2
    Psychiatric disorders
    Anxiety 15/261 (5.7%) 16 5/131 (3.8%) 6 5/85 (5.9%) 5 0/30 (0%) 0
    Depression 22/261 (8.4%) 31 3/131 (2.3%) 3 5/85 (5.9%) 7 3/30 (10%) 3
    Insomnia 0/261 (0%) 0 0/131 (0%) 0 11/85 (12.9%) 13 3/30 (10%) 3
    Renal and urinary disorders
    Proteinuria 99/261 (37.9%) 604 4/131 (3.1%) 5 26/85 (30.6%) 126 12/30 (40%) 24
    Haematuria 18/261 (6.9%) 22 3/131 (2.3%) 4 6/85 (7.1%) 9 0/30 (0%) 0
    Dysuria 15/261 (5.7%) 17 1/131 (0.8%) 1 0/85 (0%) 0 0/30 (0%) 0
    Reproductive system and breast disorders
    Pelvic pain 0/261 (0%) 0 0/131 (0%) 0 0/85 (0%) 0 3/30 (10%) 4
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain 43/261 (16.5%) 86 2/131 (1.5%) 2 9/85 (10.6%) 13 4/30 (13.3%) 4
    Dyspnoea 47/261 (18%) 65 21/131 (16%) 29 16/85 (18.8%) 26 5/30 (16.7%) 5
    Haemoptysis 12/261 (4.6%) 17 12/131 (9.2%) 14 9/85 (10.6%) 10 3/30 (10%) 4
    Epistaxis 36/261 (13.8%) 58 1/131 (0.8%) 1 14/85 (16.5%) 20 5/30 (16.7%) 6
    Cough 77/261 (29.5%) 114 24/131 (18.3%) 36 23/85 (27.1%) 30 8/30 (26.7%) 13
    Dysphonia 87/261 (33.3%) 135 7/131 (5.3%) 8 33/85 (38.8%) 55 10/30 (33.3%) 13
    Productive cough 13/261 (5%) 23 8/131 (6.1%) 8 3/85 (3.5%) 3 2/30 (6.7%) 3
    Dyspnoea exertional 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 2 2/30 (6.7%) 5
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform 0/261 (0%) 0 0/131 (0%) 0 4/85 (4.7%) 5 2/30 (6.7%) 4
    Alopecia 34/261 (13%) 39 7/131 (5.3%) 7 9/85 (10.6%) 14 6/30 (20%) 8
    Dry skin 32/261 (12.3%) 35 8/131 (6.1%) 8 10/85 (11.8%) 11 2/30 (6.7%) 3
    Rash 55/261 (21.1%) 81 2/131 (1.5%) 4 14/85 (16.5%) 16 6/30 (20%) 8
    Palmar-plantar erythrodysaesthesia syndrome 86/261 (33%) 268 1/131 (0.8%) 1 24/85 (28.2%) 85 9/30 (30%) 44
    Hyperkeratosis 19/261 (7.3%) 36 2/131 (1.5%) 3 0/85 (0%) 0 0/30 (0%) 0
    Pruritus 19/261 (7.3%) 25 6/131 (4.6%) 6 0/85 (0%) 0 0/30 (0%) 0
    Decubitus ulcer 0/261 (0%) 0 0/131 (0%) 0 5/85 (5.9%) 6 0/30 (0%) 0
    Hyperhidrosis 0/261 (0%) 0 0/131 (0%) 0 2/85 (2.4%) 2 2/30 (6.7%) 2
    Skin fissures 0/261 (0%) 0 0/131 (0%) 0 1/85 (1.2%) 1 2/30 (6.7%) 2
    Vascular disorders
    Hypotension 0/261 (0%) 0 0/131 (0%) 0 8/85 (9.4%) 12 4/30 (13.3%) 5
    Hypertension 181/261 (69.3%) 720 19/131 (14.5%) 36 52/85 (61.2%) 84 21/30 (70%) 69

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Results Point of Contact

    Name/Title Eisai Medical Information
    Organization Eisai, Inc.
    Phone 1-888-274-2378
    Email esi_oncmedinfo@eisai.com
    Responsible Party:
    Eisai Inc.
    ClinicalTrials.gov Identifier:
    NCT01321554
    Other Study ID Numbers:
    • E7080-G000-303
    • 2010-023783-41
    First Posted:
    Mar 23, 2011
    Last Update Posted:
    Apr 2, 2020
    Last Verified:
    Mar 1, 2020