Trial Outcomes & Findings for An Open-Label, 2-Cohort, Multicenter, Study of Lenvatinib in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma (NCT NCT01136967)

NCT ID: NCT01136967

Last Updated: 2019-11-13

Results Overview

ORR, (ORR = CR + PR) was defined as the percentage of participants in each cohort who had a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans and independent radiologic review (IRR). A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than (\<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 182 participants
• Primary outcome timeframe: From date of treatment start until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to end of Cycle 6 (up to 24 weeks)
• Results posted on: 2019-11-13

Participant Flow

A total of 298 participants were screened. Of these, 116 were screen failures and 182 received treatment (93 participants in Cohort 1 and 89 participants in Cohort 2).

Participant milestones

Measure	Cohort 1 (V600E BRAF Negative) Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Overall Study STARTED	93	89
Overall Study Disease Progression	55	56
Overall Study Treatment Ongoing at Data Cutoff	14	6
Overall Study COMPLETED	69	62
Overall Study NOT COMPLETED	24	27

Reasons for withdrawal

Measure	Cohort 1 (V600E BRAF Negative) Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Overall Study Adverse Event	9	12
Overall Study Participant Choice	8	3
Overall Study Lost to Follow-up	0	1
Overall Study Withdrawal by Subject	1	2
Overall Study Clinical Progression	3	5
Overall Study Radiation	1	0
Overall Study Non-compliance	1	0
Overall Study Investigator's Choice	1	1
Overall Study Increase in Lesion Size	0	2
Overall Study Diagnosis of Second Primary Cancer	0	1

Baseline Characteristics

An Open-Label, 2-Cohort, Multicenter, Study of Lenvatinib in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma

Baseline characteristics by cohort

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Total n=182 Participants Total of all reporting groups
Age, Continuous	62.5 Years STANDARD_DEVIATION 11.71 • n=5 Participants	55.0 Years STANDARD_DEVIATION 14.18 • n=7 Participants	58.8 Years STANDARD_DEVIATION 13.47 • n=5 Participants
Sex/Gender, Customized Female	29 Participants n=5 Participants	39 Participants n=7 Participants	68 Participants n=5 Participants
Sex/Gender, Customized Male	64 Participants n=5 Participants	50 Participants n=7 Participants	114 Participants n=5 Participants
AJCC Melanoma Tumor, Node, Metastasis (TNM) Stage at Study Entry Unresectable Stage III	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
AJCC Melanoma Tumor, Node, Metastasis (TNM) Stage at Study Entry Unresectable Stage IV	88 Participants n=5 Participants	82 Participants n=7 Participants	170 Participants n=5 Participants

PRIMARY outcome

Timeframe: From date of treatment start until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to end of Cycle 6 (up to 24 weeks)

Population: Full Analysis Set (Intent-to-Treat \[ITT\] Analysis Set) included all participants who received at least 1 dose study drug.

ORR, (ORR = CR + PR) was defined as the percentage of participants in each cohort who had a best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans and independent radiologic review (IRR). A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to have a reduction in short axis to less than (<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Objective Response Rate (ORR)	8.6 Percentage of participants Interval 3.8 to 16.2	9.0 Percentage of participants Interval 4.0 to 16.9

SECONDARY outcome

Timeframe: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Population: Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

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 from any cause (whichever occurred first), as determined by IRR and Investigator based on RECIST v1.1. 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. PFS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% confidence interval (CI) when an adequate number of at risk participants warranted the estimates in the table below.

Outcome measures

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Progression Free Survival (PFS) Determined by IRR	3.7 Months Interval 2.5 to 4.2	1.8 Months Interval 1.8 to 2.2
Progression Free Survival (PFS) Determined by Investigator	3.7 Months Interval 3.6 to 4.2	2.3 Months Interval 1.9 to 3.4

SECONDARY outcome

Timeframe: From date of treatment start until date of death from any cause or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Population: Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

OS was defined as the length of time in months from the date of first administration of study drug until the date of death from any cause, and was based on the data cutoff date for each cohort. OS was analyzed using Kaplan-Meier (1958) product-limit estimates. Data were presented with 2-sided 95% CI when an adequate number of at risk participants warranted the estimates in the table below.

Outcome measures

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Overall Survival (OS)	8.9 Months Interval 8.3 to NA: Not applicable since the upper limit of the 95% confidence interval was not yet reached at the time of analysis.	6.3 Months Interval 5.2 to 8.8

SECONDARY outcome

Timeframe: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Population: Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

DCR, (DCR = CR + PR + SD) was defined as the percentage of participants who had a BOR of CR or PR or stable disease (SD) based on RECIST v1.1 for target lesions assessed by MRI/CT and IRR. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a reduction in short axis to <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; Overall Response (OR) = CR + PR. SD defined as reduction in tumor volume of < 30% or an increase in the volume of 1 or more measurable lesions of < 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to disease progression. BOR of SD, time from first administration of study drug until date of documented SD needed to be >=7 weeks based on IRR and Investigator's assessment.

Outcome measures

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Disease Control Rate (DCR) Determined by IRR	52.7 Percentage of participants Interval 42.1 to 63.1	34.8 Percentage of participants Interval 25.0 to 45.7
Disease Control Rate (DCR) Determined by Investigator	64.5 Percentage of participants Interval 53.9 to 74.2	48.3 Percentage of participants Interval 37.6 to 59.2

SECONDARY outcome

Timeframe: From date of treatment start until documentation of disease progression or death from any cause (whichever occurred first) or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 8 months

Population: Full Analysis Set (ITT Analysis Set) included all participants who received at least 1 dose study drug.

CBR, (CBR = CR + PR + durable SD rate) was defined as the percentage of participants who had a BOR of CR or PR or durable SD (dSD, SD lasting >=23 weeks) based on RECIST v1.1 for target lesions assessed by MRI/CT, IRR and Investigator's assessment. A BOR of CR required confirmation by a subsequent CR assessment at least 4 weeks later. A BOR of PR required confirmation by a subsequent assessment of CR or PR at least 4 weeks later. CR was defined as the disappearance of all target lesions, any pathological lymph nodes (target or non-target) had to have a 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; OR = CR + PR. A BOR of dSD, the time from the first administration of study drug until the date of documented dSD needed to be ≥23 weeks based on IRR and Investigator's assessment.

Outcome measures

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Clinical Benefit Rate (CBR) Determined by IRR	31.2 Percentage of participants Interval 22.0 to 41.6	14.6 Percentage of participants Interval 8.0 to 23.7
Clinical Benefit Rate (CBR) Determined by Investigator	33.3 Percentage of participants Interval 23.9 to 43.9	20.2 Percentage of participants Interval 12.4 to 30.1

SECONDARY outcome

Timeframe: From date of treatment start up to 30 days after the last dose, or up to data cutoff (Cohort 1; 15 Jan 2012 and Cohort 2; 15 Apr 2013), up to approximately 2 years 9 months

Population: Safety Analysis Set included those participants who received at least 1 dose of study drug and had at least 1 post baseline safety evaluation.

Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECGs), and multi-gated acquisition (MUGA) scans or echocardiogram.

Outcome measures

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib AEs	93 Participants	89 Participants
Number of Participants With Adverse Events (AEs)/ Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib SAEs	39 Participants	36 Participants

SECONDARY outcome

Timeframe: Cycle 1 Day 15 (C1 D15), Cycle 2 Day 1 (C2 D1), Cycle 3 Day 1 (C3 D1), Off-Treatment/Phase Visit 98 (V98)

Population: The Safety Analysis set was used and included all participants who received at least one dose of lenvatinib and had at least 1 postbaseline safety evaluation. Number analyzed (n) signifies participants who were evaluable at specific time points for this outcome measure.

Blood samples were drawn at specific time points. Utilizing a standard protocol, the deoxyribonucleic acid (DNA) from whole blood was extracted and analyzed for specific biomarkers of absorption, distribution, metabolism, and excretion of lenvatinib. Some of the biomarkers analyzed included; Angiopoietin, Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), FMS Like Tyrosine Kinase 3 Ligand (Flt3l) Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macro Colony Stimulating Factor (GM-CSF), Interleukin 1 Receptor Antagonist (IL-1RA), Interferon (IFN), Macrophage Inflammatory Protein (MIP) 1 alpha, Platelet Derived Growth Factor (PDGF), Stromal Cell Derived Factor (SDF) 1 alpha, Interleukin (IL), Transforming Growth Factor (TGF), Tumor Necrosis Factor (TNF), Vascular Endothelial Growth Factor (VEGF).

Outcome measures

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Eotaxin-4 C3D1	89.878 pg/mL Standard Deviation 108.6392	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Eotaxin-4 V98	104.613 pg/mL Standard Deviation 157.7527	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 2 C1D15	-4.294 pg/mL Standard Deviation 51.3985	8.325 pg/mL Standard Deviation 136.3433
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 3 C2D1	-1320.738 pg/mL Standard Deviation 3138.3810	-2523.257 pg/mL Standard Deviation 3550.7291
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Eotaxin-4 C1D15	51.456 pg/mL Standard Deviation 117.1266	46.538 pg/mL Standard Deviation 128.398
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 76 C1D15	-1015.69 pg/mL Standard Deviation 946.596	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 76 C2D1	-832.29 pg/mL Standard Deviation 1257.287	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 76 C3D1	-923.82 pg/mL Standard Deviation 969.285	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 76 V98	-947.00 pg/mL Standard Deviation 825.037	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 90 C1D15	—	-1225.322 pg/mL Standard Deviation 1950.4525
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 90 C2D1	—	-1100.235 pg/mL Standard Deviation 1378.4621
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 1 C1D15	-3033.030 pg/mL Standard Deviation 8808.2059	-2717.533 pg/mL Standard Deviation 16689.4536
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 1 C2D1	-2802.306 pg/mL Standard Deviation 10202.7814	-1743.569 pg/mL Standard Deviation 15546.4804
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 1 C3D1	-859.021 pg/mL Standard Deviation 9994.6711	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 1 V98	8107.400 pg/mL Standard Deviation 17740.0516	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 C1D15	-1462.552 pg/mL Standard Deviation 1541.8074	-2154.269 pg/mL Standard Deviation 3560.0029
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 C2D1	-1225.462 pg/mL Standard Deviation 1872.5841	-1884.439 pg/mL Standard Deviation 2357.1979
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 C3D1	-1255.485 pg/mL Standard Deviation 1738.0891	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Angiopoietin 2 V98	-1374.183 pg/mL Standard Deviation 1158.2897	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood CD40 Ligand C1D15	-24020.778 pg/mL Standard Deviation 62788.2464	-4678.661 pg/mL Standard Deviation 41191.7303
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood CD40 Ligand C2D1	-22957.613 pg/mL Standard Deviation 73677.4378	-7254.754 pg/mL Standard Deviation 37794.5541
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood CD40 Ligand C3D1	-16700.900 pg/mL Standard Deviation 48016.0710	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood CD40 Ligand V98	2192.177 pg/mL Standard Deviation 86909.9688	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 2 C1D15	-46.493 pg/mL Standard Deviation 101.0772	-0.516 pg/mL Standard Deviation 219.9787
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 2 C2D1	-39.636 pg/mL Standard Deviation 125.0664	-29.803 pg/mL Standard Deviation 121.1705
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 2 C3D1	-37.600 pg/mL Standard Deviation 113.8543	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 2 V98	-2.230 pg/mL Standard Deviation 191.4129	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 59 C1D15	-37.07 pg/mL Standard Deviation 81.051	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 59 C2D1	-31.58 pg/mL Standard Deviation 96.200	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 59 C3D1	-24.49 pg/mL Standard Deviation 93.102	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 59 V98	10.17 pg/mL Standard Deviation 137.755	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 80 C1D15	—	-31.519 pg/mL Standard Deviation 126.2579
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood EGF 80 C2D1	—	-32.171 pg/mL Standard Deviation 121.7805
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Eotaxin-4 C2D1	99.974 pg/mL Standard Deviation 207.0243	60.919 pg/mL Standard Deviation 114.6134
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 2 C2D1	-8.085 pg/mL Standard Deviation 48.8273	-8.003 pg/mL Standard Deviation 144.9054
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 2 C3D1	7.443 pg/mL Standard Deviation 45.7310	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 2 V98	-3.917 pg/mL Standard Deviation 62.3623	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 23 C1D15	6.549 pg/mL Standard Deviation 22.5297	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 23 C2D1	6.496 pg/mL Standard Deviation 27.2305	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 23 C3D1	6.691 pg/mL Standard Deviation 24.5203	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 23 V98	13.430 pg/mL Standard Deviation 36.7130	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 4 C1D15	-24.226 pg/mL Standard Deviation 100.6823	50.369 pg/mL Standard Deviation 253.9626
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 4 C2D1	-15.491 pg/mL Standard Deviation 104.9991	55.785 pg/mL Standard Deviation 264.4585
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 4 C3D1	5.283 pg/mL Standard Deviation 130.3452	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF 4 V98	33.860 pg/mL Standard Deviation 185.4616	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF Basic Form C1D15	-0.597 pg/mL Standard Deviation 18.6851	43.457 pg/mL Standard Deviation 224.9856
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF Basic Form C2D1	-1.212 pg/mL Standard Deviation 38.4131	64.237 pg/mL Standard Deviation 328.6676
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF Basic Form C3D1	2.060 pg/mL Standard Deviation 29.2405	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood FGF Basic Form V98	18.384 pg/mL Standard Deviation 28.6214	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Flt3l C1D15	-0.037 pg/mL Standard Deviation 32.5371	-8.877 pg/mL Standard Deviation 23.0368
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Flt3l C2D1	5.135 pg/mL Standard Deviation 28.0359	-1.362 pg/mL Standard Deviation 39.2251
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Flt3l C3D1	5.439 pg/mL Standard Deviation 24.1985	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Flt3l V98	13.367 pg/mL Standard Deviation 17.7279	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Fractalkine C1D15	-11.700 pg/mL Standard Deviation 94.5115	38.670 pg/mL Standard Deviation 237.5045
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Fractalkine C2D1	-1.175 pg/mL Standard Deviation 70.0858	4.663 pg/mL Standard Deviation 58.1950
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Fractalkine C3D1	-5.588 pg/mL Standard Deviation 116.3955	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Fractalkine V98	15.838 pg/mL Standard Deviation 90.6004	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood G-CSF C1D15	4.329 pg/mL Standard Deviation 20.8343	6.368 pg/mL Standard Deviation 61.7181
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood G-CSF C2D1	7.366 pg/mL Standard Deviation 32.5552	12.601 pg/mL Standard Deviation 72.5113
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood G-CSF C3D1	11.292 pg/mL Standard Deviation 24.1828	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood G-CSF V98	34.653 pg/mL Standard Deviation 101.7055	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood GM-CSF C1D15	0.767 pg/mL Standard Deviation 16.9314	44.665 pg/mL Standard Deviation 220.9124
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood GM-CSF C2D1	4.371 pg/mL Standard Deviation 38.3355	139.491 pg/mL Standard Deviation 725.0903
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood GM-CSF C3D1	10.036 pg/mL Standard Deviation 49.8538	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood GM-CSF V98	-1.495 pg/mL Standard Deviation 5.1831	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Growth Regulated Oncogene C1D15	—	-141.838 pg/mL Standard Deviation 410.3579
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Growth Regulated Oncogene C2D1	—	-120.148 pg/mL Standard Deviation 456.3073
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Hepatocyte Growth Factor C1D15	102.527 pg/mL Standard Deviation 1309.4077	-91.790 pg/mL Standard Deviation 781.2225
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Hepatocyte Growth Factor C2D1	-126.667 pg/mL Standard Deviation 693.2257	-147.796 pg/mL Standard Deviation 411.1836
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Hepatocyte Growth Factor C3D1	61.257 pg/mL Standard Deviation 1062.3266	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Hepatocyte Growth Factor V98	404.700 pg/mL Standard Deviation 456.8130	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interferon Gamma C1D15	4.072 pg/mL Standard Deviation 19.3994	33.743 pg/mL Standard Deviation 100.3678
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interferon Gamma C2D1	-0.392 pg/mL Standard Deviation 14.8083	-10.164 pg/mL Standard Deviation 170.9869
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interferon Gamma C3D1	2.986 pg/mL Standard Deviation 5.7591	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interferon Gamma V98	2.455 pg/mL Standard Deviation 5.2255	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 1 alpha C1D15	0.159 pg/mL Standard Deviation 7.9441	67.203 pg/mL Standard Deviation 200.9806
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 1 alpha C2D1	0.226 pg/mL Standard Deviation 8.2728	-36.352 pg/mL Standard Deviation 198.1416
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 1 alpha C3D1	-0.140 pg/mL Standard Deviation 13.7136	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 1 Beta C1D15	0.279 pg/mL Standard Deviation 1.9668	59.768 pg/mL Standard Deviation 137.6657
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 1 Beta C2D1	1.198 pg/mL Standard Deviation 5.0044	27.690 pg/mL Standard Deviation 61.2456
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 1 Beta C3D1	1.882 pg/mL Standard Deviation 11.1737	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood IL-1RA C1D15	14.490 pg/mL Standard Deviation 63.5869	46.381 pg/mL Standard Deviation 132.3985
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood IL-1RA C2D1	20.295 pg/mL Standard Deviation 61.9799	38.131 pg/mL Standard Deviation 142.7521
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood IL-1RA C3D1	7.048 pg/mL Standard Deviation 30.9383	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood IL-1RA V98	84.614 pg/mL Standard Deviation 178.1590	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 12 (p40) C1D15	14.514 pg/mL Standard Deviation 73.9806	5.458 pg/mL Standard Deviation 28.8514
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 12 (p40) C2D1	16.052 pg/mL Standard Deviation 40.3849	918.03 pg/mL Standard Deviation 3917.8689
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 12 (p40) C3D1	11.183 pg/mL Standard Deviation 36.3506	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 12 (p40) V98	-8.130 pg/mL Standard Deviation 5.7276	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 12 (p70) C1D15	1.241 pg/mL Standard Deviation 18.8429	27.919 pg/mL Standard Deviation 62.8944
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 12 (p70) C2D1	-5.622 pg/mL Standard Deviation 28.6381	7.820 pg/mL Standard Deviation 71.1505
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 12 (p70) C3D1	-6.099 pg/mL Standard Deviation 19.5015	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 12 (p70) V98	11.275 pg/mL Standard Deviation 20.0182	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 10 C1D15	-5.170 pg/mL Standard Deviation 38.0092	-7.611 pg/mL Standard Deviation 22.1926
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 10 C2D1	-1.901 pg/mL Standard Deviation 33.6203	1.687 pg/mL Standard Deviation 72.7629
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 10 C3D1	4.136 pg/mL Standard Deviation 10.8185	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 10 V98	-28.065 pg/mL Standard Deviation 41.7547	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 13 C1D15	0.961 pg/mL Standard Deviation 5.0066	8.574 pg/mL Standard Deviation 13.4754
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 13 C2D1	2.451 pg/mL Standard Deviation 7.6374	8.536 pg/mL Standard Deviation 18.5220
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 13 C3D1	5.404 pg/mL Standard Deviation 16.4719	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 15 C1D15	0.128 pg/mL Standard Deviation 2.2957	85.619 pg/mL Standard Deviation 234.7106
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 15 C2D1	1.403 pg/mL Standard Deviation 4.1630	574.776 pg/mL Standard Deviation 1709.9272
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 15 C3D1	-0.178 pg/mL Standard Deviation 3.6993	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 15 V98	3.930 pg/mL Standard Deviation NA Standard deviation could not be calculated since only 1 participant was available for analysis.	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 17 C1D15	3.434 pg/mL Standard Deviation 8.6463	4.567 pg/mL Standard Deviation 12.1008
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 17 C2D1	1.264 pg/mL Standard Deviation 8.0963	3.035 pg/mL Standard Deviation 15.8736
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 17 C3D1	0.011 pg/mL Standard Deviation 3.4100	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 17 V98	8.440 pg/mL Standard Deviation 11.7663	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 2 C1D15	-1.004 pg/mL Standard Deviation 7.1024	173.878 pg/mL Standard Deviation 397.2754
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 2 C2D1	5.853 pg/mL Standard Deviation 20.3294	191.410 pg/mL Standard Deviation 461.1991
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 2 C3D1	2.647 pg/mL Standard Deviation 19.5979	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 4 C1D15	8.169 pg/mL Standard Deviation 30.0305	12.815 pg/mL Standard Deviation 77.4310
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 4 C2D1	20.167 pg/mL Standard Deviation 77.0619	7.815 pg/mL Standard Deviation 54.5735
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 4 C3D1	6.583 pg/mL Standard Deviation 20.3824	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 5 C1D15	0.311 pg/mL Standard Deviation 1.1314	6.088 pg/mL Standard Deviation 7.5239
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 5 C2D1	0.205 pg/mL Standard Deviation 1.5931	11.382 pg/mL Standard Deviation 9.8663
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 5 C3D1	-0.327 pg/mL Standard Deviation 1.1102	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 6 C1D15	0.166 pg/mL Standard Deviation 6.8774	3.784 pg/mL Standard Deviation 30.0715
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 6 C2D1	4.778 pg/mL Standard Deviation 34.0254	5.524 pg/mL Standard Deviation 32.1205
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 6 C3D1	2.027 pg/mL Standard Deviation 7.3121	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 6 V98	3.160 pg/mL Standard Deviation 6.6276	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 7 C1D15	1.267 pg/mL Standard Deviation 7.3732	2.167 pg/mL Standard Deviation 8.8122
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 7 C2D1	2.413 pg/mL Standard Deviation 8.8367	5.744 pg/mL Standard Deviation 18.4339
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 7 C3D1	0.616 pg/mL Standard Deviation 5.0590	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 7 V98	20.760 pg/mL Standard Deviation 28.0439	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 8 C1D15	-5.801 pg/mL Standard Deviation 46.1572	-20.769 pg/mL Standard Deviation 52.1135
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 8 C2D1	-5.431 pg/mL Standard Deviation 43.4197	-14.303 pg/mL Standard Deviation 57.9561
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 8 C3D1	-7.348 pg/mL Standard Deviation 43.0509	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Interleukin 8 V98	26.982 pg/mL Standard Deviation 32.7795	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood IFN gamma Induced Protein 10 C1D15	453.684 pg/mL Standard Deviation 1446.5825	184.891 pg/mL Standard Deviation 501.5782
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood IFN gamma Induced Protein 10 C2D1	246.194 pg/mL Standard Deviation 246.194	306.075 pg/mL Standard Deviation 792.5621
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood IFN gamma Induced Protein 10 C3D1	201.923 pg/mL Standard Deviation 483.5088	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood IFN gamma Induced Protein 10 V98	359.872 pg/mL Standard Deviation 501.1082	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Monocyte Chemotactic Protein 1 C1D15	0.733 pg/mL Standard Deviation 423.2721	-101.580 pg/mL Standard Deviation 371.5381
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Monocyte Chemotactic Protein 1 C2D1	-19.036 pg/mL Standard Deviation 372.5242	128.749 pg/mL Standard Deviation 541.1034
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Monocyte Chemotactic Protein 1 C3D1	13.542 pg/mL Standard Deviation 370.3700	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Monocyte Chemotactic Protein 1 V98	-128.627 pg/mL Standard Deviation 1234.5888	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood MIP 1 alpha C1D15	-1.842 pg/mL Standard Deviation 11.9129	-0.320 pg/mL Standard Deviation 38.5273
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood MIP 1 alpha C2D1	-2.098 pg/mL Standard Deviation 12.0121	-0.473 pg/mL Standard Deviation 35.4447
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood MIP 1 alpha C3D1	-1.167 pg/mL Standard Deviation 15.9038	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood MIP 1 alpha V98	7.563 pg/mL Standard Deviation 7.8802	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood MIP 1 beta C1D15	0.032 pg/mL Standard Deviation 20.1490	5.746 pg/mL Standard Deviation 64.1386
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood MIP 1 beta C2D1	-1.198 pg/mL Standard Deviation 31.4522	31.277 pg/mL Standard Deviation 261.3460
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood MIP 1 beta C3D1	1.850 pg/mL Standard Deviation 15.208	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood MIP 1 beta V98	7.518 pg/mL Standard Deviation 11.9566	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF AA 31 P1 C1D15	—	-183.36 pg/mL Standard Deviation 2260.110
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF AA 31 P1 C2D1	—	-268.83 pg/mL Standard Deviation 2054.666
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF AB C1D15	-36.637 pg/mL Standard Deviation 353.6898	-121.278 pg/mL Standard Deviation 325.1308
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF AB C2D1	-99.852 pg/mL Standard Deviation 338.5816	-80.778 pg/mL Standard Deviation 363.1249
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF AB C3D1	-7.702 pg/mL Standard Deviation 311.6834	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF AB V98	130.800 pg/mL Standard Deviation 382.6282	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF BB C1D15	-120.317 pg/mL Standard Deviation 1758.7655	-567.664 pg/mL Standard Deviation 1385.6740
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF BB C2D1	-435.311 pg/mL Standard Deviation 1961.7449	-371.888 pg/mL Standard Deviation 1186.1
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF BB C3D1	333.637 pg/mL Standard Deviation 1516.1506	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood PDGF BB V98	174.083 pg/mL Standard Deviation 3221.9009	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Placental Derived Growth Factor C1D15	55.444 pg/mL Standard Deviation 55.0671	55.0671 pg/mL Standard Deviation 29.8457
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Placental Derived Growth Factor C2D1	50.439 pg/mL Standard Deviation 58.2571	51.359 pg/mL Standard Deviation 76.6390
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Placental Derived Growth Factor C3D1	61.080 pg/mL Standard Deviation 58.2969	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Placental Derived Growth Factor V98	112.683 pg/mL Standard Deviation 110.3416	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Chemokine Ligand 5 C1D15	—	-2373.94 pg/mL Standard Deviation 46225.695
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Chemokine Ligand 5 C2D1	—	551.64 pg/mL Standard Deviation 49492.450
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood SDF 1 alpha C1D15	441.305 pg/mL Standard Deviation 385.8988	506.768 pg/mL Standard Deviation 487.7603
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood SDF 1 alpha C2D1	520.051 pg/mL Standard Deviation 510.8558	647.435 pg/mL Standard Deviation 470.0962
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood SDF 1 alpha C3D1	509.483 pg/mL Standard Deviation 550.4383	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood SDF 1 alpha V98	836.532 pg/mL Standard Deviation 686.4434	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Soluble IL2 Receptor alpha C1D15	-25.869 pg/mL Standard Deviation 86.0991	-414.669 pg/mL Standard Deviation 765.1544
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Soluble IL2 Receptor alpha C2D1	-13.695 pg/mL Standard Deviation 65.5643	-290.918 pg/mL Standard Deviation 1023.3392
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Soluble IL2 Receptor alpha C3D1	-12.233 pg/mL Standard Deviation 31.5415	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Soluble IL2 Receptor alpha V98	-19.238 pg/mL Standard Deviation 43.0942	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood TGF alpha C1D15	-0.874 pg/mL Standard Deviation 4.6605	21.148 pg/mL Standard Deviation 168.7766
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood TGF alpha C2D1	-0.350 pg/mL Standard Deviation 6.5375	-6.019 pg/mL Standard Deviation 24.3258
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood TGF alpha C3D1	1.165 pg/mL Standard Deviation 11.8825	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood TGF alpha V98	2.590 pg/mL Standard Deviation 3.4672	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Tie-2 C1D15	-2971.948 pg/mL Standard Deviation 2397.5234	-3573.856 pg/mL Standard Deviation 2996.7139
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Tie-2 C2D1	-3447.692 pg/mL Standard Deviation 3577.1791	-4088.214 pg/mL Standard Deviation 3191.9812
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Tie-2 C3D1	-2811.765 pg/mL Standard Deviation 3459.1934	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood Tie-2 V98	-1924.000 pg/mL Standard Deviation 3215.5684	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood TNF alpha C1D15	-0.233 pg/mL Standard Deviation 4.9747	1.451 pg/mL Standard Deviation 24.8216
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood TNF alpha C2D1	0.039 pg/mL Standard Deviation 3.9540	1.741 pg/mL Standard Deviation 15.0677
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood TNF alpha C3D1	0.614 pg/mL Standard Deviation 4.6336	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood TNF alpha V98	3.027 pg/mL Standard Deviation 4.7343	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF C1D15	-13.294 pg/mL Standard Deviation 112.6871	10.709 pg/mL Standard Deviation 285.2533
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF C2D1	-11.523 pg/mL Standard Deviation 122.6064	-26.215 pg/mL Standard Deviation 239.4960
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF C3D1	16.732 pg/mL Standard Deviation 160.3096	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF V98	155.638 pg/mL Standard Deviation 352.8309	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF A C1D15	78.868 pg/mL Standard Deviation 174.8011	92.748 pg/mL Standard Deviation 273.6190
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF A C2D1	76.041 pg/mL Standard Deviation 194.1394	140.664 pg/mL Standard Deviation 336.9135
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF A C3D1	116.800 pg/mL Standard Deviation 233.1657	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF A V98	465.833 pg/mL Standard Deviation 515.7676	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF D C1D15	0.953 pg/mL Standard Deviation 87.6513	3.404 pg/mL Standard Deviation 42.7585
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF D C2D1	-9.776 pg/mL Standard Deviation 98.0905	11.043 pg/mL Standard Deviation 116.5445
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF D C3D1	9.894 pg/mL Standard Deviation 57.1140	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF D V98	-21.317 pg/mL Standard Deviation 88.6689	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 1 C1D15	593.613 pg/mL Standard Deviation 3109.3343	-221.867 pg/mL Standard Deviation 799.9202
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 1 C2D1	-3.971 pg/mL Standard Deviation 739.7875	-243.661 pg/mL Standard Deviation 1031.2376
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 1 C3D1	-209.863 pg/mL Standard Deviation 809.7744	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 1 V98	-15.567 pg/mL Standard Deviation 90.6274	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 2 C1D15	-10110.096 pg/mL Standard Deviation 5626.0125	-8842.040 pg/mL Standard Deviation 6078.7151
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 2 C2D1	-9369.165 pg/mL Standard Deviation 17982.0625	-10676.563 pg/mL Standard Deviation 7064.0825
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 2 C3D1	-11389.576 pg/mL Standard Deviation 10955.1596	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 2 V98	-9021.217 pg/mL Standard Deviation 5921.9619	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 3 C1D15	-1174.650 pg/mL Standard Deviation 2226.7893	-2251.867 pg/mL Standard Deviation 3231.1485
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 3 C3D1	-1488.140 pg/mL Standard Deviation 3687.8774	—
Change From Baseline in the Concentration of Clinical Biomarkers in Whole Blood VEGF Rec 3 V98	-1201.680 pg/mL Standard Deviation 2441.5741	—

SECONDARY outcome

Timeframe: Predose and 2 to 12 hours postdose at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), and Cycle 2 Day 1 (C2D1)

Population: The PK analysis set was used for analysis and included all participants who received at least one dose of lenvatinib and had at least one quantifiable lenvatinib concentration. Number analyzed (n) signifies participants who were evaluable at specific time points for this outcome measure.

Blood samples for the quantification of lenvatinib in plasma were obtained and processed using a standardized protocol. The lower limit of quantification was 0.25 ng/mL. Pharmacokinetic (PK) analysis was conducted using nonlinear mixed effects modeling. Descriptive statistics were used to summarize lenvatinib plasma concentration data.

Outcome measures

Measure	Cohort 1 (V600E BRAF Negative) n=93 Participants Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 Participants Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Summary of Plasma Concentration of Lenvatinib C1D1 Pre-dose	0 ng/mL Standard Deviation 0	0 ng/mL Standard Deviation 0
Summary of Plasma Concentration of Lenvatinib C1D1 Post-dose	229.6 ng/mL Standard Deviation 148.98	287.6 ng/mL Standard Deviation 168.97
Summary of Plasma Concentration of Lenvatinib C1D15 Pre-dose	56.8 ng/mL Standard Deviation 82	71.9 ng/mL Standard Deviation 104.09
Summary of Plasma Concentration of Lenvatinib C1D15 Post-dose	284.0 ng/mL Standard Deviation 141.71	332.1 ng/mL Standard Deviation 221.98
Summary of Plasma Concentration of Lenvatinib C2D1 Pre-dose	38.7 ng/mL Standard Deviation 32.94	52.0 ng/mL Standard Deviation 48.73
Summary of Plasma Concentration of Lenvatinib C2D1 Post-dose	244.5 ng/mL Standard Deviation 182.67	270.4 ng/mL Standard Deviation 143.64

Adverse Events

Cohort 1 (V600E BRAF Negative)

Serious events: 39 serious events

Other events: 93 other events

Deaths: 0 deaths

Cohort 2 (V600E BRAF Positive)

Serious events: 36 serious events

Other events: 88 other events

Deaths: 0 deaths

Serious adverse events

Measure	Cohort 1 (V600E BRAF Negative) n=93 participants at risk Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 participants at risk Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
General disorders Fatigue	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders General physical health deterioration	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Blood and lymphatic system disorders Anaemia	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Endocrine disorders Hypothyroidism	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Impaired healing	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Pain	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Injury, poisoning and procedural complications Chemical peritonitis	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Vascular disorders Hypertension	5.4% 5/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Vascular disorders Deep vein thrombosis	3.2% 3/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Vascular disorders Aortic aneurysm	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Vascular disorders Hypertensive crisis	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Vascular disorders Hypotension	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Nausea	3.2% 3/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	3.4% 3/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Pancreatitis	2.2% 2/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Vomiting	2.2% 2/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Abdominal pain	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	3.4% 3/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Abdominal pain upper	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Colitis	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Oesophageal spasm	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Rectal perforation	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Constipation	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Diarrhoea	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Enterocolitis	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Intestinal perforation	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Pneumonia	2.2% 2/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Appendicitis	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Catheter site infection	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Incision site infection	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Oral herpes	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Pelvic abscess	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Urinary tract infection	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Cellulitis	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Infection	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Peritonitis	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Sepsis	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Septic shock	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Upper respiratory tract infection	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Wound infection	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Cerebrovascular accident	2.2% 2/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Hypoaesthesia	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Somnolence	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Syncope	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Cranial nerve palsies multiple	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Haemorrhage intracranial	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Headache	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Presyncope	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Spinal cord compression	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Renal and urinary disorders Renal failure	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Renal and urinary disorders Renal failure acute	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Renal and urinary disorders Urethral obstruction	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Renal and urinary disorders Urinary retention	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Cardiac disorders Atrial thrombosis	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Cardiac disorders Cardiac failure congestive	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Cardiac disorders Supraventricular tachycardia	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Cardiac disorders Atrioventricular block second degree	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Cardiac disorders Myocardial infarction	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Cardiac disorders Pericardial effusion	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Back pain	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Myopathy	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Pain in extremity	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Groin pain	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Infected neoplasm	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic pain	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Psychiatric disorders Mental status changes	2.2% 2/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Psychiatric disorders Confusional state	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.2% 3/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Hepatobiliary disorders Cholelithiasis	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Hepatobiliary disorders Gallbladder perforation	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Hepatobiliary disorders Cholecystitis	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Hepatobiliary disorders Hepatic failure	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Ejection fraction decreased	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Lipase increased	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Weight decreased	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Metabolism and nutrition disorders Hyponatraemia	2.2% 2/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Metabolism and nutrition disorders Dehydration	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Metabolism and nutrition disorders Failure to thrive	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Metabolism and nutrition disorders Hyperuricaemia	0.00% 0/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Skin and subcutaneous tissue disorders Angioedema	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Skin and subcutaneous tissue disorders Dermatitis bullous	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Pyrexia	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.

Other adverse events

Measure	Cohort 1 (V600E BRAF Negative) n=93 participants at risk Cohort 1 (V600E BRAF negative) enrolled participants not harboring the V600E BRAF mutation with disease progression following up to 2 prior systemic anticancer regimens (excluding anti-VEGF) for unresectable Stage III or Stage IV melanoma. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.	Cohort 2 (V600E BRAF Positive) n=89 participants at risk Cohort 2 (V600E BRAF positive) enrolled participants harboring the activating BRAF mutations (mainly the V600E mutation) with disease progression following BRAF V600E-targeted therapy. Participants received lenvatinib 24 mg orally, once daily continuously in 28-day cycles.
Blood and lymphatic system disorders Anaemia	5.4% 5/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	6.7% 6/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Blood and lymphatic system disorders Thrombocytopenia	8.6% 8/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	10.1% 9/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Endocrine disorders Hypothyroidism	18.3% 17/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	27.0% 24/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Abdominal pain	22.6% 21/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	21.3% 19/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Abdominal pain upper	11.8% 11/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	6.7% 6/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Constipation	26.9% 25/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	31.5% 28/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Diarrhoea	47.3% 44/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	29.2% 26/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Dry mouth	15.1% 14/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	11.2% 10/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Dyspepsia	5.4% 5/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	10.1% 9/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Flatulence	12.9% 12/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Gastrooesophageal reflux disease	10.8% 10/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	6.7% 6/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Glossodynia	6.5% 6/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Nausea	51.6% 48/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	40.4% 36/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Oral pain	10.8% 10/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Stomatitis	17.2% 16/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	13.5% 12/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Gastrointestinal disorders Vomiting	38.7% 36/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	36.0% 32/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Asthenia	6.5% 6/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Chills	6.5% 6/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	4.5% 4/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Fatigue	66.7% 62/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	46.1% 41/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Oedema peripheral	15.1% 14/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	11.2% 10/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Pain	6.5% 6/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
General disorders Pyrexia	7.5% 7/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	11.2% 10/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Oral herpes	5.4% 5/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	0.00% 0/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Upper respiratory tract infection	5.4% 5/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	4.5% 4/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Infections and infestations Urinary tract infection	10.8% 10/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	10.1% 9/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Aspartate aminotransferase increased	3.2% 3/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Blood alkaline phosphatase increased	7.5% 7/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	3.4% 3/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Blood thyroid stimulating hormone increased	15.1% 14/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	7.9% 7/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Gamma-glutamyltransferase increased	5.4% 5/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Lipase increased	7.5% 7/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	3.4% 3/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Investigations Weight decreased	23.7% 22/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	13.5% 12/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Metabolism and nutrition disorders Decreased appetite	43.0% 40/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	33.7% 30/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Metabolism and nutrition disorders Dehydration	6.5% 6/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	13.5% 12/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Metabolism and nutrition disorders Hypokalaemia	6.5% 6/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Metabolism and nutrition disorders Hyponatraemia	8.6% 8/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	4.5% 4/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Arthralgia	31.2% 29/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	22.5% 20/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Back pain	18.3% 17/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	13.5% 12/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Muscle spasms	7.5% 7/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Muscular weakness	8.6% 8/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	3.4% 3/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	3.2% 3/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	6.7% 6/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	6.5% 6/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	6.7% 6/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	7.5% 7/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	4.5% 4/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Myalgia	14.0% 13/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	10.1% 9/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Musculoskeletal and connective tissue disorders Pain in extremity	17.2% 16/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	10.1% 9/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Dizziness	10.8% 10/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	18.0% 16/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Dysgeusia	12.9% 12/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	18.0% 16/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Headache	31.2% 29/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	23.6% 21/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Lethargy	1.1% 1/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Nervous system disorders Peripheral sensory neuropathy	10.8% 10/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	2.2% 2/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Psychiatric disorders Confusional state	2.2% 2/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Psychiatric disorders Depression	4.3% 4/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Psychiatric disorders Insomnia	7.5% 7/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	9.0% 8/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Renal and urinary disorders Haematuria	5.4% 5/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	3.4% 3/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Renal and urinary disorders Proteinuria	24.7% 23/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	19.1% 17/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Respiratory, thoracic and mediastinal disorders Cough	19.4% 18/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	12.4% 11/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Respiratory, thoracic and mediastinal disorders Dysphonia	28.0% 26/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	37.1% 33/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	15.1% 14/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	14.6% 13/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Respiratory, thoracic and mediastinal disorders Epistaxis	8.6% 8/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	9.0% 8/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	14.0% 13/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Skin and subcutaneous tissue disorders Dry skin	17.2% 16/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	7.9% 7/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Skin and subcutaneous tissue disorders Pruritus	7.5% 7/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Skin and subcutaneous tissue disorders Rash	17.2% 16/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	5.6% 5/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Vascular disorders Hot flush	5.4% 5/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	1.1% 1/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Vascular disorders Hypertension	57.0% 53/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	53.9% 48/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.
Vascular disorders Hypotension	4.3% 4/93 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.	6.7% 6/89 • From date of administration of first dose up to 30 days after the last dose, or up to data cutoff (15 Jan 2012 and 15 Apr 2013 for Cohort 1 and Cohort 2, respectively), up to approximately 33 months.

Additional Information

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