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

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

Time frame: From the date of first administration of study treatment until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to the end of Cycle 6 (as of 21 May 2012 data cut-off)

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

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

Time frame: From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, or up to approximately 26 months (as of 21 May 2012 data cut-off)

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

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

Time frame: From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, or up to approximately 26 months (as of 21 May 2012 data cut-off)

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

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

Time frame: From the administration of first dose up to 30 days after the last dose, or up to data cut-off (21 May 2012), or up to approximately 26 months.

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

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

Time frame: From date of first administration of study treatment until the date of death, or up to approximately 32 months (as of 26 Nov 2012 data cut-off)

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

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

Time frame: From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression or up to approximately 26 months (as of 21 May 2012 data cut-off)

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

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

Time frame: Cycle 1 Day 5

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

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

Time frame: Cycle 1 Day 5

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

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

Time frame: Cycle 1 Day 5

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

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

Time frame: Predose and 2 hours postdose on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1

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