Clinical Trial Results:
An Open-Label, Single-Arm, Multicenter Phase 2 Study of E7080 [Lenvatinib] in Subjects with Advanced Endometrial Cancer and Disease Progression Following First-Line Chemotherapy
Summary
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EudraCT number |
2009-016858-41 |
Trial protocol |
HU BG BE |
Global end of trial date |
10 Oct 2015
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Results information
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Results version number |
v2(current) |
This version publication date |
06 Jan 2017
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First version publication date |
30 Oct 2016
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
E7080-G000-204
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT01111461 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Eisai
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Sponsor organisation address |
100 Tice Boulevard, Woodcliff Lake, United States,
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Public contact |
Eisai Call Center, Eisai Inc., 888 422-4743,
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Scientific contact |
Eisai Call Center, Eisai Inc., 888 422-4743,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 May 2012
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 May 2012
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Oct 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the objective response rate (ORR: complete response + partial response [CR+ PR]) of E7080 in subjects with unresectable endometrial cancer and disease progression following platinum-based, first-line chemotherapy.
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Protection of trial subjects |
This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following:
- Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008)
- International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal
Products, Committee for Proprietary Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for Human Use
- Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312
- European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states.
- Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Mar 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 7
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Country: Number of subjects enrolled |
Romania: 9
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Country: Number of subjects enrolled |
Belgium: 10
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Country: Number of subjects enrolled |
Bulgaria: 5
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Russian Federation: 30
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Country: Number of subjects enrolled |
Ukraine: 10
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Country: Number of subjects enrolled |
United States: 58
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Worldwide total number of subjects |
133
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EEA total number of subjects |
35
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
81
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From 65 to 84 years |
52
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
Pre-assignment
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Screening details |
A total of 167 participants were screened for entry into the study. Of these 167 participants, 133 participants met inclusion/exclusion criteria and were treated with at least 1 dose of lenvatinib 24 mg. | ||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Arm title
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Lenvatinib | ||||||||||||||||||
Arm description |
Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Lenvatinib
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Investigational medicinal product code |
E7080
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Other name |
Lenvima
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Lenvatinib hard capsules, 24 mg (two 10-mg capsules and one 4-mg capsule) were self-administered orally once a day in the morning (without regard to food intake) in 28-day cycles. Dose reduction or interruption was allowed for participants who experienced lenvatinib-related toxicity.
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Baseline characteristics reporting groups
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Reporting group title |
Lenvatinib
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Reporting group description |
Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Lenvatinib
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Reporting group description |
Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles | ||
Subject analysis set title |
Prior Platinum-based Chemotherapy Regimen
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
80 participants previously received carboplatin, 47 participants previously received cisplatin, 4 participants previously received cisplatin with doxorubicin, and 10 participants previously received Taxol (paclitaxel) with carboplatin. Participants could have received more than one prior platinum-based chemotherapy regimen.
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End point title |
Objective Response Rate (ORR) [1] | ||||||||
End point description |
ORR was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans, as determined by independent radiologic review. BOR of CR was confirmed by a subsequent CR assessment at least 4 weeks later. BOR of PR was confirmed by a subsequent CR or PR assessment at least 4 weeks later. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. The null hypothesis ORR was ≤10% was tested using 1-sided exact test of a single proportion, at 1-sided 0.05 level. ORR was presented with corresponding 2-sided, 95% confidence interval (CI). ORR=CR+PR
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End point type |
Primary
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End point timeframe |
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)
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The null hypothesis that ORR (CR + PR) was ≤10% was tested using the 1-sided exact test of a single proportion, at the 1-sided 0.05 level. ORR (CR + PR) was presented with corresponding 2- sided, 95% confidence interval (CI). |
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Notes [2] - Full Analysis Set (ITT population)-all participants who received at least 1 dose of lenvatinib. |
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No statistical analyses for this end point |
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End point title |
Progression Free Survival (PFS) | ||||||||||||
End point description |
PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death (whichever occurred first), as determined by independent radiologic review (IRR) and Investigator based on RECIST 1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.
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End point type |
Secondary
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End point timeframe |
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)
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Notes [3] - Full Analysis Set (ITT population)-all participants who received at least 1 dose of lenvatinib. |
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No statistical analyses for this end point |
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End point title |
Overall Survival (OS) | ||||||||
End point description |
OS was the length time in months from the date of first treatment until the date of death from any cause. If death was not observed, OS was censored at the last known alive date or data cut-off. Additional survival follow-up data was collected for all participants who had not withdrawn consent and were alive at the time of the initial survival follow-up as of 26 Nov 2012 data cut-off. Participants who were lost to follow-up at the time of the initial assessment may have been contacted again at the investigator's discretion. Updated survival (based on 26 Nov 2012 cut-off) was derived for these participants if the contact was made successfully.
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End point type |
Secondary
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End point timeframe |
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)
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Notes [4] - Full Analysis Set (ITT population)-all participants who received at least 1 dose of lenvatinib. |
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No statistical analyses for this end point |
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End point title |
Disease Control Rate (DCR) | ||||||||||||
End point description |
DCR was defined as the percentage of participants with BOR of CR or PR or stable disease (SD) based on RECIST 1.1 and SD lasting greater than or equal to 7 weeks, as determined by IRR and Investigator.
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End point type |
Secondary
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End point timeframe |
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)
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Notes [5] - Full Analysis Set (ITT population)-all participants who received at least 1 dose of lenvatinib. |
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No statistical analyses for this end point |
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End point title |
Clinical Benefit Rate (CBR) | ||||||||||||
End point description |
CBR was defined as the percentage of participants with BOR of CR or PR or durable stable disease (dSD) [CR + PR + dSD] based on RECIST 1.1. The dSD rate was defined as the percentage of participants with dSD (based on RECIST 1.1 and defined as SD lasting greater than or equal to 23 weeks), as determined by the IRR and Investigator.
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End point type |
Secondary
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End point timeframe |
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)
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Notes [6] - Full Analysis Set (ITT population)-all participants who received at least 1 dose of lenvatinib. |
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No statistical analyses for this end point |
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End point title |
Number of Participants with Adverse events (AEs) /Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | ||||||||||||
End point description |
Safety was assessed by monitoring and recording all AEs and SAEs, regular monitoring of hematology, clinical chemistry, and urine values, regular measurement of vital signs, electrocardiograms (ECGs), and echocardiograms.
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End point type |
Secondary
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End point timeframe |
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.
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No statistical analyses for this end point |
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End point title |
Summary of Plasma Concentration of Lenvatinib | ||||||||||||||||||||
End point description |
A total of 6 blood samples for pharmacokinetic (PK) analysis were collected from each participant who received lenvatinib once daily.
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End point type |
Other pre-specified
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End point timeframe |
Predose and 2 hours postdose on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1
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No statistical analyses for this end point |
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End point title |
Percentage Change from Baseline for the Imaging Biomarker Parameter of the Area Under the Plasma Concentration Curve Blood Normalized (90) (AUCBN (90)) Median for Total Volume | ||||||||
End point description |
The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of 2 dynamic contrast-enhanced magnetic resonance imaging/diffusion-weighted magnetic resonance imaging (DCE-MRI/DWI MRI) scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included percentage change in initial area under the gadolinium contrast agent time-concentration curve (first 90 seconds, blood normalized) from baseline. 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.
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End point type |
Other pre-specified
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End point timeframe |
Cycle 1 Day 5
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No statistical analyses for this end point |
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End point title |
Percentage Change from Baseline in the Contrast Volume Transfer Coefficient (Ktrans) Median | ||||||||
End point description |
The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of two DCE-MRI/DWI MRI scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included the percentage change in Ktrans for gadolinium chelate movement from the vasculature into the tissue extracellular space from baseline. 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.
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End point type |
Other pre-specified
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End point timeframe |
Cycle 1 Day 5
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No statistical analyses for this end point |
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End point title |
Percentage Change from Baseline in the Apparent Diffusion Coefficient (ADC) Median | ||||||||
End point description |
The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of two DCE-MRI/DWI MRI scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included the percentage change in ADC for gadolinium chelate movement from the vasculature into the tissue extracellular space from baseline. 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.
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End point type |
Other pre-specified
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End point timeframe |
Cycle 1 Day 5
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From date of administration of first dose up to 30 days after the last dose, or up to data cut-off (21 May 2012), or up to approximately 26 months.
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Adverse event reporting additional description |
Treatment-emergent adverse events (TEAEs) and serious TEAEs were collected and reported. Safety analysis set included all participants who received at least one dose of study drug. AEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
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Reporting groups
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Reporting group title |
Lenvatinib
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Reporting group description |
Lenvatinib 24 mg was administered orally, once daily continuously in 28-day cycles | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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16 Apr 2010 |
Amendment 01:
1) Addition of DWI-MRI-based metrics; originally protocols included only DCE-MRI-based metrics.
2) Updated inclusion criterion with regards to baseline blood pressures and renal function to be consistent with other lenvatinib Phase 2 protocols.
3) Clarified that only Grade 2 toxicities judged to be intolerable required a dose adjustment and that the dose adjustment for intolerable Grade 2 toxicities was the same as for Grade 3.
4) Updated management of hypertension and proteinuria to be consistent with lenvatinib Phase 2 program.
5) Added pharmacogenomics as an exploratory endpoint.
6) Added clarification that the analysis of the primary endpoint (ORR) would be based on IRR.
7) Clarified the number of subjects required for the ITT analysis (130) based on Simon’s Optimal 2-Stage Design.
8) Permitted skeletal x-ray for documenting tumor progression.
9) Stipulated that progressive disease should not be recorded as an AE and that the severity of each AE should be assessed using CTCAE.
10) Expanded the window for screening/baseline tumor assessments.
11) Updated the FIGO staging classification for endometrial carcinoma.
Rationale: To provide clarification and to be consistent with other Phase 2 studies in the lenvatinib program. |
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11 Jul 2011 |
Amendment 02
1) Clarified treatment requirements after disease progression prior to study inclusion.
2) Clarified size of lesion to qualify as measurable disease.
3) Clarified that subjects with any malignancy (except for endometrial cancer, basal or squamous cell carcinoma of the skin, melanoma in situ, or carcinoma in situ of the cervix) would be excluded.
4) Allowed a 48-hour window to assess hematology and clinical chemistry results.
5) Clarified that blood pressure and heart rate were to be assessed immediately prior to echocardiogram.
6) Increased the number of sites.
Rationale: To provide clarification; the number of sites was updated throughout the revised protocol to reflect the actual number of sites that
were used. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |