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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT00784303
Registration number
NCT00784303
Ethics application status
Date submitted
30/10/2008
Date registered
2/11/2008
Date last updated
22/04/2020
Titles & IDs
Public title
Evaluating the Safety and Efficacy of Oral Lenvatinib in Medullary and Iodine-131 Refractory, Unresectable Differentiated Thyroid Cancers, Stratified by Histology
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Scientific title
Phase II, Multicenter, Open-label, Single Arm Trial to Evaluate the Safety and Efficacy of Oral E7080 in Medullary and Iodine-131 Refractory, Unresectable Differentiated Thyroid Cancers, Stratified by Histology
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Secondary ID [1]
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E7080-G000-201
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Thyroid Cancer
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Condition category
Condition code
Cancer
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Thyroid
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Metabolic and Endocrine
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Other endocrine disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Lenvatinib (DTC Cohort)
Treatment: Drugs - Lenvatinib (MTC Cohort)
Experimental: DTC cohort - This arm will enroll participants with radioiodine (131 I)-refractory/resistant differentiated thyroid cancer.
Experimental: MTC cohort - This arm will enroll participants with medullary thyroid cancer.
Treatment: Drugs: Lenvatinib (DTC Cohort)
24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily, or 10 mg lenvatinib orally twice daily (20 mg total). Out of 58 participants in the DTC cohort, 56 participants received 24 mg lenvatinib once daily and 2 participants received 10 mg lenvatinib twice daily (total 20 mg daily), given continuously in 28-day treatment cycles.
Treatment: Drugs: Lenvatinib (MTC Cohort)
24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily given continuously in 28-day treatment cycles.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Objective Response Rate (ORR)
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Assessment method [1]
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ORR was the percentage of participants with best overall response (BOR) of complete response (CR) and partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 for target lesions using magnetic resonance imaging/computed tomography (MRI/CT) scans, as determined by independent imaging review (IIR). CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. ORR=CR+PR, was presented with 2-sided 95% confidence interval (CI) by the method of Clopper and Pearson.
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Timepoint [1]
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From date of treatment start until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice to stop study treatment, or up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
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Primary outcome [2]
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Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC)
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Assessment method [2]
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Up to 9 samples per participant were obtained at specific time points. Plasma concentrations of lenvatinib were analyzed using standard analysis methods. Due to the sparse PK sampling in this study, the data were pooled with data from other Phase 1 studies conducted in participants with solid tumors for PK model development and covariate analysis. Individual exposure (steady state AUC) to lenvatinib in MTC and DTC subjects in this study was derived based on the individual predicted steady state AUC from the final PK model. Only data for participants taking 24 mg lenvatinib daily were reported (participants taking 20 mg lenvatinib daily were not included in this data set).
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Timepoint [2]
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Cycle 1 Day 1 (predose and at 0.5 and 2 hours postdose), Cycle 1 Day 8 (predose), Cycle 2 Day 1 (predose and at 0.5 and 2 hours postdose), and Cycle 3 Day 1 (predose and at 2 hours postdose) (Cycle length= 28 days)
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Secondary outcome [1]
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Change From Baseline in Free Thyroxine (T4)
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Assessment method [1]
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Blood samples to measure free T4 were collected at Screening (Baseline), Cycle 1 Day 15 (MTC cohort), Day 1 of Cycles 2 to 20, and Final Visit. Changes in free T4 concentration values from baseline to specific time points were calculated. Only participants with both baseline and relevant visit values were included.
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Timepoint [1]
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Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 20, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
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Secondary outcome [2]
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Change From Baseline in Free Thyroid Stimulating Hormone (TSH)
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Assessment method [2]
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Blood samples to measure free TSH were collected at Screening (Baseline), Cycle 1 Day 15 (MTC cohort), Day 1 of Cycles 2 to 20, and Final Visit. Changes in free TSH concentration values from baseline to specific time points were calculated. Only participants with both baseline and relevant visit values were included. For any free TSH result that was reported as <0.008 mIU/L, 0.004 mIU/L was used for calculating summary statistics.
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Timepoint [2]
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Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 20, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
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Secondary outcome [3]
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Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only)
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Assessment method [3]
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Blood samples to obtain serum were collected at Cycle 1 Day 1 (Baseline), Day 1 of Cycles 2 to 19, Final Visit, and were analyzed for thyroglobulin concentration. Percent changes in thyroglobulin concentration values from baseline to specific time points were calculated. Only participants with both baseline and relevant visit values were included.
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Timepoint [3]
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Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 19, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
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Secondary outcome [4]
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Percent Change From Baseline in Concentrations of Calcitonin (MTC Only)
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Assessment method [4]
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Blood samples to obtain serum were collected at Cycle 1 Day 1(Baseline), Day 1 of Cycles 2 to 20, Final Visit, and were analyzed for calcitonin concentration. Percent changes in calcitonin concentration values from baseline to specific time points were calculated. Only participants with both baseline and relevant visit values were included.
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Timepoint [4]
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Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 20, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
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Secondary outcome [5]
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Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only)
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Assessment method [5]
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Blood samples were collected at Cycle 1 Day 1(Baseline), Day 1 of Cycles 2 to 20, Final Visit, and were analyzed for CEA concentration. Percent changes in CEA concentration values from baseline to specific time points were calculated. Only participants with both baseline and relevant visit values were included.
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Timepoint [5]
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Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 20, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
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Secondary outcome [6]
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Change From Baseline in Concentrations of Cytochrome C (CytoC)
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Assessment method [6]
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Blood samples to obtain serum were collected at Cycle 1 Day 1(Baseline), Cycle 1 Day 8, Cycle 2 Days 1,8 &15, Cycles 3 to 9,11,13 Day 1, Final Visit, and analyzed for CytoC concentration. Changes in CytoC concentration values from baseline to specific time points were calculated. Only participants with both baseline and relevant visit values were included. For results reported as below quantifiable level (BQL), zero was used for calculating summary statistics. If more than 50% of the results at a visit were BQL, then only 'n', 'minimum' and 'maximum' were calculated for summary statistics.
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Timepoint [6]
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Cycle 1 (Day 8), Cycle 2 (Days 1, 8 and 15), Cycles 3, 4, 5, 6, 7, 8, 9, 11, & 13 (Day 1), and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
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Secondary outcome [7]
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Change From Baseline in Concentrations of M-30 Neo-Antigen
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Assessment method [7]
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Blood samples to obtain serum were collected at Cycle 1 Day 1(Baseline), Cycle 1 Day 8, Cycle 2 Days 1,8 &15, Cycles 3 to 9,11,13 Day 1, Final Visit, and analyzed for M-30 concentration. Changes in M-30 concentration values from baseline to specific time points were calculated. Only participants with both baseline and relevant visit values were included. For results reported as BQL, zero was used for calculating summary statistics. If more than 50% of the results at a visit were BQL, then only 'n', 'minimum' and 'maximum' were calculated for summary statistics.
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Timepoint [7]
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Cycle 1 (Day 8), Cycle 2 (Days 1, 8 & 15), Cycles 3, 4, 5, 6, 7, 8, 9, 11 & 13 (Day 1) and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
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Secondary outcome [8]
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Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7)
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Assessment method [8]
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Blood samples to obtain serum were collected at Cycle 1 Day 1 (Baseline), Cycle 1 Day 8, Cycle 2 Days 1, 8, and 15, Cycles 3 to 9, 11, 13 (Day 1), Final Visit, and analyzed for Casp 3/7 concentration. Changes in Casp 3/7 concentration values from baseline to specific time points were calculated. Only participants with both baseline and relevant visit values were included. The concentrations of Casp 3/7 were BQL for most participants at most time points. For results reported as BQL, zero was used for calculating summary statistics. If more than 50% of the results at a visit were BQL, then only 'n', 'minimum' and 'maximum' were calculated for summary statistics.
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Timepoint [8]
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Cycle 1 (Day 8), Cycle 2 (Days 1, 8, & 15), Cycles 3, 4, 5, 6, 7, 8, 9, 11, & 13 (Day 1) and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
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Secondary outcome [9]
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Duration of Response (DoR) Assessed as Per Independent Imaging Reviewers (IIR)
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Assessment method [9]
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DoR was based on IIR was the time from date of the first CR or PR until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, for the participants who had BOR of CR or PR. Participants without progressive disease or death were censored at the date of last adequate tumor assessment. Duration of response = End Date - Date of first CR or PR + 1
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Timepoint [9]
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From date of the first CR or PR until the date of first documentation of disease progression or date of death, assessed up to data cutoff date 11 April 2011
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Secondary outcome [10]
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Disease Control Rate (DCR) Assessed as Per IIR
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Assessment method [10]
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DCR was the percentage of the participants who had BOR of CR, PR, and stable disease (SD) with the minimum duration of SD lasting greater than or equal to 7 weeks, based on assessments by IIR. DCR = CR+PR+SD greater than or equal to 7 weeks
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Timepoint [10]
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From date of treatment start until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice to stop study treatment, or up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
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Secondary outcome [11]
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Clinical Benefit Rate (CBR) Assessed as Per IIR
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Assessment method [11]
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CBR was the percentage of the participants who had BOR of CR, PR, and SD with the minimum duration of SD lasting greater than or equal to 23 weeks, based on assessments by IIR. CBR = CR+PR+SD greater than or equal to 23 weeks
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Timepoint [11]
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From date of treatment start until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice to stop study treatment, or up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
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Secondary outcome [12]
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Time to Response (TTR) Assessed as Per IIR
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Assessment method [12]
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TTR was defined as "time from start of treatment to the time when a participant first achieves a response of PR/CR" based on assessments by IIR. TTR was only calculated for participants with confirmed PR or CR.
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Timepoint [12]
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From date of treatment start until date of first CR or PR, assessed up to data cutoff date 11 April 2011
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Secondary outcome [13]
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Progression Free Survival (PFS) Assessed as Per IIR
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Assessment method [13]
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PFS was defined as the time from the date of treatment start until progressive disease or death from any cause in the absence of progressive disease. Disease progression was defined as at least a 20% increase in the sum of the longest diameter 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 as assessed by IIR using RECIST 1.0. The duration of PFS was calculated as end date minus date of first drug plus 1, based on assessments by IIR. PFS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% Cl.
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Timepoint [13]
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From date of treatment start until date of progressive disease or death from any cause, assessed up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
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Secondary outcome [14]
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Overall Survival (OS)
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Assessment method [14]
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OS was defined as the time from the date of treatment start until death from any cause. The duration of OS was calculated as 'end date minus date of first drug plus 1', based on assessments by IIR. Participants without a reported death or those lost to follow-up were censored at their last known alive date at the database cutoff. OS was calculated using Kaplan-Meier estimate and presented with 2-sided 95% Cl.
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Timepoint [14]
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From date of treatment start until date of death from any cause, assessed up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
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Secondary outcome [15]
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Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib
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Assessment method [15]
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Safety assessments consisted of monitoring and recording all AEs (serious and non-serious) and SAEs; concomitant medications, regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, New York Heart Association (NYHA) assessments, electrocardiograms (ECGs), echocardiograms; and performance of physical examinations.
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Timepoint [15]
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For each participant, from the first dose till 30 days after the last dose of study treatment (up to approximately 10 years 4 months)
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Eligibility
Key inclusion criteria
Inclusion criteria:
1. Histologically or cytologically confirmed diagnosis of medullary thyroid cancer (MTC)
or differentiated thyroid cancer (DTC).
2. Measurable disease meeting the following criterion:
1. At least one lesion (greater than or equal to 1.5 cm in longest diameter for
non-lymph nodes and greater than or equal to 2.0 cm in longest diameter for lymph
nodes) which is serially and accurately measurable according to modified response
evaluation criteria in solid tumours (RECIST) using either computed tomography
(CT) or magnetic resonance imaging (MRI).
2. Lesions that have had electron beam radiotherapy must show evidence of
progressive disease based on modified RECIST to be deemed a target lesion.
3. Evidence of disease progression by RECIST using site assessment of CT/MRI scans within
12 months (+1 month to allow for variances in patient scanning intervals) prior to
study entry.
4. DTC must be 131-I refractory/resistant: never demonstrated 131-I uptake, progression
despite 131-I uptake, or cumulative dose of 131-I of greater than 600 millicurie (mCi)
(last dose given at least 6 months prior to study entry).
5. Well controlled blood pressure prior to study entry.
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Minimum age
18
Years
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Maximum age
99
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Exclusion criteria:
1. Anaplastic thyroid carcinoma, thyroid lymphoma, mesenchymal tumors of the thyroid,
metastases to the thyroid.
2. Brain or leptomeningeal metastases.
3. Significant cardiovascular impairment (history of congestive heart failure, New York
Heart Association [NYHA] Class II, unstable angina or myocardial infarction within 6
months of study start, or serious cardiac arrhythmia).
4. Marked baseline prolongation of QT/corrected QT (QTc) interval.
5. Proteinuria greater than 1+ or greater than 30 mg in dipstick testing.
6. Active hemoptysis (bright red blood of at least one-half teaspoon) in the 28 days
prior to study entry.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
6/11/2008
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
29/03/2019
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Sample size
Target
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Accrual to date
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Final
117
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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- St Leonards
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Recruitment hospital [2]
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- Brisbane
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Recruitment hospital [3]
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- Melbourne
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Recruitment postcode(s) [1]
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- St Leonards
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Recruitment postcode(s) [2]
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- Brisbane
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Recruitment postcode(s) [3]
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- Melbourne
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Recruitment outside Australia
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United States of America
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State/province [1]
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Arkansas
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United States of America
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California
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United States of America
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Colorado
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Florida
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Georgia
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Illinois
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Maryland
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Massachusetts
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Minnesota
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Missouri
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New Hampshire
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New Jersey
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Texas
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Washington
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Wisconsin
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France
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Lyon
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France
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Paris
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France
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Reims
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France
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Villejuif Cedex
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Italy
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Ferrara
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Italy
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Milan
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Italy
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Naples
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Italy
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Pisa
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Italy
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Rome
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Italy
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Siena
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Poland
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Gliwice
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Poland
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Poznan
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United Kingdom
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Cardiff
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United Kingdom
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Glasgow
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United Kingdom
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London
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United Kingdom
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Sutton
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Eisai Inc.
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
The purpose of this study is to determine the safety and efficacy of oral lenvatinib in
participants with medullary thyroid cancer (MTC) or radioiodine (131 I)-refractory/resistant
differentiated thyroid cancer (DTC), unresectable differentiated thyroid cancers, stratified
by Histology.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT00784303
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Address
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT00784303
Download to PDF