Thyroid Cancer
Conditions
Keywords
Thyroid Cancer
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.
Detailed description
This study contained 3 Phases: the Pretreatment Phase, the Treatment Phase, and the Extension Phase. The Pretreatment Phase lasted no longer than 28 days. Informed consent was obtained and protocol eligibility and disease characteristics were established prior to treatment. The Treatment Phase consisted of a Treatment Period and a Follow-up Period. The Treatment Period of the Treatment Phase began at the time that the first participant began study drug administration and ended at the time when all participants enrolled completed 8 cycles of treatment or discontinued study treatment prior to the eighth cycle (ie, time of data cutoff for the primary study analysis \[Primary Completion Date\]). All participants then entered the Extension Phase. The Extension Phase consisted of a Treatment Period and a Follow-up Period. The Extension Phase began immediately after the Treatment Phase ended and included all participants that were either still receiving treatment or in follow-up. The time of data cutoff for the primary study analysis occurred when all subjects in the study completed 8 cycles of treatment or discontinued study treatment prior to the eighth cycle.
Interventions
DRUGLenvatinib (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.
DRUGLenvatinib (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.
Sponsors
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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.
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 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 | 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. |
| Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC) | 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) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | 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) | 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. |
| Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | 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) | 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. |
| Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | 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) | 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. |
| Change From Baseline in Concentrations of Cytochrome C (CytoC) | 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) | 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. |
| Change From Baseline in Concentrations of M-30 Neo-Antigen | 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) | 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. |
| Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | 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) | 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. |
| Change From Baseline in Free Thyroxine (T4) | 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) | 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. |
| Disease Control Rate (DCR) Assessed as Per IIR | 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 | 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 |
| Clinical Benefit Rate (CBR) Assessed as Per IIR | 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 | 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 |
| Time to Response (TTR) Assessed as Per IIR | From date of treatment start until date of first CR or PR, assessed up to data cutoff date 11 April 2011 | 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. |
| Progression Free Survival (PFS) Assessed as Per IIR | 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 | 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. |
| Overall Survival (OS) | 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 | 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. |
| Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | For each participant, from the first dose till 30 days after the last dose of study treatment (up to approximately 10 years 4 months) | 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. |
| Duration of Response (DoR) Assessed as Per Independent Imaging Reviewers (IIR) | 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 | 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 |
| Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | 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) | 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. |
Countries
Australia, France, Italy, Poland, United Kingdom, United States
Participant flow
Recruitment details
162 participants were screened for entry into the study, from which 45 were screening failures and 117 entered into the study and were treated.
Participants by arm
| Arm | Count |
|---|---|
| DTC Cohort Participants with radioiodine (131 I)-refractory/resistant differentiated thyroid cancer (DTC) received 24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) orally, once daily or 10 mg lenvatinib orally twice daily in 28-day treatment cycles. 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. | 58 |
| MTC Cohort Participants with medullary thyroid cancer (MTC) received 24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily continuously in 28-day treatment cycles. | 59 |
| Total | 117 |
Baseline characteristics
| Characteristic | DTC Cohort | MTC Cohort | Total |
|---|---|---|---|
| Age, Continuous | 60.9 Years STANDARD_DEVIATION 9.49 | 51.6 Years STANDARD_DEVIATION 14.11 | 56.2 Years STANDARD_DEVIATION 12.88 |
| Sex: Female, Male Female | 24 Participants | 22 Participants | 46 Participants |
| Sex: Female, Male Male | 34 Participants | 37 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 44 / 58 | 37 / 59 |
| other Total, other adverse events | 58 / 58 | 59 / 59 |
| serious Total, serious adverse events | 32 / 58 | 42 / 59 |
Outcome results
Primary
Objective Response Rate (ORR)
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.
Time frame: 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
Population: The Intent to Treat (ITT) Population included all participants who received at least one dose of the study drug and was the primary analysis set used for efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DTC Cohort | Objective Response Rate (ORR) | 50.0 Percentage of participants |
| MTC Cohort | Objective Response Rate (ORR) | 35.6 Percentage of participants |
Primary
Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC)
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).
Time frame: 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)
Population: PK population included all participants who received the 24 mg daily lenvatinib dose and had concentration values above the limit of quantification and non-missing PK sampling/dose time.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DTC Cohort | Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC) | 3840 ng·h/mL |
| MTC Cohort | Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC) | 3350 ng·h/mL |
Secondary
Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7)
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.
Time frame: 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)
Population: All participants who received at least 1 dose of study drug. Only participants with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 2 Day 1, for MTC cohort at Cycle 2 Day 15, Day 1 of Cycle 11 and 13 because no participant was evaluable at these time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 6 Day 1 | 0.0046 U/W | Standard Deviation 0.00605 |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 3 Day 1 | NA U/W | — |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 7 Day 1 | 0.0058 U/W | Standard Deviation 0.00496 |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 2 Day 8 | NA U/W | — |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 8 Day 1 | 0.0078 U/W | Standard Deviation 0.00771 |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 4 Day 1 | NA U/W | — |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 9 Day 1 | 0.0067 U/W | Standard Deviation 0.0048 |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 1 Day 8 | NA U/W | — |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 11 Day 1 | NA U/W | — |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 13 Day 1 | NA U/W | — |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Final Visit/Study Termination | NA U/W | — |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 5 Day 1 | NA U/W | — |
| DTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 2 Day 15 | 0.0110 U/W | — |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 5 Day 1 | 0.0042 U/W | Standard Deviation 0.00666 |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 1 Day 8 | 0.0030 U/W | Standard Deviation 0.0061 |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 2 Day 1 | 0.0080 U/W | — |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 2 Day 8 | 0.0039 U/W | Standard Deviation 0.00822 |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 3 Day 1 | 0.0026 U/W | Standard Deviation 0.00691 |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 4 Day 1 | 0.0019 U/W | Standard Deviation 0.00743 |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Final Visit/Study Termination | NA U/W | — |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 6 Day 1 | NA U/W | — |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 7 Day 1 | 0.0044 U/W | Standard Deviation 0.00692 |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 8 Day 1 | NA U/W | — |
| MTC Cohort | Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) | Cycle 9 Day 1 | 0.0068 U/W | Standard Deviation 0.01329 |
Secondary
Change From Baseline in Concentrations of Cytochrome C (CytoC)
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.
Time frame: 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)
Population: All participants who received at least 1 dose of study drug. Only participants with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 2 Day 1, for MTC cohort at Cycle 2 Day 15, Day 1 of Cycle 11 and 13 because no participant was evaluable at these time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 1 Day 8 | 155.57 pg/mL | Standard Deviation 825.091 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 2 Day 15 | -215.50 pg/mL | — |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 3 Day 1 | -175.43 pg/mL | Standard Deviation 435.635 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 4 Day 1 | 1.38 pg/mL | Standard Deviation 268.354 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 5 Day 1 | -21.32 pg/mL | Standard Deviation 85.469 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 6 Day 1 | 721.58 pg/mL | Standard Deviation 1234.215 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 7 Day 1 | 858.05 pg/mL | Standard Deviation 1383.962 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 8 Day 1 | 1358.51 pg/mL | Standard Deviation 1364.706 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 9 Day 1 | 1356.40 pg/mL | Standard Deviation 913.685 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 11 Day 1 | 139.60 pg/mL | — |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 13 Day 1 | 129.60 pg/mL | — |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Final Visit/Study Termination | 249.31 pg/mL | Standard Deviation 765.148 |
| DTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 2 Day 8 | -218.45 pg/mL | Standard Deviation 591.217 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 1 Day 8 | 502.84 pg/mL | Standard Deviation 2146.291 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 2 Day 1 | 1679.40 pg/mL | — |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 8 Day 1 | 451.36 pg/mL | Standard Deviation 254.305 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 2 Day 8 | 374.46 pg/mL | Standard Deviation 2279.207 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 6 Day 1 | 1411.29 pg/mL | Standard Deviation 3855.502 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Final Visit/Study Termination | -45.97 pg/mL | Standard Deviation 1294.476 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 3 Day 1 | 311.85 pg/mL | Standard Deviation 2363.97 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 7 Day 1 | 2184.30 pg/mL | Standard Deviation 4689.181 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 4 Day 1 | 63.01 pg/mL | Standard Deviation 1738.149 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 9 Day 1 | 459.38 pg/mL | Standard Deviation 1572.717 |
| MTC Cohort | Change From Baseline in Concentrations of Cytochrome C (CytoC) | Cycle 5 Day 1 | 1078.85 pg/mL | Standard Deviation 3793.235 |
Secondary
Change From Baseline in Concentrations of M-30 Neo-Antigen
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.
Time frame: 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)
Population: All participants who received at least 1 dose of study drug. Only participants with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 2 Day 1, for MTC cohort at Cycle 2 Day 15, Day 1 of Cycle 11 and 13 because no participant was evaluable at these time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 6 Day 1 | -99.30 U/L | Standard Deviation 321.554 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 3 Day 1 | 19.70 U/L | Standard Deviation 296.01 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 7 Day 1 | -168.50 U/L | Standard Deviation 378.071 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 2 Day 8 | -26.41 U/L | Standard Deviation 257.723 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 8 Day 1 | -180.22 U/L | Standard Deviation 386.682 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 4 Day 1 | -7.89 U/L | Standard Deviation 336.124 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 9 Day 1 | -111.92 U/L | Standard Deviation 189.411 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 1 Day 8 | -5.22 U/L | Standard Deviation 108.639 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 13 Day 1 | -263.50 U/L | — |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Final Visit/Study Termination | -151.73 U/L | Standard Deviation 322.159 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 11 Day 1 | 55.00 U/L | — |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 5 Day 1 | -24.83 U/L | Standard Deviation 397.337 |
| DTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 2 Day 15 | 35.30 U/L | — |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Final Visit/Study Termination | -158.99 U/L | Standard Deviation 355.903 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 1 Day 8 | 46.32 U/L | Standard Deviation 197.509 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 2 Day 1 | -77.80 U/L | — |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 2 Day 8 | -49.33 U/L | Standard Deviation 289.525 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 3 Day 1 | -90.21 U/L | Standard Deviation 314.343 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 4 Day 1 | -97.53 U/L | Standard Deviation 296.832 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 5 Day 1 | -161.36 U/L | Standard Deviation 265.548 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 6 Day 1 | -161.30 U/L | Standard Deviation 214.299 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 7 Day 1 | -52.79 U/L | Standard Deviation 129.671 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 8 Day 1 | -92.44 U/L | Standard Deviation 57.828 |
| MTC Cohort | Change From Baseline in Concentrations of M-30 Neo-Antigen | Cycle 9 Day 1 | -85.22 U/L | Standard Deviation 161.751 |
Secondary
Change From Baseline in Free Thyroid Stimulating Hormone (TSH)
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.
Time frame: 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)
Population: All participants who received at least 1 dose of study drug. For each change from baseline assessment time point, only participants with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 1 Day 15 and Cycle 20 Day 1 because no participant was evaluable at these time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 4 Day 1 | 0.6296 mIU/L | Standard Deviation 2.2942 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 10 Day 1 | -0.3277 mIU/L | Standard Deviation 2.87114 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 3 Day 1 | 0.5161 mIU/L | Standard Deviation 2.79122 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 11 Day 1 | -0.2940 mIU/L | Standard Deviation 3.28192 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Final Visit/Study Termination | 1.0281 mIU/L | Standard Deviation 2.07161 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 12 Day 1 | 0.3500 mIU/L | Standard Deviation 5.43946 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 5 Day 1 | 0.5024 mIU/L | Standard Deviation 2.22721 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 13 Day 1 | -0.2799 mIU/L | Standard Deviation 3.31518 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 2 Day 1 | 0.4779 mIU/L | Standard Deviation 3.07666 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 14 Day 1 | -0.6232 mIU/L | Standard Deviation 3.09954 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 7 Day 1 | 0.6660 mIU/L | Standard Deviation 2.08608 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 15 Day 1 | -0.5911 mIU/L | Standard Deviation 3.21447 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 6 Day 1 | 0.8603 mIU/L | Standard Deviation 3.09079 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 16 Day 1 | -0.3396 mIU/L | Standard Deviation 3.68903 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 8 Day 1 | 0.2118 mIU/L | Standard Deviation 3.16324 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 17 Day 1 | -1.0352 mIU/L | Standard Deviation 3.92286 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 19 Day 1 | 0.7805 mIU/L | Standard Deviation 1.87674 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 18 Day 1 | 0.0331 mIU/L | Standard Deviation 0.2452 |
| DTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 9 Day 1 | 0.1270 mIU/L | Standard Deviation 3.5302 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 17 Day 1 | 7.4624 mIU/L | Standard Deviation 16.18545 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 1 Day 15 | 2.8030 mIU/L | — |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 18 Day 1 | 4.1232 mIU/L | Standard Deviation 7.01461 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 2 Day 1 | 4.1585 mIU/L | Standard Deviation 7.34946 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 3 Day 1 | 5.5788 mIU/L | Standard Deviation 13.766 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 4 Day 1 | 2.8751 mIU/L | Standard Deviation 6.50098 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 5 Day 1 | 3.7098 mIU/L | Standard Deviation 6.60386 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 19 Day 1 | -0.2080 mIU/L | Standard Deviation 0.29698 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 20 Day 1 | 0.0000 mIU/L | — |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Final Visit/Study Termination | 3.4905 mIU/L | Standard Deviation 7.39625 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 6 Day 1 | 3.9822 mIU/L | Standard Deviation 10.65477 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 7 Day 1 | 8.4308 mIU/L | Standard Deviation 22.51715 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 8 Day 1 | 11.4131 mIU/L | Standard Deviation 32.65896 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 9 Day 1 | 6.6620 mIU/L | Standard Deviation 18.89412 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 10 Day 1 | 6.1934 mIU/L | Standard Deviation 17.99762 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 11 Day 1 | 2.7928 mIU/L | Standard Deviation 9.42343 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 12 Day 1 | 5.1879 mIU/L | Standard Deviation 14.81415 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 13 Day 1 | 2.0983 mIU/L | Standard Deviation 7.03903 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 14 Day 1 | 9.6490 mIU/L | Standard Deviation 32.4891 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 15 Day 1 | 0.9955 mIU/L | Standard Deviation 4.93549 |
| MTC Cohort | Change From Baseline in Free Thyroid Stimulating Hormone (TSH) | Cycle 16 Day 1 | 0.2971 mIU/L | Standard Deviation 3.33103 |
Secondary
Change From Baseline in Free Thyroxine (T4)
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.
Time frame: 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)
Population: All participants who received at least 1 dose of study drug. Only participants with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 1 Day 15 and Cycle 20 Day 1 because no participant was evaluable at these time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 12 Day 1 | -1.60 pmol/L | Standard Deviation 6.331 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 7 Day 1 | -2.32 pmol/L | Standard Deviation 5.098 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 13 Day 1 | -0.09 pmol/L | Standard Deviation 5.416 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 3 Day 1 | -0.92 pmol/L | Standard Deviation 4.985 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 14 Day 1 | -0.54 pmol/L | Standard Deviation 5.772 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 8 Day 1 | -1.74 pmol/L | Standard Deviation 5.504 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 15 Day 1 | 0.63 pmol/L | Standard Deviation 6.703 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 5 Day 1 | -1.03 pmol/L | Standard Deviation 5.563 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 16 Day 1 | -0.98 pmol/L | Standard Deviation 7.15 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 9 Day 1 | -0.39 pmol/L | Standard Deviation 5.295 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 17 Day 1 | 1.20 pmol/L | Standard Deviation 7.075 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 2 Day 1 | -0.46 pmol/L | Standard Deviation 5.149 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 18 Day 1 | 0.38 pmol/L | Standard Deviation 4.648 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 10 Day 1 | -0.26 pmol/L | Standard Deviation 6.397 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 19 Day 1 | -0.65 pmol/L | Standard Deviation 4.042 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 6 Day 1 | -2.19 pmol/L | Standard Deviation 5.373 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 11 Day 1 | -0.27 pmol/L | Standard Deviation 6.384 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Final Visit/Study Termination | -0.36 pmol/L | Standard Deviation 6.175 |
| DTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 4 Day 1 | -1.05 pmol/L | Standard Deviation 5.581 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 20 Day 1 | 5.20 pmol/L | — |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 1 Day 15 | -3.80 pmol/L | — |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Final Visit/Study Termination | 1.27 pmol/L | Standard Deviation 4.584 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 2 Day 1 | -0.86 pmol/L | Standard Deviation 3.913 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 3 Day 1 | -1.00 pmol/L | Standard Deviation 4.028 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 4 Day 1 | 0.34 pmol/L | Standard Deviation 4.192 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 5 Day 1 | -0.46 pmol/L | Standard Deviation 3.878 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 6 Day 1 | -0.17 pmol/L | Standard Deviation 4.719 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 7 Day 1 | -1.07 pmol/L | Standard Deviation 5.403 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 8 Day 1 | -1.13 pmol/L | Standard Deviation 5.691 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 9 Day 1 | 0.52 pmol/L | Standard Deviation 5.213 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 10 Day 1 | 1.33 pmol/L | Standard Deviation 6.319 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 11 Day 1 | 0.30 pmol/L | Standard Deviation 5.551 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 12 Day 1 | -0.43 pmol/L | Standard Deviation 5.38 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 13 Day 1 | 0.07 pmol/L | Standard Deviation 4.347 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 14 Day 1 | -0.82 pmol/L | Standard Deviation 6.394 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 15 Day 1 | -1.01 pmol/L | Standard Deviation 5.505 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 16 Day 1 | 0.60 pmol/L | Standard Deviation 4.142 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 17 Day 1 | 0.45 pmol/L | Standard Deviation 3.528 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 18 Day 1 | 2.17 pmol/L | Standard Deviation 4.831 |
| MTC Cohort | Change From Baseline in Free Thyroxine (T4) | Cycle 19 Day 1 | 3.25 pmol/L | Standard Deviation 4.596 |
Secondary
Clinical Benefit Rate (CBR) Assessed as Per IIR
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
Time frame: 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
Population: ITT population. Participants who were evaluable for this given measure at a given time point were included for this assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DTC Cohort | Clinical Benefit Rate (CBR) Assessed as Per IIR | 77.6 Percentage of participants |
| MTC Cohort | Clinical Benefit Rate (CBR) Assessed as Per IIR | 64.4 Percentage of participants |
Secondary
Disease Control Rate (DCR) Assessed as Per IIR
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
Time frame: 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
Population: ITT population. Participants who were evaluable for this given measure at a given time point were included for this assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DTC Cohort | Disease Control Rate (DCR) Assessed as Per IIR | 93.1 Percentage of participants |
| MTC Cohort | Disease Control Rate (DCR) Assessed as Per IIR | 79.7 Percentage of participants |
Secondary
Duration of Response (DoR) Assessed as Per Independent Imaging Reviewers (IIR)
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
Time frame: 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
Population: ITT population. Participants who were evaluable for this given measure at a given time point were included for this assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DTC Cohort | Duration of Response (DoR) Assessed as Per Independent Imaging Reviewers (IIR) | 12.7 Months |
| MTC Cohort | Duration of Response (DoR) Assessed as Per Independent Imaging Reviewers (IIR) | NA Months |
Secondary
Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib
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.
Time frame: For each participant, from the first dose till 30 days after the last dose of study treatment (up to approximately 10 years 4 months)
Population: Safety population included all participants who received at least 1 dose of study drug and had at least 1 posttreatment safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DTC Cohort | Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Non-Serious AEs | 58 Participants |
| DTC Cohort | Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | SAEs | 32 Participants |
| MTC Cohort | Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Non-Serious AEs | 59 Participants |
| MTC Cohort | Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | SAEs | 42 Participants |
Secondary
Overall Survival (OS)
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.
Time frame: 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
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DTC Cohort | Overall Survival (OS) | 27.7 Months |
| MTC Cohort | Overall Survival (OS) | 16.6 Months |
Secondary
Percent Change From Baseline in Concentrations of Calcitonin (MTC Only)
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.
Time frame: 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)
Population: All participants who received at least 1 dose of study drug. For each change from baseline assessment time point, only participants with both baseline and relevant visit/time point values were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 2 Day 1 | -42.27 percent change | Standard Deviation 38.754 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 3 Day 1 | -48.11 percent change | Standard Deviation 30.976 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 4 Day 1 | -44.54 percent change | Standard Deviation 38.794 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 5 Day 1 | -49.97 percent change | Standard Deviation 34.634 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 6 Day 1 | -41.73 percent change | Standard Deviation 46.653 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 7 Day 1 | -38.18 percent change | Standard Deviation 62.721 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 8 Day 1 | -47.29 percent change | Standard Deviation 46.101 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 9 Day 1 | -37.52 percent change | Standard Deviation 72.588 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 10 Day 1 | -39.57 percent change | Standard Deviation 60.118 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 11 Day 1 | -42.68 percent change | Standard Deviation 61.797 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 12 Day 1 | -29.25 percent change | Standard Deviation 105.44 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 13 Day 1 | -36.26 percent change | Standard Deviation 89.612 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 14 Day 1 | -18.16 percent change | Standard Deviation 148.928 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 15 Day 1 | -65.26 percent change | Standard Deviation 24.553 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 16 Day 1 | -64.24 percent change | Standard Deviation 30.394 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 17 Day 1 | -66.03 percent change | Standard Deviation 23.777 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 18 Day 1 | -64.57 percent change | Standard Deviation 27.982 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 19 Day 1 | -44.30 percent change | Standard Deviation 18.668 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Cycle 20 Day 1 | -29.40 percent change | — |
| DTC Cohort | Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) | Final Visit/Study Termination | -36.70 percent change | Standard Deviation 28.296 |
Secondary
Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only)
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.
Time frame: 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)
Population: All participants who received at least 1 dose of study drug. For each change from baseline assessment time point, only participants with both baseline and relevant visit/time point values were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 2 Day 1 | -26.07 percent change | Standard Deviation 45.864 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 3 Day 1 | -37.68 percent change | Standard Deviation 42.236 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 4 Day 1 | -41.49 percent change | Standard Deviation 48.035 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 5 Day 1 | -44.62 percent change | Standard Deviation 42.138 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 6 Day 1 | -41.91 percent change | Standard Deviation 47.388 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 7 Day 1 | -41.39 percent change | Standard Deviation 45.677 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 8 Day 1 | -42.89 percent change | Standard Deviation 47.818 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 9 Day 1 | -49.31 percent change | Standard Deviation 32.185 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 10 Day 1 | -47.35 percent change | Standard Deviation 31.621 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 11 Day 1 | -51.75 percent change | Standard Deviation 29.671 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 12 Day 1 | -49.91 percent change | Standard Deviation 32.597 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 13 Day 1 | -46.44 percent change | Standard Deviation 35.967 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 14 Day 1 | -47.98 percent change | Standard Deviation 38.324 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 15 Day 1 | -56.62 percent change | Standard Deviation 34.051 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 16 Day 1 | -59.83 percent change | Standard Deviation 34.762 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 17 Day 1 | -53.80 percent change | Standard Deviation 37.981 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 18 Day 1 | -46.00 percent change | Standard Deviation 39.905 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 19 Day 1 | -45.65 percent change | Standard Deviation 18.738 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Cycle 20 Day 1 | -61.40 percent change | — |
| DTC Cohort | Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) | Final Visit/Study Termination | -29.43 percent change | Standard Deviation 31.453 |
Secondary
Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only)
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.
Time frame: 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)
Population: All participants who received at least 1 dose of study drug. For each change from baseline assessment time point, only participants with both baseline and relevant visit/time point values were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 2 Day 1 | -62.21 percent change | Standard Deviation 39.997 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 3 Day 1 | -77.80 percent change | Standard Deviation 22.278 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 4 Day 1 | -79.25 percent change | Standard Deviation 26.639 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 5 Day 1 | -76.00 percent change | Standard Deviation 25.085 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 6 Day 1 | -20.36 percent change | Standard Deviation 373.19 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 7 Day 1 | -73.38 percent change | Standard Deviation 45.489 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 8 Day 1 | -79.96 percent change | Standard Deviation 27.461 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 9 Day 1 | -73.98 percent change | Standard Deviation 31.366 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 10 Day 1 | -78.26 percent change | Standard Deviation 25.524 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 11 Day 1 | -75.54 percent change | Standard Deviation 37.327 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 12 Day 1 | -73.51 percent change | Standard Deviation 46.397 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 13 Day 1 | -74.05 percent change | Standard Deviation 37.091 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 14 Day 1 | -78.70 percent change | Standard Deviation 17.348 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 15 Day 1 | -80.28 percent change | Standard Deviation 16.029 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 16 Day 1 | -76.38 percent change | Standard Deviation 27.736 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 17 Day 1 | -62.99 percent change | Standard Deviation 38.74 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 18 Day 1 | -72.67 percent change | Standard Deviation 27.226 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Cycle 19 Day 1 | -50.65 percent change | Standard Deviation 46.9 |
| DTC Cohort | Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) | Final Visit/Study Termination | -68.60 percent change | — |
Secondary
Progression Free Survival (PFS) Assessed as Per IIR
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.
Time frame: 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
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DTC Cohort | Progression Free Survival (PFS) Assessed as Per IIR | 12.6 Months |
| MTC Cohort | Progression Free Survival (PFS) Assessed as Per IIR | 9.0 Months |
Secondary
Time to Response (TTR) Assessed as Per IIR
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.
Time frame: From date of treatment start until date of first CR or PR, assessed up to data cutoff date 11 April 2011
Population: The Efficacy Evaluable Population included all participants who received at least one dose of the study treatment, had a baseline and at least one posttreatment tumor response evaluation. Participants who were evaluable for this given measure at a given time point were included for this assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DTC Cohort | Time to Response (TTR) Assessed as Per IIR | 3.6 Months |
| MTC Cohort | Time to Response (TTR) Assessed as Per IIR | 3.5 Months |