Evaluating the Safety and Efficacy of Oral Lenvatinib in Medullary and Iodine-131 Refractory, Unresectable Differentiated Thyroid Cancers, Stratified by Histology

• ClinicalTrials.gov Identifier: NCT00784303
• Recruitment Status: Completed
• First Posted: November 2, 2008
• Results First Posted: August 1, 2019
• Last Update Posted: April 22, 2020
• Sponsor: Eisai Inc.
• Information provided by (Responsible Party): Eisai Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Thyroid Cancer	Drug: Lenvatinib (DTC Cohort); Drug: Lenvatinib (MTC Cohort)	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 117 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: November 6, 2008
• Actual Primary Completion Date: April 11, 2011
• Actual Study Completion Date: March 29, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: DTC cohort; This arm will enroll participants with radioiodine (131 I)-refractory/resistant differentiated thyroid cancer.	Drug: 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.; Other Name: E7080, LENVIMA
Experimental: MTC cohort; This arm will enroll participants with medullary thyroid cancer.	Drug: 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.; Other Name: E7080, LENVIMA

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) [ 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 ]
   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.
2. Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC) [ 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) ]
   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 Outcome Measures :

1. Change From Baseline in Free Thyroxine (T4) [ 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) ]
   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.
2. Change From Baseline in Free Thyroid Stimulating Hormone (TSH) [ 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) ]
   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.
3. Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) [ 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) ]
   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.
4. Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) [ 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) ]
   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.
5. Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) [ 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) ]
   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.
6. Change From Baseline in Concentrations of Cytochrome C (CytoC) [ 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) ]
   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.
7. Change From Baseline in Concentrations of M-30 Neo-Antigen [ 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) ]
   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.
8. Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) [ 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) ]
   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.
9. Duration of Response (DoR) Assessed as Per Independent Imaging Reviewers (IIR) [ 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 ]
   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
10. Disease Control Rate (DCR) Assessed as Per IIR [ 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 ]
    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
11. Clinical Benefit Rate (CBR) Assessed as Per IIR [ 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 ]
    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
12. Time to Response (TTR) Assessed as Per IIR [ Time Frame: 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.
13. Progression Free Survival (PFS) Assessed as Per IIR [ 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 ]
    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.
14. Overall Survival (OS) [ 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 ]
    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.
15. Number of Participants With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib [ 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) ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

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.

Contacts and Locations

Locations

United States, Arkansas

Little Rock, Arkansas, United States

United States, California

Los Angeles, California, United States

Los Gatos, California, United States

Mission Viejo, California, United States

Santa Monica, California, United States

Torrance, California, United States

United States, Colorado

Aurora, Colorado, United States

United States, Florida

Orlando, Florida, United States

Tampa, Florida, United States

United States, Georgia

Roswell, Georgia, United States

United States, Illinois

Chicago, Illinois, United States

United States, Maryland

Baltimore, Maryland, United States

Bethesda, Maryland, United States

United States, Massachusetts

Boston, Massachusetts, United States

United States, Minnesota

Minneapolis, Minnesota, United States

United States, Missouri

Columbia, Missouri, United States

Jefferson City, Missouri, United States

United States, New Hampshire

Lebanon, New Hampshire, United States

United States, New Jersey

Montclair, New Jersey, United States

United States, Texas

Houston, Texas, United States

United States, Washington

Long Beach, Washington, United States

Seattle, Washington, United States

United States, Wisconsin

Madison, Wisconsin, United States

Australia, New South Wales

St Leonards, New South Wales, Australia

Australia

Brisbane, Australia

Melbourne, Australia

France

Lyon, France

Paris, France

Reims, France

Villejuif Cedex, France

Italy

Ferrara, Italy

Milan, Italy

Naples, Italy

Pisa, Italy

Rome, Italy

Siena, Italy

Poland

Gliwice, Poland

Poznan, Poland

United Kingdom

Cardiff, United Kingdom

Glasgow, United Kingdom

London, United Kingdom

Sutton, United Kingdom

Sponsors and Collaborators

Eisai Inc.

More Information

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT00784303
• Other Study ID Numbers: E7080-G000-201
• First Posted: November 2, 2008
• Results First Posted: August 1, 2019
• Last Update Posted: April 22, 2020
• Last Verified: March 2019

Keywords provided by Eisai Inc.:

Thyroid Cancer

Additional relevant MeSH terms:

Thyroid Neoplasms; Thyroid Diseases; Endocrine System Diseases; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Lenvatinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action