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NCT00784303

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

Completed Phase 2 Results posted Last updated 22 April 2020
What this trial tests

Phase 2 trial testing Lenvatinib (DTC Cohort) in Thyroid Cancer in 117 participants. Completed in 29 March 2019.

Timeline
6 November 2008
Primary endpoint
11 April 2011
29 March 2019

Quick facts

Lead sponsorEisai Inc.
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment117
Start date6 November 2008
Primary completion11 April 2011
Estimated completion29 March 2019
Sites42 locations across France, Italy, United Kingdom, Poland, Australia, United States

Drugs / interventions tested

Conditions studied

Sponsor

Eisai Inc. — full company profile →

Who can join

Adults 18 to 99, any sex, with Thyroid Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Objective Response Rate (ORR) Primary · 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% confid

GroupValue95% CI
DTC Cohort50.036.6 – 63.4
MTC Cohort35.623.6 – 49.1
Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC) Primary · 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

GroupValue95% CI
DTC Cohort38401610 – 6960
MTC Cohort33501040 – 6840
Change From Baseline in Free Thyroxine (T4) Secondary · 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.

Cycle 1 Day 15
GroupValue95% CI
MTC Cohort-3.80
Cycle 2 Day 1
GroupValue95% CI
DTC Cohort-0.46± 5.149
MTC Cohort-0.86± 3.913
Cycle 3 Day 1
GroupValue95% CI
DTC Cohort-0.92± 4.985
MTC Cohort-1.00± 4.028
Cycle 4 Day 1
GroupValue95% CI
DTC Cohort-1.05± 5.581
MTC Cohort0.34± 4.192
Cycle 5 Day 1
GroupValue95% CI
DTC Cohort-1.03± 5.563
MTC Cohort-0.46± 3.878
Cycle 6 Day 1
GroupValue95% CI
DTC Cohort-2.19± 5.373
MTC Cohort-0.17± 4.719
Cycle 7 Day 1
GroupValue95% CI
DTC Cohort-2.32± 5.098
MTC Cohort-1.07± 5.403
Cycle 8 Day 1
GroupValue95% CI
DTC Cohort-1.74± 5.504
MTC Cohort-1.13± 5.691
Change From Baseline in Free Thyroid Stimulating Hormone (TSH) Secondary · 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.

Cycle 1 Day 15
GroupValue95% CI
MTC Cohort2.8030
Cycle 2 Day 1
GroupValue95% CI
DTC Cohort0.4779± 3.07666
MTC Cohort4.1585± 7.34946
Cycle 3 Day 1
GroupValue95% CI
DTC Cohort0.5161± 2.79122
MTC Cohort5.5788± 13.76600
Cycle 4 Day 1
GroupValue95% CI
DTC Cohort0.6296± 2.29420
MTC Cohort2.8751± 6.50098
Cycle 5 Day 1
GroupValue95% CI
DTC Cohort0.5024± 2.22721
MTC Cohort3.7098± 6.60386
Cycle 6 Day 1
GroupValue95% CI
DTC Cohort0.8603± 3.09079
MTC Cohort3.9822± 10.65477
Cycle 7 Day 1
GroupValue95% CI
DTC Cohort0.6660± 2.08608
MTC Cohort8.4308± 22.51715
Cycle 8 Day 1
GroupValue95% CI
DTC Cohort0.2118± 3.16324
MTC Cohort11.4131± 32.65896
Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) Secondary · 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.

Cycle 2 Day 1
GroupValue95% CI
DTC Cohort-62.21± 39.997
Cycle 3 Day 1
GroupValue95% CI
DTC Cohort-77.80± 22.278
Cycle 4 Day 1
GroupValue95% CI
DTC Cohort-79.25± 26.639
Cycle 5 Day 1
GroupValue95% CI
DTC Cohort-76.00± 25.085
Cycle 6 Day 1
GroupValue95% CI
DTC Cohort-20.36± 373.190
Cycle 7 Day 1
GroupValue95% CI
DTC Cohort-73.38± 45.489
Cycle 8 Day 1
GroupValue95% CI
DTC Cohort-79.96± 27.461
Cycle 9 Day 1
GroupValue95% CI
DTC Cohort-73.98± 31.366
Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) Secondary · 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.

Cycle 2 Day 1
GroupValue95% CI
MTC Cohort-42.27± 38.754
Cycle 3 Day 1
GroupValue95% CI
MTC Cohort-48.11± 30.976
Cycle 4 Day 1
GroupValue95% CI
MTC Cohort-44.54± 38.794
Cycle 5 Day 1
GroupValue95% CI
MTC Cohort-49.97± 34.634
Cycle 6 Day 1
GroupValue95% CI
MTC Cohort-41.73± 46.653
Cycle 7 Day 1
GroupValue95% CI
MTC Cohort-38.18± 62.721
Cycle 8 Day 1
GroupValue95% CI
MTC Cohort-47.29± 46.101
Cycle 9 Day 1
GroupValue95% CI
MTC Cohort-37.52± 72.588
Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) Secondary · 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.

Cycle 2 Day 1
GroupValue95% CI
MTC Cohort-26.07± 45.864
Cycle 3 Day 1
GroupValue95% CI
MTC Cohort-37.68± 42.236
Cycle 4 Day 1
GroupValue95% CI
MTC Cohort-41.49± 48.035
Cycle 5 Day 1
GroupValue95% CI
MTC Cohort-44.62± 42.138
Cycle 6 Day 1
GroupValue95% CI
MTC Cohort-41.91± 47.388
Cycle 7 Day 1
GroupValue95% CI
MTC Cohort-41.39± 45.677
Cycle 8 Day 1
GroupValue95% CI
MTC Cohort-42.89± 47.818
Cycle 9 Day 1
GroupValue95% CI
MTC Cohort-49.31± 32.185
Change From Baseline in Concentrations of Cytochrome C (CytoC) Secondary · 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.

Cycle 1 Day 8
GroupValue95% CI
DTC Cohort155.57± 825.091
MTC Cohort502.84± 2146.291
Cycle 2 Day 1
GroupValue95% CI
MTC Cohort1679.40
Cycle 2 Day 8
GroupValue95% CI
DTC Cohort-218.45± 591.217
MTC Cohort374.46± 2279.207
Cycle 2 Day 15
GroupValue95% CI
DTC Cohort-215.50
Cycle 3 Day 1
GroupValue95% CI
DTC Cohort-175.43± 435.635
MTC Cohort311.85± 2363.970
Cycle 4 Day 1
GroupValue95% CI
DTC Cohort1.38± 268.354
MTC Cohort63.01± 1738.149
Cycle 5 Day 1
GroupValue95% CI
DTC Cohort-21.32± 85.469
MTC Cohort1078.85± 3793.235
Cycle 6 Day 1
GroupValue95% CI
DTC Cohort721.58± 1234.215
MTC Cohort1411.29± 3855.502
Change From Baseline in Concentrations of M-30 Neo-Antigen Secondary · 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.

Cycle 1 Day 8
GroupValue95% CI
DTC Cohort-5.22± 108.639
MTC Cohort46.32± 197.509
Cycle 2 Day 1
GroupValue95% CI
MTC Cohort-77.80
Cycle 2 Day 8
GroupValue95% CI
DTC Cohort-26.41± 257.723
MTC Cohort-49.33± 289.525
Cycle 2 Day 15
GroupValue95% CI
DTC Cohort35.30
Cycle 3 Day 1
GroupValue95% CI
DTC Cohort19.70± 296.010
MTC Cohort-90.21± 314.343
Cycle 4 Day 1
GroupValue95% CI
DTC Cohort-7.89± 336.124
MTC Cohort-97.53± 296.832
Cycle 5 Day 1
GroupValue95% CI
DTC Cohort-24.83± 397.337
MTC Cohort-161.36± 265.548
Cycle 6 Day 1
GroupValue95% CI
DTC Cohort-99.30± 321.554
MTC Cohort-161.30± 214.299
Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7) Secondary · 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

Cycle 1 Day 8
GroupValue95% CI
DTC CohortNA± NA
MTC Cohort0.0030± 0.00610
Cycle 2 Day 1
GroupValue95% CI
MTC Cohort0.0080
Cycle 2 Day 8
GroupValue95% CI
DTC CohortNA± NA
MTC Cohort0.0039± 0.00822
Cycle 2 Day 15
GroupValue95% CI
DTC Cohort0.0110
Cycle 3 Day 1
GroupValue95% CI
DTC CohortNA± NA
MTC Cohort0.0026± 0.00691
Cycle 4 Day 1
GroupValue95% CI
DTC CohortNA± NA
MTC Cohort0.0019± 0.00743
Cycle 5 Day 1
GroupValue95% CI
DTC CohortNA± NA
MTC Cohort0.0042± 0.00666
Cycle 6 Day 1
GroupValue95% CI
DTC Cohort0.0046± 0.00605
MTC CohortNA± NA
Duration of Response (DoR) Assessed as Per Independent Imaging Reviewers (IIR) Secondary · 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

GroupValue95% CI
DTC Cohort12.78.8 – NA
MTC CohortNA5.7 – NA
Disease Control Rate (DCR) Assessed as Per IIR Secondary · 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

GroupValue95% CI
DTC Cohort93.183.3 – 98.1
MTC Cohort79.767.2 – 89.0

Adverse events — posted to ClinicalTrials.gov

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). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

DTC Cohort
Serious: 32/58 (55%)
Deaths: 44/58
MTC Cohort
Serious: 42/59 (71%)
Deaths: 37/59

Serious adverse events (129 terms)

ReactionSystemDTC CohortMTC Cohort
Pulmonary embolismRespiratory, thoracic and mediastinal disorders
DehydrationMetabolism and nutrition disorders
PneumoniaInfections and infestations
HypotensionVascular disorders
Abdominal painGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
Lung infectionInfections and infestations
AmenorrhoeaReproductive system and breast disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Respiratory failureRespiratory, thoracic and mediastinal disorders
Abdominal pain lowerGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
DysphagiaGastrointestinal disorders
PancreatitisGastrointestinal disorders
Pneumonia staphylococcalInfections and infestations
HypertensionVascular disorders
BradycardiaCardiac disorders
Renal failureRenal and urinary disorders
AstheniaGeneral disorders
Premature menopauseReproductive system and breast disorders
AspirationRespiratory, thoracic and mediastinal disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
Obstructive airways disorderRespiratory, thoracic and mediastinal disorders
Oesophagobronchial fistulaRespiratory, thoracic and mediastinal disorders
Other adverse events (191 terms — click to expand)

ReactionSystemDTC CohortMTC Cohort
DiarrhoeaGastrointestinal disorders
HypertensionVascular disorders
ProteinuriaRenal and urinary disorders
Weight decreasedInvestigations
FatigueGeneral disorders
Decreased appetiteMetabolism and nutrition disorders
NauseaGastrointestinal disorders
CoughRespiratory, thoracic and mediastinal disorders
HeadacheNervous system disorders
VomitingGastrointestinal disorders
DysphoniaRespiratory, thoracic and mediastinal disorders
Back painMusculoskeletal and connective tissue disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Dry mouthGastrointestinal disorders
Abdominal painGastrointestinal disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
StomatitisGastrointestinal disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Abdominal pain upperGastrointestinal disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
ConstipationGastrointestinal disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
RashSkin and subcutaneous tissue disorders
PyrexiaGeneral disorders
Palmar-plantar erythrodysaesthesia syndromeSkin and subcutaneous tissue disorders
DysphagiaGastrointestinal disorders
AstheniaGeneral disorders
Oedema peripheralGeneral disorders
Musculoskeletal chest painMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
HypotensionVascular disorders
Blood thyroid stimulating hormone increasedInvestigations
Muscle spasmsMusculoskeletal and connective tissue disorders
DizzinessNervous system disorders
InsomniaPsychiatric disorders
GlossodyniaGastrointestinal disorders
Upper respiratory tract infectionInfections and infestations
HypocalcaemiaMetabolism and nutrition disorders
DysgeusiaNervous system disorders

Most-reported serious reactions: Pulmonary embolism, Dehydration, Pneumonia, Hypotension, Abdominal pain, Decreased appetite, Lung infection, Amenorrhoea.

Data from ClinicalTrials.gov NCT00784303 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment.
    Cabanillas ME, Schlumberger M, Jarzab B, Martins RG, et al · · 2015 · cited 139× · PMID 25913680 · DOI 10.1002/cncr.29395
  2. Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment.
    Liu G, Chen T, Ding Z, Wang Y, et al · · 2021 · cited 131× · PMID 33655556 · DOI 10.1111/cpr.13009
  3. The Adverse Effect of Hypertension in the Treatment of Thyroid Cancer with Multi-Kinase Inhibitors.
    Ancker OV, Wehland M, Bauer J, Infanger M, et al · · 2017 · cited 48× · PMID 28335429 · DOI 10.3390/ijms18030625
  4. Thyroid cancer: pathogenesis and targeted therapy.
    Liebner DA, Shah MH. · · 2011 · cited 42× · PMID 23148184 · DOI 10.1177/2042018811419889
  5. Sporadic Medullary Thyroid Carcinoma: Towards a Precision Medicine.
    Matrone A, Gambale C, Prete A, Elisei R. · · 2022 · cited 36× · PMID 35422765 · DOI 10.3389/fendo.2022.864253
  6. Update on the Diagnosis and Management of Medullary Thyroid Cancer: What Has Changed in Recent Years?
    Kaliszewski K, Ludwig M, Ludwig B, Mikuła A, et al · · 2022 · cited 34× · PMID 35892901 · DOI 10.3390/cancers14153643
  7. Target Therapy in Thyroid Cancer: Current Challenge in Clinical Use of Tyrosine Kinase Inhibitors and Management of Side Effects.
    Puliafito I, Esposito F, Prestifilippo A, Marchisotta S, et al · · 2022 · cited 29× · PMID 35872981 · DOI 10.3389/fendo.2022.860671
  8. Medullary thyroid carcinoma: recent advances in identification, treatment, and prognosis.
    Bartz-Kurycki MA, Oluwo OE, Morris-Wiseman LF. · · 2021 · cited 26× · PMID 34659736 · DOI 10.1177/20420188211049611

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