NCT02702388

A Trial of Lenvatinib (E7080) in Subjects With Iodine-131 Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 Milligram (mg) Daily Will Provide Comparable Efficacy to a 24 mg Starting Dose, But Have a Better Safety Profile

Completed Phase 2 Results posted Last updated 24 November 2021

What this trial tests

Phase 2 trial testing Lenvatinib in Thyroid Cancer in 241 participants. Completed in 10 September 2020.

Timeline

8 June 2017

Primary endpoint
12 December 2019

10 September 2020

Quick facts

Lead sponsor	Eisai Inc.
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	241
Start date	8 June 2017
Primary completion	12 December 2019
Estimated completion	10 September 2020
Sites	101 locations across Denmark, France, Italy, Russia, Belgium, Sweden, United Kingdom, Germany

Drugs / interventions tested

• Lenvatinib (LENVATINIB) — full drug profile →
• Lenvatinib matching placebo — full drug profile →

Conditions studied

• Thyroid Cancer — all drugs for Thyroid Cancer →

Sponsor

Eisai Inc. — full company profile →

Who can join

18 and older, 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) as of Week 24 (ORR24wk) Primary · From the date of randomization up to Week 24

ORR as of Week 24 was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) as of the Week 24 time point or earlier, as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.

Group	Value	95% CI
Lenvatinib 24 mg	57.3	46.1 – 68.5
Lenvatinib 18 mg	40.3	29.3 – 51.2

Percentage of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) in the First 24 Weeks Primary · Baseline up to Week 24

This outcome measure reports TEAEs in the first 24 weeks only. A TEAE was defined as any adverse event (AE) that had an onset date on or after the first dose of study drug up to 28 days following the last dose of study drug, or a worsening in severity from Baseline (pretreatment). In addition, if an AE reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, it was also counted as a TEAE. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as

Group	Value	95% CI
Lenvatinib 24 mg	61.3
Lenvatinib 18 mg	57.1

Progression-free Survival (PFS) Secondary · Time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurs first up to approximately 2 years 6 months

PFS, defined as the time from the date of randomization to the date of first documentation of PD, or date of death, whichever occurs first, as measured by RECIST V1.1. PD: 20% increase in the sum of the pertinent diameters (SOD) of target lesions, taking as reference the smallest sum SOD recorded since the treatment started or the appearance of one or more new lesions. PFS was analyzed using the Kaplan-Meier method. As planned, data for this endpoint was analyzed and collected till Primary completion date.

Group	Value	95% CI
Lenvatinib 24 mg	NA	22.1 – NA
Lenvatinib 18 mg	24.4	14.7 – NA

PFS After Next Line of Treatment (PFS2) Secondary · Time from randomization to PD on next-line treatment or death from any cause, whichever occurs first up to approximately 2 years 6 months

PFS2, defined as the time from randomization to PD on next-line treatment, or death from any cause, whichever occurred first, as measured by RECIST V1.1. PD: 20% increase in the SOD of target lesions, taking as reference the smallest sum SOD recorded since the treatment started or the appearance of one or more new lesions. PFS was analyzed using the Kaplan-Meier method. As planned, data for this endpoint was analyzed and collected till Primary completion date.

Group	Value	95% CI
Lenvatinib 24 mg	NA	NA – NA
Lenvatinib 18 mg	NA	22.1 – NA

Number of Participants With TEAE and Serious Adverse Events (SAEs) Secondary · From date of first administration of study drug up to 28 days after last dose of study drug up to approximately 3 years 3 months

TEAEs were defined as those AEs that occurred (or worsened, if present at Baseline) after the first dose of study drug through 28 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. SAE was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapa

TEAE

Group	Value	95% CI
Lenvatinib 24 mg	75
Lenvatinib 18 mg	76

SAE

Group	Value	95% CI
Lenvatinib 24 mg	26
Lenvatinib 18 mg	35

Time to Treatment Discontinuation Due to an Adverse Event (AE) Secondary · From date of first administration of study drug up to approximately 2 years 6 months

Time to Treatment Discontinuation due to an AE (such as abdominal distention, appendicitis perforated, arthralgia, anemia, etc) was analyzed using the Kaplan-Meier method. As planned, data for this endpoint was analyzed and collected till Primary completion date.

Group	Value	95% CI
Lenvatinib 24 mg	NA	NA – NA
Lenvatinib 18 mg	NA	84.3 – NA

Number of Dose Reductions Secondary · From date of first administration of study drug up to approximately 2 years 6 months

Number of dose reduction was reported as number of participants who underwent one or more number of dose reductions. As planned, data for this endpoint was analyzed and collected till Primary completion date.

Group	Value	95% CI
Lenvatinib 24 mg	17
Lenvatinib 18 mg	20
Lenvatinib 24 mg	20
Lenvatinib 18 mg	13
Lenvatinib 24 mg	13
Lenvatinib 18 mg	8
Lenvatinib 24 mg	3
Lenvatinib 18 mg	4

Time to First Dose Reduction Secondary · From date of first administration of study drug up to approximately 2 years 6 months

Time to First Dose Reduction was analyzed using the Kaplan-Meier method. As planned, data for this endpoint was analyzed and collected till Primary completion date.

Group	Value	95% CI
Lenvatinib 24 mg	15.3	12.1 – 20.1
Lenvatinib 18 mg	24.1	11.1 – 35.9

Model Predicted Apparent Total Clearance (CL/F) Following Oral Dosing of Lenvatinib Secondary · Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days)

Sparse pharmacokinetic (PK) samples (approximately 9 per participant) were collected and analyzed using a population PK approach to estimate PK parameters. Lenvatinib total plasma concentration data were pooled with data from studies E7080-G000-303 (NCT01321554) and E7080-G000-201 (NCT00784303), and a population PK model was applied to the pooled dataset. Individual predicted CL/F for lenvatinib was then derived from the PK model by starting dose.

Group	Value	95% CI
Lenvatinib 24 mg	6.408	± 1.945
Lenvatinib 18 mg	6.243	± 2.278

Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib Secondary · Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days)

Sparse PK samples (approximately 9 per participant) were collected and analyzed using a population PK approach to estimate PK parameters. Lenvatinib total plasma concentration data were pooled with data from studies E7080-G000-303 (NCT01321554) and E7080-G000-201 (NCT00784303), and a population PK model was applied to the pooled dataset. Individual predicted AUC for lenvatinib was then derived from the PK model by starting dose.

Group	Value	95% CI
Lenvatinib 24 mg	3747	± 1295
Lenvatinib 18 mg	3370	± 4438

Baseline Level Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Vascular Endothelial Growth Factor (VEGF), Soluble Tie-2, Angiopoietin-2 (Ang-2) and Fibroblast Growth Factor-23 (FGF23) Levels Secondary · Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days)

Per the planned population PK/PD analysis for this endpoint, Arms/Groups were combined and lenvatinib total plasma concentration and serum biomarker data for VEGF, Ang-2, soluble Tie-2, and FGF23 from this study were combined with data from study E7080-G000-303 (NCT01321554). The relationship between lenvatinib exposure at the time of measurement of biomarker was described using PK/PD modelling. Initially, PK/PD models were developed individually for each biomarker and then combined into a single combined model. Changes in biomarker levels over time related to lenvatinib exposure were best des

VEGF

Group	Value	95% CI
Lenvatinib or Placebo - All Participants	0.370	0.355 – 0.385

Tie-2

Group	Value	95% CI
Lenvatinib or Placebo - All Participants	14.6	14.4 – 14.8

Ang-2

Group	Value	95% CI
Lenvatinib or Placebo - All Participants	3.36	3.26 – 3.46

FGF23

Group	Value	95% CI
Lenvatinib or Placebo - All Participants	0.0990	0.0949 – 0.103

Mean Residence Time (MRT) Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and VEGF, Soluble Tie-2, Ang-2 and FGF23 Levels Secondary · Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 8: predose, Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 22: optionally at predose; Cycle 2 Day 1: predose and 2-12 hours postdose (Cycle length=28 days)

Per the planned population PK/PD analysis for this endpoint, Arms/Groups were combined and lenvatinib total plasma concentration and serum biomarker data for VEGF, Ang-2, soluble Tie-2, and FGF23 from this study were combined with data from study E7080-G000-303 (NCT01321554). The relationship between lenvatinib exposure at the time of measurement of biomarker was described using PK/PD modelling. Initially, PK/PD models were developed individually for each biomarker and then combined into a single combined model. Changes in biomarker levels over time related to lenvatinib exposure were best des

VEGF

Group	Value	95% CI
Lenvatinib or Placebo - All Participants	58.3	23.4 – 93.2

Tie-2

Group	Value	95% CI
Lenvatinib or Placebo - All Participants	354	314 – 394

Ang-2

Group	Value	95% CI
Lenvatinib or Placebo - All Participants	173	134 – 212

FGF23

Group	Value	95% CI
Lenvatinib or Placebo - All Participants	265	185 – 345

Adverse events — posted to ClinicalTrials.gov

Time frame: From date of first administration of study drug up to 28 days after last dose of study drug up to approximately 3 years 3 months. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Lenvatinib 24 mg

Serious: 26/75 (35%)

Deaths: 11/75

Lenvatinib 18 mg

Serious: 35/77 (45%)

Deaths: 19/77

Serious adverse events (85 terms)

Reaction	System	Lenvatinib 24 mg	Lenvatinib 18 mg
Pneumonia	Infections and infestations	—	—
Sepsis	Infections and infestations	—	—
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Malignant pleural effusion	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Cardiac failure	Cardiac disorders	—	—
Cholecystitis	Hepatobiliary disorders	—	—
Post procedural complication	Injury, poisoning and procedural complications	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Pathological fracture	Musculoskeletal and connective tissue disorders	—	—
Pneumothorax	Respiratory, thoracic and mediastinal disorders	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Thrombotic microangiopathy	Blood and lymphatic system disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Coronary artery disease	Cardiac disorders	—	—
Myocardial infarction	Cardiac disorders	—	—
Pleuropericarditis	Cardiac disorders	—	—
Ventricular fibrillation	Cardiac disorders	—	—
Retinal vascular occlusion	Eye disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Colitis	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Impaired gastric emptying	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—

Other adverse events (456 terms — click to expand)

Reaction	System	Lenvatinib 24 mg	Lenvatinib 18 mg
Hypertension	Vascular disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Proteinuria	Renal and urinary disorders	—	—
Weight decreased	Investigations	—	—
Nausea	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	—	—
Stomatitis	Gastrointestinal disorders	—	—
Asthenia	General disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Dysphonia	Respiratory, thoracic and mediastinal disorders	—	—
Headache	Nervous system disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—
Oedema peripheral	General disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—
Aspartate aminotransferase increased	Investigations	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Hypocalcaemia	Metabolism and nutrition disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Dizziness	Nervous system disorders	—	—
Dry mouth	Gastrointestinal disorders	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Non-cardiac chest pain	General disorders	—	—
Electrocardiogram QT prolonged	Investigations	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—
Pyrexia	General disorders	—	—
Lipase increased	Investigations	—	—

Most-reported serious reactions: Pneumonia, Sepsis, Malignant neoplasm progression, Malignant pleural effusion, Cardiac failure, Cholecystitis, Post procedural complication, Osteoarthritis.

Data from ClinicalTrials.gov NCT02702388 adverse events section.

Sponsor's own description

This is a multicenter, randomized, double-blind study being conducted as a postmarketing requirement to the US Food and Drug Administration (FDA) to evaluate whether there is a lower starting dosage of lenvatinib 24 mg once daily (QD) that provides comparable efficacy but has a better safety profile in participants with radioiodine-refractory differentiated thyroid cancer RR-DTC with radiographic evidence of disease progression within the prior 12 months.

Publications & conference data

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

1. 2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer.
   Fugazzola L, Elisei R, Fuhrer D, Jarzab B, et al · · 2019 · cited 195× · PMID 31768334 · DOI 10.1159/000502229
2. Updates on the Management of Thyroid Cancer.
   Araque KA, Gubbi S, Klubo-Gwiezdzinska J. · · 2020 · cited 115× · PMID 32040962 · DOI 10.1055/a-1089-7870
3. A Randomized Study of Lenvatinib 18 mg vs 24 mg in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer.
   Brose MS, Panaseykin Y, Konda B, de la Fouchardiere C, et al · · 2022 · cited 64× · PMID 34664662 · DOI 10.1210/clinem/dgab731
4. Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice.
   Tirrò E, Martorana F, Romano C, Vitale SR, et al · · 2019 · cited 63× · PMID 31540307 · DOI 10.3390/genes10090709
5. Novel Targeted Therapies for Metastatic Thyroid Cancer-A Comprehensive Review.
   Al-Jundi M, Thakur S, Gubbi S, Klubo-Gwiezdzinska J. · · 2020 · cited 56× · PMID 32751138 · DOI 10.3390/cancers12082104
6. Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities.
   Lorusso L, Cappagli V, Valerio L, Giani C, et al · · 2021 · cited 51× · PMID 33803747 · DOI 10.3390/ijms22063117
7. 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
8. Real-World Data for Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer (RELEVANT): A Retrospective Multicentric Analysis of Clinical Practice in Austria.
   Rendl G, Sipos B, Becherer A, Sorko S, et al · · 2020 · cited 29× · PMID 33312196 · DOI 10.1155/2020/8834148