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

NCT02702388 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: E7080-G000-2112014-005199-27
• Study Type: interventional
• Target: 241
• Locations: 16 countries
• Sites: 101

Brief Summary

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.

Conditions

Thyroid Cancer

Keywords

Lenvatinib; E7080; Iodine-131 Refractory Differentiated Thyroid Cancer; Lenvima; Phase 2; RR-DTC

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate (ORR) as of Week 24 (ORR24wk)

  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.

  From the date of randomization up to Week 24

• Percentage of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) in the First 24 Weeks

  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 Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.

  Baseline up to Week 24

Secondary Outcomes (31)

• Progression-free Survival (PFS)

  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 After Next Line of Treatment (PFS2)

  Time from randomization to PD on next-line treatment or death from any cause, whichever occurs first up to approximately 2 years 6 months

• Number of Participants With TEAE and Serious Adverse Events (SAEs)

  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

• Time to Treatment Discontinuation Due to an Adverse Event (AE)

  From date of first administration of study drug up to approximately 2 years 6 months

• Number of Dose Reductions

  From date of first administration of study drug up to approximately 2 years 6 months

Study Arms (2)

24 mg Lenvatinib

EXPERIMENTAL

Participants will receive 24 mg once daily (QD) as the starting dose. Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, or 8 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.

Drug: Lenvatinib; Drug: Lenvatinib matching placebo

18 mg Lenvatinib

EXPERIMENTAL

Participants will receive 18mg QD as the starting dose. Dose reductions will occur in succession based on the previous dose level (18,14, 10, 8, or 4 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.

Drug: Lenvatinib; Drug: Lenvatinib matching placebo

Interventions

Lenvatinib DRUG

Lenvatinib capsule.

Also known as: Lenvima, E7080

18 mg Lenvatinib; 24 mg Lenvatinib

Lenvatinib matching placebo DRUG

Lenvatinib matching placebo capsule.

18 mg Lenvatinib; 24 mg Lenvatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically or cytologically confirmed diagnosis of one of the following differentiated thyroid cancer (DTC) subtypes:
• Papillary thyroid cancer (PTC)
• Follicular variant
• Variants (including but not limited to tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin's-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated)
• Follicular thyroid cancer (FTC)
• Hurthle cell
• Clear cell
• Insular
• Measurable disease meeting the following criteria and confirmed by central radiographic review:
• At least 1 lesion of greater than or equal to (\>=)1.0 centimeter (cm) in the longest diameter for a non-lymph node or \>=1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) using computed tomography/magnetic resonance imaging (CT/MRI). If there is only 1 target lesion and it is a non-lymph node, it should have a longest diameter of \>=1.5 cm.
• Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.
• Participants must show evidence of disease progression within 12 months (an additional month will be allowed to accommodate actual dates of performance of screening scans, that is, within less than or equal to \<=13 months) prior to signing informed consent, according to RECIST 1.1 assessed and confirmed by central radiographic review of CT and/or MRI scans.
• Participants must be Iodine-131 refractory/resistant as defined by at least one of the following:
• One or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan.
• One or more measurable lesions that have progressed according to RECIST 1.1 within 12 months (an additional month will be allowed to accommodate actual dates of performance of screening scans, ie, within ≤13 months) after Iodine-131 therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or posttreatment scanning. These participants must not be eligible for possible curative surgery.

You may not qualify if:

• Anaplastic or medullary carcinoma of the thyroid.
• Diagnosed with meningeal carcinomatosis.
• Two or more prior vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR)-targeted therapies or any ongoing treatment for RR-DTC other than TSH-suppressive thyroid hormone therapy.
• Prior treatment with lenvatinib.
• Participants who have received any anticancer treatment within 21 days or any investigational agent within 30 days (or 5 half-lives) prior to the first dose of study drug and should have recovered from any toxicity related to previous anticancer treatment. This does not apply to the use of TSH suppressive thyroid hormone therapy.
• Major surgery (example, laparotomy, thoracotomy or joint replacement) within 3 weeks prior to randomization or elective surgery scheduled to be performed during the study.
• Participants having \>1+ proteinuria on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein \>=1 g/24 h will be ineligible.
• Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of study drug.
• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebral vascular accident within 6 months of the first dose of study drug, or cardiac arrhythmia associated with hemodynamic instability.
• Prolongation of corrected QT interval (QTc) to \>480 ms as demonstrated by a repeated electrocardiogram (ECG) or a clinically significant ECG abnormality, including a marked prolonged QT/QTc interval (example, a repeated demonstration of a QTc interval \>500 ms).
• Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
• Active infection (any infection requiring treatment).
• Active malignancy (except for DTC or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 24 months.
• Bleeding or thrombotic disorders.
• Known intolerance to study drug (or any of the excipients).

Sponsors & Collaborators

• Eisai Inc.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (101)

Facility#1

La Jolla, California, 92093, United States

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San Diego, California, 92307, United States

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Torrance, California, 90502, United States

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Washington D.C., District of Columbia, 20010, United States

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Boston, Massachusetts, 02114, United States

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Facility #2

Boston, Massachusetts, 02115, United States

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Ann Arbor, Michigan, 48109, United States

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Detroit, Michigan, 48201, United States

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Facility#2

Morristown, New Jersey, 07962, United States

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Summit, New Jersey, 07902, United States

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The Bronx, New York, 10461, United States

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Columbus, Ohio, 43210, United States

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Portland, Oregon, 97239, United States

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Philadelphia, Pennsylvania, 19104, United States

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Philadelphia, Pennsylvania, 19111, United States

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Seattle, Washington, 98109, United States

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Darlinghurst, New South Wales, Australia

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Saint Leonards, New South Wales, Australia

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Royal Brisbane and Women's Hospital

Brisbane, Queensland, 4006, Australia

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Facility#2

Chermside, Queensland, Australia

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Herston, Queensland, Australia

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Melbourne, Victoria, Australia

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Nedlands, Western Australia, Australia

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Melbourne, Australia

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Saint Leonards, Australia

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Edegem, Antwerpen, 2650, Belgium

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Brussels, Brussels Capital, 1200, Belgium

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Namur, 5000, Belgium

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Namur, Belgium

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Calgary, Alberta, Canada

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Toronto, Ontario, Canada

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Québec, Canada

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Odense, Region Syddanmark, DK-5000, Denmark

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Strasbourg, Bas-Rhin, France

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Caen, Calvados, 14076, France

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Dijon, Cote-d'Or, 21079, France

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Bordeaux, Gironde, France

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Angers, Maine-et-Loire, France

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Villejuif, Val-de-Marne, 94805, France

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Villejuif, Val-de-Marne, France

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Angers, 49933, France

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Bordeaux, 33076, France

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Caen, France

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Dijon, 21079, France

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Lyon, 69373, France

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Paris, 75013, France

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Tübingen, Baden-Wurttemberg, 72076, Germany

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Würzburg, Bavaria, 97080, Germany

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Hanover, Lower Saxony, 30625, Germany

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Essen, North Rhine-Westphalia, Germany

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Essen, North Rhine-Westphalia, Germany

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Essen, 45147, Germany

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Leipzig, Germany

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Petah Tikva, Israel

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Facility #6

Rome, Lazio, 144, Italy

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Rome, Lazio, Italy

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Facility #2

Rome, Lazio, Italy

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Facility #3

Rome, Lazio, Italy

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Milan, Lombardy, Italy

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Milan, Lombardy, Italy

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Milan, Lombardy, Italy

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Milan, Lombardy, Italy

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Livorno, Tuscany, 57100, Italy

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Pisa, Tuscany, Italy

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Facility #6

Milan, 20122, Italy

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Milan, 20149, Italy

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Pisa, 56124, Italy

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Roma, Italy

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Rozzano, Italy

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Torino, Italy

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Viagrande, Italy

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Kielce, Poland

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Cluj-Napoca, Cluj, 400058, Romania

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Bucharest, 11863, Romania

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Saint Petersburg, Leningradskaya O, 197758, Russia

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Moscow, 115478, Russia

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Moscow, 117036, Russia

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Moscow, Russia

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Moscow, Russia

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Obninsk, 249036, Russia

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Saint Petersburg, 197758, Russia

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Saint Petersburg, Russia

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Saint Petersburg, Russia

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Busan, 49241, South Korea

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Goyang-si, South Korea

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Seoul, 135-710, South Korea

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Seoul, 137-701, South Korea

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Seoul, South Korea

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Seoul, South Korea

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Barcelona, Catalonia, Spain

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Madrid, Madrid, Communidad Delaware, Spain

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Badalona, 8035, Spain

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Barcelona, 8036, Spain

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Madrid, 28034, Spain

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Madrid, Spain

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Madrid, Spain

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Málaga, 29010, Spain

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Gothenburg, SE-41345, Sweden

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Lund, SE-22185, Sweden

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London, City of London, United Kingdom

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Glasgow, Glasgow City, United Kingdom

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Related Publications (2)

• Taylor MH, Leboulleux S, Panaseykin Y, Konda B, de La Fouchardiere C, Hughes BGM, Gianoukakis AG, Park YJ, Romanov I, Krzyzanowska MK, Garbinsky D, Sherif B, Pan JJ, Binder TA, Sauter N, Xie R, Brose MS. Health-related quality-of-life analyses from a multicenter, randomized, double-blind phase 2 study of patients with differentiated thyroid cancer treated with lenvatinib 18 or 24 mg/day. Cancer Med. 2023 Feb;12(4):4332-4342. doi: 10.1002/cam4.5308. Epub 2022 Dec 4.

  PMID: 36464853 DERIVED

• Brose MS, Panaseykin Y, Konda B, de la Fouchardiere C, Hughes BGM, Gianoukakis AG, Joo Park Y, Romanov I, Krzyzanowska MK, Leboulleux S, Binder TA, Dutcus C, Xie R, Taylor MH. A Randomized Study of Lenvatinib 18 mg vs 24 mg in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer. J Clin Endocrinol Metab. 2022 Feb 17;107(3):776-787. doi: 10.1210/clinem/dgab731.

  PMID: 34664662 DERIVED

MeSH Terms

Conditions

Thyroid Neoplasms

Interventions

lenvatinib

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Results Point of Contact

• Title: Eisai Medical Information
• Organization: Eisai Inc.

esi_oncmedinfo@eisai.com

1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2016
• First Posted: March 8, 2016
• Study Start: June 8, 2017
• Primary Completion: December 12, 2019
• Study Completion: September 10, 2020
• Last Updated: November 24, 2021
• Results First Posted: January 11, 2021

Record last verified: 2020-12

Locations

GB (2); BE (4); IL (1); RO (2); PL (1); CA (3); SE (2); IT (17); DK (1); ES (8); FR (13); AU (9); RU (9); KR (6); US (16); DE (7)