A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer (DTC)

NCT ID: NCT01321554

Last Updated: 2023-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 392 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-03-17
• Study Completion Date: 2019-03-19

Brief Summary

This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study to compare the progression free survival, overall response rate (ORR) and safety of participants treated with lenvatinib 24 mg by continuous once daily oral dosing versus placebo. The study is conducted in 3 phases: a Prerandomization Phase (screening and baseline period), a Randomization Phase (double-blind treatment period), and an Extension Phase (Optional Open Label (OOL) Lenvatinib Treatment Period and a follow-up period).

Detailed Description

Randomization Phase: Participants will receive blinded study drug (lenvatinib/placebo) in 2:1 ratio until documentation of disease progression (confirmed by independent imaging review), development of unacceptable toxicity, or withdrawal of consent. After having completed the primary analysis, subjects treated with lenvatinib who have not experienced disease progression may request to continue open label lenvatinib at the same dose, according to the clinical judgment of the investigator. Participants who discontinue treatment for any reason other than disease progression will be followed in the Randomization Phase until disease progression or start of another anticancer treatment; these participants then enter the Extension Phase for survival follow-up. Extension Phase: Participants in the placebo arm who have disease progression confirmed by IIR could request to enter the OOL Lenvatinib Treatment Period and receive lenvatinib treatment. Participants will receive lenvatinib treatment until disease progression (investigator's assessment), development of intolerable toxicity, or withdrawal of consent. Participants who had disease progression during the Randomization Phase and did not enter the OOL Lenvatinib Treatment Period and all participants who discontinued lenvatinib treatment in the OOL Lenvatinib Treatment Period will enter the follow-up period. Participants will be followed for survival, and all anticancer treatments will be recorded until the time of death.

Conditions

Thyroid Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Lenvatinib (Randomization Phase)

Participants randomly assigned in a 2:1 ratio to receive blinded study drug (lenvatinib or matching placebo) until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

Lenvatinib 24 mg (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity.

Placebo (Randomization Phase)

Participants randomly assigned in a 2:1 ratio to receive blinded study drug (lenvatinib or matching placebo) until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Matching placebo (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously.

Lenvatinib 24 mg (OOL Lenvatinib Treatment Period)

Participants will receive lenvatinib 24 mg, orally once daily until documentation of disease progression (confirmed by investigator's assessment), development of unacceptable toxicity, or withdrawal of consent. Placebo treated participants in the Randomization Phase who have progressive disease confirmed by IIR could request to receive lenvatinib treatment in the OOL Treatment Period.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

Lenvatinib 24 mg (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity.

Lenvatinib 20 mg (OOL Lenvatinib Treatment Period)

Participants will receive lenvatinib 20 mg, orally once daily until documentation of disease progression (confirmed by investigator's assessment), development of unacceptable toxicity, or withdrawal of consent. Placebo treated participants in the Randomization Phase who have progressive disease confirmed by IIR could request to receive lenvatinib treatment in the OOL Treatment Period.

Group Type: EXPERIMENTAL

Lenvatinib

Intervention Type: DRUG

Lenvatinib 20 mg (two 10-mg capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity.

The dose of lenvatinib during the OOL Lenvatinib Treatment Period was 24 mg once daily from 03 Oct 2011 until 15 Feb 2013. The dose was lowered at the request of the Data Monitoring Committee to 20 mg on 16 Feb 2013. Thus, more subjects were treated with 24 mg starting dose and the treatment duration was longer for these participants than those whose starting dose was 20 mg.

Interventions

Lenvatinib

Lenvatinib 24 mg (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity.

Intervention Type: DRUG

Placebo

Matching placebo (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously.

Intervention Type: DRUG

Lenvatinib

Lenvatinib 20 mg (two 10-mg capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity.

The dose of lenvatinib during the OOL Lenvatinib Treatment Period was 24 mg once daily from 03 Oct 2011 until 15 Feb 2013. The dose was lowered at the request of the Data Monitoring Committee to 20 mg on 16 Feb 2013. Thus, more subjects were treated with 24 mg starting dose and the treatment duration was longer for these participants than those whose starting dose was 20 mg.

Intervention Type: DRUG

Other Intervention Names

Lenvatinib (Lenvima, E7080); Lenvatinib (Lenvima, E7080)

Eligibility Criteria

Inclusion Criteria

1. Histologically or cytologically confirmed diagnosis of one of the following DTC subtypes: Papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC).

2. Measurable disease according to (RECIST 1.1) and confirmed by central radiographic review.

3. 131 I-refractory/resistant disease.

4. Evidence of disease progression within 12 months prior to signing informed consent (+1 month screening window).

5. Prior treatment with 0 or 1 vascular endothelial growth-factor (VEGF) or vascular endothelial growth-factor receptors (VEGFR) targeted therapy.

6. Adequate renal, liver, bone marrow, and blood coagulation function, as defined in the protocol.

Participants were eligible for lenvatinib treatment in the OOL Lenvatinib Treatment Period if the met the following criteria:

1. Placebo-treated participants in the Randomization Phase who had progressive disease (PD) confirmed by IIR, and who requested treatment with lenvatinib.

Exclusion Criteria

1. Anaplastic or medullary carcinoma of the thyroid

2. 2 or more prior VEGF/ VEGFR-targeted therapies

3. Received any anticancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug.

3. Participants with maximum interval between the day of confirmation of PD by IIR and Cycle 1/Day 1 of the OOL Lenvatinib Treatment Period of less than or equal to 3 months.

4. No systemic anticancer treatment during the interval between the day of confirmation of PD by the IIR and Cycle 1/Day 1 of the OOL Lenvatinib Treatment Period.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eisai Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Facility 1

Little Rock, Arkansas, United States

Facility 1

La Jolla, California, United States

Facility 1

Los Gatos, California, United States

Facility 1

Mission Viejo, California, United States

Facility 1

Orange, California, United States

Facility 2

Orange, California, United States

Facility 1

Sacramento, California, United States

Facility 1

Torrance, California, United States

Facility 1

Aurora, Colorado, United States

Facility 1

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

Facility 1

Orlando, Florida, United States

Facility 1

Weston, Florida, United States

Facility 1

Chicago, Illinois, United States

Facility 2

Chicago, Illinois, United States

Facility 1

Indianapolis, Indiana, United States

Facility 1

Lexington, Kentucky, United States

Facility 1

Baltimore, Maryland, United States

Facility 1

Boston, Michigan, United States

Facility 2

Boston, Michigan, United States

Facility 1

Detroit, Michigan, United States

Facility 1

Lansing, Michigan, United States

Facility 1

Minneapolis, Minnesota, United States

Facility 1

Columbia, Missouri, United States

Facility 1

Omaha, Nebraska, United States

Facility 1

Lebanon, New Hampshire, United States

Facility 1

Morristown, New Jersey, United States

Facility 1

Neptune City, New Jersey, United States

Facility 1

New York, New York, United States

Facility 2

New York, New York, United States

Facility 1

The Bronx, New York, United States

Facility 1

Columbus, Ohio, United States

Facility 1

Portland, Oregon, United States

Facility 1

Philadelphia, Pennsylvania, United States

Facility 2

Philadelphia, Pennsylvania, United States

Facility 1

Houston, Texas, United States

Facility 1

Seattle, Washington, United States

Facility 1

Morgantown, West Virginia, United States

Facility 1

Milwaukee, Wisconsin, United States

Facility 1

Rosario, , Argentina

Facility 1

San Miguel de Tucumán, , Argentina

Facility 1

San Salvador de Jujuy, , Argentina

Facility 1

Saint Leonards, New South Wales, Australia

Facility 1

Herston, Queensland, Australia

Facility 1

Hobart, Tasmania, Australia

Facility 1

Melbourne, Victoria, Australia

Facility 1

Heidelberg, , Australia

Facility 1

Vienna, , Austria

Facility 1

Brussels, , Belgium

Facility 1

Edegem, , Belgium

Facility 1

Namur, , Belgium

Facility 1

Brasília, , Brazil

Facility 1

Joinville, , Brazil

Facility 1

Novo Hamburgo, , Brazil

Facility 1

Rio de Janeiro, , Brazil

Facility 1

Salvador, , Brazil

Facility 1

São Paulo, , Brazil

Facility 2

São Paulo, , Brazil

Facility 1

London, Ontario, Canada

Facility 1

Toronto, Ontario, Canada

Facility 1

Montreal, Quebec, Canada

Facility 1

Québec, , Canada

Facility 1

Santiago, , Chile

Facility 2

Santiago, , Chile

Facility 3

Santiago, , Chile

Facility 1

Temuco, , Chile

Facility 1

Viña del Mar, , Chile

Facility 1

Olomouc, , Czechia

Facility 1

Odense, , Denmark

Facility 1

Angers, , France

Facility 1

Bordeaux, , France

Facility 1

Caen, , France

Facility 1

Clermont-Ferrand, , France

Facility 1

Dijon, , France

Facility 1

Lille, , France

Facility 1

Lyon, , France

Facility 1

Marseille, , France

Facility 1

Nice, , France

Facility 1

Paris, , France

Facility 2

Paris, , France

Facility 1

Strasbourg, , France

Facility 1

Vandœuvre-lès-Nancy, , France

Facility 1

Villejuif, , France

Facility 1

Essen, , Germany

Facility 1

Hanover, , Germany

Facility 1

Leipzig, , Germany

Facility 1

Mainz, , Germany

Facility 1

München, , Germany

Facility 1

Tübingen, , Germany

Facility 1

Würzburg, , Germany

Facility 1

Catania, , Italy

Facility 1

Livorno, , Italy

Facility 1

Milan, , Italy

Facility 2

Milan, , Italy

Facility 3

Milan, , Italy

Facility 4

Milan, , Italy

Facility 5

Milan, , Italy

Facility 1

Monserrato, , Italy

Facility 1

Napoli, , Italy

Facility 1

Padua, , Italy

Facility 1

Pisa, , Italy

Facility 1

Roma, , Italy

Facility 2

Roma, , Italy

Facility 1

Rozzano, , Italy

Facility 1

Torino, , Italy

Facility 1

Viagrande, , Italy

Eisai Trial Site 1

Nagoya, Aichi-ken, Japan

Eisai Trial Site 2

Nagoya, Aichi-ken, Japan

Eisai Trial Site 1

Kashiwa, Chiba, Japan

Eisai Trial Site 1

Fukui-shi, Fukui, Japan

Eisai Trial Site 1

Kobe, Hyōgo, Japan

Eisai Trial Site 1

Koto-ku, Tokyo, Japan

Facility 1

Gliwice, , Poland

Facility 1

Kielce, , Poland

Facility 1

Poznan, , Poland

Facility 1

Lisbon, , Portugal

Facility 1

Porto, , Portugal

Facility 1

Bucharest, , Romania

Facility 2

Bucharest, , Romania

Facility 1

Cluj-Napoca, , Romania

Facility 1

Krasnodar, , Russia

Facility 1

Kursk, , Russia

Facility 1

Obninsk, , Russia

Facility 1

Ufa, , Russia

Facility 1

Daejeon, , South Korea

Facility 1

Gyeonggi-do, , South Korea

Facility 1

Seoul, , South Korea

Facility 2

Seoul, , South Korea

Facility 3

Seoul, , South Korea

Facility 1

Uijeongbu-si, , South Korea

Facility 2

Málaga, Andalusia, Spain

Facility 1

Barcelona, Catalonia, Spain

Facility 1

A Coruña, Galicia, Spain

Facility 2

Barcelona, , Spain

Facility 1

L'Hospitalet de Llobregat, , Spain

Facility 1

Madrid, , Spain

Facility 2

Madrid, , Spain

Facility 3

Madrid, , Spain

Facility 4

Madrid, , Spain

Facility 5

Madrid, , Spain

Facility 1

Gothenburg, , Sweden

Facility 1

Lund, , Sweden

Facility 1

Stockholm, , Sweden

Facility 1

Bangkok, , Thailand

Facility 2

Bangkok, , Thailand

Facility 1

Chiang Mai, , Thailand

Facility 1

Khon Kaen, , Thailand

Facility 1

Pathumwan, , Thailand

Facility 1

Aberdeen, , United Kingdom

Facility 1

Glasgow, , United Kingdom

Facility 2

London, , United Kingdom

Facility 3

London, , United Kingdom

Facility 1

Manchester, , United Kingdom

Facility 2

Manchester, , United Kingdom

Facility 1

Sheffield, , United Kingdom

Facility 1

Sutton, , United Kingdom

Countries

United States; Argentina; Australia; Austria; Belgium; Brazil; Canada; Chile; Czechia; Denmark; France; Germany; Italy; Japan; Poland; Portugal; Romania; Russia; South Korea; Spain; Sweden; Thailand; United Kingdom

References

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Tahara M, Kiyota N, Hoff AO, Badiu C, Owonikoko TK, Dutcus CE, Suzuki T, Ren M, Wirth LJ. Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2021 Apr;147:51-57. doi: 10.1016/j.ejca.2020.12.032. Epub 2021 Feb 19.

Reference Type: DERIVED

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Reference Type: DERIVED

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Robinson B, Schlumberger M, Wirth LJ, Dutcus CE, Song J, Taylor MH, Kim SB, Krzyzanowska MK, Capdevila J, Sherman SI, Tahara M. Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer. J Clin Endocrinol Metab. 2016 Nov;101(11):4103-4109. doi: 10.1210/jc.2015-3989. Epub 2016 Aug 22.

Reference Type: DERIVED

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Kiyota N, Schlumberger M, Muro K, Ando Y, Takahashi S, Kawai Y, Wirth L, Robinson B, Sherman S, Suzuki T, Fujino K, Gupta A, Hayato S, Tahara M. Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine-refractory differentiated thyroid cancer. Cancer Sci. 2015 Dec;106(12):1714-21. doi: 10.1111/cas.12826. Epub 2015 Nov 2.

Reference Type: DERIVED

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Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, Dutcus CE, de las Heras B, Zhu J, Sherman SI. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015 Feb 12;372(7):621-30. doi: 10.1056/NEJMoa1406470.

Reference Type: DERIVED

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Other Identifiers

2010-023783-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

E7080-G000-303

Identifier Type: -

Identifier Source: org_study_id