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

Thyroid Cancer Clinical Trial

— SELECT  

Official title:

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01321554
• Other study ID #: E7080-G000-303
• Secondary ID: 2010-023783-41
• Status: Completed
• Phase: Phase 3
• Start date: March 17, 2011
• Est. completion date: March 19, 2019

Study information

• Verified date: March 2020
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 392
• Est. completion date: March 19, 2019
• Est. primary completion date: November 15, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

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.

Inclusion criteria for OOL Lenvatinib Treatment Period :

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.

2. Participants who continued to satisfy specified inclusion and exclusion criteria as presented in the study protocol.

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.

Related Conditions & MeSH terms

• Thyroid Cancer
• Thyroid Diseases
• Thyroid Neoplasms

Intervention

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

Locations

Country	Name	City	State
Argentina	Facility 1	Rosario
Argentina	Facility 1	San Salvador de Jujuy
Argentina	Facility 1	Tucuman
Australia	Facility 1	Heidelberg
Australia	Facility 1	Herston	Queensland
Australia	Facility 1	Hobart	Tasmania
Australia	Facility 1	Melbourne	Victoria
Australia	Facility 1	Saint Leonards	New South Wales
Austria	Facility 1	Wien
Belgium	Facility 1	Bruxelles
Belgium	Facility 1	Edegem
Belgium	Facility 1	Namur
Brazil	Facility 1	Brasilia
Brazil	Facility 1	Joinville
Brazil	Facility 1	Novo Hamburgo
Brazil	Facility 1	Rio de Janeiro
Brazil	Facility 1	Salvador
Brazil	Facility 1	Sao Paulo
Brazil	Facility 2	Sao Paulo
Canada	Facility 1	London	Ontario
Canada	Facility 1	Montreal	Quebec
Canada	Facility 1	Quebec
Canada	Facility 1	Toronto	Ontario
Chile	Facility 1	Santiago
Chile	Facility 2	Santiago
Chile	Facility 3	Santiago
Chile	Facility 1	Temuco
Chile	Facility 1	Vina del Mar
Czechia	Facility 1	Olomouc
Denmark	Facility 1	Odense
France	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	Vandoeuvre Les Nancy
France	Facility 1	Villejuif
Germany	Facility 1	Essen
Germany	Facility 1	Hannover
Germany	Facility 1	Leipzig
Germany	Facility 1	Mainz
Germany	Facility 1	Munchen
Germany	Facility 1	Tubingen
Germany	Facility 1	Wurzburg
Italy	Facility 1	Catania
Italy	Facility 1	Livorno
Italy	Facility 1	Milano
Italy	Facility 2	Milano
Italy	Facility 3	Milano
Italy	Facility 4	Milano
Italy	Facility 5	Milano
Italy	Facility 1	Monserrato
Italy	Facility 1	Napoli
Italy	Facility 1	Padova
Italy	Facility 1	Pisa
Italy	Facility 1	Roma
Italy	Facility 2	Roma
Italy	Facility 1	Rozzano
Italy	Facility 1	Torino
Italy	Facility 1	Viagrande
Japan	Eisai Trial Site 1	Fukui-city	Fukui
Japan	Eisai Trial Site 1	Kashiwa	Chiba
Japan	Eisai Trial Site 1	Kobe-city	Hyogo
Japan	Eisai Trial Site 1	Koto-ku	Tokyo
Japan	Eisai Trial Site 1	Nagoya	Aichi
Japan	Eisai Trial Site 2	Nagoya	Aichi
Korea, Republic of	Facility 1	Daejeon
Korea, Republic of	Facility 1	Gyeonggi-do
Korea, Republic of	Facility 1	Seoul
Korea, Republic of	Facility 2	Seoul
Korea, Republic of	Facility 3	Seoul
Korea, Republic of	Facility 1	Uijeongbu
Poland	Facility 1	Gliwice
Poland	Facility 1	Kielce
Poland	Facility 1	Poznan
Portugal	Facility 1	Lisbon
Portugal	Facility 1	Porto
Romania	Facility 1	Bucharest
Romania	Facility 2	Bucharest
Romania	Facility 1	Cluj-Napoca
Russian Federation	Facility 1	Krasnodar
Russian Federation	Facility 1	Kursk
Russian Federation	Facility 1	Obninsk
Russian Federation	Facility 1	Ufa
Spain	Facility 1	Barcelona	Cataluna
Spain	Facility 2	Barcelona
Spain	Facility 1	L'Hospitalet de Llobregat
Spain	Facility 1	La Coruna	Galicia
Spain	Facility 1	Madrid
Spain	Facility 2	Madrid
Spain	Facility 3	Madrid
Spain	Facility 4	Madrid
Spain	Facility 5	Madrid
Spain	Facility 2	Malaga	Andalucia
Sweden	Facility 1	Goteborg
Sweden	Facility 1	Lund
Sweden	Facility 1	Stockholm
Thailand	Facility 1	Bangkok
Thailand	Facility 2	Bangkok
Thailand	Facility 1	Chiang Mai
Thailand	Facility 1	Khon Kaen
Thailand	Facility 1	Pathumwan
United Kingdom	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 States	Facility 1	Aurora	Colorado
United States	Facility 1	Baltimore	Maryland
United States	Facility 1	Boston	Michigan
United States	Facility 2	Boston	Michigan
United States	Facility 1	Bronx	New York
United States	Facility 1	Chicago	Illinois
United States	Facility 2	Chicago	Illinois
United States	Facility 1	Columbia	Missouri
United States	Facility 1	Columbus	Ohio
United States	Facility 1	Detroit	Michigan
United States	Facility 1	Houston	Texas
United States	Facility 1	Indianapolis	Indiana
United States	Facility 1	La Jolla	California
United States	Facility 1	Lansing	Michigan
United States	Facility 1	Lebanon	New Hampshire
United States	Facility 1	Lexington	Kentucky
United States	Facility 1	Little Rock	Arkansas
United States	Facility 1	Los Gatos	California
United States	Facility 1	Milwaukee	Wisconsin
United States	Facility 1	Minneapolis	Minnesota
United States	Facility 1	Mission Viejo	California
United States	Facility 1	Morgantown	West Virginia
United States	Facility 1	Morristown	New Jersey
United States	Facility 1	Neptune	New Jersey
United States	Facility 1	New York	New York
United States	Facility 2	New York	New York
United States	Facility 1	Omaha	Nebraska
United States	Facility 1	Orange	California
United States	Facility 2	Orange	California
United States	Facility 1	Orlando	Florida
United States	Facility 1	Philadelphia	Pennsylvania
United States	Facility 2	Philadelphia	Pennsylvania
United States	Facility 1	Portland	Oregon
United States	Facility 1	Sacramento	California
United States	Facility 1	Seattle	Washington
United States	Facility 1	Torrance	California
United States	Facility 1	Washington	District of Columbia
United States	Facility 1	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  Czechia,  Denmark,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Poland,  Portugal,  Romania,  Russian Federation,  Spain,  Sweden,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	PFS was defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurred first), as determined by blinded IIR using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for the double-blind treatment period (Randomization Phase). Disease progression per RECIST v1.1 was defined as at least a 20 percent (%) relative increase and 5 millimeter (mm) absolute increase in the sum of diameters 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.	Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
Secondary	Overall Response Rate (ORR)	ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by blinded IIR using RECIST 1.1 for target lesions and assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans (for double blind treatment period i.e. Randomization Phase). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR.	Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
Secondary	Overall Survival (OS)	Overall survival measured from the date of randomization until date of death from any cause. Overall survival is adjusted with rank preserving structural failure time.	Date of randomization until date of death from any cause, assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
Secondary	Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve		Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose