Clinical trial NCT01321554: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer (DTC)
Official title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Lenvatinib (E7080) in 131I-Refractory Differentiated Thyroid Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Thyroid Cancer
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2011-03-23
Enrollment: 392
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 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 outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: 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
measure: Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve
timeFrame: Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Facility 1
state: Arkansas
city: La Jolla
country: United States
facility: Facility 1
state: California
city: Los Gatos
country: United States
facility: Facility 1
state: California
city: Mission Viejo
country: United States
facility: Facility 1
state: California
city: Orange
country: United States
facility: Facility 1
state: California
city: Orange
country: United States
facility: Facility 2
state: California
city: Sacramento
country: United States
facility: Facility 1
state: California
city: Torrance
country: United States
facility: Facility 1
state: California
city: Aurora
country: United States
facility: Facility 1
state: Colorado
city: Washington
country: United States
facility: Facility 1
state: District of Columbia
city: Orlando
country: United States
facility: Facility 1
state: Florida
city: Weston
country: United States
facility: Facility 1
state: Florida
city: Chicago
country: United States
facility: Facility 1
state: Illinois
city: Chicago
country: United States
facility: Facility 2
state: Illinois
city: Indianapolis
country: United States
facility: Facility 1
state: Indiana
city: Lexington
country: United States
facility: Facility 1
state: Kentucky
city: Baltimore
country: United States
facility: Facility 1
state: Maryland
city: Boston
country: United States
facility: Facility 1
state: Michigan
city: Boston
country: United States
facility: Facility 2
state: Michigan
city: Detroit
country: United States
facility: Facility 1
state: Michigan
city: Lansing
country: United States
facility: Facility 1
state: Michigan
city: Minneapolis
country: United States
facility: Facility 1
state: Minnesota
city: Columbia
country: United States
facility: Facility 1
state: Missouri
city: Omaha
country: United States
facility: Facility 1
state: Nebraska
city: Lebanon
country: United States
facility: Facility 1
state: New Hampshire
city: Morristown
country: United States
facility: Facility 1
state: New Jersey
city: Neptune
country: United States
facility: Facility 1
state: New Jersey
city: Bronx
country: United States
facility: Facility 1
state: New York
city: New York
country: United States
facility: Facility 1
state: New York
city: New York
country: United States
facility: Facility 2
state: New York
city: Columbus
country: United States
facility: Facility 1
state: Ohio
city: Portland
country: United States
facility: Facility 1
state: Oregon
city: Philadelphia
country: United States
facility: Facility 1
state: Pennsylvania
city: Philadelphia
country: United States
facility: Facility 2
state: Pennsylvania
city: Houston
country: United States
facility: Facility 1
state: Texas
city: Seattle
country: United States
facility: Facility 1
state: Washington
city: Morgantown
country: United States
facility: Facility 1
state: West Virginia
city: Milwaukee
country: United States
facility: Facility 1
state: Wisconsin
city: Rosario
country: Argentina
facility: Facility 1
city: San Salvador de Jujuy
country: Argentina
facility: Facility 1
city: Tucuman
country: Argentina
facility: Facility 1
city: Saint Leonards
country: Australia
facility: Facility 1
state: New South Wales
city: Herston
country: Australia
facility: Facility 1
state: Queensland
city: Hobart
country: Australia
facility: Facility 1
state: Tasmania
city: Melbourne
country: Australia
facility: Facility 1
state: Victoria
city: Heidelberg
country: Australia
facility: Facility 1
city: Wien
country: Austria
facility: Facility 1
city: Bruxelles
country: Belgium
facility: Facility 1
city: Edegem
country: Belgium
facility: Facility 1
city: Namur
country: Belgium
facility: Facility 1
city: Brasilia
country: Brazil
facility: Facility 1
city: Joinville
country: Brazil
facility: Facility 1
city: Novo Hamburgo
country: Brazil
facility: Facility 1
city: Rio de Janeiro
country: Brazil
facility: Facility 1
city: Salvador
country: Brazil
facility: Facility 1
city: Sao Paulo
country: Brazil
facility: Facility 1
city: Sao Paulo
country: Brazil
facility: Facility 2
city: London
country: Canada
facility: Facility 1
state: Ontario
city: Toronto
country: Canada
facility: Facility 1
state: Ontario
city: Montreal
country: Canada
facility: Facility 1
state: Quebec
city: Quebec
country: Canada
facility: Facility 1
city: Santiago
country: Chile
facility: Facility 1
city: Santiago
country: Chile
facility: Facility 2
city: Santiago
country: Chile
facility: Facility 3
city: Temuco
country: Chile
facility: Facility 1
city: Vina del Mar
country: Chile
facility: Facility 1
city: Olomouc
country: Czechia
facility: Facility 1
city: Odense
country: Denmark
facility: Facility 1
city: Angers
country: France
facility: Facility 1
city: Bordeaux
country: France
facility: Facility 1
city: Caen
country: France
facility: Facility 1
city: Clermont-Ferrand
country: France
facility: Facility 1
city: Dijon
country: France
facility: Facility 1
city: Lille
country: France
facility: Facility 1
city: Lyon
country: France
facility: Facility 1
city: Marseille
country: France
facility: Facility 1
city: Nice
country: France
facility: Facility 1
city: Paris
country: France
facility: Facility 1
city: Paris
country: France
facility: Facility 2
city: Strasbourg
country: France
facility: Facility 1
city: Vandoeuvre Les Nancy
country: France
facility: Facility 1
city: Villejuif
country: France
facility: Facility 1
city: Essen
country: Germany
facility: Facility 1
city: Hannover
country: Germany
facility: Facility 1
city: Leipzig
country: Germany
facility: Facility 1
city: Mainz
country: Germany
facility: Facility 1
city: Munchen
country: Germany
facility: Facility 1
city: Tubingen
country: Germany
facility: Facility 1
city: Wurzburg
country: Germany
facility: Facility 1
city: Catania
country: Italy
facility: Facility 1
city: Livorno
country: Italy
facility: Facility 1
city: Milano
country: Italy
facility: Facility 1
city: Milano
country: Italy
facility: Facility 2
city: Milano
country: Italy
facility: Facility 3
city: Milano
country: Italy
facility: Facility 4
city: Milano
country: Italy
facility: Facility 5
city: Monserrato
country: Italy
facility: Facility 1
city: Napoli
country: Italy
facility: Facility 1
city: Padova
country: Italy
facility: Facility 1
city: Pisa
country: Italy
facility: Facility 1
city: Roma
country: Italy
facility: Facility 1
city: Roma
country: Italy
facility: Facility 2
city: Rozzano
country: Italy
facility: Facility 1
city: Torino
country: Italy
facility: Facility 1
city: Viagrande
country: Italy
facility: Facility 1
city: Nagoya
country: Japan
facility: Eisai Trial Site 1
state: Aichi
city: Nagoya
country: Japan
facility: Eisai Trial Site 2
state: Aichi
city: Kashiwa
country: Japan
facility: Eisai Trial Site 1
state: Chiba
city: Fukui-city
country: Japan
facility: Eisai Trial Site 1
state: Fukui
city: Kobe-city
country: Japan
facility: Eisai Trial Site 1
state: Hyogo
city: Koto-ku
country: Japan
facility: Eisai Trial Site 1
state: Tokyo
city: Daejeon
country: Korea, Republic of
facility: Facility 1
city: Gyeonggi-do
country: Korea, Republic of
facility: Facility 1
city: Seoul
country: Korea, Republic of
facility: Facility 1
city: Seoul
country: Korea, Republic of
facility: Facility 2
city: Seoul
country: Korea, Republic of
facility: Facility 3
city: Uijeongbu
country: Korea, Republic of
facility: Facility 1
city: Gliwice
country: Poland
facility: Facility 1
city: Kielce
country: Poland
facility: Facility 1
city: Poznan
country: Poland
facility: Facility 1
city: Lisbon
country: Portugal
facility: Facility 1
city: Porto
country: Portugal
facility: Facility 1
city: Bucharest
country: Romania
facility: Facility 1
city: Bucharest
country: Romania
facility: Facility 2
city: Cluj-Napoca
country: Romania
facility: Facility 1
city: Krasnodar
country: Russian Federation
facility: Facility 1
city: Kursk
country: Russian Federation
facility: Facility 1
city: Obninsk
country: Russian Federation
facility: Facility 1
city: Ufa
country: Russian Federation
facility: Facility 1
city: Malaga
country: Spain
facility: Facility 2
state: Andalucia
city: Barcelona
country: Spain
facility: Facility 1
state: Cataluna
city: La Coruna
country: Spain
facility: Facility 1
state: Galicia
city: Barcelona
country: Spain
facility: Facility 2
city: L'Hospitalet de Llobregat
country: Spain
facility: Facility 1
city: Madrid
country: Spain
facility: Facility 1
city: Madrid
country: Spain
facility: Facility 2
city: Madrid
country: Spain
facility: Facility 3
city: Madrid
country: Spain
facility: Facility 4
city: Madrid
country: Spain
facility: Facility 5
city: Goteborg
country: Sweden
facility: Facility 1
city: Lund
country: Sweden
facility: Facility 1
city: Stockholm
country: Sweden
facility: Facility 1
city: Bangkok
country: Thailand
facility: Facility 1
city: Bangkok
country: Thailand
facility: Facility 2
city: Chiang Mai
country: Thailand
facility: Facility 1
city: Khon Kaen
country: Thailand
facility: Facility 1
city: Pathumwan
country: Thailand
facility: Facility 1
city: Aberdeen
country: United Kingdom
facility: Facility 1
city: Glasgow
country: United Kingdom
facility: Facility 1
city: London
country: United Kingdom
facility: Facility 2
city: London
country: United Kingdom
facility: Facility 3
city: Manchester
country: United Kingdom
facility: Facility 1
city: Manchester
country: United Kingdom
facility: Facility 2
city: Sheffield
country: United Kingdom
facility: Facility 1
city: Sutton
country: United Kingdom
facility: Facility 1
Study officials:
References:
citation: Taylor MH, Takahashi S, Capdevila J, Tahara M, Leboulleux S, Kiyota N, Dutcus CE, Xie R, Robinson B, Sherman S, Habra MA, Elisei R, Wirth LJ. Correlation of Performance Status and Neutrophil-Lymphocyte Ratio with Efficacy in Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Lenvatinib. Thyroid. 2021 Aug;31(8):1226-1234. doi: 10.1089/thy.2020.0779. Epub 2021 Apr 29.
citation: 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.
citation: Tahara M, Brose MS, Wirth LJ, Suzuki T, Miyagishi H, Fujino K, Dutcus CE, Gianoukakis A. Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2019 Jan;106:61-68. doi: 10.1016/j.ejca.2018.10.002. Epub 2018 Nov 22.
citation: Tahara M, Schlumberger M, Elisei R, Habra MA, Kiyota N, Paschke R, Dutcus CE, Hihara T, McGrath S, Matijevic M, Kadowaki T, Funahashi Y, Sherman SI. Exploratory analysis of biomarkers associated with clinical outcomes from the study of lenvatinib in differentiated cancer of the thyroid. Eur J Cancer. 2017 Apr;75:213-221. doi: 10.1016/j.ejca.2017.01.013. Epub 2017 Feb 24.
citation: 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.
citation: 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.
citation: 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.