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

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.

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.