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

INCLUSION

1. Subjects must have histologically or cytologically confirmed diagnosis of one of the following differentiated thyroid cancer (DTC) subtypes:

   a. Papillary thyroid cancer (PTC) i. Follicular variant ii. 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) b. Follicular thyroid cancer (FTC) i. Hürthle cell ii. Clear cell iii. Insular

2. Measurable disease meeting the following criteria and confirmed by central radiographic review:

   1. At least 1 lesion of ≥ 1.0 cm in the longest diameter for a non-lymph node or ≥ 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI). If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of ≥ 1.5 cm
   2. Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion
3. Subjects must show evidence of disease progression within 12 months (an additional month will be allowed to accommodate actual dates of performance of screening scans, i.e., within ≤ 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

4. Subjects must be 131I-refractory / resistant as defined by at least one of the following:

   1. One or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan
   2. One or more measurable lesions that has progressed by RECIST 1.1 within 12 months of 131I therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or post-treatment scanning. These subjects must not be eligible for possible curative surgery
   3. Cumulative activity of 131I of > 600 mCi or 22 gigabequerels (GBq), with the last dose administered at least 6 months prior to study entry
5. Subjects may have received 0 or 1 prior VEGF / VEGFR-targeted therapy ( for example sorafenib, sunitinib, pazopanib, etc.)
6. Subjects with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection, will be eligible if they have remained clinically stable, asymptomatic and off of steroids for one month
7. Subjects must be receiving thyroxine suppression therapy and thyroid stimulating hormone (TSH) should not be elevated (TSH should be ≤ 5.50 mcu/mL). When tolerated by the subject, thyroxine dose should be changed to achieve TSH suppression (TSH < 0.50 mcu/mL) and this dose can be changed concurrently upon starting lenvatinib
8. All chemotherapy or radiation-related toxicities must have resolved to < Grade 2 severity, except alopecia and infertility
9. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 − 2
10. Adequately controlled blood pressure with or without antihypertensive medications, defined as BP < 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1
11. Adequate renal function defined as calculated creatinine clearance ≥ 30 mL/min per the Cockcroft and Gault formula

12. Adequate bone marrow function:

    1. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 × 103/μL)
    2. Platelets ≥ 100,000/mm3 (≥ 100 × 109/L)
    3. Hemoglobin ≥ 9.0 g/dL
13. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5

14. Adequate liver function:

    1. Bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome
    2. Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases). if alkaline phosphatase is > 3 × ULN (in absence of liver metastases) or > 5 × ULN (in presence of liver metastases) AND the subject also is known to have bone metastases, the liver-specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of total alkaline phosphatase
15. Males or females age ≥ 18 years at the time of informed consent
16. All females must have a negative serum or urine pregnancy test. Females of childbearing potential and male subjects who are partners of women of childbearing potential must use or their partners must use a highly effective method of contraception
17. Voluntary provision of written informed consent and the willingness and ability to comply with all aspects of the protocol

EXCLUSION

1. Anaplastic or Medullary carcinoma of the thyroid
2. Two or more prior VEGF / VEGFR-targeted therapies or any ongoing treatment for 131I-refractory DTC other than TSH-suppressive thyroid hormone therapy
3. Prior treatment with lenvatinib (E7080)
4. Subjects who have received any anti-cancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug and should have recovered from any toxicity related to previous anti-cancer treatment. This does not apply to the use of TSH-suppressive thyroid hormone therapy
5. Major surgery within 3 weeks prior to the first dose of study drug
6. Subjects having > 1+ proteinuria on urine dipstick testing will undergo 24h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥ 1 g/24h will be ineligible
7. Gastrointestinal malabsorption, or any other condition in the opinion of the investigator that might affect the absorption of lenvatinib (E7080). Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment

9. Prolongation of QTc interval to > 480 msec 10. Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, or similar agents requiring therapeutic international normalized ration (INR) monitoring. (Treatment with low molecular weight heparin (LMWH) is allowed) 11. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug 12. Active infection (any infection requiring treatment) 13. Active malignancy (except for differentiated thyroid carcinoma, 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 14. Known intolerance to any of the study drugs (or any of the excipients) 15. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial 16. Females who are pregnant or breastfeeding