| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 131I-refractory differentiated thyroid cancer (DTC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced thyroid cancer which no longer responds to radioactive iodine therapy. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055107 |
| E.1.2 | Term | Thyroid cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the progression-free survival of subjects with 131I-refractory differentiated thyroid cancer with radiographic evidence of disease progression within the prior 12 months treated with E7080 versus placebo. |
|
| E.2.2 | Secondary objectives of the trial |
SECONDARY OBJECTIVES
To compare ORR (CR and PR) of subjects treated with E7080 versus placebo
To compare Overall Survival of subjects treated with E7080 versus placebo
To compare safety and tolerability of E7080 versus placebo
To assess the PK profile of E7080 in subjects with 131I-refractory DTC
EXPLORATORY OBJECTIVES
To compare Disease Control rate (DCR) (CR, PR, or stable disease [SD]), Clinical Benefit Rate (CBR) (CR, PR + durable SD) and durable SD (duration of SD ≥ 23 weeks) of subjects treated with E7080 versus Placebo
To identify and validate blood and tumor biomarkers which correlate with efficacyrelated endpoints of this study
To identify and validate DNA-sequence variants in genes influencing E7080 ADME
To assess safety and efficacy in the Optional Open Label treatment period |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must have histologically or cytologically confirmed diagnosis of one of the following DTC subtypes:
a. 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. FTC
i. Hürthle cell
ii. Clear cell
iii. Insular
2. Measurable disease meeting the following criteria and confirmed by central radiographic review:
a. 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 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
b. Lesions that have had EBRT or loco-regional therapies such as 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 month
4. Subjects must be 131I-refractory/resistant as defined by at least one of the following:
a. One or more measurable lesions that do not demonstrate iodine uptake on any radioiodine scan
b. 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.
c. Cumulative activity of 131I of >600 mCi or 22 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. Each of the VEGF/VEGFR targeted agents will be counted individually
6. Patients 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 TSH should not be elevated. When tolerated by the subject, thyroxine dose should be changed to achieve TSH suppression and this dose can be changed concurrently upon starting E7080
8. All chemotherapy or radiation-related toxicities must have resolved to <Grade 2 severity, except alopecia and infertility
9. Subjects must have an 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: a. ANC ≥1500/mm3 b. Platelets ≥100,000/mm3 c. Hemoglobin ≥9.0 g/dL
13. Adequate blood coagulation function as evidenced by an INR ≤1.5
14. Adequate liver function: a. Bilirubin ≤1.5 × the ULN except for unconjugated hyperbilirubinemia or Gilbert’s syndrome b. Alkaline phosphatase, ALT and AST ≤3 × the ULN. 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
16. Females must not be lactating or pregnant at Screening or Baseline
17. All females will be considered to be of CBP unless they are postmenopausal or have been sterilized surgically at least 1 month before dosing
18. Females of CBP must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a doublebarrier method, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double-barrier method as described above if she becomes sexually active during study or 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation
19. Male subjects must have had a successful vasectomy or they and their female partners must meet the criteria above.
20. Voluntary agreement to provide informed consent and the willingness and ability to comply with all aspects of the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Anaplastic or Medullary carcinoma of the thyroid
2. Two or more prior VEGF / VEGFR-targeted therapies or any ongoing treatment for 131Irefractory DTC other than TSH-suppressive thyroid hormone therapy
3. Prior treatment with 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 E7080
8. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for all subjects will be progression free survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of PFS will be performed when approximately 214
progression events or deaths without disease progression have occurred in the study population, which is estimated to be approximately 29 months after the first subject is randomized. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are ORR as determined by blinded IIR using RECIST 1.1 and Overall Survival (OS).
Exploratory Efficacy Endpoints are disease control rate (DCR), clinical benefit rate (CBR), and durable stable disease (SD) rate (duration of SD ≥ 23 weeks). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR: CT/MRI neck/chest/abdomen/pelvis and other areas of known disease or newly suspected disease: at screening, every 8 weeks (Randomization Phase) once every 12 weeks and no less frequently than once every 24 weeks (Extension Phase); bone scan every 24 weeks. CT/MRI brain at screening and, if negative, to be repeated if clinically indicated, and within 1 week after a subject achieves a CR. For subjects with a history of treated brain metastases, brain scans at screening and every 8 weeks
OS: every 4 weeks
PK: predose, 0.5-4 hours, and 6-10 hours postdose on C1D1 and C1D15, and predose and 2-12 hours postdose on C2D1. Subsequently, predose only on Day 1 of Cycles 3, 4, 5, and 6.
AEs/SAEs: throughout the study. AEs and concomitant meds collected 30 days from last dose.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Czech Republic |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Spain |
| Thailand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last patient, last visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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