| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066474 |
| E.1.2 | Term | Thyroid cancer |
| 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 determine whether a starting dose of lenvatinib 20 mg or 14 mg once daily (QD) will provide comparable efficacy (based on ORR6M) with an improved safety profile compared to 24 mg QD (based on treatment-emergent adverse events [TEAEs] of Grade 3 or higher in the first 6 months after randomization). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate PFS in subjects treated with lenvatinib doses of 24 mg, 20 mg, and 14 mg QD.
To evaluate the PFS after next line of treatment (PFS2) in subjects treated with lenvatinib doses of 24 mg, 20 mg, and 14 mg QD.
To evaluate the safety and tolerability of lenvatinib doses of 24 mg, 20 mg, and 14 mg QD.
To evaluate the pharmacokinetic (PK)/pharmacodynamic relationship between exposure and biomarkers/efficacy/safety.
To evaluate the impact of lenvatinib treatment on Health-Related Quality of Life (HRQoL) as measured by the instruments EQ-5D-3L and FACT-G. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must have histologically confirmed diagnosis of one of the following differentiated thyroid cancersubtypes:
a. Papillary thyroid cancer ◦ Follicular variant ◦ 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 ◦ Hürthle cell ◦ Clear cell ◦ 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 that is serially measurable according to RECIST 1.1 using CT/MRI. If there is only 1 target lesion and it is a non-lymph node, it should have a longest diameter of ≥1.5 cm.
b. Lesions that have had external beam radiotherapy or locoregional therapies such as radiofrequency 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, ie, 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.
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 have progressed according to RECIST 1.1 within 12 months after 131I therapy, despite demonstration of radioiodine avidity at the time of that treatment by pre- or posttreatment 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 with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection, if they have remained clinically stable, asymptomatic, and off steroids for one month.
6.Subjects must be receiving thyroxine suppression therapy and TSH should not be elevated (TSH should be ≤5.50 mCi/mL).When tolerated by the subject, thyroxine dose should be changed to achieve TSH suppression.
7.All chemotherapy- or radiation-related toxicities must have resolved to Grade <2 severity per CTCAE v4.03, except alopecia and infertility.
8. Subjects must have an ECOG Performance Status of 0, 1 or 2.
9.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.
10. Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the Cockcroft and Gault formula.
11.Adequate bone marrow function: a. Absolute neutrophil count ≥1500/mm3 b. Platelets ≥100,000/mm3 c. Hemoglobin ≥9.0 g/dL
12. Adequate blood coagulation function INR ≤1.5.
13.Adequate liver function:
a. Bilirubin ≤1.5 × upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert’s syndrome.
b. Alkaline phosphatase, ALT, and AS ≤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.
14.see protocol
15.see protocol
16.see protocol
17.Females of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with lenvatinib and for at least 1 month after finishing treatment. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, 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. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. Women using oral hormonal contraceptives should add a barrier method.
18.see protocol.
19.see protocol.
|
|
| E.4 | Principal exclusion criteria |
1. Anaplastic or medullary carcinoma of the thyroid.
2. Diagnosed with meningeal carcinomatosis.
3. Two or more prior VEGF/VEGFR-targeted therapies or any ongoing treatment for RR-DTC other
than TSH-suppressive thyroid hormone therapy.
4. Prior treatment with lenvatinib.
5. Subjects who have received any anticancer treatment within 21 days or any investigational agent
within 30 days (or 5 half-lives) prior to the first dose of study drug and should have recovered
from any toxicity related to previous anticancer treatment. This does not apply to the use of TSHsuppressive
thyroid hormone therapy.
6. Major surgery within 3 weeks prior to randomization or elective surgery scheduled to performed
during the study.
7. Subjects having >1+ proteinuria on urine dipstick testing will undergo 24-hour urine collection
for quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24 h will be
ineligible.
8. Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might
affect the absorption of study drug.
9. 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.
10. Prolongation of corrected QT interval (QTc) to >480 ms as demonstrated by a repeated
electrocardiogram (ECG) or a clinically significant ECG abnormality, including a marked
prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval >500 ms).
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 DTC 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 study drug (or any of the excipients).
15. Any medical or other condition that in the opinion of the investigator(s) would preclude the
subject’s participation in a clinical study.
16. Females who are pregnant or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR6M as assessed by investigator using RECIST 1.1. ORR6M is defined as the proportion of subjects with BOR of CR or PR at the Week 24 time point or earlier. Rate of TEAE with CTCAE grades of 3 or higher within 6 months after randomization (as of the Week 24 time point). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ORR6M as assessed by investigator using RECIST 1.1. Rate of TEAE with CTCAE grades of 3 or higher within 6 months after randomization. |
|
| E.5.2 | Secondary end point(s) |
PFS, defined as the time from the date of randomization to the date of first
documentation of disease progression, or date of death, whichever occurs first. PFS censoring rules will be defined in the SAP and will follow FDA guidance. PFS2, defined as the time from randomization to second objective disease progression,
or death from any cause, whichever occurs first. Overall safety profile and tolerability. Time to treatment discontinuation due to an AE. Number of dose reductions.
Time to first dose reduction.
Plasma PK lenvatinib exposure parameters.
Inter-relationships of lenvatinib exposure, changes in thyroglobulin and/or TSH, other exploratory serum biomarkers, and changes in tumor burden and PFS.
Relationship of lenvatinib exposure and changes in BP, and AEs of weight loss, fatigue, nausea, vomiting, diarrhea, and proteinuria CTCAE grades derived from urine protein measurements. Impact of lenvatinib treatment on HRQoL as assessed using the validated instruments EQ-5D-3L and FACT-G. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| lPFS, PFS2, overall safety and tolerability |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| Denmark |
| France |
| Germany |
| Israel |
| Italy |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
The End of Study will occur at the end of the Randomization Phase,
which is defined as when the last subject enrolled completes the Week 24 tumor assessments or discontinues study treatment before Week 24. |
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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