| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Medullary thyroid cancer [MTC] or radioiodine (131*I) refractory/resistant differentiated thyroid cancer[DTC]:
Note: *= to the power. |
|
| E.1.1.1 | Medical condition in easily understood language |
Medullary Thyroid Cancer [MTC]
Differentiated Thyroid Cancer [DTC] that is refractory/resistant to Iodine-131 treatment and unresectable (the cancer cannot be removed) |
|
| 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 | 10027105 |
| E.1.2 | Term | Medullary thyroid cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016935 |
| E.1.2 | Term | Follicular thyroid cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10066474 |
| E.1.2 | Term | Thyroid cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033701 |
| E.1.2 | Term | Papillary 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 |
In patients with medullary thyroid cancer [MTC] or radioiodine (131*I) refractory/resistant differentiated thyroid cancer[DTC]:
• Determine the effect of E7080 on the objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) by independent imaging review (IIR).
|
|
| E.2.2 | Secondary objectives of the trial |
•Determine effect on duration of response by IIR
•Measure effect on the disease control rate and clinical benefit rate by IIR
•Determine time to response by IIR
•Evaluate effect on progression free survival by IIR and overall survival
•Evaluate safety and tolerability
•Determine PK profile and PK/PD relationships
•Assess the influence of DNA sequence variants on metabolic enzymes and transporters possibly involved in variability of PK parameters
•Determine biochemical response using tumor markers (thyroglobulin for DTC patients or calcitonin and CEA for MTC patients)
•Assess effect of somatic DNA sequence variants in BRAF, H-, K- and N-Ras and RET/PTC1, 2 and 3 and germline DNA sequence variants in RET and near FOXE1 (rs965513) and NKX2-1 (rs944289) on patient response to study treatment
•Investigate potential correlation of the following biomarkers with efficacy:
•Serum proteome expression
•Serum biomarkers of apoptosis (CASP 3/7, Cytochrome C and M-30 neo-antigen) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must have histologically or cytologically confirmed diagnosis of one of the following:
A. DTC, including any of the following subtypes:
a. Papillary thyroid cancer (PTC)
- Papillary classical (Added per Amendment 02)
- Papillary follicular variant (Revised per Amendment 02)
- Papillary 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) (Revised per Amendment 02)
b. Follicular thyroid cancer (FTC)
- Follicular invasive: minimally or widely (Added per Amendment 02)
- Hürthle cell
- Clear cell
- Insular
B. MTC
2. Measurable disease meeting the following criterion (revised per Amendment 01):
a. At least one lesion (≥ 1.5 cm in longest diameter for non-lymph nodes and ≥2.0 cm in longest diameter for lymph nodes) which is serially and accurately measurable according to Modified RECIST using either CT/MRI
b. Lesions that have had EBRT must show evidence of progressive disease based on Modified RECIST to be deemed a target lesion
3. Patients must show evidence of disease progression by RECIST using site assessment of CT/MRI scans within 12 months (+1 month to allow for variances in patient scanning intervals) prior to study entry (revised per Amendment 01).
4. Patients with DTC must be 131I refractory/resistant as defined by at least one of the following:
a. One or more measurable lesions that have never demonstrated 131I uptake on any radioiodine scan based on either collected scans or reports,
b. One or more measurable lesions with disease progression by RECIST within 12 months (+1 month to allow for variances in patient scanning intervals) of 131I therapy despite 131I uptake on radioiodine scan based on site assessment of CT/MRI scans (revised per Amendment 01).
c. 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. ( Moved to Criterion 2 per Amendment 1)
5. Patients must have unresectable disease. Patients must not be amenable to surgery.
6. Patients with DTC must be receiving thyroxine suppression therapy and TSH should not be elevated (TSH should be ≤ 5.50 mcu/mL) (revised per Amendment 01). When tolerated by the patient, thyroxine dose should be changed to achieve TSH suppression (TSH < 0.50 mcu/mL) and this dose can be changed concurrently upon starting E7080.
7. Patients must not have had chemotherapy, major surgery, monoclonal antibody therapy or experimental therapy within the 30 days prior to the start of E7080 administration (6 weeks for nitrosoureas or mitomycin C).
• Prior exposure to receptor tyrosine kinase inhibitors and antiangiogenic agents (including but not limited to AEE788, AG-013736, AMG706, AZD2171, bevacizumab, CP-547,632, dasatinib, enzataurin, imatinib mesylate, lenalidomide, pazopanib, sorafenib, sunitinib, thalidomide, vatalanib [PTK787/ZK 222584], VEGF Trap, and ZD6474) is allowed with at least 30 days between this therapy and the start of E7080 treatment.
8. All chemotherapy or radiation-related toxicities must have resolved to < Grade 2 severity, except alopecia and infertility.
9. Prior thyroidectomy is allowed.
10. Blood pressure should be well controlled (≤140/90 mm Hg at Pre-Treatment) with or without antihypertensive medications (revised per Amendment 01).
11. Patients must be aged ≥18 years.
12. Patients must have an ECOG Performance Status of 0 to 2.
13. Patients must have signed a written informed consent prior to any study specific Pre-Treatment procedures with the understanding that the patient may withdraw consent at any time without prejudice (revised per Amendment 01).
14. Patients must be willing and able to comply with the protocol guidelines for the duration of the study.
Note: * = to the power.
|
|
| E.4 | Principal exclusion criteria |
Patients with any one of the following are not eligible to participate in this study:
1. Anaplastic thyroid carcinoma, thyroid lymphoma, mesenchymal tumors of the thyroid, metastases to the thyroid
2. Any of the following laboratory measurements:
a. hemoglobin < 9 g/dL (5.6 mmol/L) (may be corrected with growth factor or transfusions);
b. neutrophils < 1.5 x 109/L; platelets < 100 x 109/L
c. bilirubin > 1.5 times the upper limit of normal (ULN) and other liver function tests (AST, ALT and alkaline phosphatase) with values greater than three times ULN; (in the case of liver metastases > five times ULN). If alkaline phosphatase is greater than three times the ULN (in the absence of liver metastasis) or greater than five times the ULN (in the presence of liver metastasis), and the patient is known to have bone metastasis, the liver specific alkaline phosphatase must be separated from the total and the liver specific alkaline phosphatase alone should be used to assess liver function
d. Creatinine clearance is greater than or equal to 60 mL/min per the Cockcroft and Gault formula, patient is eligible (Appendix 9) (revised per Amendment 02)
3. Significant cardiovascular impairment (history of congestive heart failure > NYHA Class II, unstable angina or myocardial infarction within 6 months of study start, or serious cardiac arrhythmia)
4. Active hemoptysis (bright red blood of at least ½ teaspoon) in the 28 days prior to study entry
5. Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, with a therapeutic international normalized ratio (INR)
6. Positive history of HIV, active hepatitis B or active hepatitis C or severe/uncontrolled intercurrent illness or infection
7. Organ allografts requiring immunosuppressive treatment
8. Prior malignancy, other than non-melanoma skin cancer or cervical carcinoma in situ, unless the prior malignancy was diagnosed and definitively treated ≥ 5 years previously with no subsequent evidence of recurrence
9. Brain or leptomeningeal (central nervous system [CNS]) metastases. Patients with stable or previously irradiated brain metastases are also excluded (Revised per Amendment 01)
10. Marked baseline prolongation of QT/QTc interval (QTc interval ≥ 500 msec) using the Fridericia method (QTc = QT/RR0.33) for QTc analysis
11. > 1+ proteinuria on urine dipstick testing or >30 mg/dL. Patients with proteinuria > 1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Subjects with 24-hour protein ≥1 g/24 hours will be ineligible (revised per Amendment 02).
12. History of gastrointestinal malabsorption or having undergone surgery requiring gastrointestinal anastomoses within 4 weeks of starting therapy or who have not recovered from major surgery within 4 weeks of starting therapy
13. Women who are pregnant or breast-feeding; women of childbearing potential with a positive pregnancy test at Pre-Treatment or no pregnancy test. Women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception (including two forms of contraception, one of which must be a barrier method) in the opinion of the investigator (revised per Amendment 01)
• Perimenopausal women must be amenorrheic for at least 12 months to be considered of non childbearing potential.
• Fertile males with female partners who are not willing to use contraception or whose female partners are not using adequate contraceptive protection are excluded.
14. Other significant disease or disorder that, in the investigator’s opinion, would exclude the patient from the study
15. Previous E7080 therapy
16. Previous treatment with an investigational drug, with the exception of those identified in inclusion criteria 8, within the 30 days prior to the start of E7080 administration
(Previous 17. Deleted per Amendment 01)
17. History of alcoholism, drug addiction, psychiatric or psychological condition, or social situation which, in the opinion of the investigator, would impair study compliance
18. Legal incapacity.
Note: * = to the power.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Key outcomes measured
Determine the effect of E7080 on the objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) by independent imaging review (IIR)
Determine the pharmacokinetic (PK) profile and the pharmacokinetic/pharmacodynamic (PK/PD) relationships of E7080 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients will continue study treatment until disease progression, development of unacceptable toxicity, death, withdrawal of consent or sponsor discontinuation of E7080 development.
For patients who have achieved SD for at least 6 months or a PR and have no alternative treatment options and 1) develop a single site of disease progression (DP) which can be treated with external beam radiotherapy or 2) develop DP during interruption of E7080 treatment, the investigator may request the sponsor to allow continuation of E7080 until the next DP using the Modified RECIST Criteria. Patients who satisfy these criteria and are allowed to continue E7080 beyond DP will be required to continue all the Schedule of Assessments until discontinuation of E7080 (Amendment 03). |
|
| E.5.2 | Secondary end point(s) |
Determine the effect of E7080 on duration of response by IIR
Measure the effect of E7080 on the disease control rate (DCR) and clinical benefit rate (CBR) by IIR
Determine the time to response by IIR
Evaluate the effect of E7080 on progression free survival (PFS) by IIR and overall survival (OS)
Evaluate the safety and tolerability of E7080
Assess the influence of DNA sequence variants on metabolic enzymes and transporters possibly involved in variability of E7080 PK parameters by genotyping patient’s genomic DNA using the Affymetrix DMET™ array
Determine the biochemical response using tumor markers (either thyroglobulin for patients with DTC or calcitonin and carcinoembryonic antigen [CEA] for patients with MTC)
Assess the effect of somatic DNA sequence variants in BRAF, H-, K- and N-Ras and RET/PTC1, 2 and 3 andgermline DNA sequence variants in RET and near FOXE1 (rs965513) and NKX2-1 (rs944289) on patient response to study treatment
- Investigate the potential correlation of the following biomarkers with efficacy:
-Serum proteome expression
-Serum biomarkers for monitoring markers of apoptosis |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will continue study treatment until disease progression, development of unacceptable toxicity, death, withdrawal of consent or sponsor discontinuation of E7080 development.
For patients who have achieved SD for at least 6 months or a PR and have no alternative treatment options and 1) develop a single site of disease progression (DP) which can be treated with external beam radiotherapy or 2) develop DP during interruption of E7080 treatment, the investigator may request the sponsor to allow continuation of E7080 until the next DP using the Modified RECIST Criteria. Patients who satisfy these criteria and are allowed to continue E7080 beyond DP will be required to continue all the Schedule of Assessments until discontinuation of E7080 (Amendment 03). |
|
| 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 | No |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
|
| 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 primary analysis will be conducted when all patients enrolled in each histologic stratum complete 8 cycles of study treatment or are off study treatment, whichever occurs first.
End of study is when all patients are no longer being followed for survival. Sponsor may terminate survival follow-up during the Extension Phase after completion of the primary study analysis. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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