Medullary thyroid cancer [MTC] or radioiodine (131*I) refractory/resistant differentiated thyroid cancer[DTC]: Note: *= to the power. MedDRA version: 16.1 Level: PT Classification code 10027105 Term: Medullary thyroid cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 16.1 Level: PT Classification code 10016935 Term: Follicular thyroid cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl
Conditions
Interventions
Product Name: HOPE
Product Code: E7080
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Lenvatinib
Current Sponsor code: E7080
Concentration unit: mg milligram(s)
Concentration type: equal
Sponsors
Eisai Limited
Eligibility
Sex/Gender
All
Inclusion criteria
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. Pat
Exclusion criteria
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 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 contra
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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). ;Secondary Objective: •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);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;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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;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). | — |
Countries
Australia, France, Italy, Poland, United Kingdom, United States
Contacts
Public ContactMedical Information
Eisai Ltd
Outcome results
None listed