| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anaplastic Thyroid Cancer (ATC) |
| Carcinoma anaplastico della tiroide (ATC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with Anaplastic Thyroid cancer who have not responded to surgery followed by radiotherapy, or drug treatment |
| Soggetti con carcinoma anaplastico della tiroide che non hanno risposto a chirurgia seguita da radioterapia o trattamento farmacologico |
|
| 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 | 10002240 |
| E.1.2 | Term | Anaplastic 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 evaluate ORR (CR and PR) by investigator
review in subjects with ATC treated with lenvatinib. |
| Valutare il tasso di risposta obiettiva (ORR) (risposta completa [RC] e risposta parziale [RP]) in base alla valutazione dello sperimentatore, in soggetti con ATC trattati con lenvatinib |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate 12-week PFS
- To evaluate 6-month OS
- To evaluate median PFS and median OS
- To evaluate safety and tolerability of lenvatinib in subjects with ATC |
- Valutare la sopravvivenza libera da progressione (PFS) a 12 settimane
- Valutare la sopravvivenza complessiva (OS) a 6 mesi
- Valutare la PFS mediana e l’OS mediana
- Valutare la sicurezza e la tollerabilità di lenvatinib in soggetti con ATC
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females age ≥ 18 years at the time of informed consent form (ICF).
2. Subjects must have histological diagnosis consistent of ATC. Cytologic diagnosis by fine needle aspiration alone is not sufficient. Histologic diagnosis may be made by core needle biopsy, incisional biopsy, thyroidectomy, or other surgical biopsy. Fresh tumor biopsies (re-biopsy) should be obtained whenever feasible. The central pathology review may take place prior to or after the subject starts treatment with lenvatinib.
a. Central review of pathology is required for study participation, but not required prior to enrollment or start of treatment in order to avoid delay. If the results of central pathology review are not available prior to the start of study treatment, the confirmation of diagnosis of ATC at the local laboratory is mandatory prior to scheduled start of treatment with lenvatinib.
b. If central pathology review indicates a diagnosis other than ATC, the subject may continue treatment with lenvatinib per standard of care, at the discretion of the treating investigator. Subjects deemed to have another diagnosis (not ATC) will be taken off this study and replaced for the purpose of efficacy analyses.
c. Differentiated thyroid carcinoma (DTC) with focus loci of ATC is allowed. If a subject has pathology showing a small focus of ATC arising out of DTC and the measurable disease is not fully consistent with ATC, confirmation of ATC by biopsy is required.
d. An incidental focus of medullary thyroid cancer (MTC), DTC, and/or poorly differentiated thyroid cancer in a subject with ATC is allowed.
e. Histological diagnosis of ATC made through surgical resection is also acceptable.
3. Prior neoadjuvant, adjuvant or palliative chemotherapy for ATC is allowed.
4. Measurable disease based on investigator’s assessments meeting the following criteria:
a. At least 1 lesion of ≥ 10 mm in the longest diameter for a non-lymph node or ≥ 15 mm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computerized tomography (CT) or magnetic resonance imaging (MRI).
b. Lesions that have had external beam radiotherapy or locoregional therapies such as radiofrequency ablation must show evidence of subsequent progressive disease (substantial size increase of ≥ 20%) to be deemed a target lesion.
5. 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 steroids for 1 month prior to enrollment.
6. All previous chemotherapy or radiation therapy-related toxicities, except dry mouth, dysphagia, esophagitis, mucositis, alopecia, and irreversible late sequelae of radiation therapy, must have resolved to Grade 0 or 1 per Common Terminology Criteria for Adverse Events (CTCAE v 4.03), and all wounds from prior surgery must have adequately recovered.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Blood pressure (BP) ≤ 140/90 mmHg at screening with or without antihypertensive medications and no change in antihypertensive medications within 1 week prior to
Cycle 1/Day 1.
9. Adequate renal function as evidenced by calculated creatinine clearance ≥ 30 mL/min according to the Cockcroft and Gault formula.
10. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L and
b. Hemoglobin ≥ 9.0 g/dL (can be corrected by growth factor or transfusion) and
c. Platelet count ≥ 100 x 109/L
11. Adequate blood coagulation function as evidenced by an International Normalized Ratio
(INR) ≤ 1.5
12. Adequate liver function:
a. Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated
hyperbilirubinemia or Gilbert’s syndrome
b. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases). If
ALP is > 3 × ULN (in the absence of liver metastases) or > 5 × ULN (in the presence of liver metastases) AND subjects are also known to have bone metastases, the liver-specific ALP must be separated from the total and used to assess the liver function instead of the total ALP.
13. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
|
1. Males or females age ≥ 18 years at the time of informed consent form (ICF).
2. Subjects must have histological diagnosis consistent of ATC. Cytologic diagnosis by fine needle aspiration alone is not sufficient. Histologic diagnosis may be made by core needle biopsy, incisional biopsy, thyroidectomy, or other surgical biopsy. Fresh tumor biopsies (re-biopsy) should be obtained whenever feasible. The central pathology review may take place prior to or after the subject starts treatment with lenvatinib.
a. Central review of pathology is required for study participation, but not required prior to enrollment or start of treatment in order to avoid delay. If the results of central pathology review are not available prior to the start of study treatment, the confirmation of diagnosis of ATC at the local laboratory is mandatory prior to scheduled start of treatment with lenvatinib.
b. If central pathology review indicates a diagnosis other than ATC, the subject may continue treatment with lenvatinib per standard of care, at the discretion of the treating investigator. Subjects deemed to have another diagnosis (not ATC) will be taken off this study and replaced for the purpose of efficacy analyses.
c. Differentiated thyroid carcinoma (DTC) with focus loci of ATC is allowed. If a subject has pathology showing a small focus of ATC arising out of DTC and the measurable disease is not fully consistent with ATC, confirmation of ATC by biopsy is required.
d. An incidental focus of medullary thyroid cancer (MTC), DTC, and/or poorly differentiated thyroid cancer in a subject with ATC is allowed.
e. Histological diagnosis of ATC made through surgical resection is also acceptable.
3. Prior neoadjuvant, adjuvant or palliative chemotherapy for ATC is allowed.
4. Measurable disease based on investigator’s assessments meeting the following criteria:
a. At least 1 lesion of ≥ 10 mm in the longest diameter for a non-lymph node or ≥ 15 mm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computerized tomography (CT) or magnetic resonance imaging (MRI).
b. Lesions that have had external beam radiotherapy or locoregional therapies such as radiofrequency ablation must show evidence of subsequent progressive disease (substantial size increase of ≥ 20%) to be deemed a target lesion.
5. 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 steroids for 1 month prior to enrollment.
6. All previous chemotherapy or radiation therapy-related toxicities, except dry mouth, dysphagia, esophagitis, mucositis, alopecia, and irreversible late sequelae of radiation therapy, must have resolved to Grade 0 or 1 per Common Terminology Criteria for Adverse Events (CTCAE v 4.03), and all wounds from prior surgery must have adequately recovered.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Blood pressure (BP) ≤ 140/90 mmHg at screening with or without antihypertensive medications and no change in antihypertensive medications within 1 week prior to
Cycle 1/Day 1.
9. Adequate renal function as evidenced by calculated creatinine clearance ≥ 30 mL/min according to the Cockcroft and Gault formula.
10. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L and
b. Hemoglobin ≥ 9.0 g/dL (can be corrected by growth factor or transfusion) and
c. Platelet count ≥ 100 x 109/L
11. Adequate blood coagulation function as evidenced by an International Normalized Ratio
(INR) ≤ 1.5
12. Adequate liver function:
a. Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated
hyperbilirubinemia or Gilbert’s syndrome
b. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases). If
ALP is > 3 × ULN (in the absence of liver metastases) or > 5 × ULN (in the presence of liver metastases) AND subjects are also known to have bone metastases, the liver-specific ALP must be separated from the total and used to assess the liver function instead of the total ALP.
13. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Differentiated thyroid cancer (DTC) or MTC. However, ATC arising out of DTC is allowed, as long as the measurable disease is clinically consistent with ATC ie, rapidly progressive and/or 18F fluorodeoxyglucose (FDG)-avid.
2. Newly diagnosed patients who are considered appropriate candidates for comprehensive multimodality treatment (involving surgery and/or external beam radiotherapy or chemo
radiotherapy).
3. Prior treatment with lenvatinib or any tyrosine kinase inhibitor (except for combination therapy of radiation and reduced dose of TKI given for the purpose of radiosensitization).
4. Major surgery within 2 weeks prior to the first dose of lenvatinib.
5. Any anti-cancer treatment within 14 days or any investigational agent within 30 days before the first dose of study drug.
6. Radiotherapy within 3 weeks prior to the first dose of lenvatinib.
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 hours will be ineligible.
8. Significant cardiovascular impairment: History of (a) congestive heart failure greater than New York Heart Association (NYHA) Class II, (b) unstable angina, (c) myocardial infarction,
(d) stroke, or (e) cardiac arrhythmia associated with impairment within 6 months of the first dose of study drug.
9. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval >500 msec).
10. Active infection requiring systemic therapy.
11. Clinically significant hemoptysis or tumor bleeding within two weeks prior to first dose of lenvatinib
12. Radiographic evidence of major blood vessel invasion/infiltration.
13. Other active malignancy (except definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within past 24 months.
14. Scheduled for major surgery during the study.
15. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin
[hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained
more than 72 hours before the first dose of study drug.
16. Females of childbearing potential who:
• Do not agree to use a highly effective method of contraception (eg, total abstinence [if it is their preferred and usual lifestyle], an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) within 30 days before study entry and throughout the entire study period or for 30 days
after study drug discontinuation.
•Are currently totally abstinent (as their preferred and usual lifestyle), and who do not agree to be totally abstinent during the study period or for 30 days after study drug discontinuation.
•Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study or for 30 days after study drug discontinuation.
• Are using oral hormonal contraceptives and who do not agree to add a barrier method.
•(NOTE: All females will be considered to be of childbearing potential unless they are
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]).
For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide.
17. Evidence of clinically significant disease (eg, cardiovascular, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject’s safety or
interfere with the study assessments.
18. Known intolerance to the study drug or any of the excipients.
19. Any medical or other condition that in the opinion of the investigator(s) would preclude the subject’s participation in a clinical study.
|
1. Differentiated thyroid cancer (DTC) or MTC. However, ATC arising out of DTC is allowed, as long as the measurable disease is clinically consistent with ATC ie, rapidly progressive and/or 18F fluorodeoxyglucose (FDG)-avid.
2. Newly diagnosed patients who are considered appropriate candidates for comprehensive multimodality treatment (involving surgery and/or external beam radiotherapy or chemo
radiotherapy).
3. Prior treatment with lenvatinib or any tyrosine kinase inhibitor (except for combination therapy of radiation and reduced dose of TKI given for the purpose of radiosensitization).
4. Major surgery within 2 weeks prior to the first dose of lenvatinib.
5. Any anti-cancer treatment within 14 days or any investigational agent within 30 days before the first dose of study drug.
6. Radiotherapy within 3 weeks prior to the first dose of lenvatinib.
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 hours will be ineligible.
8. Significant cardiovascular impairment: History of (a) congestive heart failure greater than New York Heart Association (NYHA) Class II, (b) unstable angina, (c) myocardial infarction,
(d) stroke, or (e) cardiac arrhythmia associated with impairment within 6 months of the first dose of study drug.
9. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval >500 msec).
10. Active infection requiring systemic therapy.
11. Clinically significant hemoptysis or tumor bleeding within two weeks prior to first dose of lenvatinib
12. Radiographic evidence of major blood vessel invasion/infiltration.
13. Other active malignancy (except definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within past 24 months.
14. Scheduled for major surgery during the study.
15. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin
[hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained
more than 72 hours before the first dose of study drug.
16. Females of childbearing potential who:
• Do not agree to use a highly effective method of contraception (eg, total abstinence [if it is their preferred and usual lifestyle], an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) within 30 days before study entry and throughout the entire study period or for 30 days
after study drug discontinuation.
•Are currently totally abstinent (as their preferred and usual lifestyle), and who do not agree to be totally abstinent during the study period or for 30 days after study drug discontinuation.
•Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study or for 30 days after study drug discontinuation.
• Are using oral hormonal contraceptives and who do not agree to add a barrier method.
•(NOTE: All females will be considered to be of childbearing potential unless they are
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]).
For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide.
17. Evidence of clinically significant disease (eg, cardiovascular, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject’s safety or
interfere with the study assessments.
18. Known intolerance to the study drug or any of the excipients.
19. Any medical or other condition that in the opinion of the investigator(s) would preclude the subject’s participation in a clinical study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is ORR as determined by investigator review, using RECIST 1.1. ORR is the proportion of subjects who have best overall response (BOR) of CR or PR. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Timepoint will be approximately 6 months following the enrollment of the last subject (Section 9.7.1.6.4) |
|
| E.5.2 | Secondary end point(s) |
| The secondary endpoints of the study are: - To evaluate 12-week PFS - To evaluate 6-month OS - To evaluate median PFS and median OS - To evaluate safety and tolerability of lenvatinib in subjects with ATC |
| Gli obiettivi secondari dello studio sono: • Valutare la sopravvivenza libera da progressione (PFS) a 12 settimane • Valutare la sopravvivenza complessiva (OS) a 6 mesi • Valutare la PFS mediana e l’OS mediana • Valutare la sicurezza e la tollerabilità di lenvatinib in soggetti con ATC |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoint will be approximately 6 months following the enrollment of the last subject (Section 9.7.1.6.4) |
| Il Timepoint sarà di circa 6 mesi dopo l'iscrizione dell'ultimo soggetto (sezione 9.7.1.6.4) |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 | Information not present in EudraCT |
| 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 |
| Australia |
| France |
| Italy |
| Poland |
| 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 time of data cutoff of the formal analysis or the time of the last subject/last treatment, whichever occurs later. |
| The time of data cutoff of the formal analysis or the time of the last subject/last treatment, whichever occurs later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| 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 | 2 |
| 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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