| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced/metastatic, histologically confirmed, grade 1/2 (G1/G2) of 2010 WHO classification neuroendocrine tumors of the pancreas after progression to a previous targeted agent (cohort A) or gastrointestinal tract after progression to somatostatin analogues (cohort B). |
|
| E.1.1.1 | Medical condition in easily understood language |
Pancreas tumor
Gastrointestinal tumor
Neuroendocrine tumor |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062476 |
| E.1.2 | Term | Neuroendocrine tumor |
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068909 |
| E.1.2 | Term | Pancreatic neuroendocrine tumour 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary objective
To assess the efficacy of lenvatinib on tumor objective response rate in two independent cohorts of patients with advanced neuroendocrine tumors: patients with advanced/metastatic G1/G2 pancreatic neuroendocrine tumors after progression to a previous targeted agent (cohort A), and patients with advanced/metastatic G1/G2 neuroendocrine tumors of gastrointestinal tract after failure to somatostatin analogues therapy (cohort B). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives
To determine the safety and tolerability of lenvatinib.
To estimate the early tumor shrinkage rate and the deepness of response of lenvatinib in each cohort of patients.
To estimate progression-free survival in both cohorts of patients.
Exploratory objectives
To evaluate biochemical response (changes in CgA and NSE levels) and its association with response rate and progression-free survival.
To assess whether baseline tumor and blood biomarkers may be predictive of response to lenvatinib.
To explore additional hypotheses related to biomarkers and relationship to lenvatinib, neuroendocrine tumors, other endocrine disorders and/or cancer which may arise from internal or external research activities. |
|
| 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 advanced/metastatic neuroendocrine tumor types:
a) WHO Classification G1/G2 (Ki67<20% and mitotic count ≤20 mitoses x 10 HPF) pancreatic neuroendocrine tumor
b) WHO Classification G1/G2 (Ki67<20% and mitotic count ≤20 mitoses x 10 HPF) gastrointestinal neuroendocrine tumor (including stomach, small intestine and colorectal origins).
2. Subjects must have evidence of measurable disease meeting the following criteria:
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 (Appendix I) using computerized tomography/magnetic resonance imaging (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 external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation or liver embolization 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 by radiologic image techniques within 12 months (an additional month will be allowed to accommodate actual dates of performance of scans, i.e., within ≤ 13 months) prior to signing
informed consent, according to RECIST 1.1 (Appendix I).
4. Subjects must meet the following inclusion criterion regarding primary tumor site:
a) Pancreatic origin: progression after a previous targeted Agent (including mTOR inhibitors, such as everolimus or antiangiogenic therapies, such as sunitinib, sorafenib, axitinib, bevacizumab withinothers). Combination therapies in the same treatment line (such as sorafenib plus bevacizumab, chemotherapy plus antiangiogenic drugs) are considered one treatment line and are allowed to be included in the study. Patients must be treated with only one previous line of
targeted agent(s)-based therapy. Previous therapy with somatostatin analogues and/or interferon is allowed and is not considered as a previous targeted agent therapy.
b) Gastrointestinal origin: progression after therapy with antitumoral doses of somatostatin analogs (octreotide LAR 30 mg every 28 days or Lanreotide 120 mg every 28 days) and/or interferon treatment.
5. Only for patients with pancreatic origin neuroendocrine tumors, one previous line with chemotherapy is allowed.
6. Concomitant somatostatin analogues are allowed in both cohorts during the study.
7. 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 at least one month.
8. All prior chemotherapy or radiation-related toxicities must have resolved to < Grade 2 (following CTCAE V 4.03 grade levels), except alopecia and infertility.
9. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (Appendix II).
10. Previous liver locoregional therapies, such as (chemo) embolization, radiofrequency or liver-directed radioembolization, or systemic peptide-receptor radionucleotide therapy are allowed if the procedure was performed at least 6 months previous the informed consent form signature.
11. 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 the Screening Visit.
12. Adequate renal function defined as calculated creatinine clearance ≥ 30 mL/min per the Cockcroft and Gault formula (Appendix III).
13. Adequate bone marrow function, defined as:
a) Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 × 103/μL)
b) Platelets ≥ 100,000/mm3 (≥ 100 × 109/L)
c) Hemoglobin ≥ 9.0 g/dL
14. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5. Prophylactic low molecular weight heparin therapy is allowed.
15. Adequate liver function:
a) Bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert’s syndrome.
b) Alkalin phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 × the ULN (≤ 5 × ULN if subject has liver metastases).
16. Males or females age ≥ 18 years at the time of informed consent.
17. All females must have a negative serum or urine pregnancy test. Females of childbearing potential must agree to use a highly effective method of contraception.
18. Male subjects who are partners of women of childbearing potential must use or their partners must use a highly effective method of contraception
19. Voluntary provision of written informed consent and the willingness and ability to comply with all aspects of the protocol. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be excluded from this study:
1. WHO Classification G3 neuroendocrine tumors of the pancreas and gastrointestinal tract.
2. Two or more prior lines of targeted agents-based therapy in pancreatic origin and any previous line of targeted therapy for gastrointestinal origin or any ongoing antiproliferative treatment for advanced/metastatic neuroendocrine tumors, with the exception of somatostatin analogues therapy.
3. More than one previous line of chemotherapy in pancreatic neuroendocrine tumors.
4. Previous chemotherapy in gastrointestinal neuroendocrine tumors.
5. Prior treatment with lenvatinib.
6. 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 somatostatin analogues for symptomatic therapy.
7. Major surgery within 3 weeks prior to the first dose of study drug.
8. 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.
9. Gastrointestinal malabsorption, or any other condition in the opinion of the investigator that might affect the absorption of lenvatinib.
10. 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 prior to the first dose of study drug, or cardiac arrhythmia requiring medical treatment. The left ventricular ejection fraction in the echocardiogram must be of at least 50%.
11. Prolongation of QTcF interval to > 480 msec.
12. 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.
13. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
14. Active infection (any infection requiring treatment).
15. Active malignancy within the past 5 years (except for melanoma in-situ, basal orsquamous cell carcinoma of the skin, or carcinoma in-situ of the cervix).
16. Known intolerance or hypersensitivity to the active substance (or any of the excipients).
17. Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial.
18. Females who are pregnant or breastfeeding.
19. Documented active alcohol or drug abuse.
20. Patients with a prior history of non-compliance with medical regimens. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is overall response rate (ORR) by RECIST v1.1
? ORR is the proportion of subjects who have best overall response of CR or PR. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Data cut-off for the primary study analysis will happen following after the last patient included in the study has performed the second tumor evaluation (week 18 after first dose of study drug as first evaluation will take place 6 weeks after first dose, following tumor assessment will take place every 12 weeks until documentation of disease progression or start of another anticancer therapy |
|
| E.5.2 | Secondary end point(s) |
? Progression-free survival (PFS) is defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurs first) using RECIST 1.1. PFS censoring rules will follow FDA guidance in 2007.
? Early tumor shrinkage (ETS) rate defined as 20% reduction in target lesions after the first 6 weeks of treatment (first tumor evaluation)
? Deepness of response (DpR) defined as percentage of maximum tumor shrinkage observed at the nadir compared with baseline. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Data cut-off for the primary study analysis will happen following after the last patient included in the study has performed the second tumor evaluation (week 18 after first dose of study drug as first evaluation will take place 6 weeks after first dose, following tumor assessment will take place every 12 weeks until documentation of disease progression or start of another anticancer therapy |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
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