This is a prospective, international, multi-center, open label, stratified, exploratory phase II study evaluating the efficacy and safety of lenvatinib in patients with advanced/metastatic, neuroendocrine tumors of the pancreas after progression to a previous targeted agent (cohort A) or gastrointestinal tract after progression to somatostatin analogues (cohort B).

Trial to assess the efficacy of Lenvatinib in metastatic neuroendocrine tumor. The primary endpoint of the study is overall response rate (ORR) by RECIST v 1.1 upon central radiologic assessment.

Number of patients: 110 patients Estimated duration of subject participation: 24 months

INCLUSION CRITERIA

Subjects must meet all of the following criteria to be included in this study:

1. Subjects must have histologically confirmed diagnosis of one of the following advanced/metastatic neuroendocrine tumor types:

   1. WHO Classification G1/G2 (Ki67<20% and mitotic count ≤20 mitoses x 10 HPF) pancreatic neuroendocrine tumor
   2. 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:

   1. 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.
   2. Lesions that have had external beam radiotherapy (EBRT) or loco-regional 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:

   1. Pancreatic origin: progression after a previous targeted agent (including mTOR inhibitors, such as everolimus or antiangiogenic therapies, such as sunitinib, sorafenib, axitinib, bevacizumab within others). 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.

   2. 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 (radio) embolization, 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:

    1. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 ×103/μL).
    2. Platelets ≥ 100,000/mm3 (≥ 100 × 109/L).
    3. 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:

    1. Bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome.
    2. Alkaline 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 (minimum sensitivity 25 IU/L or equivalent units of beta human chorionic gonadotropin (β-hCG) at the baseline visit (and/or within 72h prior to the first dose of study drug).

    Females of childbearing potential must agree to use a highly effective method of contraception (e.g., total sexual abstinence*, an intrauterine device, a double-barrier method such as condom + spermicide or condom + diaphragm with spermicide or have a vasectomized partner with confirmed azoospermia*) throughout the entire study period and for 30 days after study drug administration. The only subjects who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or subjects who have been sterilized surgically or who are otherwise proven sterile (i.e., bilateral tubal ligation with surgery at least 1 month prior to dosing, hysterectomy, or bilateral oophorectomy with surgery at least 1 month prior to dosing).

    The women using oral hormonal contraceptives should add an additional barrier method as there is unknown whether lenvatinib may reduce the effectiveness of the hormonal contraceptives. All women who are of reproductive potential and who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.

    ** Sexual abstinence will be acceptable only when this is in line with the preferred and usual lifestyle of the subject.

18. Male subjects who are partners of women of childbearing potential must use or their partners must use a highly effective method of contraception (e.g., condom + spermicide, condom + diaphragm with spermicide, IUD) beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 30 days after the last dose of study drug, unless they are sexually abstinent or have undergone a successful vasectomy. Those with partners using hormonal contraceptives must also be using an additional approved method of contraception, as described previously.

19. Voluntary provision of written informed consent and the willingness and ability to comply with all aspects of the protocol.

EXCLUSION CRITERIA

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 definitely treated melanoma in-situ, basal or squamous 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.

18 months