A phase II study to evaluate the safety and efficacy of lenvatinib in patients with advanced grade 1/2 neuroendocrine neoplasmas of pancreatic and extrapancreatic origin.

Phase 1

Active, not recruiting

• Conditions: 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).; MedDRA version: 19.0Level: LLTClassification code 10062476Term: Neuroendocrine tumorSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 19.0Level: PTClassification code 10068909Term: Pancreatic neuroendocrine tumour metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-001467-39-AT
• Lead Sponsor: GETNE (Grupo Español de Tumores Neuroendocrinos)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-05-24
• Last Update Posted: 7 September 2020

Recruitment & Eligibility

• Status: Not Recruiting
• Sex: All
• Target Recruitment: 110

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 an

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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified