Evaluation of Cabozantinib and Lanreotide Combination in Gastroenteropancreatic and Thoracic Neuroendocrine Tumors: A Phase II Clinical Trial
- Trial ID
- 2024-516612-16-00
- Protocol
- LOLA trial
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II trial is to assess the **safety**, tolerability, and activity of the combination of cabozantinib and lanreotide in patients with well-differentiated gastroenteropancreatic (GEP) and thoracic neuroendocrine tumors (NETs). This is clinically relevant as it aims to determine the potential therapeutic benefits and risks associated with this drug combination, which could inform treatment strategies for these types of tumors.
Secondary objectives include evaluating the Progression Free Survival (PFS) and Overall Survival (OS) of patients receiving the treatment. These measures are crucial for understanding the long-term efficacy and potential survival benefits of the treatment regimen.
Participants
The clinical trial involves participants diagnosed with **gastroenteropancreatic (GEP) and thoracic neuroendocrine tumors (NETs)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include vulnerable populations. Participants must have unresectable, advanced, or metastatic well-differentiated GEP-NETs or thoracic NETs, with a Ki67 index of 10% or higher, and documented progressive disease according to RECIST v1.1 criteria. The sponsor has not provided the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the presence of at least one measurable target lesion and prior completion of any major surgery at least two months before registration. The trial excludes individuals with unresolved toxic effects from prior therapies, except for alopecia and fatigue. The sponsor has not provided information on the total number of participants.
Plans and Procedures
The clinical trial is designed to evaluate the **safety**, tolerability, and activity of a combination therapy involving **cabozantinib** and **lanreotide** in patients with well-differentiated gastroenteropancreatic (GEP) and thoracic neuroendocrine tumors (NETs). This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to last until August 31, 2026, with recruitment having commenced on July 22, 2020. The study involves multiple visits, starting with an inclusion (screening) visit to assess eligibility based on specific criteria, including the presence of unresectable, advanced, or metastatic NETs, and a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale.
Participants will undergo a series of follow-up visits to monitor the **safety** and efficacy of the treatment, with assessments based on the RECIST 1.1 criteria. The primary endpoint focuses on the rate of patients experiencing grade 3-5 toxicities according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Secondary endpoints include Progression-Free Survival (PFS) and Overall Survival (OS). The trial will also explore the immunohistochemical expression of MET, AXL, and VEGFR2 to identify predictive or prognostic molecular targets.
The expected length of participant involvement is up to 24 months, with conditions for early termination including the occurrence of unacceptable toxicity, disease progression, or withdrawal of consent. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any adverse events are addressed. The trial aims to provide valuable insights into the potential benefits of combining **cabozantinib** and **lanreotide** for treating GEP and thoracic NETs.
Treatment
The clinical trial involves the administration of **cabozantinib**, a chemical compound, in the form of a film-coated tablet. The active substance, cabozantinib, is administered orally. The trial includes three different dosing regimens of cabozantinib: 60 mg, 40 mg, and 20 mg per day. The maximum total dose for each regimen is 60 mg, and the treatment period extends up to 24 months. Participants are required to adhere to the prescribed dosing schedule, and compliance is monitored throughout the study duration.
In addition to cabozantinib, the trial also involves the administration of **lanreotide**, a protein-based compound, provided as a solution for injection in a pre-filled syringe. Lanreotide is administered via intramuscular injection, with a maximum daily and total dose of 120 mg. The treatment period for lanreotide also extends up to 24 months. The administration of lanreotide is conducted under controlled conditions to ensure accurate dosing and participant safety.
Both cabozantinib and lanreotide are utilized in combination to assess their safety, tolerability, and activity in patients with well-differentiated gastroenteropancreatic and thoracic neuroendocrine tumors. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule is closely monitored to ensure the integrity of the trial data and the safety of the participants.
Efficacy
The efficacy of the clinical trial will be assessed through several key parameters. The primary endpoint focuses on safety and tolerability, specifically measuring the rate (%) of patients experiencing grade 3-5 toxicities according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. This will provide a comprehensive understanding of the adverse effects associated with the treatment regimen.
Secondary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. These endpoints will be crucial in evaluating the long-term benefits of the treatment combination of cabozantinib and lanreotide in patients with well-differentiated gastroenteropancreatic and thoracic neuroendocrine tumors. The assessment of these endpoints will be conducted at various time points throughout the trial to monitor the progression and survival rates of the participants.
Additionally, exploratory objectives involve the assessment of immunohistochemical expression of MET, AXL, and VEGFR2 to identify predictive or prognostic molecular targets. Translational evaluations will be performed to select and identify tissue biomarkers that modulate treatment activity and/or safety. These assessments will provide insights into the molecular mechanisms underlying the treatment response and potential biomarkers for future therapeutic strategies.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Each patient must meet all of the following inclusion criteria to be enrolled in the study: voluntary written informed consent obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care; Patients with unresectable, advanced or metastatic neuroendocrine well differentiated GEP-NET (pancreatic NET (G2-G3), Small Intestinal NET, stomach NET, rectum NET) with Ki67 ≥ 10%; Patients with unresectable, advanced or metastatic neuroendocrine well differentiated thoracic NET (typical and atypical lung NET, thymus NET); Patients with unresectable, advanced or metastatic neuroendocrine well differentiated unknown primary NET with Ki67 ≥ 10%. Locally advanced or metastatic disease documented as progressive by RECIST v1.1. on CT-scan or MRI at baseline and within 12 months prior to baseline; disease that is not amenable to surgery with curative intent; presence of at least one measurable target lesion for further evaluation according to RECIST v1.1; age ≥18 years; eastern Cooperative Oncology Group (ECOG) performance status 0 or 1(see APPENDIX I) Octreoscan and/or PET 68Ga positive and/or IHC for SSTR2; Advanced GEP, thoracic and unknown origin NET limited to the treatment of patients naïve or who have received a previous therapy for advanced disease or maximum 2 lines if any of these regimens include treatment with somatostatin analogs previously administered for a short period of time (less than 12 months for Octreotide and less than 6 months for Lanreotide) Prior PRRT therapy must be completed at least 6 months prior to enrollement; Prior treatment with somatostatin analogs, biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, and/or radiation must be completed at least 28 days prior to registration; Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective internal radiation therapy) or ablative therapies must be completed at least 28 days prior to registration; Patients should have resolution of any toxic effects of prior therapy (except alopecia and fatigue) to National Cancer Institute (NCI) CTCAE, version 5.0, grade 1 or less; Patients must have completed any major surgery at least two months prior to registration and any minor surgery (including uncomplicated tooth extractions) at least 28 days prior to registration; complete wound healing from major surgery must have occurred at least 1 month prior to registration, and complete wound healing from minor surgery must have occurred at least 7 days prior to registration Functioning or non-functioning tumors; all of the following laboratory test findings: Hemoglobin > 9 g/dL (5.6 mmol/L) WBC > 2,000/mm3 Neutrophils > 1,500/mm3 Platelets > 100,000/mm3 AST or ALT < 3 x ULN (< 5 x ULN if liver metastases are present) Total Bilirubin < 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) Adequate renal function, based upon meeting the following laboratory criteria:
Exclusion Criteria
- undifferentiated, poorly differentiated GEP-NET, Thoracic or unknown primary NET; Previous therapy for advanced disease > 1 line or > 2 lines if any of these regimens include treatment with somatostatin analogs previously administered for a long period of time; - Any medical adjuvant treatment must have been stopped at least six months before entry into the study; - Prior treatment with cabozantinib; - Prior treatment with any other tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors and with non-VEGF-targeted angiogenic inhibitors such as Everolimus is permitted; -Everolimus or tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors treatment stopped less than 4 weeks prior to the start of the study; concomitant treatment with Interferon; previous treatment with chemotherapy, loco-regional therapy or interferon with last administration less than 4 weeks prior to the start of the study or with toxicity not resolved to less or equal grade 1 at the start of the study; PRRT therapy with last administration less than 6 months prior to inclusion in the study or with toxicity not resolved to less or equal grade 1 at the start of the study; diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri; cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the NYHA within the past 6 months prolongation of QT interval history of aneurysms and arterial dissections; poorly controlled hypertension; history of cerebrovascular accidents, including transient ischemic attack or untreated deep venous thrombosis (DVT) within the past 6 months; concomitant anticoagulation at therapeutic doses with oral anticoagulant or platelet inhibitors; major surgery or trauma within 28 days prior to study entry; the presence of any non-healing wound, fracture, or ulcer; known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before the start of the study. With the exclusion of inhaled steroids, chronic treatment with corticosteroids with dose superior of 10 mg/day methylprednisolone equivalent must be avoided; evidence of active bleeding or bleeding diathesis and/or clinically-significant GI bleeding within 6 months before the first dose of study treatment; 3 months for pulmonary hemorrhage and patients with tumor invading or encasing any major blood vessels; GI disorders associated with a high risk of perforation or fistula formation; major surgery within 2 months before to registration. Complete healing from major surgery must have occurred 1 month before initiation of the study. Complete healing from minor surgery must have occurred at least 7 days before registration. Subjects with clinically relevant complications from prior surgery are not eligible; clinically relevant ongoing complications from prior radiation therapy;positive test for HIV or AIDS related illness; complicated, symptomatic untreated lithiasis of the bile ducts; any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures; previous or ongoing treatment with chemotherapy, immunotherapy, target therapies, investigational therapy or hormonal therapy within 28 days or five half-lives of a drug prior to the first dose of Cabozantinib plus Lanreotide; inability to swallow tablets; rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption; allergy or hypersensitivity to to the study drugs and/or their excipients of the study treatment formulations; concomitant use of strong inhibitor of CYP3A4
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 22 Jul 2020 | 69 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CABOZANTINIB | Test | — | ORAL | 60 | 24 | SUB93452 |
CABOZANTINIB | Test | — | ORAL | 40 | 24 | SUB93452 |
LANREOTIDE | Test | — | INTRAMUSCULAR INJECTION | 120 | 24 | SUB08402MIG |
CABOZANTINIB | Test | — | ORAL | 20 | 24 | SUB93452 |