A Trial Aiming to Assess the Safety and Activity of the Combination of Cabozantinib Plus Lanreotide in GEP and NET

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    Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Updated on 12 September 2021
minor surgery
gilbert's syndrome
international normalized ratio
neutrophil count
liver metastasis
positron emission tomography
radionuclide therapy
selective internal radiation therapy
pancreatic net
intestinal neuroendocrine tumor


A Phase II trial aiming to assess the safety and activity of the combination of cabozantinib plus lanreotide in gastroenteropancreatic (GEP) and thoracic neuroendocrine tumor (NET): The LOLA trial


Phase II, multicenter, open-label, non-comparative, non-randomized study with three-stage design

Condition Neuroectodermal Tumor, Neurectoderma, neuroendocrine tumors, Neuroendocrine Tumor, neuroendocrine tumour, Metastatic Well Differentiated Neuroendocrine Neoplasm
Treatment Cabozantinib, Lanreotide
Clinical Study IdentifierNCT04427787
SponsorFondazione IRCCS Istituto Nazionale dei Tumori, Milano
Last Modified on12 September 2021


Yes No Not Sure

Inclusion Criteria

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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care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 positron emission tomography (PET) 68 Gallium-Dotatoc (68Ga) positive and/or Immuno-histochemistry (IHC) for SSTR2
advanced GEP, thoracic and unknown origin NET limited to treatment nave patients or who have received maximum 1 prior systemic regimen for metastatic disease (biological therapy, chemotherapy or somatostatin analogs, including PRRT)
Prior PRRT therapy must be completed at least 6 months prior to enrollment
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
Prior treatment with cabozantinib or lanreotide are not allowed
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
Non-functioning tumors
all of the following laboratory test findings
Hemoglobin > 9 g/dL (5.6 mmol/L)
White blood cell count (WBC) > 2,000/mm3
Neutrophils > 1,500/mm3
Platelets > 100,000/mm3
liver enzymes (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
Serum creatinine 1.5 upper limit of normal (ULN) or calculated creatinine clearance 40 mL/min using the Cockcroft-Gault equation: (140 - age) weight (kg)/(serum creatinine 72 [mg/dL]) for males. (For females multiplied by 0.85)
Urine protein/creatinine ratio (UPCR) 1 mg/mg ( 113.1 mg/mmol) or 24-hour urine protein < 1 g
Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis
prothrombin time - international normalized ratio/ partial thromboplastin time (PT/PTT) 1.5 x upper limit of normal
Availability of a representative formalin-fixed paraffin-embedded fractional Fokker-Planck equation (FFPE) tumor specimen collected before starting treatment with cabozantinib and lanreotide that enables the definitive diagnosis of NET (the archival specimen must contain adequate viable tumor tissue to enable candidate biomarkers status; the specimen may consist of a tissue block or at least 10 unstained serial sections with 3 microns of thickness; for core needle biopsy specimens, at least two cores should be available for evaluation)
Female subjects of childbearing potential must not be pregnant at screening
Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception with a failure rate of < 1% per year (eg, barrier methods, including male condom or female condom with spermicidal gel, intrauterine devices, surgical male or female sterilisation) during the study and for 4 months after the last dose of study treatment
Female subject is either: post-menopausal for at least one year before the screening visit, or surgically sterilized, or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study
Male subject, even if surgically sterilized (ie, status postvasectomy), agrees to use an acceptable method for contraception during the entire study treatment period through 4 months after the last dose of cabozantinib
Patients must be accessible for treatment and follow up as well as they must be willing and capable to comply with the requirements of the study

Exclusion Criteria

Patients with undifferentiated, poorly differentiated GEP-NET, Thoracic or unknown primary NET
Previous therapy for advanced disease > 1 line; any medical adjuvant treatment must have been stopped at least six months before entry into the study
Prior treatment with dose superior or equal to 120 mg per month of lanreotide
Prior treatment with cabozantinib
Prior treatment with any other tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors is permitted. Prior treatment with non-VEGF-targeted angiogenic inhibitors such as Everolimus is permitted
Patients who stopped Everolimus or tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors treatment less than 4 weeks prior to the start of the study
Patients with concomitant treatment with Interferon
Patients previously treated with chemotherapy, loco-regional therapy (e.g., chemoembolization) 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
history of any one or more of the following cardiovascular conditions within the past 6 months: 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 New York Heart Association (NYHA see Appendix II)
prolongation of QT interval: Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances (e.g., hypokaliemia, family history of long QT Syndrome). Corrected QT interval calculated by the Fridericia formula (QTcF) 500 ms within 28 days before registration should be shown. Only subjects with a baseline QTcF 500 ms are eligible for the study
Note: If the QTcF was > 500 ms in the first ECG, a total of 3 ECGs were to be
performed. If the average of these 3 consecutive results for QTcF was 500 ms
the subject met eligibility in this regard
history of aneurysms and arterial dissections. The use of VEGF pathway inhibitors in patients with or without hypertension may favor the formation of aneurysms and / or arterial dissections. Before starting cabozantinib, this risk must be carefully considered in patients with risk factors such as hypertension or history of aneurysm
poorly controlled hypertension [defined as systolic blood pressure (SBP) of 140 mmHg or diastolic blood pressure (DBP) of 90 millimeters of mercury(mmHg)]
history of cerebrovascular accidents, including transient ischemic attack (TIA), history of thromboembolic events (including pulmonary embolism) or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
concomitant anticoagulation at therapeutic doses with oral anticoagulant (eg. Warfarin, direct thrombin and factor 10a inhibitors) or platelet inhibitors (eg. clopidogrel)
major surgery or trauma within 28 days prior to study entry; the presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement are not considered to be major surgery)
known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before the start of the study. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of inclusion
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
patients with 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 registration. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before registration. Subjects with clinically relevant complications from prior surgery are not eligible
subjects with clinically relevant ongoing complications from prior radiation therapy
positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
patients with 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 (except for adjuvant therapies) with any of the following anti-cancer therapies: chemotherapy, immunotherapy, target therapies, investigational therapy or hormonal therapy within 28 days or five half-lives of a drug (whichever is longer) 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
previously identified allergy or hypersensitivity to to the study drugs and/or their excipients of the study treatment formulations
concomitant use of strong inhibitor of CYP3A4 (i.e. information reported in session 4.5 of the protocol)
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