Clinical Trials /

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

NCT04427787

Description:

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

Related Conditions:
  • Gastric Neuroendocrine Tumor
  • Lung Carcinoid Tumor
  • Neuroendocrine Tumor, NOS
  • Pancreatic Neuroendocrine Tumor
  • Rectal Neuroendocrine Tumor
  • Small Intestinal Neuroendocrine Tumor
  • Thymic Carcinoid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Trial Aiming to Assess the Safety and Activity of the Combination of Cabozantinib Plus Lanreotide in GEP and NET
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: INT 240-19
  • NCT ID: NCT04427787

Conditions

  • Metastatic Well Differentiated Neuroendocrine Neoplasm
  • Neuroendocrine Tumors

Interventions

DrugSynonymsArms
CabozantinibCABOMETYXCabozantinib+lanreotide
LanreotideIPSTYLCabozantinib+lanreotide

Purpose

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

Detailed Description

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

Trial Arms

NameTypeDescriptionInterventions
Cabozantinib+lanreotideExperimentalCabozantinib will be administered orally at a dose of 60 mg/day continuously in combination with Lanreotide 120 mg injection every 28 days. Both treatments will start the same day
  • Cabozantinib
  • Lanreotide

Eligibility Criteria

        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             withdrawn by the subject at any time without prejudice to future medical care;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 PET 68Ga positive and/or IHC for SSTR2;

          -  advanced GEP, thoracic and unknown origin NET limited to treatment naïve 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 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;

          -  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)

          -  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:

               1. 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)

               2. 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

          -  PT-INR/PTT ≤ 1.5 x upper limit of normal.

          -  Availability of a representative 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 ≥ 90mmHg];

          -  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.
             Clopidrogrel);

          -  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)
      
Maximum Eligible Age:90 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Respons Rate (ORR)
Time Frame:42 months
Safety Issue:
Description:according to RECIST, v1.1 defined as complete response or partial response after treatment administration

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:42 months
Safety Issue:
Description:defined as the time from first day of treatment administration until progression disease according to RECIST v 1.1 or death for every cause, whichever occurred first.
Measure:Safety Endpoint
Time Frame:42 months
Safety Issue:
Description:Adverse Event (AE) all grade according to NCI-CTCAE v5.0 grade
Measure:Clinical effectiveness endpoint
Time Frame:42 months
Safety Issue:
Description:Overall Survival (OS) defined as the time from first treatment administration until death whichever cause
Measure:Exploratory objectives analysis
Time Frame:42 months
Safety Issue:
Description:the investigation of immunohistochemical tissue expression level of MET, AXL, VEGFR2.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Last Updated

June 9, 2020