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Metastatic Well Differentiated Neuroendocrine NeoplasmPhase 2LOLANCT04427787

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

A Phase 2 study testing Cabozantinib and Lanreotide in people with Metastatic Well Differentiated Neuroendocrine Neoplasm and Neuroendocrine Tumors, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

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 Read more about this study

Who is it for?
Ages 18 to 90 years
What is being tested?
Cabozantinib and Lanreotide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
69 participants
Where
1 siteItaly
Study dates
20 Jun 2020to Nov 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care;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;
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  • 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 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 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

Who cannot join

  • 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;
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  • 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)

Trial locations and contacts

1 site in 1 country.

Sara Pusceddu, MD contact

+390223903066

sara.pusceddu@istitutotumori.mi.it

Lavinia Biamonte, Dr.ssa contact

+390223903030

lavinia.biamonte@istitutotumori.mi.it

Italy1 site, 1 recruiting

  • Fondazione IRCCS Istituto Nazionale dei Tumori

    Milan, 20133

    Sara Pusceddu, MD, +390223903066, sara.pusceddu@istitutotumori.mi.it

    Lavinia Biamonte, +390223903030, lavinia.biamonte@istitutotumori.mi.it

    Recruiting

Other trials in Italy

About this study

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

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

Read the detailed description

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

Being tested
Cabozantinib, Lanreotide
Medical subject headings
Neuroendocrine Tumors

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CabozantinibDrug

    Also called Cabometyx

    Cabozantinib will be administered orally at a dose of 60 mg/day

  • LanreotideDrug

    Also called IPSTYL

    Lanreotide will be administrated 120 mg injection every 28 days

Study groups in NCT04427787
Study groupRoleWhat they receive
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
Receives: Drug: Cabozantinib; Drug: Lanreotide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Objective Response Rate (ORR)

    according to RECIST, v1.1 defined as complete response or partial response after treatment administration

    Measured: 42 months

  2. Primary Safety Endpoint

    Adverse Events (AE) grade 3-5 according to NCI-CTCAE v5.0 grade

    Measured: 42 months

Secondary outcomes (4)

  1. Progression-free survival (PFS)

    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.

    Measured: 42 months

  2. Safety Endpoint

    Adverse Event (AE) all grade according to NCI-CTCAE v5.0 grade

    Measured: 42 months

  3. Clinical effectiveness endpoint

    Overall Survival (OS) defined as the time from first treatment administration until death whichever cause

    Measured: 42 months

  4. Exploratory objectives analysis

    the investigation of immunohistochemical tissue expression level of Mesenchymal Epithelial Transition (MET), AXL, vascular endothelial growth factor (VEGFR2) proteins.

    Measured: 42 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Jun 2020
  2. Study start20 Jun 2020
  3. Primary completionNov 2023 (estimated)
  4. Study completionNov 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
69 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04427787
Sponsor's protocol ID
2019-004506-10
Other IDs
2019
Acronym
LOLA
Status last verified
Sep 2021
First submitted
9 Jun 2020
Last updated
5 Sep 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. doi: 10.1056/NEJMoa1316158.

    PubMed 25014687

  • Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol. 2006 Dec;17(12):1733-42. doi: 10.1093/annonc/mdl105. Epub 2006 Jun 26.

    PubMed 16801334

  • Krantic S, Goddard I, Saveanu A, Giannetti N, Fombonne J, Cardoso A, Jaquet P, Enjalbert A. Novel modalities of somatostatin actions. Eur J Endocrinol. 2004 Dec;151(6):643-55. doi: 10.1530/eje.0.1510643.

    PubMed 15588232

  • Chalabi M, Duluc C, Caron P, Vezzosi D, Guillermet-Guibert J, Pyronnet S, Bousquet C. Somatostatin analogs: does pharmacology impact antitumor efficacy? Trends Endocrinol Metab. 2014 Mar;25(3):115-27. doi: 10.1016/j.tem.2013.11.003. Epub 2014 Jan 7.

    PubMed 24405892

  • Rai U, Thrimawithana TR, Valery C, Young SA. Therapeutic uses of somatostatin and its analogues: Current view and potential applications. Pharmacol Ther. 2015 Aug;152:98-110. doi: 10.1016/j.pharmthera.2015.05.007. Epub 2015 May 5.

    PubMed 25956467

  • Pola S, Cattaneo MG, Vicentini LM. Anti-migratory and anti-invasive effect of somatostatin in human neuroblastoma cells: involvement of Rac and MAP kinase activity. J Biol Chem. 2003 Oct 17;278(42):40601-6. doi: 10.1074/jbc.M306510200. Epub 2003 Aug 5.

    PubMed 12902325

  • Azar R, Najib S, Lahlou H, Susini C, Pyronnet S. Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1. Cell Mol Life Sci. 2008 Oct;65(19):3110-7. doi: 10.1007/s00018-008-8418-2.

    PubMed 18810319

  • Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Horsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. doi: 10.1056/NEJMoa1003825.

    PubMed 21306237

  • Corti F, Brizzi MP, Amoroso V, Giuffrida D, Panzuto F, Campana D, Prinzi N, Milione M, Cascella T, Spreafico C, Randon G, Oldani S, Leporati R, Scotto G, Pulice I, Stocchetti BL, Porcu L, Coppa J, Di Bartolomeo M, de Braud F, Pusceddu S. Assessing the safety and activity of cabozantinib combined with lanreotide in gastroenteropancreatic and thoracic neuroendocrine tumors: rationale and protocol of the phase II LOLA trial. BMC Cancer. 2023 Sep 26;23(1):908. doi: 10.1186/s12885-023-11287-2.

    PubMed 37752423

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cabozantinib and Lanreotide in people with Metastatic Well Differentiated Neuroendocrine Neoplasm and Neuroendocrine Tumors, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 36 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 5 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Sara Pusceddu, MD (+390223903066, sara.pusceddu@istitutotumori.mi.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Response Rate (ORR) (time frame: 42 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04427787, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Sep 2021.

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