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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Istituto Nazionale Dei Tumori

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jun 2020 → ongoing

Decision date (initial)

2024-11-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516612-16-00

EudraCT number

2019-004506-10

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

• To demonstrate safety, tolerability and activity of cabozantinib and lanreotide association in patients with well differentiated GEP and thoracic NETs

I stage
• To evaluate the safety and tolerability of cabozantinib plus lanreotide.

II and III stage (Co-primary objectives)
• To evaluate the safety and tolerability of cabozantinib plus lanreotide.
• To evaluate the activity of cabozantinib and lanreotide combination in terms of Objective Response Rate (ORR) according to the RECIST 1.1 criteria.

The exploratory objectives of this study are:
To assess the immunohistochemical expression of MET, AXL, VEGFR2 with the aim to identify predictive or prognostic molecular targets.
Translational evaluations will be performed with the aim to select and identify tissue biomarkers modulating treatment activity and/or safety.

Secondary objectives 1

1. To evaluate the Progression Free Survival (PFS) and Overall Survival (OS)

Conditions and MedDRA coding

gastroenteropancreatic (GEP) and thoracic neuroendocrine tumor (NET)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care; Patients with unresectable, advanced or metastatic neuroendocrine well differentiated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 1

1. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Safety and tolerabilitity in terms of the rate (%) of patients experiencing grade 3-5 toxicities according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0

Secondary endpoints 1

1. Secondary endpoints include Progression Free Survival (PFS) and Overall Survival (OS)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Istituto Nazionale Dei Tumori

Sponsor organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Address

Via Giacomo Venezian 1

City

Milan

Postcode

20133

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Sara Pusceddu

Public contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Sara Pusceddu

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications