Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 26;23(1):908.
doi: 10.1186/s12885-023-11287-2.

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

Francesca Corti  1 , Maria Pia Brizzi  2 , Vito Amoroso  3 , Dario Giuffrida  4 , Francesco Panzuto  5 , Davide Campana  6 , Natalie Prinzi  1 , Massimo Milione  7 , Tommaso Cascella  8 , Carlo Spreafico  8 , Giovanni Randon  1 , Simone Oldani  1 , Rita Leporati  1 , Giulia Scotto  2 , Iolanda Pulice  9 , Benedetta Lombardi Stocchetti  1 , Luca Porcu  10 , Jorgelina Coppa  11 , Maria Di Bartolomeo  1 , Filippo de Braud  1   12 , Sara Pusceddu  13
Affiliations

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

Francesca Corti et al. BMC Cancer. .

Abstract

Background: Well-differentiated (WD) neuroendocrine tumors (NETs) are a group of rare neoplasms with limited therapeutic options. Cabozantinib is an inhibitor of multiple tyrosine kinases with a pivotal role in NET pathogenesis, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). LOLA is the first prospective phase II trial aiming to assess the safety and activity of cabozantinib combined with lanreotide in WD NETs of gastroenteropancreatic (GEP), thoracic and of unknown origin.

Methods: This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥ 10%; positive 68 Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids (typical or atypical lung and thymus NETs, gastro-intestinal NETs or NETs of unknown origin). In stage I, the primary objective is to find the optimal dose of cabozantinib in combination with lanreotide and to evaluate the safety of the combination (percentage of patients experiencing grade 3-5 toxicities according to NCI-CTCAE version 5.0). Starting dose of cabozantinib is 60 mg/day continuously, plus lanreotide 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST version 1.1. The uninteresting antitumor activity is fixed in ORR ≤ 5%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of c-MET, AXL and VEGFR2 IHC expression, to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop-out rate of 5%, the maximum number of enrolled patients will be 69.

Discussion: Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of cabozantinib plus lanreotide in a group of NET patients with relatively aggressive disease and limited therapeutic options.

Trial registration: LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019-004506-10).

Keywords: Cabozantinib; Clinical trial; Lanreotide; Neuroendocrine tumors; Somatostatin analogs; Tyrosine kinase inhibitors.

PubMed Disclaimer

Conflict of interest statement

Dr. Pusceddu reported receiving honoraria from Novartis, Ipsen, Pfizer, Merck Serono, and Advanced Accelerator Applications (AAA); receiving grants from Ipsen and Pfizer; and receiving personal fees from AAA, Novartis, and Merck outside the submitted work. Dr. Prinzi reported receiving honoraria and travel accommodations from Novartis, Ipsen, Pfizer, Merck Serono, and Italfarmaco and receiving personal fees from Merck outside the submitted work. Dr. Panzuto reported receiving honoraria for speaker and advisory roles from Novartis, for an advisory role from Ipsen, and for consulting from AAA and receiving travel accommodations from Pfizer. Dr. Corti reported receiving nonfinancial support from AAA and Ipsen outside the submitted work. Dr. Porcu reported receiving honoraria for consulting from Ipsen and Italfarmaco. Dr. de Braud reported receiving honoraria for serving on advisory boards or speakers bureaus for Amgen, Novartis, Roche, Incyte, EMD Serono, Bristol Myers Squibb, Roche, Pfizer, Menarini, Sanofi, Healthcare Research & Pharmacoepidemiology, and Dephaforum; receiving research funding from Novartis, Roche, Merck Sharp & Dohme, Merck Serono, Pfizer, Servier, and Nerviano Medical Sciences; and receiving honoraria and/or personal fees from Roche, EMD Serono, Nerviano Medical Sciences, Sanofi, MSD, Novartis, Incyte, Bristol Myers Squibb, Menarini, Merck, Pfizer, Healthcare Research & Pharmacoloepidemiology, Servier, Amgen, and Dephaforum outside the submitted work. No other disclosures were reported.

Figures

Fig. 1
Fig. 1
Synergistic antiproliferative, anti-angiogenetic and immune-modulatory effects of cabozantinib combined with somatostatin analogs. cAMP: cyclic adenosine monophosphate; ERK: extracellular signal-regulated kinases; HGF: hepatocyte growth factor; NFkB: nuclear factor kappa-light-chain-enhancer of activated B cells; MDSC: myeloid-derived suppressor cell; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3 kinase; RAS: Rat sarcoma virus; RAF: Rapidly Accelerated Fibrosarcoma; SHP1: Src homology region 2 domain-containing phosphatase-1; SSA: somatostatin analog; SSTR: somatostatin receptor; TCL: T cell Lymphocyte; Treg: regulatory T cell; VEGF(R): Vascular Endothelial Growth Factor (Receptor)
Fig. 2
Fig. 2
Study design N: number; pNETs: pancreatic neuroendocrine tumors; ORR: Overall response rate; OS: overall survival; PFS: progression-free survival; WD: well-differentiated
See this image and copyright information in PMC

References

    1. Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol. 2017;3(10):1335–1342. doi: 10.1001/jamaoncol.2017.0589. - DOI - PMC - PubMed
    1. Pavel M, de Herder WW. ENETS Consensus Guidelines for the Standard of Care in Neuroendocrine Tumors. Neuroendocrinology. 2017;105(3):193–195. doi: 10.1159/000457957. - DOI - PubMed
    1. Rinke A, Muller H, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group. J Clin Oncol. 2009;27(28):4656–4663. doi: 10.1200/JCO.2009.22.8510. - DOI - PubMed
    1. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(16):1556–1557. - PubMed
    1. Perren A, Couvelard A, Scoazec JY, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Pathology: diagnosis and prognostic stratification. Neuroendocrinology. 2017;105:196–200. doi: 10.1159/000457956. - DOI - PubMed

Publication types

MeSH terms

Associated data