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.
Cabozantinib
Clinical trial
Lanreotide
Neuroendocrine tumors
Somatostatin analogs
Tyrosine kinase inhibitors
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
26 Sep 2023
26 Sep 2023
Historique:
received:
08
09
2022
accepted:
09
08
2023
medline:
28
9
2023
pubmed:
27
9
2023
entrez:
26
9
2023
Statut:
epublish
Résumé
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. 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. 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. LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019-004506-10).
Sections du résumé
BACKGROUND
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
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
CONCLUSIONS
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
BACKGROUND
LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019-004506-10).
Identifiants
pubmed: 37752423
doi: 10.1186/s12885-023-11287-2
pii: 10.1186/s12885-023-11287-2
pmc: PMC10523723
doi:
Substances chimiques
lanreotide
0G3DE8943Y
cabozantinib
1C39JW444G
Vascular Endothelial Growth Factor A
0
Banques de données
ClinicalTrials.gov
['NCT04427787']
Types de publication
Clinical Trial Protocol
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
908Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6152-8
pubmed: 15448002
Control Clin Trials. 1989 Mar;10(1):1-10
pubmed: 2702835
J Clin Oncol. 2017 Feb 20;35(6):591-597
pubmed: 28199818
Mod Pathol. 2007 Nov;20(11):1172-82
pubmed: 17873898
Ann Oncol. 2015 Sep;26(9):1987-1993
pubmed: 26063633
Lancet Oncol. 2015 Jun;16(6):695-703
pubmed: 25956795
J Transl Med. 2014 Nov 13;12:294
pubmed: 25388653
Trends Endocrinol Metab. 2014 Mar;25(3):115-27
pubmed: 24405892
Cell Mol Life Sci. 2008 Oct;65(19):3110-7
pubmed: 18810319
JAMA Oncol. 2017 Oct 01;3(10):1335-1342
pubmed: 28448665
Dig Liver Dis. 2004 Feb;36 Suppl 1:S68-77
pubmed: 15077914
Arch Pathol Lab Med. 2010 Nov;134(11):1702-5
pubmed: 21043826
J Biol Chem. 2003 Oct 17;278(42):40601-6
pubmed: 12902325
J Clin Oncol. 2009 Oct 1;27(28):4656-63
pubmed: 19704057
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
N Engl J Med. 2015 Nov 5;373(19):1814-23
pubmed: 26406150
Ital J Gastroenterol Hepatol. 1999 Oct;31 Suppl 2:S219-23
pubmed: 10604135
N Engl J Med. 2011 Feb 10;364(6):501-13
pubmed: 21306237
Neuroendocrinology. 2017 Feb 11;105(3):196-200
pubmed: 28190015
Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4464-9
pubmed: 27035983
Lancet Oncol. 2020 Nov;21(11):1500-1512
pubmed: 32966811
Pharmacol Ther. 2015 Aug;152:98-110
pubmed: 25956467
Pharmacol Ther. 2018 Jan;181:49-75
pubmed: 28723416
Clin Cancer Res. 2002 Jul;8(7):2273-85
pubmed: 12114431
N Engl J Med. 2018 Jul 05;379(1):54-63
pubmed: 29972759
J Clin Oncol. 2013 Oct 10;31(29):3639-46
pubmed: 24002501
N Engl J Med. 2014 Oct 16;371(16):1556-7
pubmed: 25317881
Nat Rev Mol Cell Biol. 2010 Dec;11(12):834-48
pubmed: 21102609
Lancet Oncol. 2020 Nov;21(11):1489-1499
pubmed: 32966810
Semin Liver Dis. 2018 Nov;38(4):379-388
pubmed: 30357775
J Clin Oncol. 2021 Jul 10;39(20):2304-2312
pubmed: 33945297
Neuroendocrinology. 2017 Feb 11;105(3):193-195
pubmed: 28190018
Diabetol Metab Syndr. 2015 Oct 01;7:84
pubmed: 26435753
Curr Opin Pharmacol. 2008 Aug;8(4):460-71
pubmed: 18579442