The VALTIVE1 study protocol: a study for the validation of Tie2 as the first tumour vascular response biomarker for VEGF inhibitors.
Humans
Receptor, TIE-2
/ blood
Female
Biomarkers, Tumor
/ blood
Vascular Endothelial Growth Factor A
/ blood
Angiogenesis Inhibitors
/ therapeutic use
Ovarian Neoplasms
/ drug therapy
Bevacizumab
/ therapeutic use
Progression-Free Survival
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Neovascularization, Pathologic
/ drug therapy
Clinical decision making
Clinical trial
Ovarian cancer
Tie2
VEGFi
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
24 Oct 2024
24 Oct 2024
Historique:
received:
01
07
2024
accepted:
17
10
2024
medline:
25
10
2024
pubmed:
25
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
Anti-angiogenic, VEGF inhibitors (VEGFi) increase progression-free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi, the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with a hazard ratio (HR) for PFS of 0.56. The aim of the VALTIVE1 study is to validate the utility of plasma Tie2 as a vascular response biomarker and to optimise the Tie2-definition of vascular response so that the subsequent randomised discontinuation VALTIVE2 study can be powered optimally. VALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, with a sample size of 205 participants (176 bevacizumab-treated participants + 29 participants receiving bevacizumab and olaparib/PARPi), who are 16 years or older, have FIGO stage IIIc/IV ovarian cancer on treatment with first-line platinum-based chemotherapy and bevacizumab. Their blood plasma samples will be collected before, during, and after treatment and the concentration of Tie2 will be determined. The primary objective is to define the PFS difference between Tie2-defined vascular responders and Tie2-defined vascular non-responders in patients receiving bevacizumab for high-risk Ovarian Cancer. Secondary objectives include defining the relationship between Tie2-defined vascular progression and disease progression assessed according to RECIST 1.1 criteria and assessing the impact of PARPi on the plasma concentration of Tie2 and, therefore, the decision-making utility of Tie2 as a vascular response biomarker for bevacizumab during combined bevacizumab-PARPi maintenance. There is an urgent need to establish a test that tells patients and their doctors when VEGFi are working and when they stop working. The data generated from this study will be used to design a second trial aiming to prove conclusively the value of the Tie2 test. ClinicalTrials.gov identifier: NCT04523116. Registered on 21 Aug 2020.
Sections du résumé
BACKGROUND
BACKGROUND
Anti-angiogenic, VEGF inhibitors (VEGFi) increase progression-free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi, the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with a hazard ratio (HR) for PFS of 0.56. The aim of the VALTIVE1 study is to validate the utility of plasma Tie2 as a vascular response biomarker and to optimise the Tie2-definition of vascular response so that the subsequent randomised discontinuation VALTIVE2 study can be powered optimally.
METHODS
METHODS
VALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, with a sample size of 205 participants (176 bevacizumab-treated participants + 29 participants receiving bevacizumab and olaparib/PARPi), who are 16 years or older, have FIGO stage IIIc/IV ovarian cancer on treatment with first-line platinum-based chemotherapy and bevacizumab. Their blood plasma samples will be collected before, during, and after treatment and the concentration of Tie2 will be determined. The primary objective is to define the PFS difference between Tie2-defined vascular responders and Tie2-defined vascular non-responders in patients receiving bevacizumab for high-risk Ovarian Cancer. Secondary objectives include defining the relationship between Tie2-defined vascular progression and disease progression assessed according to RECIST 1.1 criteria and assessing the impact of PARPi on the plasma concentration of Tie2 and, therefore, the decision-making utility of Tie2 as a vascular response biomarker for bevacizumab during combined bevacizumab-PARPi maintenance.
DISCUSSION
CONCLUSIONS
There is an urgent need to establish a test that tells patients and their doctors when VEGFi are working and when they stop working. The data generated from this study will be used to design a second trial aiming to prove conclusively the value of the Tie2 test.
TRIAL REGISTRATION
BACKGROUND
ClinicalTrials.gov identifier: NCT04523116. Registered on 21 Aug 2020.
Identifiants
pubmed: 39448911
doi: 10.1186/s12885-024-13073-0
pii: 10.1186/s12885-024-13073-0
doi:
Substances chimiques
Receptor, TIE-2
EC 2.7.10.1
Biomarkers, Tumor
0
TEK protein, human
EC 2.7.10.1
Vascular Endothelial Growth Factor A
0
Angiogenesis Inhibitors
0
Bevacizumab
2S9ZZM9Q9V
VEGFA protein, human
0
Banques de données
ClinicalTrials.gov
['NCT04523116']
Types de publication
Journal Article
Clinical Trial Protocol
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
1309Informations de copyright
© 2024. The Author(s).
Références
Pignata S, Lorusso D, Joly F, et al. Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first line treatment: The randomized phase 3 trial MITO16B-MaNGO OV2B-ENGOT OV17. J Clin Oncol. 2018;36(15_suppl):5506–5506.
doi: 10.1200/JCO.2018.36.15_suppl.5506
Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus Bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381:2416–28.
doi: 10.1056/NEJMoa1911361
pubmed: 31851799
Jayson GC, Kerbel R, Ellis LM, et al. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388:518–29. https://doi.org/10.1016/S0140-6736(15)01088-0 .
doi: 10.1016/S0140-6736(15)01088-0
pubmed: 26853587
Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16:928–36. https://doi.org/10.1016/S1470-2045(15)00086-8 .
doi: 10.1016/S1470-2045(15)00086-8
pubmed: 26115797
pmcid: 4648090
Perren TJ, Swart AM, Pfisterer J, et al. A Phase 3 Trial of Bevacizumab in Ovarian Cancer. New Engl J Med. 2011;365:2484–96. https://doi.org/10.1056/NEJMoa1103799 .
doi: 10.1056/NEJMoa1103799
pubmed: 22204725
Burger RA, Brady MF, Bookman MA, et al. Incorporation of Bevacizumab in the primary treatment of ovarian cancer. New Engl J Med. 2011;365:2473–83. https://doi.org/10.1056/NEJMoa1104390 .
doi: 10.1056/NEJMoa1104390
pubmed: 22204724
Ledermann JA, Embleton AC, Raja F, et al. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;387:1066–74. https://doi.org/10.1016/S0140-6736(15)01167-8 .
doi: 10.1016/S0140-6736(15)01167-8
pubmed: 27025186
Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase iii trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039–45. https://doi.org/10.1200/JCO.2012.42.0505 .
doi: 10.1200/JCO.2012.42.0505
pubmed: 22529265
pmcid: 3646321
Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized Phase III trial. J Clin Oncol. 2014;32:1302–8. https://doi.org/10.1200/JCO.2013.51.4489 .
doi: 10.1200/JCO.2013.51.4489
pubmed: 24637997
Pignata S, Lorusso D, Scambia G, et al. Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): A Randomised, Open-Label, Phase 2 trial. Lancet Oncol. 2015;16:561–8. https://doi.org/10.1016/S1470-2045(15)70115-4 .
doi: 10.1016/S1470-2045(15)70115-4
pubmed: 25882986
Pignata S, Lorusso D, Joly F, et al. Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first line treatment: The randomized phase 3 trial MITO16B-MaNGO OV2B-ENGOT OV17. J Clin Oncol. 2018; 36, 15 (suppl): 5506–5506, https://doi.org/10.1200/JCO.2018.36.15_suppl.5506 .
Backen A, Renehan AG, Clamp AR, et al. The combination of circulating Ang1 and Tie2 levels predicts progression-free survival advantage in bevacizumab-treated patients with ovarian cancer. Clin Cancer Res. 2014;20:4549–58. https://doi.org/10.1158/1078-0432.CCR-13-3248 .
doi: 10.1158/1078-0432.CCR-13-3248
pubmed: 24947924
pmcid: 4154862
Zhou C, Clamp A, Backen A, et al. Systematic analysis of circulating soluble angiogenesis-associated proteins in ICON7 identifies Tie2 as a biomarker of vascular progression on bevacizumab. Br J Cancer. 2016;115:228–35. https://doi.org/10.1038/bjc.2016.194 .
doi: 10.1038/bjc.2016.194
pubmed: 27351218
pmcid: 4947705
Jayson GC, Zhou C, Backen A, et al. Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer. Nat Commun. 2018;9:4672. https://doi.org/10.1038/s41467-018-07174-1 .
doi: 10.1038/s41467-018-07174-1
pubmed: 30405103
pmcid: 6220185
Daly C, Eichten A, Castanaro C, et al. Angiopoietin-2 Functions as a Tie2 Agonist in Tumor Models, where it limits the effects of VEGF inhibition. Cancer Res. 2013;73:108–18. https://doi.org/10.1158/0008-5472.CAN-12-2064 .
doi: 10.1158/0008-5472.CAN-12-2064
pubmed: 23149917
Rigamonti N, Kadioglu E, Keklikoglou I, et al. Role of Angiopoietin-2 in adaptive tumor resistance to vegf signaling blockade. Cell Rep. 2014;8:696–706. https://doi.org/10.1016/j.celrep.2014.06.059 .
doi: 10.1016/j.celrep.2014.06.059
pubmed: 25088418
Zhang L, Yang N, Park JW, et al. Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res. 2003;63:3403–12.
pubmed: 12810677
Batchelor TT, Duda DG, di Tomaso E, et al. Phase II Study of Cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010;28:2817–23. https://doi.org/10.1200/JCO.2009.26.3988 .
doi: 10.1200/JCO.2009.26.3988
pubmed: 20458050
pmcid: 2903316
Spencer SK, Pommier AJC, Morgan SR, et al. Prognostic/predictive value of 207 serum factors in colorectal cancer treated with cediranib and/or chemotherapy. Br J Cancer. 2013;109:2765–73. https://doi.org/10.1038/bjc.2013.649 .
doi: 10.1038/bjc.2013.649
pubmed: 24149180
pmcid: 3844909
Valle JW, Wasan H, Lopes A, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol. 2015;16:967–78. https://doi.org/10.1016/S1470-2045(15)00139-4 .
doi: 10.1016/S1470-2045(15)00139-4
pubmed: 26179201
pmcid: 4648082
Zhou C, O’Connor J, Backen A, et al. Plasma Tie2 trajectories identify vascular response criteria for VEGF inhibitors across advanced biliary tract, colorectal and ovarian cancers. ESMO Open. 2022;7: 100417. https://doi.org/10.1016/j.esmoop.2022.100417 .
doi: 10.1016/j.esmoop.2022.100417
pubmed: 35279528
pmcid: 9058891
Mahmood RD, Shaw D, Descamps et al. Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study. BMC Cancer. 2021;21(1):354. https://doi.org/10.1186/s12885-021-08097-9 .
Morgan RD, Clamp AR, Evans DGR, et al. PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer. Cancer Chemother Pharmacol. 2018;81:647–58. https://doi.org/10.1007/s00280-018-3532-9 .
doi: 10.1007/s00280-018-3532-9
pubmed: 29464354
pmcid: 5854713
Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. New Engl J Med. 2018;379:2495–505. https://doi.org/10.1056/NEJMoa1810858 .
doi: 10.1056/NEJMoa1810858
pubmed: 30345884
Mirza MR, Matulonis UA. Niraparib in Recurrent Ovarian Cancer. New Engl J Med. 2017;376:25801–2. https://doi.org/10.1056/NEJMc1616633 .
doi: 10.1056/NEJMc1616633
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. New Engl J Med. 2012;366:1382–92. https://doi.org/10.1056/NEJMoa1105535 .
doi: 10.1056/NEJMoa1105535
pubmed: 22452356
Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, Open-Label, Phase 2 Trial. Lancet Oncol. 2017;18:75–87. https://doi.org/10.1016/S1470-2045(16)30559-9 .
doi: 10.1016/S1470-2045(16)30559-9
pubmed: 27908594
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. New Engl J Med. 2016;375:2154–64. https://doi.org/10.1056/NEJMoa1611310 .
doi: 10.1056/NEJMoa1611310
pubmed: 27717299
Mirza MR, Lundqvist EÅ, Birrer MJ, et al. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. Lancet Oncol. 2019;20:1409–19. https://doi.org/10.1016/S1470-2045(19)30515-7 .
doi: 10.1016/S1470-2045(19)30515-7
pubmed: 31474354
Liu JF, Brady MF, Matulonis UA, et al. Olaparib with or without cediranib versus platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer (NRG-GY004): a randomized, open-label, Phase III Trial. J Clin Oncol : Official J Am Soc Clin Oncol. 2022;40:2138–47. https://doi.org/10.1200/JCO.21.02011 .
doi: 10.1200/JCO.21.02011
Alvarez Secord A, O’Malley DM, Sood AK, et al. Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review. Gynecol Oncol. 2021;162:482–95. https://doi.org/10.1016/j.ygyno.2021.05.018 .
doi: 10.1016/j.ygyno.2021.05.018
pubmed: 34090705
Kaplan AR, Gueble SE, Liu Y et al. Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Science translational medicine. 2019 ; 11 ; https://doi.org/10.1126/scitranslmed.aav4508 .
Chan N, Pires IM, Bencokova Z, et al. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res. 2010;70:8045–54. https://doi.org/10.1158/0008-5472.CAN-10-2352 .
doi: 10.1158/0008-5472.CAN-10-2352
pubmed: 20924112
pmcid: 2978949
Lim JJ, Yang K, Taylor-Harding B, et al. VEGFR3 inhibition chemosensitizes ovarian cancer stemlike cells through down-regulation of BRCA1 and BRCA2. Neoplasia. 2014;16(343–353):e341-342. https://doi.org/10.1016/j.neo.2014.04.003 .
doi: 10.1016/j.neo.2014.04.003
Wie W, Li Y, Lv S, et al. Y PARP-1 may be involved in angiogenesis in epithelial ovarian cancer. Oncol Lett. 2016;12:4561–7. https://doi.org/10.3892/ol.2016.5226 .
doi: 10.3892/ol.2016.5226
Tentori L, Lacal PM, Muzi A, et al. Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis. Eur J Cancer. 2007;1990(43):2124–33. https://doi.org/10.1016/j.ejca.2007.07.010 .
doi: 10.1016/j.ejca.2007.07.010