Hereditary Pheochromocytoma Assessment of Tumour Immunologies

Pheochromocytoma Clinical Trial

— HEPHESTOS  

Official title:

HEPHESTOS - Hereditary Pheochromocytoma Assessment of Tumour Immunologies

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06444607
• Other study ID #: 115703
• Status: Not yet recruiting
• Start date: June 1, 2024
• Est. completion date: June 1, 2029

Study information

• Verified date: May 2024
• Source: Radboud University Medical Center
• Contact: Kai Xu, M.D.
• Phone: +316 42385270
• Email: kai.xu[@]radboudumc.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

In this study, the investigators are examining the role of the immune system in pheochromocytoma and paraganglioma. The investigators aim to examine the differences in the immune system between people who have these tumors with and without a hereditary predisposition. The investigators also want to see how the immune system changes during the development of the tumor in people with a hereditary predisposition. Finally, the investigators will compare the data with a control group of people without these tumors. Ultimately, the investigators hope that the results will contribute to the discovery of new immune system-targeted medications for pheochromocytoma and paraganglioma.

Description:

Rationale: Pheochromocytoma and Paraganglioma (PPGL) represent rare, catecholamine-secreting tumours (1). Genetic or sporadic mutations, accounting for approximately 70% of cases, significantly contribute to PPGL development, and are categorized into three clusters based on tumour formation mechanisms (2,3). Current treatment options, particularly for advanced or metastatic disease, are limited (4). Understanding the immune system's role and the impact of genetics on tumour immunology in PPGL could unveil crucial insights for therapeutic advancements. Earlier studies emphasized the immunogenic nature of PPGL, highlighting the tumour microenvironment (TME) and circulatory factors as key components (5-7). However, these studies lack specific examination of genotypes' effect on the immune system. This study aims to address this gap in two parts, particularly focusing on differences between genetic clusters.

Objective: To examine the differences in the immune system in PPGL regarding genetics. Part I will examine immune cell composition and response in circulation. Part II will examine immune cell composition in TME.

Study design: Part I will be a partly cross-sectional and partly prospective cohort study. Part II will be a histological study of retrospectively and prospectively collected PPGL samples.

Study population: Part I will include 80 patients with PPGL, 80 carriers of germline mutations predisposing for PPGL, and 40 sex and age matched healthy volunteers. Part II will include histological samples of 80 patients with hereditary disease and 80 patients with sporadic disease.

Main study parameters/endpoints: The main study outcomes are inflammatory molecules and proteins produced by stimulated and unstimulated immune cells from circulation, immune cell composition in histological PPGL samples and in circulation, and their genetic determinants. Secondary outcomes will comprise of transcriptional and epigenetic signature of circulating immune cells, circulating immunomodulating metabolites, trained immunity, and clinical outcomes such as tumour metastasis, survival.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: For patients and mutation carriers, there is no direct benefit in participating in this study. However, by participating, they can contribute to the acquisition of scientific knowledge and the development of new therapeutic targets and novel disease management strategies. Such strategies might benefit patients and mutation carriers in the future if they potentially develop advanced disease. There are no risks associated with the study. There are no interventions other than those related to the regular patient care (venipuncture). Thus, this study is considered to impose a low burden on patients.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 200
• Est. completion date: June 1, 2029
• Est. primary completion date: June 1, 2029
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Part I:

• Newly diagnosed patients with PPGL or newly diagnosed patients with (metastatic) PPGL recurrence.

• OR patients with mutations which predispose for the development of PPGL.

• Aged > 18 years.

Part II:

• Confirmed PPGL on pathology.

• Aged > 18 years.

Exclusion Criteria:

• Unable to provide informed consent.

• Active inflammatory or infectious comorbidities.

• Other malignancies which are under active treatment (except for basal cell carcinoma, other in situ carcinomas).

• Using medication interfering with the immune system

• Pregnancy or breastfeeding

• A self-reported alcohol consumption of >21 units per week

Related Conditions & MeSH terms

• Paraganglioma
• Pheochromocytoma

Intervention

Procedure:
• Venepuncture
Blood draw in the context of routine patient care, when a venipuncture is already scheduled.
• Venepuncture
Volunteering for blood draw.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University Medical Center

References & Publications (7)

Cascon A, Calsina B, Monteagudo M, Mellid S, Diaz-Talavera A, Curras-Freixes M, Robledo M. Genetic bases of pheochromocytoma and paraganglioma. J Mol Endocrinol. 2023 Jan 24;70(3):e220167. doi: 10.1530/JME-22-0167. Print 2023 Apr 1. — View Citation

Gao X, Yamazaki Y, Pecori A, Tezuka Y, Ono Y, Omata K, Morimoto R, Nakamura Y, Satoh F, Sasano H. Histopathological Analysis of Tumor Microenvironment and Angiogenesis in Pheochromocytoma. Front Endocrinol (Lausanne). 2020 Nov 10;11:587779. doi: 10.3389/fendo.2020.587779. eCollection 2020. — View Citation

Jhawar S, Arakawa Y, Kumar S, Varghese D, Kim YS, Roper N, Elloumi F, Pommier Y, Pacak K, Del Rivero J. New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications. Cancers (Basel). 2022 Jan 25;14(3):594. doi: 10.3390/cancers14030594. — View Citation

Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005 Aug 20-26;366(9486):665-75. doi: 10.1016/S0140-6736(05)67139-5. — View Citation

Nolting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, Eisenhofer G, Grossman A, Pacak K. Personalized Management of Pheochromocytoma and Paraganglioma. Endocr Rev. 2022 Mar 9;43(2):199-239. doi: 10.1210/endrev/bnab019. Erratum In: Endocr Rev. 2022 Mar 9;43(2):440. doi: 10.1210/endrev/bnab044. Endocr Rev. 2022 Mar 9;43(2):437-439. doi: 10.1210/endrev/bnab045. — View Citation

Tufton N, Hearnden RJ, Berney DM, Drake WM, Parvanta L, Chapple JP, Akker SA. The immune cell infiltrate in the tumour microenvironment of phaeochromocytomas and paragangliomas. Endocr Relat Cancer. 2022 Sep 19;29(11):589-598. doi: 10.1530/ERC-22-0020. Print 2022 Nov 1. — View Citation

van der Heijden CDCC, Groh L, Keating ST, Kaffa C, Noz MP, Kersten S, van Herwaarden AE, Hoischen A, Joosten LAB, Timmers HJLM, Netea MG, Riksen NP. Catecholamines Induce Trained Immunity in Monocytes In Vitro and In Vivo. Circ Res. 2020 Jul 3;127(2):269-283. doi: 10.1161/CIRCRESAHA.119.315800. Epub 2020 Apr 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Immune cell response in circulation, both after stimulation and in an unstimulated state, measured as the concentration of inflammatory molecules and proteins.	e.g. cytokines	Before surgery, 6 weeks after surgery, after 1 year, after 2 years.
Primary	Immune cell composition in histological PPGL specimens and in circulation.		Before surgery, 6 weeks after surgery, after 1 year, after 2 years. Histological specimens will only be obtained during surgery.
Secondary	Transcriptional and epigenetic signature of circulating immune cells.		Before surgery, 6 weeks after surgery, after 1 year, after 2 years.
Secondary	Concentration of immunomodulating metabolites in circulation.	e.g. catecholamines, succinate.	Before surgery, 6 weeks after surgery, after 1 year, after 2 years.
Secondary	Trained immunity assessment of circulating immune cells.		Before surgery, 6 weeks after surgery, after 1 year, after 2 years.
Secondary	Tumour recurrence rate		After 1 year, after 2 years.
Secondary	Metastasis rate		Before surgery, after 1 year, after 2 years.
Secondary	Survival rate		After 1 year, after 2 years.