CIRCULATing Biomarkers for Individualized Surgical Therapy in gastroEsophageal Cancer - Phase 1

Cancer of Esophagus Clinical Trial

— CIRCULATE1  

Official title:

CIRCULATing Biomarkers for Individualized Surgical Therapy in gastroEsophageal Cancer - Phase 1

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04455282
• Other study ID #: 2020-06-BS
• Status: Recruiting
• Start date: February 1, 2021
• Est. completion date: January 30, 2028

Study information

• Verified date: March 2024
• Source: Heinrich-Heine University, Duesseldorf
• Contact: Nikolas H Stoecklein, MD
• Phone: 004921181
• Email: Nikolas.Stoecklein[@]med.uni-duesseldorf.de
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This is an exploratory observational biomarker study in approximately 100 eligible patients with resectable adenocarcinomas of the esophagus and gastro- esophageal junction (GEJ) type I-II (GEAC) to investigate the difference deletion frequency of circulating tumor cells (CTCs) between peripheral veins and tumor-draining veins (primary endpoint), prognostic value, relevance of a set of two additional blood-based biomarkers analyzed from a single blood sampling tube (secondary endpoints). The underlying hypothesis is that the biomarker alone or in combination improve preoperative staging and help to identify patients at risk for metastasis. This should enable a better stratification of GEAC patients to neo-adjuvant treatment, (intensified) peri-operative treatment, or even surgery alone, in selected cases. The data of the CIRCULATE study shall be used design subsequent studies testing the predictive role of these biomarkers for surgical management. Patients will provide blood samples and lymphatic fluid during the operation and annual blood samples during clinical follow up of 5 years.

Description:

This is an exploratory observational biomarker study. Around 20 mL of blood will be collected from a peripheral vein and additional 40 mL from tumor draining veins. In addition, around 5 mL of lymphatic fluid will be collected from the thoracic duct, when exposed and opened during the surgical resection. Annual blood draws (20 mL) will be performed during routine clinical follow-up or at the time point when the patients develops a (metastatic) relapse. A one tube protocol will be performed from each blood sample to assess CTCs and tumor derived extracellular Vesicles (tdEVs) using CELLSEARCH® and ACCEPT (https://github.com/LeonieZ/ACCEPT/blob/master/ACCEPT.m). In addition, tumor cells will be enumerated by CELLSEARCH® in the lymphatic fluid. ctDNA will be extracted from plasma of each blood collection tube and analyzed by mFAST-SeqS. If the mutational status of the primary tumor is known, deep sequencing of ctDNA will be applied for mutation tracking at a later time point. Tissue resected during the surgical procedure and not required for routine pathology will be collected into a biobank (cry-conserved and formalin fixed and paraffin embedded (FFPE).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: January 30, 2028
• Est. primary completion date: December 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• histologically proven adenocarcinoma of the GEJ type I and II, resectable, non-metastatic tumor
• age =18
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2,
• American Society of Anesthesiologists (ASA) < 4.
• pre-treatment stage cT1N+ M0 or cT2-4a N0/N+, M0 GEJ type I and II adenocarcinomas can be included. In case of stage cT4a, curative resectability has to be explicitly verified by the local surgical investigator prior inclusion.
• Written informed consent and the ability to understand the nature of the study and the study-related procedures and to comply with them has to be ensured.

Exclusion Criteria:

• tumors of squamous, adenosquamous or other non-adenocarcinoma histology
• patients with inoperable or metastatic GEJ type I and II adenocarcinoma, GEJ type I and II adenocarcinoma staged cT1N0 and cT4b, GEJ type I and II cT4a evaluated as not curatively resectable by the local surgical investigator
• unsigned informed consent

Related Conditions & MeSH terms

• Cancer of Esophagus
• Esophageal Neoplasms
• Esophagogastric Junction Disorder

Locations

Country	Name	City	State
Germany	University Hospital Cologne	Cologne	NRW
Germany	Universitätsklinikum Münster	Münster	North-Rhine Westfalia

Sponsors (2)

Lead Sponsor	Collaborator
Heinrich-Heine University, Duesseldorf	University Hospital of Cologne

Country where clinical trial is conducted

Germany, 

References & Publications (5)

Belic J, Koch M, Ulz P, Auer M, Gerhalter T, Mohan S, Fischereder K, Petru E, Bauernhofer T, Geigl JB, Speicher MR, Heitzer E. Rapid Identification of Plasma DNA Samples with Increased ctDNA Levels by a Modified FAST-SeqS Approach. Clin Chem. 2015 Jun;61(6):838-49. doi: 10.1373/clinchem.2014.234286. Epub 2015 Apr 20. — View Citation

Buscail E, Chiche L, Laurent C, Vendrely V, Denost Q, Denis J, Thumerel M, Lacorte JM, Bedel A, Moreau-Gaudry F, Dabernat S, Alix-Panabieres C. Tumor-proximal liquid biopsy to improve diagnostic and prognostic performances of circulating tumor cells. Mol Oncol. 2019 Sep;13(9):1811-1826. doi: 10.1002/1878-0261.12534. Epub 2019 Jul 25. — View Citation

de Wit S, Rossi E, Weber S, Tamminga M, Manicone M, Swennenhuis JF, Groothuis-Oudshoorn CGM, Vidotto R, Facchinetti A, Zeune LL, Schuuring E, Zamarchi R, Hiltermann TJN, Speicher MR, Heitzer E, Terstappen LWMM, Groen HJM. Single tube liquid biopsy for advanced non-small cell lung cancer. Int J Cancer. 2019 Jun 15;144(12):3127-3137. doi: 10.1002/ijc.32056. Epub 2019 Jan 28. — View Citation

Pernot S, Badoual C, Terme M, Castan F, Cazes A, Bouche O, Bennouna J, Francois E, Ghiringhelli F, De La Fouchardiere C, Samalin E, Bachet JB, Borg C, Ducreux M, Marcheteau E, Stanbury T, Gourgou S, Malka D, Taieb J. Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects. Eur J Cancer. 2017 Jul;79:15-22. doi: 10.1016/j.ejca.2017.03.036. Epub 2017 Apr 26. — View Citation

Reeh M, Effenberger KE, Koenig AM, Riethdorf S, Eichstadt D, Vettorazzi E, Uzunoglu FG, Vashist YK, Izbicki JR, Pantel K, Bockhorn M. Circulating Tumor Cells as a Biomarker for Preoperative Prognostic Staging in Patients With Esophageal Cancer. Ann Surg. 2015 Jun;261(6):1124-30. doi: 10.1097/SLA.0000000000001130. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in CTC detection rate between peripheral and tumor draining veins.	The difference between the CTC positivity rate (=1 CTC / 7.5 mL) in blood samples of tumor-draining veins compared to the CTC positivity rate in peripheral blood. The positivity fraction and CTC number per 7.5 mL in tumor draining veins and peripheral blood samples will be determined by CellSearch.	24 months
Secondary	tdEVs	1. The tdEV number per 7.5 mL determined from CellSearch images using the ACCEPT software tool and the fraction of tdEVs positive patients (a cut-off threshold will be applied)(de Wit, 2019). 2. The difference between tdEV measurement in the tumor-draining veins and the peripheral blood will be assessed.	24 months
Secondary	ctDNA	1. The tumor allele frequency measured by the genome-wide mFAST-SeqS assay (Belic, 2015) and the fraction of patients with high tumor allele frequency will be determined. For this, a threshold of 10% tumour allele frequency will be applied to discriminate high allele frequency (>10%) from low allele frequency (=10%) cases (Belic, 2015; de Wit, 2019). 2. The difference between ctDNA measurement in the tumor-draining veins and the peripheral blood will be assessed.	24 months
Secondary	Clinical correlation	Correlation of any of the biomarker or in combination with clinical parameters and with patient clinical outcome (OS and RFS)	84 months
Secondary	Dynamic Biobank	The number of tumor tissues (primary tumor, lymph node metastasis, biopsy material), isolated CELLSEARCH® CTCs and plasma/ctDNA samples generated from CIRCULATE1 and stored in the respective biobanks from the University Hospital of Cologne and from University Hospital Düsseldorf.	24 months