BMS_PD-L1_onco : Assessment of the PD-L1 Protein as a Biomarker in Oncology and Hematology

Sponsor

Rennes University Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT01660776

Collaborator

Roche Pharma AG (Industry), National Research Agency, France (Other)

105

Enrollment

Locations

87.8

Actual Duration (Months)

26.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Diffuse large B-cell lymphomas (DLBCLs) represent 25 to 30% of adult non-Hodgkin lymphomas in western countries. DLBCLs are aggressive cancer but potentially curable with multi-agent chemotherapy. Whereas R-CHOP regimen has led to a marked improvement in survival, this disease remains a biologically heterogeneous entity. New therapeutic strategies are required including identification of patients' subgroups with different prognostic.

This project is based on BMS_LyTrans and Goelams 075 clinical trial. A study of whole blood transcriptome in 75 DLBCL patients and in 87 controls showed that PD-L1 (CD274) gene was overexpressed in DLBCL patients. Preliminary results demonstrated that PD-L1 is detected in plasma of DLBCL patients with a significantly higher concentration than in controls. This protein was selected as a potential biomarker because of its established role in anti-tumoral immunity. Interaction between PD-L1 and its receptor PD-1 is known to inhibit activation of immune responses by inducing T-lymphocytes anergy and/or apoptosis. Moreover, a direct involvement of PD-L1 in the protection of cancer cells from lysis by activated T lymphocytes has been demonstrated. PD-L1 expression has been described in several solid tumours, including ovary cancer, breast cancer, colon cancer, renal cell carcinoma, non-small cell lung carcinoma and in hematological malignancies such as T-NHL, MM and Hodgkin's lymphoma. Furthermore the expression of PD-L1 by tumour cells is associated with poor prognosis. The blockade of PD-L1/PD-1 axis may represent a novel therapeutic approach in aggressive cancers. These first results incite to identify the cells releasing soluble PD-L1 and to investigate its role in the anti-tumoral immunity in DLBCL patients.

The aim of this study is to identify cells producing soluble PD-L1 in DLBCL patients at diagnosis in comparison to others tumours known to express PD-L1 (metastatic breast cancer, Hodgkin's lymphoma, non-small cell lung cancer).

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-cell Lymphoma Hodgkin Lymphoma Metastatic Breastcancer Non-small Cell Lung Cancer

Detailed Description

Secondary purposes are :

To confirm the presence of plasma soluble form of PD-L1 in others malignancies
To study surface expression of PD-L1 on circulating tumour cells with multiparameter fow cytometry and Veridex® technology in DLBCL and metastatic breast cancer patients
To study surface expression of PD-L1 on circulating endothelial cells in DLBCL, Hodgkin lymphoma and metastatic breast cancer patients (subpart ended in late 2012)
To study surface expression of PD-L1 on different types of leukocytes (monocytes, B and T lymphocytes)
To separate circulating tumour cells expressing PD-L1 by immunomagnetic or Cell-sorting method
To develop ELISPOT technique to study the release of soluble PD-L1 in culture supernatants of selected cells (subpart ended mid 2013)
to evaluate the correlation between the expression of PD-L1 in the plasma and *) the expression of PD-L1 in the tumor, **) the expression of PD-L1 and other molecules in the bronchoalveolar liquid (whenever available from routine) in non-small cell lung cancer
to evaluate the response to treatment according to plasma PD-L1 expression in non-small cell lung cancer
to evaluate the susceptibility to develop a disease according to the single nucleotide polymorphisms of the PD-L1 gene in DLBCL and non-small cell lung cancer
Constitution of the different cohorts and collection of samples Main cohort : de novo DLBCL at diagnosis Secondary cohorts: Hodgkin's lymphoma, metastatic breast cancer, non small cell lung cancer Control cohorts : healthy volunteers (blood donors), patients with immune thrombocytopenia (ITP)
Quantification of plasma soluble PD-L1 in the different cohorts

Study Design

Study Type:

Observational

Actual Enrollment :

105 participants

Observational Model:

Case-Crossover

Time Perspective:

Prospective

Official Title:

BMS_PD-L1_onco : Assessment of the PD-L1 Protein as a Biomarker in Oncology and Hematology

Actual Study Start Date :

Jun 7, 2012

Actual Primary Completion Date :

Oct 2, 2017

Actual Study Completion Date :

Oct 2, 2019

Arms and Interventions

Arm	Intervention/Treatment
DLBCL (diffuse large B-cell lymphoma) DLBCL (diffuse large B-cell lymphoma)
Hodgkin's lymphoma Hodgkin's lymphoma
metastatic breast cancer metastatic breast cancer or with lymph node involvement
immune thrombocytopenia (ITP) immune thrombocytopenia (ITP)
healthy volunteers healthy volunteers
non-small cell lung cancer non-small cell lung cancer

Outcome Measures

Primary Outcome Measures

Description of one or several blood cell types producing soluble PD-L1 in DLBCL, metastatic breast cancer, Hodgkin's lymphoma and non-small cell lung cancer [4 years]
Description of one or several blood cell types producing soluble PD-L1 in DLBCL, metastatic breast cancer, Hodgkin's lymphoma and non-small cell lung cancer

Secondary Outcome Measures

Analysis of PD-L1 membrane protein expression on circulating tumor cells by multiparameter flow cytometry and Veridex® in DLBCL and metastatic breast cancer, and bone marrow tumor cells by flow cytometry in DLBCL [4 years]
Analysis of PD-L1 membrane protein expression on circulating tumor cells by multiparameter flow cytometry and Veridex® in DLBCL and metastatic breast cancer, and bone marrow tumor cells by flow cytometry in DLBCL
Analysis of PD-L1 membrane protein expression on circulating endothelial cells with the Veridex® technology in DLBCL, Hodgkin's lymphoma and metastatic breast cancer (subpart ended in late 2012) [4 years]
Analysis of PD-L1 membrane protein expression on circulating endothelial cells with the Veridex® technology in DLBCL, Hodgkin's lymphoma and metastatic breast cancer (subpart ended in late 2012)
Analysis of PD-L1 membrane protein expression on monocytes, B and T lymphocytes in all cohorts [4 years]
Analysis of PD-L1 membrane protein expression on monocytes, B and T lymphocytes in all cohorts
Development of an ELISPOT technique to detect soluble PD-L1 in the supernatants of sorted primary cells (subpart ended mid 2013) [4 years]
Development of an ELISPOT technique to detect soluble PD-L1 in the supernatants of sorted primary cells (subpart ended mid 2013)
Evaluation of the techniques (by immunomagnetic or cell-sorting) used to separate circulating tumor cells expressing PD-L1 [4 years]
Evaluation of the techniques (by immunomagnetic or cell-sorting) used to separate circulating tumor cells expressing PD-L1
Correlation between the PD-L1 expression *) in the plasma, **) in the tumor and ***) in the bronchoalveolar liquid in non-small cell lung cancer [4 years]
Correlation between the PD-L1 expression *) in the plasma, **) in the tumor and ***) in the bronchoalveolar liquid in non-small cell lung cancer
Evaluation of the response to treatment according to soluble PD-L1 expression in non-small cell lung cancer [4 years]
Evaluation of the response to treatment according to soluble PD-L1 expression in non-small cell lung cancer
Evaluation of the susceptibility to develop a disease according to PD-L1 gene SNP in DLBCL and non-small cell lung cancer [4 years]
Evaluation of the susceptibility to develop a disease according to PD-L1 gene SNP in DLBCL and non-small cell lung cancer

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

General inclusion criteria :

Age ≥ 18 years and ≤ 75 years,
Life expectancy more than 4 months
Signed informed consent obtained
Social security affiliation is mandatory
Non previously treated (even by corticotherapy),
HIV negative, HBs negative, HCV negative

Inclusion criteria for DLBCL patients :

A biopsy proven diagnosis of de novo DLBCL according to the current WHO criteria,
Immunohistochemistry for GCB/nonGC classification according to Hans' algorithm
Patients with advanced-stage disease defined as Ann Arbor stages III or IV, or stages I or II with bulky disease (>7cm)

Inclusion criteria for non-small cell lung cancer patients :

A biopsy proven diagnosis of de novo non-small cell lung cancer (all stages) according to the current WHO criteria

Inclusion criteria for Hodgkin's lymphoma patients :

A biopsy proven diagnosis of Hodgkin's lymphoma according to the current WHO criteria

Inclusion criteria for metastatic breast cancer or with lymph node involvement :

A biopsy proven diagnosis infiltrating lobular or ductal breast carcinoma
with lymph node involvement or metastasis

Inclusion criteria for patients with immune thrombocytopenia (ITP) :

Primary ITP was defined by the IWG as a platelet count less than 100 G/L in the absence of other causes or disorders that may be associated with thrombocytopenia.
Bone marrow examination excluding a central aetiology of thrombocytopenia

Inclusion criteria for healthy volunteers :

Inclusion criteria for blood donation according to the Etablissement Français du Sang (EFS) criteria

Exclusion Criteria:

General non-inclusion criteria :

Age < 18 years et > 75 years,
Pregnant women,
Person legally involved in a case
No social security affiliation
Signed informed consent not obtained,
Preliminary treatment (even corticoid treatment).
HIV positive, HBs positive, HCV positive

Non-inclusion criteria for DLBCL patients :

Lymphoma other than DLBCL,
Transformation of a low grade lymphoma to a high grade lymphoma (DLBCL),
Extranodal marginal zone lymphoma of MALT lymphoma,
Post-transplant lymphoproliferative disorders,
Lymphoblastic lymphoma,
Burkitt's lymphoma,
Carcinoma or history of carcinoma except in situ cervical carcinoma.

Non-inclusion criteria for non-small cell lung cancer patients : None

Non-inclusion criteria for Hodgkin patients :

Non Hodgkin's lymphoma

Non-inclusion criteria for metastatic breast cancer or with lymph node involvement :

Carcinoma other than infiltrating lobular or ductal breast carcinoma
Chemotherapy in 30 days preceding the inclusion
Hormonotherapy in 7 days preceding the inclusion
Carcinoma or history of carcinoma except in situ cervical carcinoma.
Hemoglobin level < 10g/dl

Non-inclusion criteria for patients with immune thrombocytopenia (ITP) :

Central aetiology of the thrombocytopenia

Non-inclusion criteria for healthy volunteers :

Exclusion criteria for blood donation according to the Etablissement Français du Sang (EFS) criteria

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rennes EFS	Rennes	Brittanny	France	35000
2	Rennes University Hospital	Rennes	Brittanny	France	35000
3	Institut Paoli Calmette	Marseille		France	13000
4	Montpellier University Hospital	Montpellier		France	34000