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

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ClinicalTrials.gov Identifier: NCT01660776
Recruitment Status : Completed
First Posted : August 9, 2012
Last Update Posted : November 6, 2019
Sponsor:
Collaborators:
Roche Pharma AG
National Research Agency, France
Information provided by (Responsible Party):
Rennes University Hospital

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
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

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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 : June 7, 2012
Actual Primary Completion Date : October 2, 2017
Actual Study Completion Date : October 2, 2019


Group/Cohort
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



Primary Outcome Measures :
  1. 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 [ Time Frame: 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 :
  1. 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 [ Time Frame: 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

  2. 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) [ Time Frame: 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)

  3. Analysis of PD-L1 membrane protein expression on monocytes, B and T lymphocytes in all cohorts [ Time Frame: 4 years ]
    Analysis of PD-L1 membrane protein expression on monocytes, B and T lymphocytes in all cohorts

  4. Development of an ELISPOT technique to detect soluble PD-L1 in the supernatants of sorted primary cells (subpart ended mid 2013) [ Time Frame: 4 years ]
    Development of an ELISPOT technique to detect soluble PD-L1 in the supernatants of sorted primary cells (subpart ended mid 2013)

  5. Evaluation of the techniques (by immunomagnetic or cell-sorting) used to separate circulating tumor cells expressing PD-L1 [ Time Frame: 4 years ]
    Evaluation of the techniques (by immunomagnetic or cell-sorting) used to separate circulating tumor cells expressing PD-L1

  6. Correlation between the PD-L1 expression *) in the plasma, **) in the tumor and ***) in the bronchoalveolar liquid in non-small cell lung cancer [ Time Frame: 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

  7. Evaluation of the response to treatment according to soluble PD-L1 expression in non-small cell lung cancer [ Time Frame: 4 years ]
    Evaluation of the response to treatment according to soluble PD-L1 expression in non-small cell lung cancer

  8. Evaluation of the susceptibility to develop a disease according to PD-L1 gene SNP in DLBCL and non-small cell lung cancer [ Time Frame: 4 years ]
    Evaluation of the susceptibility to develop a disease according to PD-L1 gene SNP in DLBCL and non-small cell lung cancer


Biospecimen Retention:   Samples Without DNA
Biomedical research on total blood at diagnosis.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Number of DLBCL patients : 40 Number of non-small cell lung cancer patients : 100 Number of Hodgkin patients : 20 Number of metastatic breast cancer patients : 20 Number of healthy volunteers : 140 Number of patients with immune thrombocytopenia (ITP) : 5
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01660776


Locations
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France
Rennes EFS
Rennes, Brittanny, France, 35000
Rennes University Hospital
Rennes, Brittanny, France, 35000
Institut Paoli Calmette
Marseille, France, 13000
Montpellier University Hospital
Montpellier, France, 34000
Sponsors and Collaborators
Rennes University Hospital
Roche Pharma AG
National Research Agency, France
Investigators
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Principal Investigator: Thierry Fest, MD Rennes University Hospital

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Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT01660776    
Other Study ID Numbers: 2011-A01163-38
B111181-40 ( Other Identifier: AFSSAPS )
11/32-821 ( Other Identifier: CPP OUest V )
First Posted: August 9, 2012    Key Record Dates
Last Update Posted: November 6, 2019
Last Verified: November 2019
Keywords provided by Rennes University Hospital:
diffuse large B-cell lymphoma (DLBCL)
Hodgkin lymphoma
metastatic breast cancer.
non-small cell lung cancer
Additional relevant MeSH terms:
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Hodgkin Disease
Lymphoma
Carcinoma, Non-Small-Cell Lung
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Breast Neoplasms
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lymphoma, Non-Hodgkin
Breast Diseases
Skin Diseases