Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04300101 |
| Other study ID # |
IRSTB094 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 14, 2020 |
| Est. completion date |
March 2023 |
Study information
| Verified date |
February 2021 |
| Source |
Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori |
| Contact |
Oriana Nanni, Dr |
| Phone |
+39 0543739100 |
| Email |
oriana.nanni[@]irst.emr.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This is a prospective observational study. The primary objective is to identify new
prognostic biomarkers for DLBCL patients in terms of progression-free survival (PFS) and able
to add predictive capacity to recognized important clinical factors.
The secondary objectives are:
- to identify new biomarkers associated with overall survival (OS) and objective response
rate (ORR)
- to characterize tissue and circulating immune microenvironment of DLBCL patients by bulk
and single cell transcriptomics;
- to assess the correlation between the expression of immune checkpoint genes and mRNA
signature;
- to describe the mutational status of a panel of genes relevant to DLBCL pathogenesis;.
- to assess the correlation between protein expression, mutational status and the
messenger RNA (mRNA) signature.
For each enrolled patient, immunohistochemical determinations will be performed: Cell of
origin (COO) (Germinal Cell -GC- or activated B-cell - ABC- type according with Hans
algorithm ), evaluation of cluster of differentiation antigen 20 (CD20), cluster of
differentiation antigen 5 (CD5), cluster of differentiation antigen 10 (CD10), Bcl6, Bcl2
(cut off>50%), Multiple Myeloma 1 / Interferon Regulatory Factor 4 protein (MUM1/IRF4), c-myc
(cut off>40%) and Ki67, fluorescence in situ hybridization (FISH) for c-myc and if
rearranged, for Bcl2 e Bcl6 ). Moreover, paraffin embedded (FFPE) tumor specimens will be
collected for RNA extraction and mRNA expression analysis and sent to Bioscience Laboratory
of Istituto Scientifico Romagnolo per lo studio e la cura dei tumori (IRST-IRCCS).
Description:
Diffuse large B-cell lymphoma (DLBCL) is an heterogeneous group of cancers classified
together on the basis of morphology, immunophenotype, genetic alterations and clinical
behavior. The distinction of DLBCL into cell-of origin (COO) categories, based on patterns of
gene expression reminiscent ( germinal center B-cell- the GC group and activated B-cell- the
ABC group-), as defined and characterized by the Lymphoma & Leukemia Molecular Profiling
Project (LLMPP), has profound biological, prognostic and potential therapeutic implications
and in addiction, the negative prognostic effect of myelocytomatosis oncogene (MYC), B-cell
lymphoma 2 (BCL2) and B-cell lymphoma-6 (BCL6) alterations in DLBCL has been showed largely
dependent on COO subtypes . Furthermore, the combination of BCL2, MYC and BCL6 alterations
with IPI (International Prognostic Index), identifies markedly worse prognostic groups within
individual COO subtypes. The original methods used to define these entities, performed gene
expression profiling (GEP) using microarrays on RNA derived from frozen tissue (FT).
Subsequently, in an attempt to determine COO in standard practice using commonly available
formalin-fixed paraffin-embedded tissue (FFPE) less precise but relatively inexpensive binary
immunohistochemical (IHC) methods has been used . However in particular in non GC, the rate
of concordance was unsatisfactory. A high degree of agreement has been demonstrated instead
in COO determining, with a signature of 20 genes from formalin-fixed paraffin embedded (FFPE)
tumor specimens, with Lymph2Cx kit (nCounter® Technology, NanoString Technologies), becoming
the gold standard suggested in World Health Organization (WHO) classification . However
recently, was demonstrated that the COO and BCL2, MYC, BCL6 status are not enough to describe
the molecular risk of these patients, suggesting a genetic substructure that still to be
discovered . Moreover, the tumor microenvironment and in particular the ratio of immune
effectors and checkpoint molecules also have a prognostic role in DLBCL. Besides, elevated
frequency of myofibroblasts, dendritic cells, and cluster of differentiation 4 (CD4) positive
T cells correlated with better outcomes.
In conclusion, a comprehensive genomic analysis of these patients and a deep characterization
of the immune compartment and immune checkpoints (Nanostring, immunohistochemistry for BCL2,
MYC, BCL6, mutation analysis, proteomic analysis etc.) joined with IPI score, will allow the
creation of a mixed, molecular, clinical, index (MMCI) to identify extremely poor prognostic
groups, within each COO subtype, to consider a risk-adapted treatments in future.
It is a prospective observational study with a total duration of 36 months. The primary
objective is the identification of new prognostic biomarkers for DLBCL patients in terms of
progression-free survival (PFS) and able to add predictive capacity to recognized important
clinical factors.
The secondary objectives are:
- to identify new biomarkers associated with overall survival (OS) and objective response
rate (ORR);
- to characterize tissue and circulating immune microenvironment of DLBCL patients by bulk
and single cell transcriptomics;
- to assess the correlation between the expression of immune - checkpoint genes and mRNA
signature;
- to describe the mutational status of a panel of genes relevant to DLBCL pathogenesis;.
- to assess the correlation between protein expression, mutational status and the mRNA
signature.
For each enrolled patient, immunohistochemical determinations will be performed by each
Pathology Unit: COO (GC o ABC type according with Hans algorithm ), evaluation of CD20, CD5,
CD10, Bcl6, Bcl2 (cut off>50%), MUM1/IRF4, c-myc (cut off>40%) and Ki67, FISH for c-myc and
if rearranged, for Bcl2 e Bcl6). Moreover, paraffin embedded (FFPE) tumor specimens will be
collected for RNA extraction and mRNA expression analysis and centralised at IRST-IRCCS.
