HK40000537A

HK40000537A - Copanlisib biomarkers

Info

Publication number: HK40000537A
Application number: HK19123997.9A
Authority: HK
Inventors: Li Liu; Carol Pena; Jie Cheng; Karl KÖCHERT
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2016-02-01
Filing date: 2017-01-30
Publication date: 2020-02-07

Description

COPANLISIB biomarkers

Introduction to the design reside in

The present invention relates to gene expression markers and characteristics (signatures) for copenlisib therapy and to methods for use in cancer: it provides biomarkers (biomarker) based on gene expression profiling (gene expression profiling) that can distinguish between patients who respond to copanlisib therapy and/or have long progression-free survival due to copanlisib therapy, and patients who do not respond to copanlisib therapy and/or have short progression-free survival due to copanlisib therapy, among lymphomas, including indolent and aggressive non-hodgkin's lymphoma (hereinafter referred to as "NHL") and chronic lymphocytic leukemia (hereinafter referred to as "CLLs"). The present invention relates to the use of genes from BCR, PI3K, NFkB, IL6, inflammation and stromal processes as predictive biomarkers for various human cancers including but not limited to NHLs.

Background

Copalisib is a novel pan-I class PI3K inhibitor with major activity against α and delta isoforms that shows promising single agent antitumor activity in phase 2 studies in heavily pretreated patients with indolent and aggressive NHL this mechanism of action (see FIG. 1) has been shown to convert to antitumor activity in NHL identification of biomarkers predictive of sensitivity to Copanlisib can lead to biomarker driven targeted therapies that are more effective against cancer although in preclinical models, activating mutations in PIK3CA and/or changes in PTEN have been shown to be determinants of sensitivity, while RAS/RAF mutations/activation lead to resistance to PI3K pathway inhibition, predictive markers for PI3K inhibitors have not been defined in the clinical setting.

We applied tumor gene expression profiling and bioinformatics analysis to identify new genes or pathways that correlate with tumor response and benefit/outcome from copanlisib therapy and provide predictive markers and rationale for new combination considerations.

Detailed Description

Definition of terms used in the context of the present invention:

the term "compound" as used herein means copanlisib, in particular a pharmaceutically acceptable salt thereof, in particular copanlisib dihydrochloride, i.e. an active ingredient or substance to be administered to a subject for the treatment of an "indication" as defined herein.

The term "indication" as used herein means a type of cancer or tumor for which it is found that a subject having such a type of cancer may be a responder to a therapy with the compound if the cancer is characterized by a hierarchical characteristic as defined herein. The indications are characterized by "hierarchical features" as defined herein. The indication as used herein is non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL").

The term "layered characteristics" as used herein is a characteristic of the type of cancer of a subject for which treatment with an active ingredient is recommended. Said characteristic is the up-regulation of one or more genes (also called "specific markers") which predict the response to copanlisib, in particular copanlisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

and/or

PI3K pathway genes: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

- GPR18。

the term "up-regulation" (also referred to as "high expression") or "down-regulation" (also referred to as "low expression") of a gene or gene feature or gene pathway as defined herein is determined by: expression levels from measured genes or scores (e.g., WGS) calculated/derived from expression levels of all genes in a feature or pathway are compared to a threshold (also referred to as "cut off"). The cutoff can be a median value that results from tumors collected for indications of disease or established from clinical trials evaluating the relationship between the expression level or gene signature score of genes and efficacy of treatment by copanlisib. Up-regulation (or high expression): above threshold (cutoff). Downregulation (or underexpression): below a threshold (cutoff).

The term "a layered feature is positively determined" means confirming the presence of the layered feature (which may also be a reduction or absence of the specific marker).

The term "hierarchical method" means a method by which the hierarchical characteristics are determined, for example, a hierarchical method in which the expression level of the gene and the gene characteristics (pattern) are determined by the following methods such as: affymetrix arrays, RT-PCR, RNAseq, nanostrings, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway, and median gene expression signal levels for Affymetrix arrays for individual genes as cut-offs, the extent of the upregulation was statistically validated.

The term "sample" as used herein means a sample applied in a layered process, e.g. a tumor sample, a tissue sample, a biological sample, a blood sample, in particular tumor tissue of tumor cells.

In the context of the present invention, the layered features may be used to characterize an indication or a subject, as defined herein.

A first aspect of the invention relates to a biomarker for copanlisib, wherein the indication is characterized by a hierarchical character:

in a first feature of the first aspect, the invention relates to the use of copanlisib, in particular copanlisib dihydrochloride, for the preparation of a medicament for the treatment of an indication in a subject that is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), wherein the indication is characterized by a hierarchical characteristic that is an upregulation of one or more genes, the one or more genes predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

GPR18 gene.

In one embodiment of the first feature of the first aspect, the present invention relates to said use, wherein the hierarchical feature is determined by a hierarchical approach, the hierarchical feature being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.

In a second embodiment of the first feature of the first aspect, the invention relates to said use, wherein the subject to be treated is a subject for whom a stratification profile has been positively determined in tumor tissue or tumor cells from the subject, said stratification profile being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in a third embodiment of the first feature of the first aspect, the present invention relates to said use, wherein the subject or the cancer of said subject is characterized by a hierarchical feature, said hierarchical feature being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in a third embodiment of the first feature of the first aspect, the present invention relates to said use, wherein the subject's cancer is determined by a stratification method, said subject's cancer is characterized by a stratification profile, said stratification profile is an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18；

In one variant of an embodiment of the first feature of the first aspect, the invention relates to the use of copanlisib, in particular copanlisib dihydrochloride, for the preparation of a medicament for the treatment of an indication which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), wherein the subject has been identified as a responder/stratified/identified by a method according to a stratification method, wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.

In a second feature of the first aspect, the present invention relates to the use of copanlisib, in particular copanlisib dihydrochloride, for the preparation of a medicament for a method of treating an indication in a subject, in particular a relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular a follicular lymphoma (hereinafter abbreviated as "FL"), a chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), a marginal zone lymphoma (hereinafter abbreviated as "MZL"), a diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), a Mantle Cell Lymphoma (MCL), a transformed lymphoma (hereinafter abbreviated as "TL"), or a peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), the method comprising the steps of:

a) determining tumor tissue or tumor cells from a subject by a hierarchical approach, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, Nancluster, RNAscope, e.g., using as cut-off the median weighted gene expression score (WGS) for genes within a particular pathway, and the median gene expression signal level for Affymetrix arrays for individual genes, the extent of said upregulation being statistically validated, and

b) determining the presence or absence of a stratification feature, said stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes being selected from the group consisting of:

a BCR pathway gene: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

the PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

◦ GPR18；

and

c) administering a therapeutically effective amount of copanlisib, in particular copanlisib dihydrochloride, if the stratification profile is positively determined.

In a third feature of the first aspect, the invention relates to a method for identifying a subject having an indication, in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), which is prone to respond favorably to copanlisib, in particular copanlisib dihydrochloride, wherein the method comprises detecting a stratification feature in tumor tissue or tumor cells from the subject, the stratification feature is an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

• GPR18。

in a first embodiment of the third feature of the first aspect, the present invention relates to said method, wherein a hierarchical feature is detected in the tumor tissue or tumor cells, said hierarchical feature being the up-regulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression-free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in a second embodiment of the third feature of the first aspect, the present invention relates to said method, wherein said hierarchical feature is determined by a hierarchical method, said hierarchical feature being the upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18；

In a fourth feature of the first aspect, the present invention relates to a method for identifying a subject having an indication, in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "bcdll"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), said subject being more likely to respond to a therapy comprising copanlisib, in particular copanlisib dihydrochloride, said method comprising:

a) determining in vitro a stratification feature in tumor tissue or tumor cells from said subject, said stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes being selected from the group consisting of:

◦ GPR18；

b) identifying the subject as more likely to respond to a therapy comprising copanlisib, particularly copanlisib dihydrochloride, when a stratification feature is present, the stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, particularly copanlisib dihydrochloride, and/or progression-free survival, and the one or more genes are selected from:

◦ GPR18。

in a fifth feature of the first aspect, the present invention relates to a method for identifying a subject having an indication that is non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "bcdll"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), the subject being unlikely to respond to a therapy comprising copanlisib, in particular copanlisib dihydrochloride, the method comprising:

a) determining a stratification characteristic in tumor tissue or tumor cells from said subject, said stratification characteristic being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes being selected from the group consisting of:

◦ GPR18；

b) identifying the subject as unlikely to respond to a therapy comprising copanlisib, particularly copanlisib dihydrochloride, when the stratification feature is lacking.

In a sixth feature of the first aspect, the invention relates to the use of tumor tissue or tumor cells for stratifying an indication, in particular a relapsed/refractory, indolent or aggressive non-hodgkin lymphoma (NHL), in particular a follicular lymphoma (hereinafter abbreviated as "FL"), a chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), a marginal zone lymphoma (hereinafter abbreviated as "MZL"), a diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), a Mantle Cell Lymphoma (MCL), a transformed lymphoma (hereinafter abbreviated as "TL"), or a peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), from a subject predisposed to advantageously responding to copanlisib, in particular copanlisib dihydrochloride.

In a seventh feature of the first aspect, the invention relates to a method of predicting/determining whether a subject with an indication, which is non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), will be non-responsive/responsive to treatment with copanlisib, in particular copanlisib dihydrochloride, wherein the method comprises detecting a stratifying feature in tumor tissue or tumor cells from the subject, the stratification feature is an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

• GPR18。

in one embodiment of the seventh feature of the first aspect, the invention relates to the method, wherein the sample is tumor tissue or tumor cells.

In a second embodiment of the seventh feature of the first aspect, the invention relates to said method, wherein said hierarchical features are determined by a hierarchical method, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. applying as cut-off values the median weighted gene expression score (WGS) for genes within a specific pathway, and the median gene expression signal level for Affymetrix arrays of individual genes, the extent of said upregulation being statistically validated.

In an eighth feature of the first aspect, the present invention relates to a method of determining the likelihood that a subject having an indication other than hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), particularly follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), will benefit from treatment with copanlisib, particularly copanlisib dihydrochloride, the method comprising:

◦ GPR18；

b) when the stratification feature is positively determined, identifying the subject as more likely to respond to a therapy comprising copanlisib, particularly copanlisib dihydrochloride.

In a ninth feature of the first aspect, the present invention relates to a method of optimizing the therapeutic efficacy of a subject having an indication that is non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), to be more likely to respond to a therapy comprising copanlisib, in particular copanlisib dihydrochloride, said method comprising:

a) determining the presence of an indication, which is non-Hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), in a tumor tissue or tumor cells of a subject, characterized by a hierarchical characteristic, which is an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression-free survival, and the one or more genes are selected from:

◦ GPR18；

b) identifying the subject as more likely to respond to a therapy comprising copanlisib, particularly copanlisib dihydrochloride, when the stratification feature is positively determined;

c) administering a therapeutically effective amount of copanlisib, in particular copanlisib dihydrochloride, if the stratification profile is positively determined;

d) determining whether the stratification profile in tumor tissue or tumor cells of a subject administered a therapeutically effective amount of copanlisib, in particular copanlisib dihydrochloride, is increased/decreased,

e) treatments by lower/higher dosing, other dosing regimens, etc. are employed.

In a tenth feature of the first aspect, the invention relates to a method of monitoring the response of a treatment in a subject treated with copanlisib, in particular copanlisib dihydrochloride, said subject having an indication that is non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), wherein the method comprises:

a) detecting a stratification feature in tumor tissue or tumor cells from said subject, said stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes being selected from the group consisting of:

◦ GPR18；

b) comparing the hierarchical features with those from responders and non-responders, and

c) identifying whether the subject has a responder or non-responder pattern to determine whether to continue treatment.

In one embodiment of the tenth feature of the first aspect, the invention relates to said method, wherein the hierarchical feature is an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and is selected from the group consisting of:

• GPR18；

In an eleventh feature of the first aspect, the invention relates to copanlisib, in particular copanlisib dihydrochloride, for use in a method of treating the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18。

in one embodiment of the eleventh feature of the first aspect, the present invention relates to copanlisib, in particular copanlisib dihydrochloride, wherein the characterization of an indication, which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), is performed in tumor tissue or tumor cells (or, where applicable, corresponding tissue samples).

In a second embodiment of the eleventh feature of the first aspect, the invention relates to copanlisib, in particular copanlisib dihydrochloride, wherein the hierarchical features are determined by a hierarchical approach wherein the expression levels and gene characteristics (patterns) of the genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. applying median weighted gene expression scores (WGS) for genes within a specific pathway and median gene expression signal levels for Affymetrix arrays of individual genes as cut-offs, the extent of the upregulation being statistically validated.

In another embodiment of the eleventh feature of the first aspect, the invention relates to copanlisib, in particular copanlisib dihydrochloride, for use in a method of treating a subject diagnosed with an indication, in particular a relapsed/refractory, indolent or aggressive non-hodgkin lymphoma (NHL), in particular a follicular lymphoma (hereinafter abbreviated as "FL"), a chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), a marginal zone lymphoma (hereinafter abbreviated as "MZL"), a diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), a Mantle Cell Lymphoma (MCL), a transformed lymphoma (hereinafter abbreviated as "TL"), or a peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a stratification feature, which is an upregulation of one or more genes, the one or more genes predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

• GPR18；

the method comprises the following steps:

a) determining tumor tissue or tumor cells from a subject by a hierarchical approach, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-clusters, RNAscope, e.g. using as cut-off the median weighted gene expression score (WGS) for genes within a specific pathway, and the median gene expression signal level for Affymetrix arrays for individual genes, the extent of said upregulation being statistically validated; and

b) determining the hierarchical features; and

In a twelfth feature of the first aspect, the present invention relates to the use of copanlisib, in particular copanlisib dihydrochloride, for the treatment and/or prophylaxis of an indication which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL") or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), characterized by a stratification feature which is an upregulation of one or more genes which are predicted for copanlisib, copanlisib dihydrochloride, In particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

• GPR18。

in one embodiment of the twelfth feature of the first aspect, the invention relates to said use, wherein said hierarchical features are determined by a hierarchical approach, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. the degree of said upregulation is statistically validated using as cut-off the median weighted gene expression scores (WGS) for genes within a specific pathway and the median gene expression signal levels for Affymetrix arrays of individual genes.

In a second embodiment of the twelfth feature of the first aspect, the invention relates to said use, wherein the subject to be treated is a subject for which said hierarchical feature has been determined in tumor tissue or tumor cells from the subject.

In a thirteenth feature of the first aspect, the present invention relates to the use of a stratification feature, which is an up-regulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression-free survival, as a stratification marker in the treatment of an indication with copanlisib, in particular copanlisib dihydrochloride, and the one or more genes are selected from the group consisting of:

• GPR18；

the indication is non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL").

In one embodiment of the thirteenth feature of the first aspect, the invention relates to said use, wherein said hierarchical features are determined by a hierarchical approach, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. the degree of said upregulation is statistically validated using as cut-off the median weighted gene expression scores (WGS) for genes within a specific pathway and the median gene expression signal levels for Affymetrix arrays of individual genes.

In a second embodiment of the thirteenth feature of the first aspect, the invention relates to said use, wherein the subject to be treated is a subject for which said hierarchical feature has been determined in tumor tissue or tumor cells from said subject.

In a fourteenth feature of the first aspect, the present invention relates to a method for treating and/or preventing an indication, which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), particularly follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), characterized by a stratification feature, which is an upregulation of one or more genes predicted to copanlisib, which is predicted to be upregulated, In particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

• GPR18。

in one embodiment of the fourteenth feature of the first aspect, the invention relates to said method of treatment, wherein said hierarchical features are determined by a hierarchical method wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. using as cut-offs the median weighted gene expression scores (WGS) for genes within a specific pathway, and the median gene expression signal levels for Affymetrix arrays of individual genes, the extent of said upregulation being statistically validated.

In a second embodiment of the fourteenth feature of the first aspect, the invention relates to said method of treatment, wherein the subject to be treated is a subject for which said hierarchical features have been determined in tumor tissue or tumor cells from the subject.

In a variation of the second embodiment of the fourteenth feature of the first aspect, the invention relates to said method of treatment, wherein said hierarchical features are determined by a hierarchical approach, wherein the expression levels and gene characteristics (patterns) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. using as cut-offs the median weighted gene expression scores (WGS) for genes within a specific pathway, and the median gene expression signal levels for Affymetrix arrays of individual genes, the extent of said upregulation being statistically validated.

In a fifteenth feature of the first aspect, the present invention relates to a method of treating a subject diagnosed with an indication, the indication being non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), the method comprising the steps of:

GPR 18; and

In a sixteenth feature of the first aspect, the present invention relates to a method of treating a subject having an indication, which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), particularly relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), particularly follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"),

the methods comprise administering a therapeutically effective amount of copanlisib, particularly copanlisib dihydrochloride, to a subject selected for the therapy based on a stratification profile, the stratification profile being an upregulation of one or more genes that are predictive of response to copanlisib, particularly copanlisib dihydrochloride, and/or progression-free survival, and the one or more genes are selected from the group consisting of:

• GPR18；

thereby treating the subject.

In a seventeenth feature of the first aspect, the present invention relates to a pharmaceutical combination comprising copanlisib, in particular copanlisib dihydrochloride, in combination with at least one or more further active substances for use in a method for the treatment and/or prophylaxis of an indication in a subject which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL") or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), which is characterized by a layered characteristic, the stratification feature is an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

• GPR18。

in one embodiment of the seventeenth feature of the first aspect, the invention relates to said pharmaceutical combination, wherein said hierarchical features are determined by a hierarchical approach, wherein the expression levels and gene characteristics (patterns) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. using as cut-offs median weighted gene expression scores (WGS) for genes within a specific pathway, and median gene expression signal levels for Affymetrix arrays of individual genes, the extent of said upregulation being statistically validated.

In a second embodiment of the seventeenth feature of the first aspect, the invention relates to said pharmaceutical combination, wherein said hierarchical features are determined in tumor tissue or tumor cells from the subject.

In an eighteenth feature of the first aspect, the invention relates to the use of a pharmaceutical combination comprising copanlisib, in particular copanlisib dihydrochloride, in combination with at least one or more further active substances for the preparation of a medicament for the treatment and/or prophylaxis of an indication which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL") or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"),

wherein a stratification feature is determined in tumor tissue or tumor cells from a subject, said stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in one embodiment of the eighteenth feature of the first aspect, the invention relates to said use of a pharmaceutical combination, wherein said hierarchical features are determined by a hierarchical approach, wherein the expression levels and gene characteristics (patterns) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. using as cut-offs median weighted gene expression scores (WGS) for genes within a specific pathway, and median gene expression signal levels for Affymetrix arrays of individual genes, the extent of said upregulation being statistically validated.

In a nineteenth feature of the first aspect, the present invention relates to a pharmaceutical formulation comprising copanlisib, in particular copanlisib dihydrochloride, in combination with an inert, non-toxic and/or pharmaceutically suitable adjuvant for use in a method for the treatment and/or prophylaxis of an indication which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), in particular relapsed/refractory, inert or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL") or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), which is characterized by a layered characteristic, the stratification feature is an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

• GPR18。

in one embodiment of the nineteenth feature of the first aspect, the invention relates to said pharmaceutical formulation, wherein said hierarchical features are determined by a hierarchical approach, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. using as cut-off values the median weighted gene expression scores (WGS) for genes within a specific pathway, and the median gene expression signal levels for Affymetrix arrays of individual genes, the extent of said upregulation being statistically validated.

In a second embodiment of the nineteenth feature of the first aspect, the invention relates to said pharmaceutical preparation, wherein said hierarchical features are determined in tumor tissue or tumor cells containing tumor cells from a subject.

In a third embodiment of the nineteenth feature of the first aspect, the present invention relates to the use of a pharmaceutical preparation comprising copanlisib, in particular copanlisib dihydrochloride, in combination with an inert, non-toxic and/or pharmaceutically suitable adjuvant for the treatment and/or prophylaxis of an indication which is non-hodgkin's lymphoma (hereinafter abbreviated to "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to "FL"), chronic lymphocytic leukemia (hereinafter abbreviated to "CLL"), marginal zone lymphoma (hereinafter abbreviated to "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated to "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to "TL") or peripheral T-cell lymphoma (hereinafter abbreviated to "PTCL"), wherein a stratification feature is determined in tumor tissue or tumor cells from a subject, said stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in a variation of the third embodiment of the nineteenth feature of the first aspect, the invention relates to said use of said pharmaceutical formulation, wherein said hierarchical features are determined by a hierarchical approach, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-strings, RNAscope, e.g. the degree of said upregulation is statistically validated using median weighted gene expression scores (WGS) for genes within a specific pathway and median gene expression signal levels for Affymetrix arrays of individual genes as cut-offs.

A second aspect of the invention relates to a biomarker for copanlisib, wherein the subject is characterized by a hierarchical character:

in a first feature of the second aspect, the invention relates to the use of copanlisib, in particular copanlisib dihydrochloride, for the preparation of a medicament for the treatment of a subject as follows: non-Hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular, follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), wherein the object is selected by having a hierarchical characteristic, the hierarchical characteristic being an upregulation of one or more genes, the one or more genes predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

•GPR18。

in one embodiment of the first feature of the second aspect, the present invention relates to said use, wherein said hierarchical feature is determined by a hierarchical approach, said hierarchical feature being the up-regulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN,

• GPR18，

In a second embodiment of the first feature of the second aspect, the present invention relates to said use, wherein the stratification feature has been positively determined in the sample, the stratification feature is an up-regulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

• GPR18，

said sample is a tumor tissue or tumor cells of said subject, and said upregulation of said genes is determined and compared to a degree of expression in a predetermined cut-off value.

In a second feature of the second aspect, the invention relates to the use of copanlisib, in particular copanlisib dihydrochloride, for the preparation of a medicament for the treatment of the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), wherein the subject has been identified as a responder by a method comprising the steps of:

a) determining a sample, which is a tumor tissue or tumor cells of said subject, by a hierarchical approach, wherein the expression level and gene signature (pattern) of said genes is determined by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, applying as cut-off the median weighted gene expression score (WGS) for genes within a specific pathway, and the median gene expression signal level for Affymetrix array of individual genes, the extent of said upregulation being statistically validated; and

b) determining the stratification profile, which is an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and which is selected from the group consisting of:

• GPR18；

and

In a third feature of the second aspect, the invention relates to copanlisib, in particular copanlisib dihydrochloride, for use in a method of treating the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18。

in one embodiment of the third feature of the second aspect, the present invention relates to copanlisib, in particular copanlisib dihydrochloride, wherein the characterization is performed in tumor tissue or tumor cells from the subject.

In a second embodiment of the third feature of the second aspect, the present invention relates to copanlisib, in particular copanlisib dihydrochloride, wherein the hierarchical feature is determined by a hierarchical approach, the hierarchical feature being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

• GPR18；

wherein the level of expression and gene signature (pattern) of said genes is determined by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, applying median weighted gene expression scores (WGS) for genes within a specific pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs, the extent of said upregulation is statistically verified.

In a fourth feature of the second aspect, the invention relates to copanlisib, in particular copanlisib dihydrochloride, for use in a method of treating the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18；

the method comprises the following steps:

• GPR18；

and

In a fifth feature of the second aspect, the invention relates to the use of copanlisib, in particular copanlisib dihydrochloride, for the treatment and/or prevention of: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18。

in one embodiment of the fifth feature of the second aspect, the present invention relates to said use, wherein said hierarchical feature is determined by a hierarchical approach, said hierarchical feature being the up-regulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B; PI3K pathway genes: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN; GPR 18;

In a second embodiment of the fifth feature of the second aspect, the present invention relates to said use, wherein said hierarchical feature has been determined in tumor tissue or tumor cells from said subject, said hierarchical feature being an up-regulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and progression-free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in a sixth feature of the second aspect, the invention relates to a method for treating and/or preventing the following in a subject using an effective amount of copanlisib, in particular copanlisib dihydrochloride: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18。

in one embodiment of the sixth feature of the second aspect, the present invention relates to said method of treatment, wherein said hierarchical feature is determined by a hierarchical method, said hierarchical feature being the up-regulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18；

In a second embodiment of the sixth feature of the second aspect, the present invention relates to said method of treatment, wherein said stratification feature has been determined in tumor tissue or tumor cells from said subject, said stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in a variant of the second embodiment of the sixth feature of the second aspect, the invention relates to said method of treatment, wherein said hierarchical feature is determined by a hierarchical approach, said hierarchical feature being the up-regulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18；

In a seventh feature of the second aspect, the invention relates to a pharmaceutical combination comprising copanlisib, in particular copanlisib dihydrochloride, in combination with at least one or more further active substances for use in a method for the treatment and/or prophylaxis of: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18。

in one embodiment of the seventh feature of the second aspect, the present invention relates to the pharmaceutical combination, wherein the hierarchical feature is determined by a hierarchical approach, the hierarchical feature being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

• GPR18；

In a second embodiment of the seventh feature of the second aspect, the present invention relates to the pharmaceutical combination, wherein the hierarchical feature is determined by a hierarchical approach, the hierarchical feature being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

• GPR18；

In another embodiment of the seventh feature of the second aspect, the present invention relates to said pharmaceutical combination, wherein said stratification feature has been determined in tumor tissue or tumor cells from said subject, said stratification feature is an upregulation of one or more genes that are predictive for response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in an eighth feature of the second aspect, the invention relates to the use of a pharmaceutical combination comprising copanlisib, in particular copanlisib dihydrochloride, in combination with at least one or more further active substances for the preparation of a medicament for the treatment and/or prophylaxis of the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18。

in one embodiment of the eighth feature of the second aspect, the present invention relates to said use of a pharmaceutical preparation, wherein said hierarchical feature is determined by a hierarchical approach, said hierarchical feature being the upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18；

In a second embodiment of the eighth feature of the second aspect, the present invention relates to said use of a pharmaceutical preparation, wherein said stratification feature is determined in tumor tissue or tumor cells from said subject, said stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in a ninth feature of the second aspect, the invention relates to a pharmaceutical formulation comprising copanlisib, in particular copanlisib dihydrochloride, in combination with an inert, non-toxic and/or pharmaceutically suitable adjuvant for use in a method of treatment and/or prevention of: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18。

in one embodiment of the ninth feature of the second aspect, the present invention relates to said pharmaceutical formulation, wherein said hierarchical feature is determined by a hierarchical approach, said hierarchical feature being the up-regulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B; PI3K pathway genes: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

In a second embodiment of the ninth feature of the second aspect, the present invention relates to said pharmaceutical preparation, wherein said stratification feature has been determined in tumor tissue or tumor cells from said subject, said stratification feature being an upregulation of one or more genes that are predictive for a response to copanlisib, in particular copanlisib dihydrochloride, and/or for progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in another embodiment of the ninth feature of the second aspect, the present invention relates to said pharmaceutical preparation, wherein a stratification feature has been determined in tumor tissue or tumor cells from said subject, said stratification feature being an up-regulation of one or more genes that are predictive of a response to copanlisib, in particular copanlisib dihydrochloride, and/or progression-free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in a tenth feature of the second aspect, the invention relates to the use of a pharmaceutical combination comprising copanlisib, in particular copanlisib dihydrochloride, in combination with at least one or more further active substances for the preparation of a medicament for the treatment and/or prophylaxis of the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

• GPR18。

in one embodiment of the tenth feature of the second aspect, the present invention relates to said use of a pharmaceutical preparation, wherein said hierarchical feature is determined by a hierarchical approach, said hierarchical feature being the upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18；

In a second embodiment of the tenth feature of the second aspect, the present invention relates to said use of a pharmaceutical preparation, wherein said stratification feature is determined in tumor tissue or tumor cells from said subject, said stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from the group consisting of:

• GPR18。

in another feature of the first or second aspect, the invention relates to a test for gene expression profiling which measures:

-upregulation of one or more BCR pathway genes selected from: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4A1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR2B,

assessing the suitability of a subject for treatment with copanlisib, in particular copanlisib dihydrochloride, to characterize BCR signaling in the subject,

the test is to measure the genes and gene characteristics (patterns) using one of the following methods, for example: affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, the degree of upregulation (or high expression) is determined by: expression levels from measured genes or scores (e.g., WGS) calculated/derived from expression levels of all genes in a feature or pathway are compared to a threshold (also referred to as a cutoff). The cutoff may be a median value that results from tumors collected for indications of disease or established from clinical trials evaluating the relationship between the expression level or gene signature score of genes and efficacy of treatment by copanlisib.

-upregulation of one or more PI3K pathway genes selected from: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN,

to characterize PI3K signaling in a subject to assess the suitability of the subject for treatment with copanlisib, particularly copanlisib dihydrochloride,

-upregulation of one or more BCR pathway genes selected from: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

and

to characterize BCR and PI3K signaling in a subject to assess the suitability of the subject for treatment with copanlisib, particularly copanlisib dihydrochloride,

In another feature of the first or second aspect, the invention relates to a kit for selecting a subject suffering from: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), particularly relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), particularly follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"),

characterised by a layered feature according to any embodiment of the first or second aspect as defined above, and determining a layered feature according to any embodiment of the first or second aspect as defined above.

In one embodiment of this further feature of the first or second aspect, the invention relates to said kit, wherein said treatment is monotherapy or combination therapy.

In a second embodiment of said another feature of the first or second aspect, the invention relates to said kit, wherein said hierarchical features are determined in a tumor tissue or tumor cell sample from said subject.

In an additional feature of the first or second aspect, the invention relates to a test for gene expression profiling which measures:

-upregulation in one or more genes selected from the group consisting of: AKT1, AKT3, BLNK, BTK, CD19, CD69, CD72, CD79B, CD8B, FCGR2B, GAB1, LYN, MS4A1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R3, PIK3R4, PIK3R5, PTEN, TLR4, TNFRSF13B, VIM, GPR18,

to assess the suitability of said subject for treatment with copanlisib, in particular copanlisib dihydrochloride,

-down-regulation of one or more genes selected from the group consisting of: CD4, CD22, VCAN, TNFRSF17, NDE1, ICAM1, PIK3IP1, NFKBIA, MMP9, CD40, IL4I1, AKT2, CD79A, JAK3, MET, COL1A1, VWF, VEGFA, SPARC, FN1, SGK1, MT2A, IL1B, CD93, STAT5A, KDR, THBS1, LUM, S100A8, SERPINH1, BATF, PTGIR, CSTB, ITGB2, S100A9, SYK, CD14, CEBPB, SPHK1, NOP10, THBS2, COL5A2,

In an additional feature of the first or second aspect, the invention relates to a test for gene expression signature, which measures in a subject:

-up-regulation of one or more genes selected from: AKT1, AKT3, BLNK, BTK, CD19, CD69, CD72, CD79B, CD8B, FCGR2B, GAB1, LYN, MS4A1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R3, PIK3R4, PIK3R5, PTEN, TLR4, TNFRSF13B, VIM, GPR18,

and

In an additional feature of the first or second aspect, the invention relates to a kit for selecting a subject suffering from: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), particularly relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), particularly follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"),

characterized by a layered feature and determining a layered feature, the layered feature being defined in any of the embodiments of one additional feature of the first or second aspect defined above.

In one embodiment of additional features of the first or second aspect, the invention relates to said kit, wherein said treatment is monotherapy or combination therapy.

In a second embodiment of the additional features of the first or second aspect, the invention relates to said kit, wherein said hierarchical features are determined in a tumor tissue or tumor cell sample from said subject.

Pharmaceutical formulations of copanlisib of the invention

As mentioned above, the present invention relates to copanlisib, in particular copanlisib dihydrochloride, which may be in the form of a pharmaceutical preparation that is prepared for simultaneous (simultaneously), simultaneous (convurently), separate or sequential administration. The components may be administered independently of each other by oral, intravenous, topical (topical), local installations (local), intraperitoneal or nasal routes.

The formulation or composition may be used to achieve a desired pharmacological effect by administration to a patient in need thereof. For the purposes of the present invention, a patient is a mammal, including a human, in need of treatment for a particular condition or disease. Thus, the present invention encompasses copanlisib, particularly copanlisib dihydrochloride, in the form of a pharmaceutical formulation composition consisting of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of said copanlisib, particularly copanlisib dihydrochloride. The pharmaceutically acceptable carrier is preferably one that is relatively non-toxic and non-injurious to the patient at concentrations consistent with effective activity of the active ingredient such that any side effects caused by the carrier do not impair the beneficial effects of the components and/or combination. A pharmaceutically effective combined amount is preferably an amount that produces a result of, or exerts an effect on, the particular condition being treated. The Copanlisib, and in particular Copanlisib dihydrochloride, of the present invention may be administered using any effective conventional dosage unit form including oral, parenteral, topical, nasal, ocular (opthalmology), ocular (opticality), sublingual, rectal, vaginal, and the like immediate release, sustained release and timed release preparations, together with pharmaceutically acceptable carriers well known in the art.

For oral administration, copanlisib, in particular copanlisib dihydrochloride, may be formulated as solid or liquid preparations, such as capsules, pills, tablets, buccal tablets (trokes), lozenges (lozenes), melts (melts), powders, solutions, suspensions or emulsions, and may be prepared according to methods known in the art for the preparation of pharmaceutical compositions. The solid unit dosage form may be a capsule, which may be of the conventional hard-or soft-shelled gelatin type, containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, copanlisib, in particular copanlisib dihydrochloride, according to the invention can be tableted in combination with conventional tablet bases such as lactose, sucrose and corn starch as follows: binders, such as acacia, corn starch or gelatin, disintegrating agents intended to aid tablet breakage and dissolution after administration, such as potato starch, alginic acid, corn starch and guar gum, tragacanth, acacia, lubricants intended to improve tablet particle flow and prevent tablet material from adhering to the tablet die and punch surfaces, such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate, dyes, colorants, and flavoring agents such as peppermint, oil of wintergreen or cherry flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to patients. Suitable excipients for use in oral liquid dosage forms include dibasic calcium phosphate and diluents such as water and alcohols, for example ethanol, benzyl alcohol and polyvinyl alcohol, with or without the addition of pharmaceutically acceptable surfactants, suspending agents or emulsifiers. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for preparing aqueous suspensions. They provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, such as those described above, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally-occurring gums, such as gum acacia and gum tragacanth, (2) naturally-occurring phosphatides, such as soybean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, (4) condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredient in: vegetable oils such as, for example, peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. Oily suspensions may contain a thickening agent, such as, for example, beeswax, hard paraffin or cetyl alcohol. The suspending agent may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents, such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a slip agent (demucient) and preservatives, such as methylparaben and propylparaben, and flavoring and coloring agents.

The Copanlisib, in particular Copanlisib dihydrochloride, of the invention can also be administered parenterally, i.e. subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as injectable doses of the compound, in preferably physiologically acceptable diluents and pharmaceutical carriers which can be sterile liquids or mixtures of liquids such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or hexadecanol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, oils, fatty acids, fatty acid esters or fatty acid glycerides, or acetylated fatty acid glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, or the like, Carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

examples of oils that may be used in the parenteral formulations of the invention are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil and mineral oil suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts and suitable detergents include cationic detergents, such as dimethyl dialkyl ammonium halides, alkyl pyridine halides and alkylamine acetates, anionic detergents, such as alkyl, aryl and alkene sulfonates, alkyl, alkene, ether and monoglyceride sulfates and sulfosuccinates, nonionic detergents, such as fatty amine oxides, fatty acid alkanolamides and poly (oxyethylene-oxypropylene) or ethylene oxide or propylene oxide copolymers, and amphoteric detergents, such as alkyl- β -aminopropionates and 2-alkylimidazoline quaternary ammonium salts, and mixtures.

Parenteral compositions of the invention will generally contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously employed. To minimize or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant having a Hydrophilic Lipophilic Balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in such formulations preferably varies from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB, or may be a mixture of two or more components having the desired HLB.

Examples of surfactants for parenteral formulations are polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide with a hydrophobic base (hydrobicbase) formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. Such suspending agents can be formulated according to known methods using the following: suitable dispersing or wetting agents and suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide, such as lecithin, condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile, fixed oils (fixed oils) are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are for example cocoa butter and polyethylene glycols.

Another formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts. The construction and use of transdermal patches for delivering agents is well known in the art (see, e.g., U.S. Pat. No. 5,023,252 issued 6-11-1991, which is incorporated herein by reference). Such patches may be constructed for continuous, pulsed or on-demand delivery of the agent.

Controlled release formulations for parenteral administration include liposome, polymeric microsphere and polymeric gel formulations known in the art.

It may be desirable or necessary to introduce the pharmaceutical composition into the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents is well known in the art. Direct techniques for administering drugs, e.g., directly to the brain, typically involve placing a drug delivery catheter into the ventricular system of a patient to bypass the blood brain barrier. One such implantable delivery system for transporting a medicament to a specific anatomical region of the body is described in U.S. patent No. 5,011,472 issued 4, 30, 1991.

The compositions of the present invention may also contain other conventional pharmaceutically acceptable compounding ingredients, which are commonly referred to as carriers or diluents, as needed or desired. Conventional procedures for preparing such compositions in suitable dosage forms may be employed. These ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: powell, M.F.et al,"Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology1998, 52(5), 238-311; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1"PDA Journal of Pharmaceutical Science & Technology1999, 53(6), 324-349; and Nema, S.et al, "Excipients and Their Use inInjectable Products" PDA Journal of Pharmaceutical Science & Technology1997,51(4), 166-171。

Common pharmaceutical ingredients that may be used to formulate a composition for its intended route of administration include:

acidulants (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalizing agents (examples include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine (triethanolamine), triethanolamine (trolamine));

adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);

aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl₂F₂、F₂ClC-CClF₂And CClF₃)；

Air displacement agents (examples include, but are not limited to, nitrogen and argon);

antifungal preservatives (examples include, but are not limited to, benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate);

antimicrobial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal);

antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

adhesive materials (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

buffering agents (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, sodium citrate anhydrous, and sodium citrate dihydrate);

carrying agents (examples include, but are not limited to, acacia syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection)

Chelating agents (examples include, but are not limited to, disodium edetate and ethylenediaminetetraacetic acid)

Colorants (examples include, but are not limited to, FD & C red No. 3, FD & C red No. 20, FD & C yellow No. 6, FD & C blue No. 2, D & C green No. 5, D & C orange No. 5, D & C red No. 8, caramel, and red iron oxide);

clarifying agents (clarifying agents) (examples include, but are not limited to, bentonite);

emulsifying agents (examples include, but are not limited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate)

Flavorants (flavanants) (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);

humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol);

abrasives (levigating agents) (examples include, but are not limited to, mineral oil and glycerin);

oils (examples include, but are not limited to, arachis oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil);

ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointments, polyethylene glycol ointments, paraffin oil, hydrophilic paraffin oil, white ointment, yellow ointment, and rose water ointment);

penetration enhancers (transdermal delivery) (examples include, but are not limited to, monohydric or polyhydric alcohols, saturated or unsaturated fatty acid esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas);

plasticizers (examples include, but are not limited to, diethyl phthalate and glycerol);

solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for rinsing);

hardening agents (examples include, but are not limited to, cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax);

suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixtures));

surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10(nonoxynol 10), octoxynol 9 (oxoxynol 9), polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);

suspending agents (examples include, but are not limited to, agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, tragacanth and veegum (veegum));

sweeteners (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose);

tablet antiadherents (examples include, but are not limited to, magnesium stearate and talc);

tablet binders (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium phosphate, sorbitol, and starch);

tablet coatings (examples include, but are not limited to, liquid glucose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate phthalate, and shellac);

tablet direct compression excipients (examples include, but are not limited to, dibasic calcium phosphate);

tablet disintegrating agents (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate, and starch);

tablet glidants (examples include, but are not limited to, colloidal silicon dioxide, corn starch, and talc);

tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);

tablet/capsule opacifiers (opaquants) (examples include but are not limited to titanium dioxide);

tablet polishes (examples include, but are not limited to, carnauba wax and white wax);

thickening agents (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin wax);

tonicity agents (examples include, but are not limited to, dextrose and sodium chloride);

viscosity increasing agents (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth); and

wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

The pharmaceutical composition according to the invention can be illustrated as follows:

sterile IV solutionSterile injectable Water may be used to prepare 5mg/mL solutions of the desired compounds of the present inventionLiquid and if necessary pH adjustment. The solution was diluted with sterile 5% dextrose to 1-2mg/mL for administration and administered as an IV infusion over about 60 minutes.

Lyophilized powder for IV administration: sterile preparations may be prepared by: (i) 100-1000 mg of the desired compound of the invention as a lyophilized powder, (ii) 32-327 mg/mL sodium citrate, and (iii) 300-3000 mg dextran 40. The formulations were reconstituted with sterile injectable saline or 5% dextrose to a concentration of 10 to 20 mg/mL, further diluted with saline or 5% dextrose to 0.2-0.4 mg/mL and administered as an IV bolus or by IV infusion over a period of 15-60 minutes.

Intramuscular suspension agent: the following solutions or suspensions may be prepared for intramuscular injection:

50 mg/mL of the Water-insoluble Compound of interest in the present invention

5mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol.

Hard shell capsule:a large number of unit capsules were prepared by filling standard two-piece hard gelatin (galantine) capsules with 100mg of each of the powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft gelatin capsules:a mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100mg of the active ingredient. The capsules were washed and dried. The active ingredient may be dissolved in a mixture of polyethylene glycol, glycerol and sorbitol to prepare a water-miscible pharmaceutical mixture.

And (3) tablet preparation:a large number of tablets are prepared by conventional procedures so that the dosage unit is 100mg of active ingredient, 0.2mg of colloidal silicon dioxide, 5mg of magnesium stearate, 275mg of microcrystalline cellulose11mg starch and 98.8mg lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve aesthetics and stability, or delay absorption.

Immediate release tablets/capsules:these are solid oral dosage forms prepared by conventional and novel processes. These units are taken orally in the absence of water for immediate dissolution and delivery of the drug. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets (caplets) by freeze-drying and solid-state extraction techniques. The pharmaceutical compound may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce a porous matrix intended for immediate release without the need for water.

Methods of treating cancer

In the context of the present invention, the term "cancer" includes, but is not limited to, cancers of the breast, lung, brain, reproductive organs, digestive tract, urinary tract, liver, eye, skin, head and neck, thyroid, parathyroid and their distant metastases. These disorders also include multiple myeloma, lymphoma, sarcoma, and leukemia.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to, small cell and non-small cell lung cancers, as well as bronchial adenomas and pleural pneumococcal tumors.

Examples of brain cancers include, but are not limited to, brainstem and hypothalamic (hypophtalmic) gliomas, cerebellar and brain astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as uterine sarcomas.

Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland cancers.

Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urinary tract cancer, and human papillary renal cancer.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (with or without fibrolamellar variants), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal, lip and oral cavity cancers, and squamous cell carcinoma.

Lymphomas include, but are not limited to, AIDS-related lymphomas, non-Hodgkin's lymphomas, cutaneous T cell lymphomas, Burkitt's lymphomas, Hodgkin's disease, and lymphomas of the central nervous system.

Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, and rhabdomyosarcomas.

Leukemias include, but are not limited to, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

The present invention relates to methods of treating cancer, in particular mammalian NSCLC, CRC, melanoma, pancreatic cancer, hepatocellular carcinoma or breast cancer, as described below, using copanlisib, in particular copanlisib dihydrochloride of the present invention. In the treatment or prevention of cancer, in particular NSCLC, CRC, melanoma, pancreatic cancer, hepatocellular carcinoma or breast cancer, the salts of the invention may be used to inhibit, block, reduce cell proliferation and/or cell division etc., and/or produce apoptosis. The method comprises administering to a mammal, including man, in need thereof an amount of a combination of the invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof or the like; it is useful for the treatment or prevention of cancer, in particular NSCLC, CRC, melanoma, pancreatic cancer, hepatocellular carcinoma or breast cancer.

The terms "treating" or "treatment" as used throughout this document are used routinely, e.g., to manage or care for a subject for the purpose of combating, alleviating, reducing, ameliorating, improving the condition of a disease or disorder, such as cancer, and the like.

Dosage and administration

Effective dosages of the salts of the present invention for therapeutic indications can be readily determined by standard toxicity tests, and by standard pharmacological assays for determining the treatment of the above-identified conditions in mammals, based on evaluating known standard laboratory techniques for compounds used in the treatment or prevention of cancer, in particular NSCLC, CRC, melanoma, pancreatic cancer, hepatocellular carcinoma or breast cancer, and by comparing these results with the results of known drugs used to treat these conditions. The amount of active ingredient to be administered in the treatment of a condition may vary widely depending upon a number of considerations, including, but not limited to, the particular combination product and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

The total amount of active ingredient to be administered will generally vary from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. A clinically useful dosing schedule will vary from one to three doses per day to once every four weeks. In addition, "drug holidays" (where patients do not take drugs for a period of time) may benefit the overall balance between pharmacological effects and tolerability. A unit dose may contain from about 0.5 mg to about 1,500 mg of the active ingredient and may be administered one or more times per day or less than once per day. The average daily dose for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and using infusion techniques will preferably be 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be 0.01 to 200 mg/kg total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhaled administration regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

The specific initial and sustained dosing regimen for each patient will vary depending upon the nature and severity of the condition as determined by the attending diagnostician, the activity of the particular combination product used, the age and general condition of the patient, the time of administration, the route of administration, the rate of drug excretion, drug salt and the like. The desired therapeutic regimen and number of doses of a combination product of the invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by one skilled in the art using routine therapeutic testing.

Therapy with the salts of the invention: one or more other agents.

The Copanlisib according to the invention, in particular Copanlisib dihydrochloride, can be administered as sole agent or in combination with one or more other active ingredients without the resulting combination of the salt according to the invention and the other active ingredients causing unacceptable side effects. For example, copanlisib, in particular copanlisib dihydrochloride, according to the present invention may be combined with other active ingredients such as known anti-angiogenic agents, anti-hyperproliferative agents, anti-inflammatory agents, analgesics, immunomodulators, diuretics, antiarrhythmic agents, anti-hypercholesterolemic agents, anti-dyslipidemia agents, anti-diabetic agents or anti-viral agents and the like, as well as mixtures and salts thereof.

The other active ingredients may be selected from the following:

such drugs are not limited to the examples described above, such as 131I-chTNT, abareligio (abareligio), amitriptolide (clavulan), paclitaxel (clavulan), medroxyperazine (medroxyporine), dex (oxyproline), ritorine (oxyprolipram), epirubicin (rit), dex (ritorine), ritorizan (oxyprolipram), epirubicin (rit), adverse (oxyprolipram), rit (rit), epirubicin (rit), adverse drug(s), or(s), or(s), or(s), or(s), or (e), or (e, or(s), or (e), or (e), or (e), or (e), or (e, or (e), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or), or (e), or (e), or (e), or), or (e), or (e), or (e), or (e), or), or (e), or (e), or (e), or (e), or (e), or a), or (e), or (e), or (e), or (e), or (e), or (e), or (e), or, or (e), or a), or (e), or a), or (e), or, or, or (e), or.

In general, the use of cytotoxic and/or cytostatic agents as further active ingredients in combination with the copanlisib of the invention, in particular copanlisib dihydrochloride, will be used:

(1) better efficacy in reducing tumor growth or even eliminating tumors than either agent alone,

(2) providing for the administration of a lesser amount of the chemotherapeutic agent being administered,

(3) providing a well-tolerated chemotherapeutic treatment in patients with fewer deleterious pharmacological complications than observed with single agent chemotherapy and certain other combination therapies,

(4) provides for the treatment of a broader spectrum of different cancer types in mammals, particularly humans,

(5) provide a higher response rate in the treated patient,

(6) provides a longer survival time in the treated patient compared to standard chemotherapy treatment,

(7) provide for longer time for tumor progression, and/or

(8) Results in efficacy and tolerability at least as good as that of the agent used alone, as compared to known cases where other cancer agent salts produce antagonism.

Experimental part

Copanlisib and Copanlisib dihydrochloride can be synthesized as described in european patent application No. EP 11161111.7 and PCT application No. PCT/EP2012/055600 published as WO2012/136553, both of which are incorporated herein by reference in their entirety.

The method comprises the following steps:

individual formalin-fixed, paraffin-embedded (FFPE) samples from baseline tumor lesions in NHL patients receiving copanlisib therapy in clinical study a were subjected to RNA Gene expression studies on the Affymetrix Gene ST 1.0 array by AltheaDx inc. The best response status and progression free survival (hereinafter "PFS") from independent examination and evaluation was used for gene expression analysis. A total of 24 patients, containing 3 complete responders (1 confirmed (hereinafter "CR") and 2 unconfirmed (hereinafter "CRu")) and 5 partial responders (hereinafter "PR"), 11 stable diseases (hereinafter "SD") and 5 progressive diseases (hereinafter "PD") with follicular lymphoma (hereinafter "FL"), marginal zone lymphoma (hereinafter "MZL"), mantle cell lymphoma ("MCL"), diffuse large B-cell lymphoma (hereinafter "DLBCL"), transformed indolent lymphoma or CLL with sufficient number and quality of baseline RNA expression profiling data, were used for gene expression analysis, as listed in table 1 (given in the experimental section).

Bioinformatics and statistical analysis were performed on all 24 NHL patients. Gene set enrichment analysis (hereinafter "GSEA") (reference 1) and single gene multivariate adaptive two-way filtering methods (reference 2) were both used to identify potential predictive markers and common signal transduction pathways associated with the copanlisib response in lymphoma.

GSEA (http:// www.broadinstitute.org/GSEA/index. jsp) is a computational method that determines whether a priori defined gene sets show statistically significant, consistent differences between two biological states (e.g., phenotypes, in this case based on clinical outcome) for identifying common signaling pathways associated with copepalisib responses or lack of responses in lymphomas. For GSEA, a 34 gene set (gene sets) was selected and generated (see tables 2 and 3) that share key biological functions/processes in apoptosis, B cell receptor (hereinafter "BCR") signaling, IL6/JAK/STAT3, cytokines/chemokines, MAPK, MYC, MYD88, NFAT, NFkB, NOTCH, PI3K, or tumor microenvironment (references 3 and 4). The magnitude of the normalized enrichment score (hereinafter "NES") and false discovery (hereinafter "FDR") q-value was calculated to evaluate the effectiveness of each gene set in identifying the best candidates affecting copanlisib response/lack of response in the study. Based on NES values associated with tumor response to copanlisib treatment (where the higher the positive number, the more likely the patient will show a response to copanlisib), and low FDR q values (indicating a lower likelihood of association by chance), the gene sets were ranked for association with response. In contrast, based on negative NES values (where the lower the negative number, the more likely the patient will show a lack of response to copanlisib), and low FDR q values (indicating a lower likelihood of association by chance), the gene set was ranked for association with the lack of response.

TABLE 2 New pathway genes.

TABLE 3 pathway genes from GSEA MSigDB

Pathway(s)	ID
		Apoptosis	KEGG _ apoptosis
BCR	BIOCARTA-BCR _ Path
		BCR	KEGG _ B _ cell _ receptor _ signal transduction _ pathway
DLBCL	SHIPP _ DLBCL _ VS _ follicular lymphoma
		IL6	BIOCARTA _ IL6_ Path
IL6	HALMARK _ IL6_ JAK _ STAT3_ Signaling
		INFLA	HALLMARK inflammatory response
MAPK	KEGG _ MAPK _ signal transduction _ pathway
		MYC	COLLER _ MYC _ target
MYD88	GNF2_MYD88
		MYD88	read-MYD 88-MAL-cascade-start-on-prime-film
NFAT	BIOCARTA _ NFAT _ Path
		NFKB	BIOCARTA _ NFKB _ pathway
NFKB	HINATA_NFKB_IMMU_INF
		NFKB	JAIN _ NFKB _ signaling
NFKB	TIAN _ TNF _ signalling _ via _ NFKB
		NOTCH	KEGG _ NOTCH _ signal transduction _ pathway
PTEN	BIOCARTA _ PTEN _ PATH
		PI3K	REACTOME _ PI3K _ AKT _ ACTIVATION
TCR	KEGG _ T _ cell _ receptor _ signal transduction _ pathway

From logistic regression and Cox proportional hazards models, weighted gene expression scores (hereinafter "WGS") reflecting the overall expression level of each gene set were generated to evaluate the association with the response status (best response-WGS) and PFS (PFS-WGS), respectively.

For pathway analysis, the WGS for the target gene set for a particular patient j is defined as follows:

i: = Gene index [1, n: = Gene set size]

j = patient index

= assessor for Gene i from logistic regression (for response) and Cox (for PFS) models described above

SE _i = for evaluation Standard error of

mRNA _ij = normalized gene expression of Gene i in patient j

For each target gene set, the association of WGS with best response was evaluated using the following WGS model (pseudo-code representation), which was adapted to a Cox proportional hazards model with the same predictor for PFS:

iϵ[1, number objects (number objects)]。

Both the best response-WGS and PFS-WGS are in turn used in logistic regression or Cox regression models to assess the association of either WGS with an endpoint. Furthermore, the original best response WGS was used to calculate non-cross-validated AUC estimates for responder (CR + PR) and non-responder (SD + PD) classifications.

In addition, an adaptive bidirectional filtering method was performed that aggressively selects the few least informative genes to identify any single gene under study that is associated with copanlisib response (ref 2).

As a result:

the 24 analyzable patients comprising 3 CR, 5 PR, 11 SD and 5 PD with diagnosis of FL (n =10), MZL (n =2), MCL (n =2), DLBCL (n =5), transformation indolence (n =2) or CLL (n =3) are listed in table 1. All analyses were performed on the entire NHL population, taking into account the indolent or aggressive nature of the disease types in the multivariate model.

TABLE 1 response status and PFS of patients from clinical study A:

data by 2015 year 2 months: independent evaluation was applied for CLL-investigator evaluation.

The responder: CR + CRu + PR = 8; non-responders: SD + PD = 16

0= censored; 1= censored.

The gene characteristics and pathways associated with copanlisib response status and PFS are listed in table 4.

TABLE 4 GSEA analysis features and pathways related to copanlisib response status and PFS (progression).

^aNES: the enrichment score was normalized.^bFDR: false discovery rate.^cIncreased probability of response or lack of progression (highlighted in green): the gene set with higher expression had a positive NES response and a low FDR, indicating the correlation of genes with response; progression negative NES and low FDR, indicating the association of genes with lack of progression.^dDecreased probability of response or lack of progression (blue): the gene set with higher expression had a response negative NES and a low FDR, indicating the correlation of genes with lack of response; progression positive NES and low FDR, indicating the association of genes with progression.

As shown in Table 4, in the full panel of 24 NHLs, the highest ranked set of genes associated with both objective responses identified by GSEA (positive NES value ≧ 1.4, FDRq ≦ 0.17) and longer PFS (lack of progression, negative NES ≦ -1.4, FDRq ≦ 0.12) are those reflecting up-regulation of PI3K pathway and BCR signaling. for GESA response analysis, representative BCR gene sets (including CD19, CD20, BTK and other genes shown in FIG. 2) and PI3K gene sets (including PIK3CA, PIK3CB, PIK3 and PIK 35 encoding PI3 α, β, γ and δ catalytic subunits, respectively, and other genes shown in FIG. 3) have normalized enrichment scores of 1.92 and 1.62 (FDNES), the present rates (PWR) are 0.014) and 1.62, respectively, and the highest score (WG) of 0.2) and higher than those expressed in the BCR 3 AUC equivalent patterns with a nominal score of 1.2, WG equivalent to the PI3 equivalent map of 0.31, the highest score of 0.8, CmK equivalent to the BCHR equivalent expression of the SCH equivalent to the BCS equivalent pattern of the SCH equivalent expression of the BCS equivalent pattern of the BCS equivalent to the nominal score of the BCS equivalent pattern of the BCS equivalent to the PI3 < 1.21, the standard pattern of the BCS equivalent to the standard pattern of the standard.

TABLE 5 Gene expression profiling in clinical study A: the set of pathway genes associated with the response was upregulated (n = 24). See fig. 2 and 3 for the list of genes contained in each pathway gene set.

GSEA, gene set enrichment analysis; NES, normalized enrichment score; FDR, false hair occurrence rate; WGS, weighted gene expression score; AUC, area under the curve; BCR, B cell receptor

Based on assessing the association of WGS with optimal response, with adjustments for gender, age, and subset of indications (inert versus aggressive)

ROC curve calculation using WGS; no cross-validation was performed.

On the other hand, GSEA also identified the highest ranked set of genes associated with lack of copanlisib response and/or with shorter PFS in the overall group of 24 NHLs (table 4). Gene sets/pathways involved in stroma/metastasis and inflammatory processes are associated with a lack of copanlisib responses (negative NES ≦ -1.77, FDRq ≦ 0.01) and shorter PFS (progression positive NES value ≧ 1.46, FDRq ≦ 0.12). Both the IL6/JAK/STAT3 and NFkB pathways are associated with a lack of copanlisib response (negative NES ≦ -1.45, FDRq ≦ 0.1), but not PFS.

In addition, applying an adaptive bi-directional filtration method (ref 2) that aggressively selects the least informative genes, identifying high expression levels of GPR18(G protein-coupled receptor 18) may predict a high response probability with a trained ROC AUC value of 0.95 and a longer PFS with a consistency value of 0.73. When gene expression values were dichotomized using median expression levels as a cutoff, longer PFS were also observed in copanlisib-treated NHL patients with high (above median) expression of GPR18 when compared to patients with low values (377 vs 106 days HR =0.17, nominal Cox model p < 0.01). In contrast, high expression levels of MT2A (metallothionein-2), NOP10 (NOP10 ribonucleoprotein) and CSTB cystatin B (stefin B) genes, likely predicted to lack response, with training AUC0.86 (0.71-1.0), 0.74 (0.54-0.94) and 0.85 (0.70-1.0), respectively, and likely to have shorter PFS (using median gene expression levels as cutoff, CSTB: HR =3.3 (0.9-12), p =0.07, median PFS days 74 and 288, ROC-AUC 0.85 (0.70-1.0), concordance 0.713; NOP 10: HR =1.9 (0.7-5.4), p =0.23, median PFS days 104 and 336, ROC-AUC 0.84 (0.67-1.0), concordance 0.66, MT = 2.106, P = 2.539 2.3, p = 0.3.3-5.4), p =0.23, median PFS days 104 and 336, ROC-AUC 0.76 (0.56-0.95); consistency 0.66).

Reference to the literature

Claims

Use of copanlisib, in particular copanlisib dihydrochloride, for the preparation of a medicament for the treatment of the following in a subject: non-Hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular, follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), wherein the object is selected by having a hierarchical characteristic, the hierarchical characteristic being an upregulation of one or more genes, the one or more genes predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

GPR18 gene.
2. Use according to claim 1, wherein the stratification profile is determined by a stratification method, the stratification profile being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN,

• GPR18，

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
3. Use according to claim 1 or 2, wherein the stratification characteristic has been positively determined in the sample, the stratification characteristic being the up-regulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

said sample is a tumor tissue or tumor cells of said subject, and said upregulation of said genes is determined and compared to a degree of expression in a predetermined cut-off value.
Use of copanlisib, in particular copanlisib dihydrochloride, for the preparation of a medicament for the treatment of the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), wherein the subject has been identified as a responder by a method comprising the steps of:

a) determining a sample, which is a tumor tissue or tumor cells of said subject, by a hierarchical approach, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-clusters, RNAscope, e.g. the degree of said upregulation is statistically validated using as cut-offs median weighted gene expression scores (WGS) for genes within a specific pathway, and median gene expression signal levels for Affymetrix arrays for individual genes; and

b) determining the stratification characteristic, which stratification characteristic is an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and which one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

and

c) administering a therapeutically effective amount of copanlisib, in particular copanlisib dihydrochloride, if the stratification profile is positively determined.
Copanlisib, in particular Copanlisib dihydrochloride, for use in a method of treating the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
6. copanlisib, in particular Copanlisib dihydrochloride, according to claim 5, wherein the characterization is performed in tumor tissue or tumor cells from the subject.
7. Copanlisib, in particular Copanlisib dihydrochloride, according to claim 5 or 6, wherein the hierarchical characteristics are determined by a hierarchical approach, the hierarchical characteristics being the upregulation of one or more genes that predict response to Copanlisib, in particular Copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
Copanlisib, in particular Copanlisib dihydrochloride, for use in a method of treating the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

the method comprises the following steps:

a) determining a sample, which is a tumor tissue or tumor cells of said subject, by a hierarchical approach, wherein the expression level and gene characteristics (pattern) of said genes are determined by Affymetrix arrays, RT-PCR, RNAseq, nano-clusters, RNAscope, e.g. the degree of said upregulation is statistically validated using as cut-offs median weighted gene expression scores (WGS) for genes within a specific pathway, and median gene expression signal levels for Affymetrix arrays for individual genes; and

b) determining the stratification profile, which is an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and which is selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

and

c) administering a therapeutically effective amount of copanlisib, in particular copanlisib dihydrochloride, if the stratification profile is positively determined.
Use of copanlisib, in particular copanlisib dihydrochloride, for the treatment and/or prevention of: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
10. use according to claim 9, wherein the stratification profile is determined by a stratification method, the stratification profile being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B; PI3K pathway genes: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
11. Use according to claim 9 or 10, wherein the stratification feature has been determined in tumor tissue or tumor cells from the subject, the stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
12. a method of treating and/or preventing the following in a subject using an effective amount of copanlisib, in particular copanlisib dihydrochloride: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
13. therapeutic method according to claim 12, in which the stratification profile is determined by a stratification method, the stratification profile being the upregulation of one or more genes that are predictive of the response to copanlisib, in particular copanlisib dihydrochloride, and/or progression-free survival, and the one or more genes being selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
14. Therapeutic method according to claim 12 or 13, in which the stratification feature has been determined in tumour tissue or tumour cells from the subject, the stratification feature being the up-regulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression-free survival, and the one or more genes are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
15. therapeutic method according to claim 14, in which the stratification profile is determined by a stratification method, the stratification profile being the upregulation of one or more genes that are predictive of the response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes being selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
16. Pharmaceutical combination comprising copanlisib, in particular copanlisib dihydrochloride, in combination with at least one or more further active substances for use in a method for the treatment and/or prophylaxis of: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
17. the pharmaceutical combination according to claim 16, wherein the stratification profile is determined by a stratification method, the stratification profile being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
18. The pharmaceutical combination according to claim 16 or 17, wherein the stratification profile is determined by a stratification method, the stratification profile being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
19. The pharmaceutical combination according to any one of claims 16 to 18, wherein the stratification feature has been determined in tumor tissue or tumor cells from the subject, the stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
20. use of a pharmaceutical combination comprising copanlisib, in particular copanlisib dihydrochloride, in combination with at least one or more further active substances for the preparation of a medicament for the treatment and/or prophylaxis of the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
21. use of a pharmaceutical preparation according to claim 20, wherein the stratification profile is determined by a stratification method, the stratification profile being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
22. Use of a pharmaceutical preparation according to claim 20 or 21, wherein the stratification feature is an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, is determined in tumor tissue or tumor cells from the subject, and the one or more genes are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
23. pharmaceutical formulation comprising copanlisib, in particular copanlisib dihydrochloride, in combination with an inert, non-toxic and/or pharmaceutically suitable adjuvant for use in a method of treatment and/or prevention of: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
24. pharmaceutical preparation according to claim 23, wherein the stratification profile is determined by a stratification method, the stratification profile being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
25. Pharmaceutical preparation according to claim 23 or 24, wherein the stratification feature has been determined in tumor tissue or tumor cells from the subject, the stratification feature being an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
26. pharmaceutical preparation according to any one of claims 23 to 25, wherein a stratification characteristic has been determined in tumour tissue or tumour cells from said subject, said stratification characteristic being the up-regulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and said one or more genes are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
27. use of a pharmaceutical combination comprising copanlisib, in particular copanlisib dihydrochloride, in combination with at least one or more further active substances for the preparation of a medicament for the treatment and/or prophylaxis of the following in a subject: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), in particular relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL") or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"), characterized by a hierarchical signature which is an up-regulation of one or more genes which predict a response to pancolisib, in particular copulisib dihydrochloride, and/or progression-free survival, and which are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
28. the use of a pharmaceutical preparation according to any one of claims 23 to 26, wherein the stratification profile is determined by a stratification method, the stratification profile being an upregulation of one or more genes that predict response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival, and the one or more genes are selected from the group consisting of:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18；

wherein the degree of upregulation is statistically validated by determining the expression level and gene signature (pattern) of said genes by Affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, e.g., using median weighted gene expression scores (WGS) for genes within a particular pathway and median gene expression signal levels for Affymetrix array of individual genes as cut-offs.
29. Use of a pharmaceutical preparation according to claim 23 to 26 or 28, wherein the stratification feature is an upregulation of one or more genes that are predictive of response to copanlisib, in particular copanlisib dihydrochloride, and/or progression free survival is determined in tumour tissue or tumour cells from the subject, and the one or more genes are selected from:

BCR pathway genes: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

PI3K pathway gene: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN;

• GPR18。
30. for testing of gene expression profiles, which measure:

-upregulation of one or more BCR pathway genes selected from: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4A1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR2B,

assessing the suitability of a subject for treatment with copanlisib, in particular copanlisib dihydrochloride, to characterize BCR signaling in the subject,

the test is to measure the genes and gene characteristics (patterns) using one of the following methods, for example: affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, the degree of upregulation (or high expression) is determined by: the expression levels from the measured genes or scores (e.g., WGS) calculated/derived from the expression levels of all genes in the signature or pathway are compared to a threshold (also referred to as a cut-off), which may be a median value, that yields tumors collected from indications of disease or is established from a clinical trial evaluating the relationship between the expression levels of the genes or gene signature scores and efficacy of treatment by copanlisib.
31. For testing of gene expression profiles, which measure:

-upregulation of one or more PI3K pathway genes selected from: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN,

to characterize PI3K signaling in a subject to assess the suitability of the subject for treatment with copanlisib, particularly copanlisib dihydrochloride,

the test is to measure the genes and gene characteristics (patterns) using one of the following methods, for example: affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, the degree of upregulation (or high expression) is determined by: the expression levels from the measured genes or scores (e.g., WGS) calculated/derived from the expression levels of all genes in the signature or pathway are compared to a threshold (also referred to as a cut-off), which may be a median value, that yields tumors collected from indications of disease or is established from a clinical trial evaluating the relationship between the expression levels of the genes or gene signature scores and efficacy of treatment by copanlisib.
32. For testing of gene expression profiles, which measure:

-upregulation of one or more BCR pathway genes selected from: BLNK, BTK, CD19, CD22, CD40, CD69, CD72, CD79A, CD79B, LYN, MS4a1(CD20), SYK, TNFRSF13B, TNFRSF17, FCGR 2B;

and

-upregulation of one or more PI3K pathway genes selected from: AKT1, AKT3, GAB1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PTEN,

assessing the suitability of a subject for treatment with copanlisib, in particular copanlisib dihydrochloride, to characterize BCR and PI3K signaling in the subject,

the test is to measure the genes and gene characteristics (patterns) using one of the following methods, for example: affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, the degree of upregulation (or high expression) is determined by: the expression levels from the measured genes or scores (e.g., WGS) calculated/derived from the expression levels of all genes in the signature or pathway are compared to a threshold (also referred to as a cut-off), which may be a median value, that yields tumors collected from indications of disease or is established from a clinical trial evaluating the relationship between the expression levels of the genes or gene signature scores and efficacy of treatment by copanlisib.
33. A kit for selecting a subject having: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), particularly relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), particularly follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"),

characterized by a layered feature according to any one of claims 30, 31 and 32, and determining a layered feature according to any one of claims 30, 31 and 32.
34. The kit according to claim 33, wherein the treatment is monotherapy or combination therapy.
35. The kit according to claim 33 or 34, wherein said stratification feature is determined in a tumor tissue or tumor cell sample from said subject.
36. For testing of gene expression profiles, which measure:

-upregulation in one or more genes selected from the group consisting of: AKT1, AKT3, BLNK, BTK, CD19, CD69, CD72, CD79B, CD8B, FCGR2B, GAB1, LYN, MS4A1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R3, PIK3R4, PIK3R5, PTEN, TLR4, TNFRSF13B, VIM, GPR18,

to assess the suitability of said subject for treatment with copanlisib, in particular copanlisib dihydrochloride,

the test is to measure the genes and gene characteristics (patterns) using one of the following methods, for example: affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, the degree of upregulation (or high expression) is determined by: the expression levels from the measured genes or scores (e.g., WGS) calculated/derived from the expression levels of all genes in the signature or pathway are compared to a threshold (also referred to as a cut-off), which may be a median value, that yields tumors collected from indications of disease or is established from a clinical trial evaluating the relationship between the expression levels of the genes or gene signature scores and efficacy of treatment by copanlisib.
37. For testing of gene expression profiles, which measure:

-down-regulation of one or more genes selected from the group consisting of: CD4, CD22, VCAN, TNFRSF17, NDE1, ICAM1, PIK3IP1, NFKBIA, MMP9, CD40, IL4I1, AKT2, CD79A, JAK3, MET, COL1A1, VWF, VEGFA, SPARC, FN1, SGK1, MT2A, IL1B, CD93, STAT5A, KDR, THBS1, LUM, S100A8, SERPINH1, BATF, PTGIR, CSTB, ITGB2, S100A9, SYK, CD14, CEBPB, SPHK1, NOP10, THBS2, COL5A2,

to assess the suitability of said subject for treatment with copanlisib, in particular copanlisib dihydrochloride,

the test is to measure the genes and gene characteristics (patterns) using one of the following methods, for example: affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, the degree of upregulation (or high expression) is determined by: the expression levels from the measured genes or scores (e.g., WGS) calculated/derived from the expression levels of all genes in the signature or pathway are compared to a threshold (also referred to as a cut-off), which may be a median value, that yields tumors collected from indications of disease or is established from a clinical trial evaluating the relationship between the expression levels of the genes or gene signature scores and efficacy of treatment by copanlisib.
38. A test for gene expression profiling, which measures in a subject:

-up-regulation of one or more genes selected from: AKT1, AKT3, BLNK, BTK, CD19, CD69, CD72, CD79B, CD8B, FCGR2B, GAB1, LYN, MS4A1, PIK3AP1, PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R3, PIK3R4, PIK3R5, PTEN, TLR4, TNFRSF13B, VIM, GPR18,

and

-down-regulation of one or more genes selected from the group consisting of: CD4, CD22, VCAN, TNFRSF17, NDE1, ICAM1, PIK3IP1, NFKBIA, MMP9, CD40, IL4I1, AKT2, CD79A, JAK3, MET, COL1A1, VWF, VEGFA, SPARC, FN1, SGK1, MT2A, IL1B, CD93, STAT5A, KDR, THBS1, LUM, S100A8, SERPINH1, BATF, PTGIR, CSTB, ITGB2, S100A9, SYK, CD14, CEBPB, SPHK1, NOP10, THBS2, COL5A2,

to assess the suitability of said subject for treatment with copanlisib, in particular copanlisib dihydrochloride,

the test is to measure the genes and gene characteristics (patterns) using one of the following methods, for example: affymetrix array, RT-PCR, RNAseq, nano-cluster, RNAscope, the degree of upregulation (or high expression) is determined by: the expression levels from the measured genes or scores (e.g., WGS) calculated/derived from the expression levels of all genes in the signature or pathway are compared to a threshold (also referred to as a cut-off), which may be a median value, that yields tumors collected from indications of disease or is established from a clinical trial evaluating the relationship between the expression levels of the genes or gene signature scores and efficacy of treatment by copanlisib.
39. A kit for selecting a subject having: non-hodgkin's lymphoma (hereinafter abbreviated as "NHL"), particularly relapsed/refractory, indolent or aggressive non-hodgkin's lymphoma (NHL), particularly follicular lymphoma (hereinafter abbreviated as "FL"), chronic lymphocytic leukemia (hereinafter abbreviated as "CLL"), marginal zone lymphoma (hereinafter abbreviated as "MZL"), diffuse large B-cell lymphoma (hereinafter abbreviated as "DLBCL"), Mantle Cell Lymphoma (MCL), transformed lymphoma (hereinafter abbreviated as "TL"), or peripheral T-cell lymphoma (hereinafter abbreviated as "PTCL"),

characterized by a layered feature according to any of claims 36, 37 and 38, and determining a layered feature according to any of claims 36, 37 and 38.
40. The kit according to claim 39, wherein the treatment is monotherapy or combination therapy.
41. The kit according to claim 39 or 40, wherein said stratification feature is determined in a tumor tissue or tumor cell sample from said subject.