WO2021252905A1 - Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un lymphome diffus à grandes cellules b - Google Patents

Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un lymphome diffus à grandes cellules b Download PDF

Info

Publication number
WO2021252905A1
WO2021252905A1 PCT/US2021/037025 US2021037025W WO2021252905A1 WO 2021252905 A1 WO2021252905 A1 WO 2021252905A1 US 2021037025 W US2021037025 W US 2021037025W WO 2021252905 A1 WO2021252905 A1 WO 2021252905A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
heteroaryl
subject
protein activity
aryl
Prior art date
Application number
PCT/US2021/037025
Other languages
English (en)
Inventor
Christopher Walker
Mariano Javier Alvarez
Yosef Landesman
Andrea Califano
Yao Shen
Original Assignee
Karyopharm Therapeutics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Karyopharm Therapeutics Inc. filed Critical Karyopharm Therapeutics Inc.
Publication of WO2021252905A1 publication Critical patent/WO2021252905A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Diffuse large B-cell lymphoma is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non- Hodgkin lymphoma among adults.
  • DLBCL Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of disease subtypes, many of which are difficult to separate from one another based on well-defined and widely accepted criteria.
  • the World Health Organization, 2008, classification system defined more than a dozen subtypes, each of which was identified based on the location of the tumor, the presence of other cell types such as T cells in the tumor, and whether the patient had certain other illnesses related to DLBCL.
  • DLBCL diffuse large B-cell lymphoma
  • NOS diffuse large B-cell lymphoma
  • the remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their morphology, (i.e. microscopic appearance), immunophenotype, (i.e. expression of certain marker proteins), clinical findings, and/or association with certain pathogenic viruses.
  • the present invention is a computer program product for identifying responders and non-responders, the computer program product comprising a computer readable storage medium having program instructions embodied therewith the program instructions executable by a processor to cause the processor to perform a method comprising determining a plurality of protein activity values in a subject suffering from DLBCL, each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder,
  • the values and preferred values of the variables in the structural formula (I) are defined herein.
  • the present invention is a method of treating a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), comprising administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject suffering from DLBCL, wherein the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject.
  • the values and preferred values of the variables in the structural formula (I) are defined herein.
  • the present invention is a method of treating a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), comprising selecting the subject suffering from DLBCL only if the subject is determined to be a responder to a therapy by a compound represented by structural formula (I) based on a plurality of protein activity the subject; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof
  • DLBCL Diffuse Large B-Cell Lymphoma
  • the present invention is a method of treating a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), comprising receiving information of a plurality of protein activity values in a subject suffering from DLBCL, each protein activity value corresponding to one of a set of proteins in the subject; and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof only if the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on said plurality of protein activity values.
  • the values and preferred values of the variables in the structural formula (I) are defined herein.
  • the present invention is a method of identifying a subject as a responder or a non-responder, comprising determining a plurality of protein activity values in a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder, (I).
  • the values and preferred values of the variables in the structural formula (I) are defined herein.
  • the present invention is a computer program product for identifying responders and non-responders
  • the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising determining a plurality of protein activity values in a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof and obtaining from the classifier a classification of the subject as a responder or non- responder.
  • DLBCL Diffuse Large B-Cell Lymphoma
  • FIG.1 is a volcano plot that shows the differential expression of all quantified genes between responder and non-responder patients.
  • FIG.2 shows characteristics curves for the indicated machine learning models. Curves show predictive ability to discriminate between responder and non-responder patients using top three protein activities as determined by the First Study.
  • FIG.3A shows a characteristics curve for the integrated model combining 5 different machine learning methods to predict selinexor response in patients with GCB DLBCL, based on three protein activities.
  • FIG.3B is a bar plot showing the predicted likelihood of response of each patient. Light bars are non-responders and dark bars are responders.
  • FIG.4A shows characteristics curves for the indicated machine learning models. Curves show predictive ability to discriminate between responder and non-responder patients using top six protein activities as determined by the Second Study.
  • FIG.4B shows a bar plot (left) providing the overall predictive response score for 31 patients in the Second Study stratified by actual response, and a characteristics curve (right) for the integrated model combining four different machine learning methods to predict selinexor response in patients with DLBCL, based on six protein activities determined by the Second Study.
  • FIG.5 is a schematic of an example of a computing node DETAILED DESCRIPTION OF THE INVENTION [0018] A description of example embodiments of the invention follows.
  • Example XPO1 inhibitors useful for practicing the present invention are represented by structural formula (I): [0022] In structural formula (I): [0023] Ring A is phenyl or pyridyl; [0024] X is -N- or -C(H)-; [0025] each R 1 is independently selected from -CN, halo, - OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C3-C12 heterocycloalkyl, halo-C1-C3 alkyl, -NH2, -NO2, -NH(C1-C3 alkyl), -N(C1- C3 alkyl)(C1-C3 alkyl), -C(O)OH, -C(O)O-(C1-C6 alkyl
  • aliphatic or “aliphatic group,” as used herein, denotes a monovalent fused, bridged, and spiro-fused polycyclic).
  • An aliphatic group can be saturated or can contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, aliphatic groups contain 1–6 carbon atoms. However, in some embodiments, an aliphatic group contains 1-10 or 2-8 carbon atoms. In some embodiments, aliphatic groups contain 1– 4 carbon atoms and, in yet other embodiments, aliphatic groups contain 1–3 carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • An aliphatic group can be optionally substituted as described herein.
  • alkyl as used herein, means a saturated, straight-chain or branched aliphatic group. In one aspect, an alkyl group contains 1-6 or 1-4 carbon atoms.
  • Alkyl includes, but is not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, and the like.
  • An alkyl group can be optionally substituted as described herein.
  • an alkenyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like.
  • alkenyl encompasses radicals having carbon-carbon double bonds in the “cis” and “trans” or, alternatively, the “E” and “Z” configurations. If an alkenyl group includes more than one carbon-carbon double bond, each carbon-carbon double bond is independently a cis or trans double bond, or a mixture thereof. An alkenyl group can be optionally substituted as described herein. [0039]
  • alkynyl as used herein, means a straight-chain or branched aliphatic radical having one or more carbon-carbon triple bonds (i.e., -C ⁇ C-).
  • an alkyl group has from two to four carbon atoms, and includes, for example, and without being limited thereto, 1-propynyl (propargyl), 1-butynyl and the like.
  • An alkynyl group can be optionally substituted as described herein.
  • a cycloaliphatic group has 3-6 carbon atoms.
  • Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclooctadienyl.
  • the terms “cycloaliphatic,” “carbocyclyl,” “carbocyclo,” and “carbocyclic” also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl, tetrahydronaphthyl, decalin, or bicyclo[2.2.2]octane. These aliphatic rings can be optionally substituted as described herein.
  • cycloalkyl means a saturated cyclic aliphatic monocyclic or bicyclic ring system having from 3-18, for example 3-12 members.
  • a cycloalkyl can be optionally substituted as described herein.
  • a cycloalkyl has 3–6 carbons.
  • a cycloalkyl group can be optionally substituted as described herein.
  • heterocyclyl means a saturated or unsaturated aliphatic ring system having from 3 to 18, for example 3-12 members in which at least one carbon atom is replaced with a heteroatom selected from N, S and O.
  • a heterocyclyl can contain one or more rings, which may be attached together in a pendent manner or may be fused.
  • a heterocyclyl is a three- to seven-membered ring system and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.
  • a heterocyclyl group can be optionally substituted as described herein.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, and includes any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; and a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • alkoxy as used herein, means -O-alkyl.
  • Alkoxy can include a straight-chained or branched alkyl.
  • alkoxy has from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
  • An alkoxy group can be optionally substituted as described herein.
  • halo or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.
  • haloalkyl means an alkyl group that is substituted with one or more halogen atoms.
  • haloalkyl refers to a perhalogenated alkyl group.
  • haloalkyl refers to an alkyl group which is substituted with one or more halogen atoms.
  • Exemplary haloalkyl groups include -CF 3 , -CF 2 H, -CCl 3 , - CF 2 CH 3 , -CH 2 CF 3 , -CH 2 (CF 3 ) 2 , -CF 2 (CF 3 ) 2 , and the like.
  • haloalkyl groups include -CF3 and -CF2H.
  • a preferred haloalkyl group is -CF3.
  • alkylene means a bivalent branched or unbranched saturated hydrocarbon radical.
  • alkylene has one to six carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like.
  • An alkylene group can be optionally substituted as described herein.
  • alkenylene has two to six carbon atoms, and includes, for example, and without being limited thereto, ethenylene, n-propenylene, n-butenylene and the like.
  • An alkenylene group can be optionally substituted as described herein.
  • alkynylene means a bivalent branched or unbranched hydrocarbon radical having one or more carbon-carbon triple bonds (i.e., -C ⁇ C-).
  • alkynylene has two to six carbon atoms, and includes, for example, and without being limited thereto, ethynylene, n-propynylene, n-butynylene and the like.
  • An alkynylene group can be optionally substituted as described herein.
  • aryl alone or in combination, as used herein, means a carbocyclic aromatic system containing one or more rings, which may be attached together in a pendent manner or may be fused.
  • an aryl has one, two or three rings.
  • the aryl has six to twelve ring atoms.
  • aryl encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl and acenaphthyl.
  • An “aryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
  • heteroaryl alone or in combination, as used herein, means an aromatic system wherein at least one carbon atom is replaced by a heteroatom selected from N, S and O.
  • a heteroaryl can contain one or more rings, which may be attached together in a pendent manner or may be fused.
  • a heteroaryl has one, two or three rings.
  • the heteroaryl has five to twelve ring atoms.
  • the term “heteroaryl” encompasses pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl, oxadiazolyl, isoxazolyl, and the like.
  • a “heteroaryl” group can have 1 to 4 substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
  • substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below.
  • the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted group” can have a suitable substituent at each substitutable position of the group and, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Alternatively, an “optionally substituted group” can be unsubstituted. [0054] Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results.
  • Suitable monovalent substituents on R ⁇ are independently halogen, -(CH2)0-2R ⁇ , –(haloR ⁇ ), –(CH2)0–2OH, –(CH2)0–2OR ⁇ , –(CH2)0– 2CH(OR ⁇ )2; -O(haloR ⁇ ), –CN, –N3, –(CH2)0–2C(O)R ⁇ , –(CH2)0–2C(O)OH, –(CH2)0– 2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , –(CH 2 ) 0–2 NHR ⁇ , –(CH 2 ) 0–2 NR ⁇ 2
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , and –NO2, wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted group” include –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , – S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , and –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or -NO2, wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Example embodiments of the XPO1 inhibitors of the invention are selinexor, eltanexor, and verdinexor.
  • Eltanexor is a compound represented by the following structural formula, (1).
  • Eltanexor is a second-generation oral selective inhibitor of nuclear export (SINE) that binds to XPO1 and prevents it from shuttling its cargo from the nucleus to the cytoplasm, resulting in nuclear accumulation of tumor suppressor proteins and oncogene mRNAs.
  • SINE second-generation oral selective inhibitor of nuclear export
  • the first generation XPO1 inhibitor selinexor is approved in the USA for treatment of patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, 2 immunomodulatory agents and an anti-CD38 monoclonal antibody.
  • Verdinexor represented by structural formula (3), is an oral inhibitor or XPO1 also described in WO2013/019548.
  • Table 4 G ene P-value ( FDR-corrected) Description COL1A1 4.6x10 -67 Collagen type I, ⁇ I chain INHBA Inhibin Subunit ⁇ A (member of TGF ⁇ family) C NOT2 2.7x10-11 CCR4-NOT Transcription Complex Subunit 2 (involved in mRNA p rocessing) [0084] COL1A1, GeneID: 1277; CNOT2, GeneID: 4848 [0085] A list of top 100 proteins (ranked by p-value) used to train the classifier in the First Study, as described below, is provided in Table 5.
  • Table 5 Top 100 Protein Ranked by p-Value FDR_corrected_P ⁇ Entrez_ID Name value 3624 INHBA 8.80E ⁇ 09 54700 RRN3 8.80E ⁇ 09 389136 VGLL3 9.58E ⁇ 05 79811 SLTM 0.00015671 26051 PPP1R16B 0.00062301 4854 NOTCH3 0.00130628 92737 DNER 0.00419345 8323 FZD6 0.01316705 51776 MAP3K20 0.0165682 57451 TENM2 0.02072466 79754 ASB13 0.02485158 7472 WNT2 0.02486196 6446 SGK1 0.02490551 79603 CERS4 0.02770827 54796 BNC2 0.05118869 9200 HACD1 0.05248652 55870 ASH1L 0.05420684 1903 S1PR3 0.06547616 79973 ZNF442 0.08030105 26245 OR2M4 0.
  • Model performance was estimated using leave-one-out cross-validation (LOOCV). The best performance model was achieved using only six proteins (ASH1L, ZNF471 (GeneID: 57573), RRN3, CD248 (GeneID: 57124), ZNF750, INHBA) listed in Table 6. [0090] Table 6 [0091] When relying on the six proteins listed in Table 6, the four classifier models tested achieved the following area under the receiver operating characteristic curve (AUC-ROC): 0.917, 0.925, 0.883, and 0.875, for the LDA, LR, RF and RR, models, (p ⁇ 0.05, permutation test), respectively (FIG.4A).
  • AUC-ROC receiver operating characteristic curve
  • Table 7 Top 100 Protein Ranked by p-Value p-value Gene Gene (fdr- symbol entrezID corrected) ASH1L 55870 5.08E ⁇ 10 ZNF471 57573 1.82E ⁇ 09 RRN3 54700 4.07E ⁇ 09 CD248 57124 7.13E ⁇ 07 ZNF750 79755 5.02E ⁇ 06 INHBA 3624 8.85E ⁇ 06 TGFB1I1 7041 0.000444 ZCCHC24 219654 0.000739 CBLB 868 0.00127 RNF43 54894 0.00153 AIFM1 9131 0.00325 SUPT16H 11198 0.0049 HNRNPK 3190 0.0104 ASXL2 55252 0.0136 GAPVD1 26130 0.0148 GPR75 10936 0.0164 PTPN22 26191 0.0201 SGK1 6446 0.0206 LIMD1 8994 0.0228 ZNF778 197320 0.028 ENY2 56943 0.0318 HDGF 3068 0.0318 ZCCHC8
  • Protein activity for a population of subjects is used to identify MR proteins as described above, and to train classifiers based on sets of known responders and non-responders. Similarly, protein activity for an individual subject is used to classify that subject as a responder or non-responder.
  • a feature vector is constructed for a given subject that comprises protein activity values for one or more proteins.
  • measures of protein activity are suitable for use according to the present disclosure. For example, as described further below, VIPER provides protein activity values in terms of normalized enrichment scores, which express activity for all the regulatory proteins in the same scale.
  • alternative methods of determining protein activity provide alternative measures of protein activity values, for example, absolute or relative abundance in a sample, or absolute enrichment.
  • Various embodiments described herein employ the VIPER algorithm to determine protein activity in the form of normalized enrichment scores for a plurality of proteins based on a predetermined model of transcriptional regulation.
  • the VIPER algorithm is described further in PCT Pub. No. WO2017040311A1, which is hereby incorporated by reference in its entirety.
  • alternative methods of determining protein activity in a subject are also applicable for practicing the methods described herein.
  • Exemplary alternative algorithms for inferring protein activity from gene expression data include: ChIP- X Enrichment Analysis (ChEA), which is described further in Keenan, A. B. et al. ChEA3: transcription factor enrichment analysis by orthogonal omics integration. Nucleic Acids Res.
  • TFEA.ChIP which is described further in Puente-Santamaria, L., Wasserman, W. W. & Del Peso, L. TFEA.ChIP: a tool kit for transcription factor binding site enrichment analysis capitalizing on ChIP-seq datasets. Bioinformatics 35, 5339–5340 (2019); Binding Analysis for Regulation of Transcription (BART), which is described further in Wang, Z. et al. BART: a transcription factor prediction tool with query gene sets or epigenomic profiles.
  • MAGICTRICKS A tool for predicting transcription factors and cofactors that drive gene lists. https://doi.org/10.1101/492744; DoRothEA, which is described further in Garcia-Alonso, L. et al. Transcription factor activities enhance markers of drug sensitivity in cancer. Cancer Res.78, 769–780 (2016); and NetFactor, which is described further in Ahsen, M. E. et al. NeTFactor, a framework for identifying transcriptional regulators of gene expression-based biomarkers.
  • biochemical approaches can be used to estimate abundance of the proteins included in a given biomarker, such us immunostaining (immunofluorescence or immunochemistry) of tissue samples followed by histological examination, flow cytometry, mass cytometry or cytometric bead arrays, reverse-phase protein arrays, bead-based IVD assays such as Luminex and mass spectrometry.
  • immunostaining immunofluorescence or immunochemistry
  • flow cytometry flow cytometry
  • mass cytometry or cytometric bead arrays cytometric bead arrays
  • reverse-phase protein arrays reverse-phase protein arrays
  • bead-based IVD assays such as Luminex and mass spectrometry.
  • a set of MR proteins may be determined by a variety of methods, including those described in connection with the examples below.
  • cluster analysis may be performed with or without separate dimensionality reduction in order to determine the heterogeneity of responder and non-responder clusters in an n-dimensional vector space, with n corresponding to a number of proteins considered.
  • methods are available for dimensionality reduction, including unsupervised dimensionality feature agglomeration analysis.
  • cluster analysis methods are available, including hierarchical clustering and k-means clustering.
  • a variety of statistical methods are available for determining the correlation of a given protein value to the classification as a responder or non-responder.
  • the DarwinOncoTargetTM system is used to identify and rank potential protein predictors of responsiveness and non-responsiveness.
  • FDR False Discovery Rate
  • a subset of proteins is selected by performing a cross- validation process such as leave-one-out cross validation.
  • a model is trained on all data except for one point and a prediction is made for that point. It will be appreciated that cross-validation may be used to optimize the selection of proteins and/or the number of proteins.
  • a variable number of proteins may be selected for training a classifier as set out herein.
  • any subset of the MR proteins provided in a ranking sorted by the False Discovery Rate (FDR)-corrected p- value such as, e.g., in Table 5 above, may be used to train one or more classifier.
  • FDR False Discovery Rate
  • a classifier may be trained with all or some of the potential proteins while still arriving at a trained classifier suitable for identification of responders and non-responders.
  • a given classifier will de-emphasize low value proteins while emphasizing high value proteins by virtue of the training process.
  • a predetermined number of proteins having the highest differential activity between responder and non-responder patients are selected.
  • a training set including responders and non-responders is determined by RNA sequencing of a plurality of subjects. Normalized enrichment scores (NES) are determined for a plurality of proteins across the training set. In some embodiments, normalized enrichment scores are determined by application of VIPER.
  • protein activity scores for responsive and non-responsive subjects are determined as set forth above. A feature a classifier.
  • the classifier comprises a SVM. In some embodiments, the classifier comprises an artificial neural network. In some embodiments, the classifier comprises a random decision forest. It will be appreciated that a variety of other classifiers are suitable for use according to the present disclosure, including linear classifiers, support vector machines (SVM), Linear Discriminant Analysis (LDA), Logistic regression, Random Forest, Ridge regression methods, or neural networks such as recurrent neural networks (RNN). In addition, it will be apprecaited that an ensemble model of any of the forgoing may also be employed.
  • SVM support vector machines
  • LDA Linear Discriminant Analysis
  • RNN recurrent neural networks
  • Suitable artificial neural networks include but are not limited to a feedforward neural network, a radial basis function network, a self-organizing map, learning vector quantization, a recurrent neural network, a Hopfield network, a Boltzmann machine, an echo state network, long short term memory, a bi-directional recurrent neural network, a hierarchical recurrent neural network, a stochastic neural network, a modular neural network, an associative neural network, a deep neural network, a deep belief network, a convolutional neural networks, a convolutional deep belief network, a large memory storage and retrieval neural network, a deep Boltzmann machine, a deep stacking network, a tensor deep stacking network, a spike and slab restricted Boltzmann machine, a compound hierarchical-deep model, a deep coding network, a multilayer kernel machine, or a deep Q-network.
  • the classifier is trained to classify a subject as either responsive or non-responsive.
  • a protein activity of a given subject is determined.
  • the protein activity values are provided as a feature vector to a trained classifier, which provides an output classification as either a responder or a non- responder.
  • Methods of Treating As used above, “all aspects thereof” includes aspects numbered both before and after the given aspect.
  • the term “signature” refers to a set of proteins with a characteristic pattern of activities that is reflective of the underlying biologic state of the population of cells that exhibit the signature and that can be causally associated with specific properties of the cells such as response to drug treatment
  • a “therapeutically effective amount”, as used herein refers to an amount that is amount can refer to an amount that is sufficient to improve at least one sign or symptom of diseases or conditions disclosed herein.
  • the therapeutically effective amount of the XPO1 inhibitors of the present invention is from about 200 mg to about 20 mg. In a further particular embodiment, the therapeutically effective amount of XPO1 inhibitors of the present invention is 80 mg per administration.
  • the XPO1 inhibitors of the present invention are administered on Days 1 and 3 of each week of treatment at a dose of 80 mg per administration. In an even more particular embodiment, XPO1 inhibitors of the present invention are administered on Days 1 and 3 of each week of treatment at a dose of 80 mg per administration and 20 mg of dexamethasone is co-administered on the same days as the XPO1 inhibitors of the present invention. In a specific aspect of the dosing regimen, the XPO1 inhibitors of the present invention.
  • subject to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g.,
  • subjects are humans, such as adult humans.
  • the subject is an adult human.
  • the term “treating” means to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • Treatment includes treating a symptom of a disease, disorder or condition.
  • the phrase “combination therapy” or “co-administration” embraces the administration of the XPO1 inhibitors of the present invention and an additional therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of each.
  • the XPO1 inhibitors of the present invention and an additional therapeutic agent can be formulated as separate compositions.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” or “co-administration” is intended to embrace additional therapeutic agent) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence wherein the therapeutic agents are administered is not narrowly critical.
  • “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different therapeutic agent) and non- drug therapies (e.g., surgery or radiation).
  • the XPO1 inhibitors of the present invention are administered once per week. In a particular aspect, the amount is from about 20 mg to about 200 mg. In a more particular aspect, the amount administered is about 80 mg.
  • the XPO1 inhibitors of the present invention can be present in the form of pharmaceutically acceptable salt.
  • the salts of the XPO1 inhibitors of the present invention refer to non-toxic “pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable acidic/anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, naps
  • the XPO1 inhibitors of the present invention can be administered orally, nasally, ocularly, transdermally, topically, intravenously (both bolus and infusion), and via injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally) either as alone or as part of a pharmaceutical composition comprising the XPO1 inhibitors of the present invention and a pharmaceutically acceptable excipient.
  • the composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository.
  • a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository.
  • a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or
  • compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions.
  • prior therapies refers to known therapies for DLBCL involving administration of a therapeutic agent.
  • Prior therapies can include, but are not limited to, treatment with proteasome inhibitors (PI), Immunomodulatory agents, monoclonal antibodies or other agents typically used in the treatment of DLBCL.
  • PI proteasome inhibitors
  • Immunomodulatory agents monoclonal antibodies or other agents typically used in the treatment of DLBCL.
  • Computing node 10 is only one example of a suitable computing node and is not intended to suggest any limitation as to the scope of use or functionality of embodiments described herein. Regardless, computing node 10 is capable of being implemented and/or performing any of the functionality set forth hereinabove.
  • computing node 10 there is a computer system/server 12, which is operational with numerous other general purpose or special purpose computing system environments or configurations. Examples of well-known computing systems, environments, and/or configurations that may be suitable for use with computer system/server 12 include, but are not limited to, personal computer systems, server computer systems, thin clients, thick set top boxes, programmable consumer electronics, network PCs, minicomputer systems, mainframe computer systems, and distributed cloud computing environments that include any of the above systems or devices, and the like.
  • Computer system/server 12 may be described in the general context of computer system-executable instructions, such as program modules, being executed by a computer system.
  • program modules may include routines, programs, objects, components, logic, data structures, and so on that perform particular tasks or implement particular abstract data types.
  • Computer system/server 12 may be practiced in distributed cloud computing environments where tasks are performed by remote processing devices that are linked through a communications network.
  • program modules may be located in both local and remote computer system storage media including memory storage devices.
  • FIG.5f computer system/server 12 in computing node 10 is shown in the form of a general-purpose computing device.
  • the components of computer system/server 12 may include, but are not limited to, one or more processors or processing units 16, a system memory 28, and a bus 18 that couples various system components including system memory 28 to processor 16.
  • Bus 18 represents one or more of any of several types of bus structures, including a memory bus or memory controller, a peripheral bus, an accelerated graphics port, and a processor or local bus using any of a variety of bus architectures.
  • Computer system/server 12 typically includes a variety of computer system readable media. Such media may be any available media that is accessible by computer system/server 12, and it includes both volatile and non-volatile media, removable and non- removable media.
  • System memory 28 can include computer system readable media in the form of volatile memory, such as random access memory (RAM) 30 and/or cache memory 32.
  • Computer system/server 12 may further include other removable/non-removable, system 34 can be provided for reading from and writing to a non-removable, non-volatile magnetic media (not shown and typically called a "hard drive”).
  • a magnetic disk drive for reading from and writing to a removable, non-volatile magnetic disk (e.g., a "floppy disk")
  • an optical disk drive for reading from or writing to a removable, non-volatile optical disk such as a CD-ROM, DVD-ROM or other optical media.
  • each can be connected to bus 18 by one or more data media interfaces.
  • memory 28 may include at least one program product having a set (e.g., at least one) of program modules that are configured to carry out the functions of embodiments of the disclosure.
  • Program/utility 40 having a set (at least one) of program modules 42, may be stored in memory 28 by way of example, and not limitation, as well as an operating system, one or more application programs, other program modules, and program data. Each of the operating system, one or more application programs, other program modules, and program data or some combination thereof, may include an implementation of a networking environment.
  • Program modules 42 generally carry out the functions and/or methodologies of embodiments as described herein.
  • Computer system/server 12 may also communicate with one or more external devices 14 such as a keyboard, a pointing device, a display 24, etc.; one or more devices that enable a user to interact with computer system/server 12; and/or any devices (e.g., network card, modem, etc.) that enable computer system/server 12 to communicate with one or more other computing devices. Such communication can occur via Input/Output (I/O) interfaces 22. Still yet, computer system/server 12 can communicate with one or more networks such as a local area network (LAN), a general wide area network (WAN), and/or a public network (e.g., the Internet) via network adapter 20. As depicted, network adapter 20 communicates with the other components of computer system/server 12 via bus 18.
  • LAN local area network
  • WAN wide area network
  • public network e.g., the Internet
  • the present disclosure may be embodied as a system, a method, and/or a computer program product.
  • the computer program product may include a computer readable storage medium (or media) having computer readable program instructions thereon for [00134]
  • the computer readable storage medium can be a tangible device that can retain and store instructions for use by an instruction execution device.
  • the computer readable storage medium may be, for example, but is not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing.
  • a non- exhaustive list of more specific examples of the computer readable storage medium includes the following: a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), a static random access memory (SRAM), a portable compact disc read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanically encoded device such as punch-cards or raised structures in a groove having instructions recorded thereon, and any suitable combination of the foregoing.
  • a computer readable storage medium is not to be construed as being transitory signals per se, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through a waveguide or other transmission media (e.g., light pulses passing through a fiber-optic cable), or electrical signals transmitted through a wire.
  • Computer readable program instructions described herein can be downloaded to respective computing/processing devices from a computer readable storage medium or to an external computer or external storage device via a network, for example, the Internet, a local area network, a wide area network and/or a wireless network.
  • the network may comprise copper transmission cables, optical transmission fibers, wireless transmission, routers, firewalls, switches, gateway computers and/or edge servers.
  • Computer readable program instructions for carrying out operations of the present disclosure may be assembler instructions, instruction-set-architecture (ISA) instructions, machine instructions, machine dependent instructions, microcode, firmware instructions, state-setting data, or either source code or object code written in any combination of one or more programming languages, including an object oriented programming language such as Smalltalk, C++ or the like, and conventional procedural programming languages, such as the program instructions may execute entirely on the user’s computer, partly on the user’s computer, as a stand-alone software package, partly on the user’s computer and partly on a remote computer or entirely on the remote computer or server.
  • ISA instruction-set-architecture
  • the remote computer may be connected to the user’s computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).
  • electronic circuitry including, for example, programmable logic circuitry, field-programmable gate arrays (FPGA), or programmable logic arrays (PLA) may execute the computer readable program instructions by utilizing state information of the computer readable program instructions to personalize the electronic circuitry, in order to perform aspects of the present disclosure.
  • These computer readable program instructions may also be stored in a computer readable storage medium that can direct a computer, a programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having instructions stored therein comprises an article of manufacture including instructions which implement aspects of the function/act specified in the flowchart and/or block diagram block or blocks.
  • the computer readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.
  • each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s).
  • the functions noted in the block may occur out of the order noted in the figures. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved.
  • the present invention is a computer- assisted method of treating a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), comprising: determining a plurality of protein activity values in a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder, administering to the responder a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof.
  • DLBCL Diffuse Large B-Cell Lymphoma
  • the present invention is a computer-assisted method of treating a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), comprising: administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject suffering from DLBCL, wherein the subject is determined to be a responder to a treatment by the compound represented by structural formula (I) by: determining a plurality of protein activity values in a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), each protein of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder.
  • DLBCL Diffuse Large B-Cell Lymphoma
  • the present invention is a computer-assisted method of treating a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), comprising: selecting the subject suffering from DLBCL only if the subject is determined to be a responder to treatment by a compound represented by structural formula (I) by: determining a plurality of protein activity values in a subject suffering from Diffuse Large B- Cell Lymphoma (DLBCL), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof.
  • DLBCL Diffuse Large B-Cell Lymphoma
  • the present invention is a computer-assisted method of treating a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), comprising: receiving information of a plurality of protein activity values in a subject suffering from DLBCL, each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to treatment by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder, and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof only if the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on said plurality of protein activity values.
  • DLBCL Diffuse Large B-Cell Lymphoma
  • the present invention is a computer-assisted method of identifying a subject as a responder or a non-responder, comprising: determining a plurality of protein activity values in a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), each protein activity value corresponding to one of a set of proteins in classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder.
  • DLBCL Diffuse Large B-Cell Lymphoma
  • the present invention is a computer program product for identifying responders and non-responders
  • the computer program product comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising: determining a plurality of protein activity values in a subject suffering from Diffuse Large B-Cell Lymphoma (DLBCL), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof, and obtaining from the classifier a classification of the subject as a responder or non-responder,
  • structural formula (I) is wherein: ring A is phenyl or pyridyl; X is -C(H)- or
  • the set of proteins can consist of proteins having at least a pre-determined value of differential protein activity between responders and non-responders.
  • the protein activity value can be a normalized enrichment score.
  • Determining the plurality of protein activity values can comprise applying VIPER algorithm to gene expression data of the subject.
  • the trained classifier can comprise a support vector machine, an artificial neural network, a random forest, a linear classifier, linear discriminant analysis, logistic regression, or ridge regression.
  • the set of proteins can be selected from INHBA, RRN3, VGLL3, SLTM, PPP1R16B, NOTCH3, DNER, FZD6, MAP3K20, TENM2, SP140, ASB13, WNT2, SGK1,CERS4, BNC2, HACD1, ASH1L, S1PR3, ZNF442, OR2M4, SPOCK1, ZCCHC24, ZNF750, JADE1, ETV6, SORL1, CHRNA6, CHL1, PKNOX2, AIFM2, ZNF266, EYA3, PLPP3, CDCA7L, ARHGAP29, HEY2, TCEAL3, NFATC1, MMP2, CCM2, TNFRSF17, SMC3, GOLPH3, MAP2K6, RGS13, SOS1, TRHR, PLXND1, BHLHE22, ZNF480, PER1, PLAG1, ING4, POLB, RGS17, TNFAIP6, ASXL2, IL23R, DRD2, ZNF91, MBD4, P2RY
  • the set of proteins can be INHBA, RRN3, and VGLL3.
  • the patient can be suffering from GCB-subtype DLBCL, and the set of proteins is INHBA, COL1A1, and CNOT2.
  • the compound can be represented by the following structural formula: [00157] .
  • the compound can be represented by the following structural formula: [00159] .
  • the DLBCL can be a relapsed or refractory.
  • the subject could have received from 1 to 5 prior therapies.
  • the subject could have received at least two prior therapies.
  • the subject could have received at least three prior therapies.
  • the subject could have received at least four prior therapies.
  • the subject can be a human.
  • the human can be an adult.
  • the compound represented by formula (I) can be administered orally.
  • At least one additional therapeutic agent can be further administered.
  • EXEMPLIFICATION [00170]
  • the primary analysis population will include all patients who meet eligibility criteria and who were assigned to the 60-mg Arm under protocol Version ⁇ 6.0 (for those enrolled under protocol Version 7.0 or higher, patients must also receive at least 1 dose of selinexor).
  • This population consists of ⁇ 130 patients with R/R DLBCL.
  • DLBCL histology, DLBCL subtype (germinal center B-cell [GCB] or non-GCB), and “double hit” DLBCL (DH-DLBCL) status will be confirmed/determined in all patients.
  • Patients will be treated with a fixed milligram dose of 60 mg selinexor orally twice weekly (BIW). Study site personnel will provide all scans performed for disease assessment during the study to the central imaging laboratory and all radiology reports to Karyopharm performed for disease assessment during the study, to independently assess disease response and time of progressive disease (PD). Patients should remain on study treatment until the assessment of PD from the central imaging laboratory has been obtained (unless medically contraindicated). Patients who have PD confirmed by the central imaging laboratory will discontinue study treatment and be followed for survival.
  • BIW milligram dose of 60 mg selinexor orally twice weekly
  • the Investigator may elect to continue the patient on study and repeat imaging within 4 to 8 weeks for confirmation or negation of PD.
  • Patients who have PD assessed by the treating physician that is not confirmed by the central imaging laboratory should remain on study treatment (unless medically contraindicated). If the treating physician decides to discontinue these patients from study treatment, they will discontinue study treatment and be followed for survival.
  • Selinexor will be given at an oral fixed milligram (mg) dose of 60 mg on Days 1 and 3 (e.g., Monday and Wednesday or Tuesday and Thursday, etc.) of Weeks 1 to 4 of each 4-week cycle (total of 8 doses per cycle).
  • Patients who achieve a partial remission or better will transition to maintenance dosing.
  • the maintenance dose of selinexor will be 60 mg orally QW. Patients whose dose has been reduced such that the total weekly dose is ⁇ 60 mg will continue on that tolerated dose.
  • the dose of selinexor can be increased to 60 mg orally BIW, after discussion with the Medical Monitor.
  • Patients treated under Versions 2.0 to 6.0 of the protocol may have been randomized to the 100 mg Arm in which selinexor may have been given at an oral fixed milligram (mg) dose of 100 mg on Days 1 and 3 (e.g., Monday and Wednesday or Tuesday and Thursday, etc.) of Weeks 1 to 3 (Versions 2.0 to 4.0) or Weeks 1 to 4 (Versions 5.0 and 6.0) of each 4-week cycle (total of 8 doses per cycle).
  • the 100 mg Arm has been removed as of Version 7.0.
  • Study treatment may continue until disease progression is confirmed by the central imaging laboratory (see Overall Study Design for exception to discontinuation of study treatment), clinical progression as determined by the treating physician (see Criteria for Early Discontinuation for details), unacceptable AEs or failure to tolerate the study treatment, treatment delay of more than 28 days (except in specific cases approved by the Sponsor), any medically appropriate reason or significant protocol violation (in the opinion of the Investigator), or patient decides to discontinue study treatment, withdraws consent, or becomes pregnant. [00196] After discontinuation of study treatment, patients will be followed for survival every 3 months until the end of study (i.e., when the last patient in the study has been followed for 6 months after their last dose of study treatment, has withdrawn consent, has died, or has been lost to follow-up, whichever occurs first).
  • Example 2 Biomarkers for Selinexor Response in DLBCL
  • Ribosomal RNA-depleted total transcriptome RNA sequencing was performed on DLBCL cells from the patients’ biopsies. These RNA expression profiles of 25,132 genes were used to estimate the relative activity of 6,213 regulatory proteins for each sample using the metaVIPER algorithm, a DLBCL and Acute Myeloid Leukemia (AML) context-specific models of transcriptional regulation (interactomes), previously reverse engineered with the ARACNe algorithm from DLBCL, and AML tumors profiled in TCGA and available from (https://bioconductor.org/packages/release/data/experiment/html/aracne.networks.html).
  • AML Acute Myeloid Leukemia
  • the VIPER algorithm is described, for example, in WO2017/040311A1, the entire teachings of which are incorporated herein by reference.
  • the data was first pre-processed to remove the noisy or redundant protein features (less informative proteins). Specifically, the following criteria were applied: (1) 20% of the proteins were removed showing the lowest inter-quantile range; (2) proteins were kept whose Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER)-inferred protein activities were significant at p-value ⁇ 0.05 (i.e.
  • the protein activity signature was computed for each responder patient sample using the two methods mentioned above. More specifically, the activity of each of the 680 selected proteins in each of the responder samples was compared to their activity distribution in the pool of all non-responder samples using single-sample Student’s t-test.
  • FDR Fralse Discovery Rate
  • top 1, top 2, ..., up to top 10 MRs were selected, constructed LR, NN, LDA, RF and RR models, and tested their performance by LOOCV, respectively.
  • the accuracy of these classifiers increased as more MR proteins were included into the models, but reached a plateau at a certain number of MRs. The best performance
  • a similar method was used to identify three proteins associated with response specifically in Germinal center B-cell like (GCB) DLBCL patients.
  • GCB Germinal center B-cell like
  • a method of treating a patient suffering from Diffuse Large B-Cell Lymphoma comprising: determining a plurality of protein activity values in a subject suffering from DLBCL, each protein activity value corresponding to one of a set of proteins in the subject; determining a classification of the subject as a responder or non-responder to a therapy by a compound represented by structural formula (I); and administering a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to be responder, wherein: ring A is phenyl or pyridyl; X is -N- or -C(H)-; each R 1 is independently selected from -CN, halo, - OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 - C12 heterocycloalkyl, halo-C1-C3 alkyl, -NH2, -NO2, -
  • a method of treating a subject suffering from Diffuse Large B-Cell Lymphoma comprising: administering a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof to the subject suffering from DLBCL, wherein the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject, wherein: ring A is phenyl or pyridyl; X is -N- or -C(H)-; each R 1 is independently selected from -CN, halo, - OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 - C12 heterocycloalkyl, halo-C1-C3 alkyl, -NH2, -NO2, -NH(C1-C3 alkyl),
  • a method of treating a subject suffering from Diffuse Large B-Cell Lymphoma comprising: selecting the subject suffering from DLBCL only if the subject is determined to be a responder to a therapy by a compound represented by structural formula (I) based on a plurality of protein activity values in the subject, each protein activity value corresponding to one of a set of proteins in the subject; and administering to the selected subject a therapeutically effective amount of the compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or pyridyl; X is -N- or -C(H)-; each R 1 is independently selected from -CN, halo, - OH, C1-C3 alkyl, C3-C6 cycloalkyl, C3- C 12 heterocycloalkyl, halo-C 1 -C 3 alkyl, -NH 2 , -NO 2 , -NH(C 1 )
  • a method of treating a subject suffering from Diffuse Large B-Cell Lymphoma comprising: receiving information of a plurality of protein activity values in a subject suffering from DLBCL, each protein activity value corresponding to one of a set of proteins in the subject; and administering to the subject a therapeutically effective amount of a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof only if the subject is determined to be a responder to a therapy by the compound represented by structural formula (I) based on said plurality of protein activity values,
  • ring A is phenyl or pyridyl;
  • X is -N- or -C(H)-; each R 1 is independently selected from -CN, halo, - OH, C1-C3 alkyl, C3-C6 cycloalkyl, C3- C 12 heterocycloalkyl, halo-C 1 -C 3 alkyl, -NH 2 , -NO 2 ,
  • any one of numbered embodiments 1-6 wherein the set of proteins is selected from ASH1L, ZNF471, RRN3, CD248, ZNF750, INHBA, TGFB1I1, ZCCHC24, CBLB, RNF43, AIFM1, SUPT16H, HNRNPK, ASXL2, GAPVD1, GPR75, PTPN22, SGK1, LIMD1, ZNF778, ENY2, HDGF, ZCCHC8, ZNF841, RBM15, TP53, TXK, ARHGEF10L, TXN, ZNF480, C17orf79, NONO, TFAM, APOL3, PRPF6, RPL22, NOLC1, NFIB, TRIO, GRLF1, ZBTB20, RTF1, HMGN2, ZNF432, HEY2, ZNF75D, PLEKHG7, ACTL6A, SYDE1, NT5C2, ZNF550, PFDN1, CRKL, ZNF235, EEF2, MED4, KH
  • a method of identifying a subject as a responder or a non-responder comprising: determining a plurality of protein activity values in a subject suffering from Diffuse Large B- Cell Lymphoma (DLBCL), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I); and obtaining from the classifier a classification of the subject as a responder or non-responder, (I), wherein: ring A is phenyl or pyridyl; X is -N- or -C(H)-; each R 1 is independently selected from -CN, halo, - OH, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 - C12 heterocycloalkyl, halo-C1-C3 alkyl, -NH2,
  • the trained classifier comprises a support vector machine, an artificial neural network, a random forest, a linear classifier, linear discriminant analysis, logistic regression, or ridge regression.
  • a computer program product for identifying responders and non-responders comprising a computer readable storage medium having program instructions embodied therewith, the program instructions executable by a processor to cause the processor to perform a method comprising: determining a plurality of protein activity values in a subject suffering from Diffuse Large B- Cell Lymphoma (DLBCL), each protein activity value corresponding to one of a set of proteins in the subject; providing the plurality of protein activity values to a trained classifier, the trained classifier being trained to differentiate between responders and non-responders to a therapy by a compound represented by structural formula (I) or a pharmaceutically acceptable salt thereof and obtaining from the classifier a classification of the subject as a responder or non- responder, wherein: ring A is phenyl or pyridyl; X is -N- or -C(H)-; each R 1 is independently selected from -CN, halo, - OH, C 1 -C 3 alkyl, C 3 -

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé assisté par ordinateur pour traiter un patient atteint de LDGCB, consistant : à déterminer si le patient est un répondeur sur la base d'une sortie d'un classificateur, l'entrée du classificateur étant un vecteur de caractéristiques comprenant des valeurs d'activité de protéines correspondant à un ensemble de protéines chez le sujet ; et à administrer au répondeur une quantité thérapeutiquement efficace du composé représenté par la formule structurale (I) ou un sel pharmaceutiquement acceptable de celui-ci. Les valeurs et les valeurs préférées des variables de formule structurale (I) sont définies dans la description.
PCT/US2021/037025 2020-06-11 2021-06-11 Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un lymphome diffus à grandes cellules b WO2021252905A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202063037914P 2020-06-11 2020-06-11
US63/037,914 2020-06-11
US202063061485P 2020-08-05 2020-08-05
US63/061,485 2020-08-05

Publications (1)

Publication Number Publication Date
WO2021252905A1 true WO2021252905A1 (fr) 2021-12-16

Family

ID=76797129

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/037025 WO2021252905A1 (fr) 2020-06-11 2021-06-11 Biomarqueurs pour la réponse à des inhibiteurs de l'exportine 1 chez des patients atteints d'un lymphome diffus à grandes cellules b

Country Status (1)

Country Link
WO (1) WO2021252905A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013019548A1 (fr) 2011-07-29 2013-02-07 Karyopharm Therapeutics, Inc. Modulateurs de transport nucléaire contenant de l'hydrazide et leurs utilisations
WO2017040311A1 (fr) 2015-08-28 2017-03-09 The Trustees Of Columbia University In The City Of New York Systèmes et méthodes de mise en correspondance de signatures oncologiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013019548A1 (fr) 2011-07-29 2013-02-07 Karyopharm Therapeutics, Inc. Modulateurs de transport nucléaire contenant de l'hydrazide et leurs utilisations
WO2017040311A1 (fr) 2015-08-28 2017-03-09 The Trustees Of Columbia University In The City Of New York Systèmes et méthodes de mise en correspondance de signatures oncologiques

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
AHSEN, M. E. ET AL.: "NeTFactor, a framework for identifying transcriptional regulators of gene expression-based biomarkers", SCI. REP., vol. 9, 2019, pages 12970
ANONYMOUS: "Karyopharm Presents XPOVIO (selinexor) and Eltanexor Data at theEuropean Hematology Association2020 Virtual Annual Meeting", INTERNET CITATION, 12 June 2020 (2020-06-12), XP002803803, Retrieved from the Internet <URL:https://www.globenewswire.com/news-release/2020/06/12/2047364/0/en/Karyopharm-Presents-XPOVIO-selinexor-and-Eltanexor-Data-at-the-European-Hematology-Association-2020-Virtual-Annual-Meeting.html> *
CAVALLO FEDERICA ET AL: "Effect of Prior Therapy on the Efficacy and Safety of Oral Selinexor in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis of the Sadal Study", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 134, 13 November 2019 (2019-11-13), pages 5333, XP086670153, ISSN: 0006-4971, DOI: 10.1182/BLOOD-2019-122900 *
CROCHIERE M ET AL.: "Deciphering mechanisms of drug sensitivity and resistance to Selective Inhibitor of Nuclear Export (SINE) compounds", BMC CANCER, vol. 5, 2015, pages 910
GARCIA-ALONSO, L. ET AL.: "Transcription factor activities enhance markers of drug sensitivity in cancer", CANCER RES., vol. 78, 2018, pages 769 - 780
HING Z A ET AL: "Next-generation XPO1 inhibitor shows improved efficacy andtolerability in hematological malignancies", LEUKEMIA, vol. 30, no. 12, 2016, pages 2364 - 2372, XP037323928, ISSN: 0887-6924, DOI: 10.1038/LEU.2016.136 *
KALAKONDA N ET AL., A PHASE 2B STUDY OF SELINEXOR IN PATIENTS WITH RELAPSE/REFRACTORY (R/R) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL), 15TH INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA, 2019
KEENAN, A. B. ET AL.: "ChEA3: transcription factor enrichment analysis by orthogonal omics integration", NUCLEIC ACIDS RES., vol. 47, 2019, pages W212 - W224
MAEREVOET MARIE ET AL: "Single Agent Oral Selinexor Demonstrates Deep and Durable Responses in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in Both GCB and Non-GCB Subtypes: The Phase 2b Sadal Study", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 132, 29 November 2018 (2018-11-29), pages 1677, XP086591513, ISSN: 0006-4971, DOI: 10.1182/BLOOD-2018-99-116868 *
PUENTE-SANTAMARIA, L.WASSERMAN, W. W.DEL PESO, L.: "TFEA.ChIP: a tool kit for transcription factor binding site enrichment analysis capitalizing on ChIP-seq datasets", BIOINFORMATICS, vol. 35, 2019, pages 5339 - 5340
ROMERO DIANA: "Responses to selinexor in multiple myeloma", NATURE REVIEWS CLINICAL ONCOLOGY, NATURE, NY, US, vol. 16, no. 11, 4 September 2019 (2019-09-04), pages 661, XP036911509, ISSN: 1759-4774, [retrieved on 20190904], DOI: 10.1038/S41571-019-0275-4 *
ROOPRA A., MAGICTRICKS: A TOOL FOR PREDICTING TRANSCRIPTION FACTORS AND COFACTORS THAT DRIVE GENE LISTS, Retrieved from the Internet <URL:https://doi.org/10.1101/492744>
WANG, Z. ET AL.: "BART: a transcription factor prediction tool with query gene sets or epigenomic profiles", BIOINFORMATICS, vol. 34, 2018, pages 2867 - 2869

Similar Documents

Publication Publication Date Title
Shimony et al. Acute myeloid leukemia: 2023 update on diagnosis, risk‐stratification, and management
Hallek Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment
US11473151B2 (en) Diagnostic and therapeutic methods for cancer
Giménez et al. Mutations in the RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
Morgan et al. Metastatic cells are preferentially vulnerable to lysosomal inhibition
Jabbour et al. Allogeneic stem cell transplantation as initial salvage for patients with acute myeloid leukemia refractory to high‐dose cytarabine‐based induction chemotherapy
US20190292602A1 (en) Therapeutic treatment of select diffuse large b cell lymphomas exhibiting distinct pathogenic mechanisms and outcomes
Kohrt et al. Second‐line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single‐center experience
Martini et al. Gut microbiota correlates with antitumor activity in patients with mCRC and NSCLC treated with cetuximab plus avelumab
US20170321281A1 (en) Methods and compositions for treatment of glioblastoma
US20160258026A1 (en) Cancer biomarkers and classifiers and uses thereof
Jain et al. Blastoid mantle cell lymphoma
KR20220145891A (ko) 핵산 분자를 보호하기 위한 시스템 및 방법
US20200080157A1 (en) Prognosis and treatment of relapsing leukemia
Pieters Infant acute lymphoblastic leukemia: Lessons learned and future directions
Keener Host with the most: Targeting host cells instead of pathogens to fight infectious disease
Aldoss et al. Have any strategies in Ph-like ALL been shown to be effective?
WO2021252905A1 (fr) Biomarqueurs pour la réponse à des inhibiteurs de l&#39;exportine 1 chez des patients atteints d&#39;un lymphome diffus à grandes cellules b
WO2021252900A1 (fr) Biomarqueurs pour la réponse à des inhibiteurs de l&#39;exportine 1 chez des patients atteints d&#39;un myélome multiple
US20220178927A1 (en) Biomarkers for selinexor
Chen et al. Inhibition of NOS1 promotes the interferon response of melanoma cells
Jun et al. Phase II Clinical and Translational Study of Everolimus±Paclitaxel as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Carcinoma
US10066269B2 (en) Methods for detecting and treating multiple myeloma
Zhang et al. RUNX1/CD44 axis regulates the proliferation, migration, and immunotherapy of gliomas: A single-cell sequencing analysis
US20240117440A1 (en) Panels and methods for treatment of diffuse large b-cell lymphoma

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21737894

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21737894

Country of ref document: EP

Kind code of ref document: A1