JP2019511544A - Pharmaceutical use of resminostat in Asian patients - Google Patents

Abstract

The present invention relates to the HDAC inhibitor resminostat ((E) -3- [1- (4-dimethylaminomethyl-benzenesulfonyl) -1H-pyrrole- in the treatment of benign or malignant neoplasms in human subjects. The pharmaceutical use of 3-yl] -N-hydroxy-acrylamide) or a salt or solvate thereof, wherein said human subject is Asian and said treatment is a daily dose of less than 600 mg of resminostat The present invention relates to a pharmaceutical application comprising administering resminostat or a salt or solvate thereof to a human subject, and administering at least one additional chemotherapeutic agent to said human subject.

Description

  The present invention relates to the HDAC inhibitor resminostat ((E) -3- [1- (4-dimethylaminomethyl-benzenesulfonyl) -1H-pyrrole- in the treatment of benign or malignant neoplasms in human subjects. The pharmaceutical use of 3-yl] -N-hydroxy-acrylamide) or a salt or solvate thereof, wherein said human subject is an Asian and said treatment is a daily dose of less than 600 mg to said human subject The present invention relates to pharmaceutical uses, including administering resminostat or a salt or solvate thereof, and administering at least one additional chemotherapeutic agent to said human subject.

  Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from specific histone sites, particularly in promoter and enhancer regions, which are an integral part of the regulation of cellular gene transcription. HDAC also indirectly regulates gene expression by mediating acetylation of non-histone proteins such as DNA binding proteins, transcription factors, signal transducers, DNA repair and chaperone proteins (Ververis K et al., Biologics: Targets and Therapy 7: 47-60, 2013; Vitt D et al., Targeting Histone acetylation. In: RSC Drug Discovery Series No. 48: Epigenetics for Drug Discovery. Editor: Nessa Carey. The Royal Society of Chemistry, 2016).

  Resminostat ((E) -3- [1- (4-dimethylaminomethyl-benzenesulfonyl) -1H-pyrrol-3-yl] -N-hydroxy-acrylamide) is an orally available HDAC inhibitor It is a histone-deacetylase (HDAC) inhibitor.

  The Phase IIa SHELTER trial (searchable at https://clinicaltrials.gov for more information on clinical trials) reveals progression of radiological disease as monotherapy or under first-line sorafenib therapy Resminostat was evaluated as combined with sorafenib as a second line treatment for post-procedural HCC. This study met the primary endpoint in both monotherapy and combination therapy. Patients who received resminostat / sorafenib combination therapy show a progression-free survival (PFSR) of 70.0% at 12 weeks and a median PFS of 5.4 months with a median overall survival (OS) of 8 It became one month.

  In a phase II SAPHIRE trial of patients with advanced Hodgkin's lymphoma (HL), resminostat in monotherapy has demonstrated substantial antitumor activity, with 34 very good safety and tolerability. % Overall response rate, and clinical benefit in 54% of the highly pretreated patient population.

  In addition, resminostat was tested in a phase I dose escalation approach in patients with advanced colorectal cancer (CRC) to evaluate resminostat in combination with a standard chemotherapeutic FOLFIRI regimen.

  Recently, two phase I / II studies investigating resminostat in indications for liver cancer (HCC) and non-small cell lung cancer (NSCLC) have been completed. These studies examined resminostat in combination therapy with the traditional anticancer agents sorafenib (in HCC) and docetaxel (in NSCLC) in Asian patients in comparison to monotherapy with the respective anticancer agent. Also, Phase I clinical trials are being performed in biliary and pancreatic cancer in Asian patients.

  Sorafenib (4- [4-[[4-chloro-3- (trifluoromethyl) phenyl] carbamoylamino] phenoxy] -N-methyl-pyridine-2-carboxamide; trade name Nexavar®), https: / / En. wikipedia. org / wiki / Sorafenib is an orally available protein kinase inhibitor from the group of multikinase inhibitors. It has been evaluated in a number of clinical studies and has been approved for the treatment of advanced renal cell carcinoma, advanced hepatocellular carcinoma, and radioiodine treatment-resistant advanced thyroid carcinoma.

  It has been described that HDAC inhibitors cause growth arrest due to differentiation or apoptosis of secondary tumor cells, but normal cells are not affected. Marks et al. As summarized in the review article of (Nature Reviews Cancer, 2001, Volume 1, page 194-202), HDAC inhibitors cause cell cycle arrest in G1 and / or G2 phases. Growth inhibitory effects have been demonstrated in vitro in virtually all transformed cell types, including cell lines arising from both hematologic and epithelial tumors. The growth inhibitory cellular mechanism of HDAC inhibitors has been described as specific induction of the expression of the cell cycle inhibitor CDKN1A (p21). In addition, this review article summarizes the induction of growth arrest by HDAC inhibitors in tumor-bearing mice. The efficacy of HDAC inhibitors has been demonstrated in animal models of various cancer types such as breast cancer, prostate cancer, lung cancer and gastric cancer, neuroblastoma and leukemia.

  The treatment of many cancer types with HDAC inhibitors is described in the available literature. HDAC inhibition plays a central role in tumor-related processes such as HER2 / neu, VEGF, raf-1, cyclins A and B, Bax, Bad, p53, c-myc, caspase 3, p21 and ERα Affects expression. Villar-Garea et al. According to a review of (Int. J. Cancer: 112, 171-178 (2004)), cancer is considered to be both a genetic disease and epigenetic as well as a major goal of using HDAC inhibitors May be restoration of gene expression of a tumor suppressor gene transcriptionally repressed by promoter-related histone deacetylation. Drummond et al. (Annu. Rev. Pharmacol. Toxicol. 2005. 45: 495-528) reviews the molecular mechanisms and consequences of histone and non-histone substrates in cancer cells, which are the effectors of HDAC, which also Promotes acetylation of some important proteins other than histones. According to the above review, acetylation is a major post-translational modification of many proteins involved in the regulation of key intracellular pathways, and many of these substrates are tissue / development specific (EKLF, GATA-1, ERα MyoD), oncogenic (c-Myb), tumor suppressor (p53), and to some extent ubiquitous (TFIIE, TFIIF, TCF, HNF-4). Modulation of these proteins can lead to induction of cell cycle arrest, differentiation and apoptosis, all of which are desirable mechanisms for the treatment of cancer. Kelly et al. (Expert Opin Invest Drugs, 11 (12), 2002) provides a further review of HDAC inhibitors in general and their application in cancer treatment.

  Official website of the US NIH http: // clinicaltrials. gov has 545 clinical trials per cancer indication treated with HDAC inhibitors, among them various forms of leukemia (eg CML, CLL, AML), lymphomas including myelodysplastic syndrome, non-Hodgkin's lymphoma, multiple Sex myeloma, plasma cell neoplasm, generally solid tumor, small intestine cancer, mesothelioma, prostate, breast (male and female), lung cancer (including non-small cells and small cells), neuroendocrine, malignant epithelial neoplasia, pancreas Skin cancer (including melanoma), multiple myeloma, cervix, renal cells, head and neck, stomach, ovary, liver cancer, colon, rectum, thymoma, fallopian tube, peritoneum, nasopharynx, vestibular schwannoma , Meningioma, acoustic neuroma, neurofibromatosis type 2, thyroid, urothelial, glioma, brain, esophagus, astrocytoma, anaplastic oligodendroglioma, giant cell glioblastoma, glioblastoma Tumors, gliosarcomas, mixed gliomas, brain tumors, and ovaries And that (status: February 2016).

  WO 2005/087724 A2 describes certain N-sulfonylpyrrole derivatives and describes their use in the pharmaceutical industry for the preparation of pharmaceutical compositions.

  WO 2007/39404 A1 describes novel N-sulfonylpyrrole derivatives and certain salts of these N-sulfonylpyrrole derivatives and to be used for the preparation of pharmaceutical compositions in the pharmaceutical industry Have been described.

  WO 2009/112529 A1 describes a specific process for the preparation of N-sulfonylpyrrole derivatives and salts thereof and describes that they are used for the preparation of pharmaceutical compositions in the pharmaceutical industry.

A comparison of AUC 0-6h of a Phase I study in western and Asian 800 mg cohorts, or a Phase I portion of these studies is shown (see the Example section).

  Here, unexpectedly, Asian patients under resminostat treatment were found to benefit, for example, from Western / White patients at doses different from those previously administered.

  Thus, the present invention relates to the HDAC inhibitor resminostat ((E) -3- [1- (4-dimethylaminomethyl-benzenesulfonyl) -1H- in the treatment of benign or malignant neoplasms in human subjects. The pharmaceutical use of pyrrol-3-yl] -N-hydroxy-acrylamide) or a salt or solvate thereof, wherein said human subject is an Asian, and said treatment is a daily dose of less than 600 mg of said human. The present invention relates to pharmaceutical uses, including administering to a subject resminostat or a salt or solvate thereof, and administering to said human subject at least one additional chemotherapeutic agent.

Specific embodiments of the present invention are listed in the following section.
1. Use of resminostat or a salt or solvate thereof for the manufacture of a medicament for use in the treatment of benign or malignant neoplasms in a human subject, wherein said human subject is Asian and said treatment is Administering resminostat or a salt or solvate thereof to said human subject at a daily dose of less than 600 mg of resminostat, and administering at least one additional chemotherapeutic agent to said human subject ,use.
2. Use of resminostat or a salt or solvate thereof for the treatment of benign or malignant neoplasms in a human subject, wherein said human subject is Asian and said treatment is less than 600 mg of resminostat 1 Use in a daily dose, comprising administering to said human subject resminostat or a salt or solvate thereof and administering to said human subject at least one further chemotherapeutic agent.
3. Resminostat or a salt or solvate thereof for use in the treatment of benign or malignant neoplasms in a human subject, wherein said human subject is Asian and said treatment is less than 600 mg of resminostat per day Administration of resminostat or a salt or solvate thereof to said human subject, and administering at least one additional chemotherapeutic agent to said human subject, in a dose, resminostat or a salt or solvent thereof Hydrate.
4. A method of treating benign or malignant neoplasms in a human subject in need of treatment wherein said human subject is Asian and said method comprises administering a daily dose of less than 600 mg of resminostat to said human subject Administering a stat or a salt or solvate thereof, and administering to said human subject a therapeutically effective amount of at least one additional chemotherapeutic agent.
5. 6. The use, resminostat or salt or solvate thereof, or method for use according to any of the preceding claims, wherein the further chemotherapeutic agent is a molecular targeting agent.
6. 6. Use, resminostat or salt or solvate thereof, or method for use according to any of items 1 to 5, wherein said further chemotherapeutic agent is a VEGFR inhibitor.
7. 7. Resminostat or a salt or solvate thereof, use, or method for use according to any of paragraphs 1 to 6, wherein said further chemotherapeutic agent is sorafenib.
8. 8. Resminostat or a salt or solvate thereof, for use, or method for use according to any of items 1 to 7, wherein sorafenib is administered to said human subject at a daily dose of about 800 mg.
9. A biweekly dosing regimen in which the treatment is followed by resminostat or a salt or solvate thereof and sorafenib:
9. A method according to claim 8, comprising administering a daily dose of about 400 mg of resminostat for 5 days, followed by rest for 9 days, and b: administering a daily dose of about 800 mg of sorafenib. Resminostat or a salt or solvate thereof, use, or method for the use of
10. 10. Resminostat or a salt or solvate thereof, use or method for use according to claim 9, characterized by reduced toxicity of resminostat and / or sorafenib and maintenance of anti-tumor activity.
11. 11. Resminostat or a salt or solvate thereof, for use, or method for use according to any of items 1 to 10, wherein said human subject is a member of Southeast Asia or Northeast Asia gene group.
12. The subject according to any of items 1 to 10, wherein said human subject is a member of samoed, Mongolia, Tibet, Korea, Japan, Ainu, South Chinese, Monk Mer, Thailand, Indonesia, Philippines, or Malaysian gene group Resminostat or a salt or solvate thereof, use, or method for the described use.
13. 11. Resminostat or a salt or solvate thereof, for use, or method for use according to any of items 1 to 10, wherein said human subject is a member of the Northeast Asia gene group.
14. Use of resminostat or a salt or solvate thereof, for use according to any of items 1 to 10, wherein said human subject is a member of samoede, Mongolia, Tibet, Korea, Japan, or the Ainu gene group. Or how.
15. 11. Resminostat or a salt or solvate thereof, for use, or method for use according to any of items 1 to 10, wherein said human subject is a member of the Korean or Japanese gene group.
16. 18. Resminostat or a salt or solvate thereof, for use, or method for use according to any of items 1 to 15, wherein said salt of resminostat is resminostat mesylate.
17. 17. Resminostat or salt or solvate thereof, use or method for use according to any of items 1 to 16, wherein the benign or malignant neoplasm is a cancer, in particular a hepatocellular carcinoma.

  In the present invention, the daily dose of resminostat is less than 600 mg, especially less than 550 mg, more particularly less than 500 mg, even more particularly less than 500 mg, still more particularly less than 450 mg, still more particularly Is 400 mg or less, even more particularly 350 mg or less, even more particularly 300 mg or less, even more particularly 250 mg or less, even more particularly 200 mg or less.

Resminostat (International Common Name or INN) and (E) -3- [1- (4-Dimethylaminomethyl-benzenesulfonyl) -1H-pyrrol-3-yl]-as used herein N-hydroxy-acrylamide (its chemical name) is used interchangeably and refers both to compounds of the formula:

  In a particular embodiment of the invention said additional chemotherapeutic agent is a kinase inhibitor, in particular a class 3 kinase inhibitor, a RAF inhibitor, a VEGFR inhibitor, in particular a VEGFR from the group of multikinase inhibitors or tyrosine kinase inhibitors It is an inhibitor, even more particularly a VEGFR inhibitor selected from the group consisting of sunitinib, sorafenib, rhamsylumab and batalanib, and even more particularly sorafenib.

  As used herein, a molecular targeting agent is a chemotherapeutic agent that acts through specific interactions with one or more molecular targets in a patient, ie proteins. This is in contrast to agents that act through nonspecific interactions, such as, for example, common cytotoxic agents that act through DNA intercalation or DNA modification (such as alkylation or DNA crosslinking).

As used herein, sorafenib (International Common Name) and 4- [4-[[4-chloro-3- (trifluoromethyl) phenyl] carbamoylamino] phenoxy] -N-methyl-pyridine-2- Carboxamide (its chemical name) is used interchangeably and both refer to compounds of the formula Sorafenib is also known under the trade name Nexavar®.

  Salts suitable for resminostats are acid addition salts or salts with bases. It may in particular be mentioned that pharmaceutically acceptable inorganic and organic acids and bases are customarily used in pharmacy. On the one hand, addition salts of water-insoluble, in particular water-soluble acids, which are used for salt preparation in equimolar proportions, or which differ from this, in particular in terms of equimolar proportions, are suitable. On the other hand, depending on the substitution, salts with bases are also suitable, the bases being used for salt preparation in equimolar proportions or different therefrom. For example, non-pharmaceutically acceptable salts which can be obtained as process products during the preparation of resminostat on an industrial scale are converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. According to the invention, resminostat and its salts may contain different amounts of solvent, for example when isolated in crystalline form. Thus, included within the scope of the present invention are all solvates of resminostat, in particular all hydrates, and all solvates of resminostat, in particular all hydrates, in particular Such solvates or hydrates comprising about 0.5, 1 or 2 solvent or water molecules per molecule of minostat or salt thereof.

  Particular salts in the context of the present invention are salts of resminostat and methanesulphonic acid, in particular in a molar ratio of about 1: 1.

  Lesminostat and its salts are prepared as described in detail, for example, in WO 2005/087724 A2, WO 2007/39404 A1 and WO 2009/112529 A1, respectively. can do.

  Sorafenib is commercially available and its method of preparation is well known.

  The "Asia" "Southeast Asia, Northeast Asia, Samoeed, Mongolia, Tibet, Korea, Japan, Ainu, South China, Monkmer, Thailand, Indonesia, Philippines, Malaysia" gene cluster referred to in this specification is Cavalli-Sforza, Menozzi and Piazza, "The History and Geography of Human Genes", 1994, is to be understood as being classified in Princeton University Press (ISBN: 9780691087504).

  The term "Asian" is particularly referred to herein as a person of indigenous origin or having an ancestor, eg, at least one parent, in particular, eg, China, Mongolia, Taiwan, Singapore, Korea, Japan , Vietnam, Cambodia, Laos, Burma, Thailand, Malaysia, Indonesia, and the Philippines, but more specifically, it is defined as having aboriginal origin in the Far East or Southeast Asia excluding the Indian subcontinent.

  In the present invention, the subject is also defined herein as Asian or by assignment by a physician based on self-identification (e.g. by questionnaire) or his / her physical traits and / or country of origin or country of origin. It can be identified as any of the specific groups included in the Asian definition.

  Asian offspring can also be determined by microsatellite markers as described in the known literature.

  The biological and pharmaceutical properties of resminostat and its respective salts and sorafenib are described in detail in the prior art including the references cited herein.

  Cancer, also known as a malignant neoplasm, as used herein, is a medical condition characterized by tumor cells that metastasize to different organs or tissues. Examples of malignant neoplasms treated in embodiments of the present invention include solid and hematological tumors. Solid tumors include breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (eg thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney (kidney), liver, lung It is exemplified by tumors of the pharynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, kidney (renal), small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasms include inherited cancers exemplified by retinoblastoma and Wilms tumor. Furthermore, malignant neoplasms include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastasis"). Hematologic malignancies are high-grade and low-grade forms of leukemia and lymphoma, ie non-Hodgkin's disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkin's disease, It is exemplified by multiple myeloma and T cell lymphoma. Also included are myelodysplastic syndromes, plasma cell neoplasms, paraneoplastic syndromes, cancers of unknown primary site, and AIDS related malignancies.

  Particular types of cancer in the context of the present invention are hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), pancreatic cancer, biliary cancer and cutaneous T-cell lymphoma (CTCL), more particularly HCC, CTCL and NSCLC.

  In general, malignant tumors differ from benign tumors in four biological properties: structure, growth rate, invasive growth, and disseminated growth due to metastasis. Common to both benign and malignant tumors is the abnormal growth of cells. HDAC inhibitors can be used to treat benign neoplasms because they can inhibit growth or induce cell cycle arrest through modulation of cell cycle dependent genes and proteins, which has been demonstrated for malignant tumors. it is obvious.

  Particular forms of benign neoplasms in the context of the present invention are colon polyps, adenomas, papillomas, cystadenomas, hepatocellular adenomas, alveolar molars, tubular adenomas, squamous cell papillomas, gastric polyps, hemangiomas, osteomas , Chondroma, lipoma, fibroma, lymphangioma, leiomyoma, rhabdomyosarcoma, astrocytoma, nevi, meningioma, ganglionoma, and endometriosis. For information on endometriosis and HDAC, see Reprod Sci. 2012 May; 19 (5): 483-92.

  Drug resistance is particularly important as a frequent failure of standard cancer treatments. This drug resistance is caused by various cellular and molecular mechanisms such as fusion proteins formed by overexpression of drug efflux pumps, mutations in cellular target proteins or chromosomal translocations. The industrial applicability of resminostat is not limited to the patient's first line treatment. Patients with resistance to cancer chemotherapeutic agents or target specific anti-cancer agents may also be amenable to treatment with resminostat, eg, for a second or third choice treatment cycle. A striking example is given by patients with acute promyelocytic leukemia who have a PML-RARα fusion protein that is resistant to standard treatment with retinoid. These patients can be resensitized to retinoids by treatment with HDAC inhibitors such as resminostat.

  In the present invention, resminostat and at least one additional chemotherapeutic agent may be administered simultaneously, sequentially or separately.

  In the further context of the present invention, the term "active agent" refers to a compound that exerts a medical effect (e.g. its amelioration) on a disease or condition, said term including, in particular, resminostat and sorafenib.

  In embodiments of the present invention, the active agent may be provided in a pharmaceutical composition comprising one or more of the above-mentioned active agents and a pharmaceutically acceptable carrier or diluent. In particular, resminostat and sorafenib can be provided in the same pharmaceutical composition (also known as certain combinations) or in separate pharmaceutical compositions (eg, two separate tablets).

  Such pharmaceutical compositions may be provided in the context of a pharmaceutical, and include, for example, one or more pharmaceutical compositions and packaging materials. The packaging material typically comprises a label or package insert indicating that the active agent (s) is useful for the treatment of the diseases detailed herein. Otherwise, the packaging material, the label and the package insert are similar or similar to what is generally regarded as a standard packaging material, a label and the package insert for medicines having the associated utility.

  The pharmaceutical compositions according to the invention are prepared by methods which are known per se and which are familiar to the person skilled in the art. As a pharmaceutical composition, the active agent as such or preferably in combination with suitable pharmaceutical auxiliaries and / or excipients, for example tablets, coated tablets, capsules, caplets, suppositories, patches (eg as TTS) ), In the form of an emulsion, suspension, gel or solution, the content of active agent is preferably 0.1 to 95%, by appropriate choice of auxiliaries and / or excipients Pharmaceutical dosage forms (eg, delayed release or enteric forms) may be achieved that are just suitable for the desired onset of action.

  The person skilled in the art is familiar from his expert knowledge with auxiliaries, solvents, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulation, preparation or composition. In addition to solvents, gel formers, ointment bases and other excipients, for example, antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or penetration enhancers are used obtain.

  Depending on the specific type of benign or malignant neoplasm to be treated, an additional therapeutically active agent, usually administered to treat the benign or malignant neoplasm, optionally co-administered with resminostat and sorafenib You may

  An example of such an additional therapeutically active agent is the known chemotherapeutic anticancer agent used for cancer treatment, including but not limited to (i) cyclophosphamide (Endoxan®) Alkylated / carbamylating agents such as, ifosfamide (Holoxan®), thiotepa (Thiotehpa Lederle®), melphalan (Alkeran®), or chloroethyl nitrosourea (BCNU); (ii) Cisplatin (Platinex® BMS), platinum derivatives such as oxaliplatin or carboplatin (Cabroplat® BMS); (iii) antimitotic / tubulin inhibition such as vinca alkaloids (vincristine, vinblastine, vinorelbine) , Taxanes such as Taxol (Paclitaxel (R)), Taxotere (Docetaxel (R)) and analogues, and novel formulations and binders thereof; (iv) Anthracyclines (e.g. Doxorubicin / Adriblastin (R) ), Topoisomerase inhibitors such as epipodophyllotoxine (e.g. Etoposide / Etopophos (R)) and camptothecin analogues (e.g. Topotecan / Hycamtin (R)); (v) 5-fluorouracil (5-FU) Pyrimididis such as capecitabine (Xeloda (R)), arabinosyl cytosine / cytarabine (Alexan (R)) or gemcitabine (Gemzar (R)) Antagonists; (vi) 6-mercaptopurines (Puri-Nethol®), purine antagonists such as 6-thioguanine or fludarabine (Fludara®), and finally (vii) methotrexate (Farmitrexat®) Etc. including folate antagonists.

  Examples of target-specific anti-cancer drug classes used in experimental or standard cancer therapy include, but are not limited to: (i) Glivec (Imatinib®), ZD-1839 / Iressa (Gefitinib) Kinase inhibitors such as (registered trademark), SU11248 (Sutent (R)) or OSI-774 / Tarceva (Erlotinib (R)); (ii) Proteasome inhibition such as PS-341 (Velcade (R)) (Iii) Heat shock protein 90 inhibitor such as 17-allylaminogeldanamycin (17-AAG); (iv) VEGF antibody Avastin (Bevacizumab®) or KDR tyrosine kinase inhibitor PTK787 / ZK2225 Vascular targeting agents (VTA) such as 4 (Vatalanib®) and anti-angiogenic agents; (v) monoclonal antibodies such as Herceptin (Trastuzumab®) or Mab Thera / Rituxan (Rituximab®), mutations And conjugates of monoclonal antibodies and antibody fragments; (vi) oligonucleotide-based therapeutic agents such as G-3139 / Genasense (Oblimersen (R)); (vii) protease inhibitors (viii) anti-estrogens (e.g. tamoxifen) Hormone therapeutic agents such as anti-androgens (eg flutamide or casodex), LHRH analogues (eg leuprolide, goserelin or triptorelin) and aromatase inhibitors No.

  Other known anticancer agents that can be used in combination therapy include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as the 2-deoxycytidine derivative decitabine (Docagen®) , Cytokines such as alanosine, interleukin-2, interferons such as interferon α2 or interferon-γ, TRAIL, DR4 / 5 agonist antibodies, FasL and TNF-R agonists, and finally, SAHA, PXD101, MS275, MGCD0103, depsipeptides / Histone deacetylase inhibitors different from the sulfonylpyrrole derivatives according to the invention such as FK228, NVP-LBH 589, valproic acid (VPA) and butyrate are included Be

  Exemplary anti-cancer agents for use in combination with a compound of the invention in the combination therapy described herein may include, but are not limited to: 5FU, Actinomycin D, Abarelix, Abciximab, aclarubicin, adapalene, alemtuzumab, altretamine, aminoglutethimide, aminoglutethimide, amiprilose, amrubicin, anastrozole, ancitabine, artemisinin, azathioprine, basiliximab, bendamustine, bleomycin, broxuridine, busulfan, capecitabine, carpaplatin , Cetrorelix, chlorambucil, chlormethine, cisplatin, cladribine, clomiphene, cyclophosphamide, dacarbazine, daclizumab, Cutinomycin, daunorubicin, desrorelin, dexrazoxane, docetaxel, doxifluridine, doxorubicin, droloxifin, drostanophone, drostanolone, edelfosine, eflothin, emiteful, epirubicin, epithiostanol, eptaplatin, erbitux, estramustine, etoposide, etoposide, etoposide, Floxuridine, Flucytosine, Fludarabine, Fluorouracil, Flutamide, Formestane, Foscarnet, Fosfestrol, Fotemustine, Fulvestrant, Gefitinib, Gemcitabine, Gleevec, Goserelin, Gusperims, Herceptin, Idarubicin, Idoxuridine, Ifosfamide, Imatinib, Implosulfan, Inflixi B, irinotecan, lanreotide, letrozole, leuprorelin, lovaplatin, lombastine, melphalan, mercaptopurine, methotrexate, methotrexate, mivoplatin, mifepristone, miltefosine, mirimostimum, mitoguazone, mitocutol, mitomycin, mitoxantrone, mizoribine, mitoxivatin , Nartograstim, nebaplatinum, nedaplatin, nilutamide, nimustine, octreotide, olmeloxifene, oxaliplatin, paclitaxel, palivizumab, pegiasparagase, pegylgrastim, pentetheotide, pentostatin, perphosphamide, piposulfan, pirarubicin, plicamycin, predinimustine , Procarbazine, propagermanium, prospidial chloride , Ralchitrexed, ranimustine, lanpirnase, rasburicase, lazoxican, rituximab, rifampicin, lyotrophane, romultide, ruboxistaurin, salgamostim, satraplatin, sirolimus, sobozoxan, spiropustin, tamoxifen, tamoxifen, tamisotrope motecho motechoportiove , Teniposide, test lactone, thiotepa, timarfacine, thiamiprin, topotecan, toremifene, trastuzumab, treosulfan, triazicon, trimetrexate, tripretrinate, triphosphamide, urodepa, vallebicine, verteporfin, vincristine, vincricin, vindesin, vorolozole Be

  Other known anticancer agents that can be used for combination therapy include immune checkpoint inhibitors or short checkpoint inhibitors, ie, inhibiting inhibitory checkpoint molecules such as inhibitory checkpoint molecules Drugs, Adenosine A2A Receptor (A2AR), B7-H3 (also called CD276), B7-H4 (also called VTCN1), B and T Lymphocyte Attenuator (BTLA, also called CD272), cytotoxic Abbreviation of T lymphocyte related protein 4 (also called CTLA-4, CD152), indoleamine 2,3-dioxygenase (IDO), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation Gene-3 (LAG3), Programmed death 1 receptor (PD-1), Programed death 1 receptor ligand (PD-L1), T cell immunoglobulin domain and mucin domain 3 (TIM-3), T cell activation And agents commonly known as V domain Ig suppressors (VISTA, also referred to as C10 or f54). Examples of such checkpoint inhibitors include MGA 271 (MacroGenics), ipilimumab (Yervoy®), tremelimumab (previously CP-675, 206), lirilumab, BMS-986016 (BMS), BMS-936559 / MDX-1105 (manufactured by BMS), penbrolizumab (Keytruda (registered trademark)), nivolumab (Opdivo (registered trademark)), galiximab, IMP 321 (manufactured by Immuntep), BMS-663513 (manufactured by BMS), PF -05082566 (manufactured by Pfizer), IPH 2101 (manufactured by Innate Pharma / BMS), KW-0761 (manufactured by Kyowa Kirin), CDX-1127 (manufactured by CellDex Therapeutics), M DI-6469 (made by MedImmune / AstraZeneca), MEDI 4736 (made by AstraZeneca), CP-870, 893 (made by Genentech), Pidilizumab, MPDL 3280A (made by Genentech), AMP-514 (made by MedImmune / AZ), MEDI 4736 (MedImmune / AZ), AUNP12 peptide (Aurigene and Pierre Fabre), MSB 0010718C (Merck Serono).

  In the practice of the present invention, the active agents according to the present invention may be separately, sequentially, simultaneously or temporally offset (e.g. as combined unit dosage forms), depending on the details, characteristics or purpose of use mentioned above. They may be administered as separate unit dosage forms or adjacent separate unit dosage forms, as a fixed or indeterminate combination, as a kit, or as a mixture).

  A "constant combination" is defined as a combination wherein the first active ingredient (eg, resminostat) and at least one additional active ingredient (eg, sorafenib) are present together as one unit dose or as a single entity. Be done. An example of a "certain combination" is a pharmaceutical composition, wherein said first active ingredient and said further active ingredient are present as a mixture for simultaneous administration, such as a single preparation. Another example of a "constant combination" is a pharmaceutical combination wherein the said first active ingredient and the said further active ingredient are present in one unit without being mixed.

  A "kit" is defined as a combination wherein the first active ingredient and the further active ingredient are present in two or more units. An example of a "kit" is a combination wherein the first active ingredient and the further active ingredient are present separately. The components of the kit may be administered separately, sequentially, simultaneously or staggered in time.

  The first and further active ingredients of the combination or kit according to the invention are provided as separate formulations (ie independently of each other), which are then simultaneously, sequentially, separately or temporally in the combination therapy Presented together as a separate component of a combination pack for simultaneous, sequential, separate or staggered use in combination therapy, or may be presented together for staggered use It may be done.

  The types of pharmaceutical formulations of the first and further active ingredients of the combination or kit according to the invention may be similar, ie both components may be formulated in separate tablets or capsules or they may be different That is, for example, one active ingredient may be formulated as a tablet or capsule and the other active ingredient may be suitable for different administration forms, for example, formulated for intravenous administration.

  A further aspect of the present invention is that in amorphous form, resminostat or a salt thereof, in particular resminostat mesylate (i.e. methanesulfonate), and one or more standard therapeutic agents known in the art, in particular the said Chemotherapeutic agents known in the art or target specific anti-cancer agents (such as those mentioned above), in particular sorafenib, for sequential, separate, simultaneous or staggered use in treatment in any order Including, is a combination. Optionally, the combination comprises instructions for its use in therapy.

  A further aspect of the present invention is, for example, a kit comprising a preparation of Reminostat or a salt thereof and a pharmaceutically acceptable carrier or diluent; a formulation of a further active ingredient, especially sorafenib, and a pharmaceutically acceptable carrier or dilution. And optionally, combination preparations such as instructions for simultaneous, sequential, separate or staggered use in therapy.

  A further aspect of the invention is a kit comprising a unit dose of resminostat or a salt thereof, a unit dose of a further active ingredient, in particular sorafenib, and optionally instructions for simultaneous, sequential or separate use in therapy. is there.

  A further aspect of the invention is resminostat, or one or more pharmaceutical compositions comprising said compound; and one or more art-known therapeutic agents, in particular sorafenib, or simultaneously, sequentially or separately in treatment And one or more pharmaceutical compositions containing the therapeutic agent. Optionally, the medicament comprises instructions for use in said treatment.

  A further aspect of the invention is resminostat or a salt thereof, a standard therapeutic agent known in the art, a further active ingredient, in particular sorafenib, and optionally a pharmaceutically acceptable carrier, diluent Alternatively, it is a pharmaceutical composition as a unit dosage form containing an excipient in a mixture.

  A further aspect of the invention is a commercial package comprising resminostat or a salt thereof together with instructions for use simultaneously, sequentially or separately with one or more standard therapeutic agents known in the art, especially sorafenib. It is.

  Furthermore, the combination according to the invention can be used for the pre- or post-surgical treatment of benign or malignant neoplasms.

  Furthermore, the combination according to the invention can be used concomitantly in sensitization of the patient to radiation therapy, in particular standard radiation therapy.

  Administration of the combination according to the invention and the pharmaceutical composition according to the invention may be performed by any of the generally accepted modes of administration available in the art. Examples of suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous delivery is preferred.

  In an embodiment of the present invention, dose refers to the amount of compound in the free form of said compound, ie the free acid or free base form of said compound. As a result, such free acid or adducts in free base form, salts and the like should be administered at a correspondingly higher dose, taking into account the weight of the counterion or adduct partner. For example, with respect to resminostat mesylate, the "dose of 400 mg of resminostat" relates to 510 mg (rounded) of resminostat mesylate containing 400 mg of resminostat free base and 110 mg of methanesulfonic acid Molecular weight of = 349.4; molecular weight of resminostat mesylate = 445.5; thus, 400 ÷ 349.4 x 445.5 = 510).

  Although the present invention has been described in detail, the scope of the present invention is not limited only to the described features or embodiments. As is apparent to those skilled in the art, modifications, analogies, variations, derivations, approvals and adaptations to the described invention are based on the knowledge known in the art and / or in particular the present disclosure (eg explicit, (Implicit or implicit disclosure) and can be made without departing from the spirit and scope of the present invention as defined by the appended claims.

  In the present invention, administration of the active agent may be according to a specific schedule which may include a period of daily administration of the active agent and a period of time when the active agent is not administered. For example, such a schedule may consist of 5 days of active agent (or resminostat) administration, followed by 9 days without active agent ("drug holiday") (14 day cycle), 5 days of active agent (or Resminostat) administration followed by a 16-day washout period (21-day cycle) or repeated 14-day active agent (or resminostat) administration followed by a 7-day washout period (21-day cycle) It may consist of cycles.

  The following examples are intended to further illustrate the invention without restricting it.

Clinical trial:
Human first dose study (FIM; 7341 / EM-001): This was an open label, dose escalation, phase I trial of orally administered resminostat in patients with advanced malignancy. The test was conducted in the United Kingdom. Patients with standard tumors or those with histologically or cytologically proven primary or metastatic solid tumors who were resistant to or without standard therapies were included. Tumors were progressive (new or progressive lesions or rising PSA). In addition, patients had to have good performance status (ECOG 0-1) and adequate liver, kidney, heart and bone marrow function, and an estimated average life expectancy of more than 12 weeks. Treatment with resminostat consisted of oral administration once daily on days 1 to 5 and a washout of 9 days thereafter during the 14 day treatment cycle. Serial cohorts of patients were treated with increasing doses of resminostat, which included 800 patients at 7 patients.

  SAPHIRE (4SC-201-2-2009): This was an open label phase II trial of orally administered resminostat in patients with advanced Hodgkin's lymphoma (HL). The primary objective of the study was to determine the objective response rate (ORR) of repeated oral administration of resminostat. The second objective was to evaluate the safety and tolerability, efficacy, pharmacokinetics and pharmacodynamics of treatment with resminostat. Endpoints included OS, PFS, TTP, and duration of response (DOR). The study was conducted at five centers in the Czech Republic, Poland and Romania. The study included patients with relapsed or refractory HL, as demonstrated histologically or cytologically, based on the International Working Group (IWG) response criteria. Patients had to have good performance status (ECOG 0-1) and proper liver, kidney, heart and bone marrow function. In the main part of the study, patients were treated once daily with 600 mg or 800 mg of resminostat on days 1 to 5 during a 14 day treatment cycle and then rested for 9 days. Patients were treated for at least 12 weeks (6 treatment cycles) or until tumor progression. After 12 weeks, patients without progressive disease had the option to continue treatment with resminostat for up to 1 year in the follow-up portion of the study.

  SHORE (4SC-201-3-2010): This was an open-label phase I / II trial of orally administered resminostat in patients with advanced colorectal cancer (CRC). Lesminostat was administered in combination with the standard FOLFIRI regimen. The Phase I dose escalation portion of the study was conducted at two centers in Germany. The study included patients with histologically or cytologically confirmed advanced CRC. Patients had to be treated previously for advanced CRC and had to have foreseen chemotherapy with FOLFIRI in second or third line treatment. The primary eligibility criteria included ECOG 0-1 performance status, adequate liver, kidney, heart and bone marrow function and life expectancy of 12 weeks or more. Treatment with resminostat consists of oral administration of resminostat once or twice daily on days 1 to 5 during a 14 day treatment cycle, followed by a 9 day washout. FOLFIRI was administered on days 3 and 4 of each resminostat treatment cycle. During dose escalation, a continuous cohort of 3-8 patients was treated with increasing doses, of which 8 received 2 x 400 mg of resminostat + FOLFIRI daily.

  Test YHI-1001-ST-01: This was an open label phase I trial of orally administered resminostat in Asian patients with advanced solid tumors. The primary objective of the study was to determine the maximum tolerated dose (MTD) of resminostat in the Asian patient population based on dose-limiting toxicity (DLT) and safety. The second objective was to evaluate the pharmacokinetics, pharmacodynamics and efficacy of repeated oral administration of resminostat. The trial was conducted at a single facility in Japan. Patients with histologically or cytologically confirmed advanced solid tumors who failed standard treatment or did not have treatment options were included in this study. The primary eligibility criteria included ECOG 0-2 performance status, adequate liver, kidney, heart and bone marrow function and life expectancy> 12 weeks. 400 mg (N = 3), 600 mg (N = 3) or 800 mg (N = 6) of a continuous cohort of 3 to 6 patients on days 1 to 5 during a 14-day treatment cycle Treated with increasing doses once daily and then rested for 9 days. In total, 12 patients were treated for at least 2 treatment cycles, or until tumor progression or patient withdrawal.

  Study YHI-1001-HCC-02: This is a systemic chemotherapy (first line therapy) to determine MTD and evaluate the safety and efficacy of resminostat in combination with sorafenib in an Asian patient population An open label, multicenter phase I / II trial in patients with advanced HCC untreated). This research is conducted in Japan and Korea. The primary eligibility criteria included ECOG 0-1 performance status, adequate liver, kidney, heart and bone marrow function and life expectancy> 12 weeks.

  In the Phase I portion, a continuous cohort of 3 to 6 patients was treated with increasing doses of 400 mg (N = 3) or 600 mg (N = 6) of resminostat in combination with 800 mg of sorafenib. The treatment consists of administering a daily dose of 400 mg of resminostat for 5 days, followed by a rest of 9 days during a 14-day treatment cycle, and administering a daily dose of 800 mg of sorafenib. In total, nine patients were treated for at least two treatment cycles, or until tumor progression or patient withdrawal. At a dose of 400 mg resminostat, 2 patients achieved partial response (PR) and 1 patient had disease stability (SD). At a dose of 600 mg resminostat, none of the patients achieved PR and 4 patients had SD. Only one dose limiting toxicity (grade 4 thrombocytopenia) was observed at a dose of 600 mg resminostat. The major toxicities observed during the first two cycles and associated with resminostat administration are shown in Table 3 below.

Collection and preparation of plasma samples:
Venous blood samples (2 ml) were taken in 3 ml K ₂ EDTA vacutainer (Becton Dickinson 13 × 75 mm) and then carefully swirled 8-10 times and placed on ice. Within 15 minutes of blood collection, samples were centrifuged at 2700 × g and + 4 ° C. for 10 minutes. The supernatant (plasma) was transferred to a polypropylene tube and immediately frozen at -80 ° C.

PK measurement:
For each PK measurement, 200 μL of human plasma sample was added to 50 μL of internal standard working solution (20 μg / L of D ₆ -resminostat [di (tri-deutero Methyl) -aminomethyl-derivative] was added. Subsequently, 600 μL of diisopropyl ether / isoamyl alcohol (80/20 v / v) was pipetted into each cavity. After sealing the deep well block, it was vigorously mixed automatically (5 minutes) and then centrifuged (5 minutes, 3000 rpm). The 500 μL organic layer (upper layer) from each well was transferred to a second deep well plate. After evaporation under a stream of nitrogen, the residue was reconstituted with 30 μL of DMSO and 30 μL of water. 10 μL was injected into the 2 μL sample loop for HPLC-MS / MS analysis. Chromatography was performed on a Luna (Phenomenex®) C18, 5 μm, 100 Å, 50 mm × 2 mm analytical column, in a dual column mode with column switching technology, at a flow rate of 0.5 mL / min. Mobile phase A: 5 mM ammonium formate (315.3 mg / L) in water containing 0.2% formic acid (v / v) Mobile phase B: acetonitrile / water 95 containing 0.2% (v / v) formic acid 5 mM ammonium formate (315.3 mg / L) in 5 / v (v / v);

  Mass spectrometry was performed on an API 3000 (MDS Sciex) triple quadrupole mass spectrometer in MRM mode (multiple reaction monitoring) using a TurboIonSpray® interface. The mass spectrometer was operated in positive ion mode using a linear gradient of 4.75% to 95% acetonitrile in 5 mM aqueous ammonium formate. The selected precursor and product ions of the resminostat were m / z 350.0 and m / z 317.0, respectively. The precursor and product ions selected for the internal standard were m / z 356.2 and m / z 323.0, respectively. The lower limit of quantification (LLOQ) of BYK 409578 based on 200 μL of human plasma was 0.100 μg / L, and the upper limit of quantification (ULOQ) was 100 μg / L. The standard curve was linear using weighted linear regression analysis (1 / × 2; concentration squared weighting). The correlation coefficient (r) of the calibration curve was in the range of 0.9965 to 0.9988.

Adverse Events Adverse events related to resminostat administration were recorded in both the FIM and YHI-1001-ST-01 dose-setting studies. The results for cytopenia are shown in the following table.

  From the results of the phase I portion, 400 mg of resminostat in combination with sorafenib showed higher efficacy and tolerability than the administration of 600 mg of resminostat.

  More than one Asian patient experienced such an event with treatment with resminostat, whereas Western patients only had one incidence of cytopenia.

  In particular, a dose of 600 mg / day exhibits an increase in cytopenias not observed in Asian patients in Asian patients, and 400 mg / day is well tolerated in Asian patients.

PK Comparison Western / Asian Exploratory data analysis and determination of AUC values were based on non-compartmental analysis (NCA) performed in the tests listed below using the software program WinNonLin. AUC _0-6h comparison of 800 mg cohorts from Asian and Western phase I patients on day 1 of cycle 1 (FIM, SAP HIRE and SHORE combination vs. YHI-1001-ST-01 trial) No significant differences (two-tailed t-test) occurred in the mean AUC mean values of humans versus Asians. The results are shown in FIG.

  These results indicate that the impact on tolerability in Asian patients is independent of pharmacokinetic effects.

Claims (19)

  Use of resminostat or a salt or solvate thereof for the manufacture of a medicament for use in the treatment of benign or malignant neoplasms in a human subject, wherein said human subject is Asian and said treatment is Administering resminostat or a salt or solvate thereof to said human subject at a daily dose of less than 600 mg of resminostat, and administering at least one additional chemotherapeutic agent to said human subject ,use.   Use of resminostat or a salt or solvate thereof for the treatment of benign or malignant neoplasms in a human subject, wherein said human subject is Asian and said treatment is less than 600 mg of resminostat 1 Use in a daily dose, comprising administering to said human subject resminostat or a salt or solvate thereof and administering to said human subject at least one further chemotherapeutic agent.   Resminostat or a salt or solvate thereof for use in the treatment of benign or malignant neoplasms in a human subject, wherein said human subject is Asian and said treatment is less than 600 mg of resminostat per day Administration of resminostat or a salt or solvate thereof to said human subject, and administering at least one additional chemotherapeutic agent to said human subject, in a dose, resminostat or a salt or solvent thereof Hydrate.   A method of treating benign or malignant neoplasms in a human subject in need of treatment wherein said human subject is Asian and said method comprises administering a daily dose of less than 600 mg of resminostat to said human subject Administering a stat or a salt or solvate thereof, and administering to said human subject a therapeutically effective amount of at least one additional chemotherapeutic agent.   5. The use, resminostat or salt or solvate thereof, or method for use according to any one of claims 1 to 4, wherein said further chemotherapeutic agent is a molecular targeting agent.   6. The use, resminostat or salt or solvate thereof, or method for use according to any one of the preceding claims, wherein the further chemotherapeutic agent is a VEGFR inhibitor.   7. Resminostat or a salt or solvate thereof, use, or method for use according to any one of claims 1 to 6, wherein said further chemotherapeutic agent is sorafenib.   8. Resminostat or a salt or solvate thereof, use or method for use according to any one of claims 1 to 7, wherein sorafenib is administered to the human subject in a daily dose of about 800 mg. A biweekly dosing regimen in which the treatment is followed by resminostat or a salt or solvate thereof and sorafenib:
9. A method according to claim 8, comprising administering a daily dose of about 400 mg of resminostat for 5 days, followed by rest for 9 days, and b: administering a daily dose of about 800 mg of sorafenib. Resminostat or a salt or solvate thereof, use, or method for the use of   10. Resminostat or a salt or solvate thereof, use or method for use according to claim 9, characterized by reduced toxicity of resminostat and / or sorafenib and maintenance of anti-tumor activity.   11. Resminostat or a salt or solvate thereof, use, or method for use according to any one of claims 1 to 10, wherein said human subject is a member of Southeast Asia or Northeast Asia gene group.   11. The human subject is a member of samoed, Mongolia, Tibet, Korea, Japan, Ainu, South Chinese, Monk Mer, Thailand, Indonesia, Philippines, or Malaysia gene group. Lesminostat or a salt or solvate thereof, use, or method for use according to one aspect.   A resminostat or a salt or solvate thereof, a use or a method for use according to any one of claims 1 to 10, wherein said human subject is a member of the Northeast Asian gene group.   11. The resminostat or salt or solvate thereof for use according to any one of claims 1 to 10, wherein said human subject is a member of samoed, Mongolia, Tibet, Korea, Japan, or the Ainu gene group. , Use, or method.   11. Resminostat or a salt or solvate thereof, use or method for use according to any one of claims 1 to 10, wherein said human subject is a member of the Korean or Japanese gene group.   Resminostat or a salt or solvate thereof, use, or method for use according to any one of the preceding claims, wherein the salt of resminostat is resminostat mesylate.   17. Resminostat or a salt or solvate thereof, use or method for use according to any one of claims 1 to 16, wherein the benign or malignant neoplasm is a cancer, in particular a hepatocellular carcinoma.   Breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (eg thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney (kidney), liver, lung, pharynx and lower Illustrated by pharynx, mesothelioma, ovary, pancreas, prostate, rectum, kidney (renal), small intestine, soft tissue, testis, stomach, skin, ureter, solid tumors of the vagina and vulva, and retinoblastoma and Wilms tumor Cancers and malignant neoplasms that may be selected from the group consisting of primary tumors in said organs and corresponding secondary tumors ("tumor metastases") in distant organs, and leukemias of high-grade and low-grade forms and leukemia Lymphoma, ie non-Hodgkin's disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkin's disease, multiple myeloma Solid tumor selected from the group consisting of hematologic malignancies selected from the group consisting of T cell lymphoma and myelodysplastic syndrome, plasma cell neoplasm, paraneoplastic syndrome, cancer of unknown primary site, and AIDS related malignant tumor 18. Resminostat or a salt or solvate thereof, use, or method for use according to any one of claims 1 to 17, wherein malignant neoplasms including hematologic malignancies are treated.   The benign or malignant neoplasm is selected from the group consisting of hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), pancreatic cancer, biliary cancer and cutaneous T cell lymphoma (CTCL), more particularly HCC, CTCL 18. Resminostat or a salt or solvate thereof, used, or method for use according to any one of claims 1 to 17, selected from the group consisting of and NSCLC.

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