WO2017178577A1 - Medical application of resminostat in asian patients - Google Patents
Medical application of resminostat in asian patients Download PDFInfo
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- WO2017178577A1 WO2017178577A1 PCT/EP2017/058902 EP2017058902W WO2017178577A1 WO 2017178577 A1 WO2017178577 A1 WO 2017178577A1 EP 2017058902 W EP2017058902 W EP 2017058902W WO 2017178577 A1 WO2017178577 A1 WO 2017178577A1
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the invention relates to medical applications of the HDAC inhibitor resminostat ((E)-3-[1- ⁇ 4- dimethylaminomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylamide) or a salt or solvate thereof in the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg, and administering at least one further ehemotherapeutic agent to said human subject.
- Histone deacetylases are enzymes that catalyze the removal of acetyl groups from specific histone sites in particular at promotor and enhancer regions, which is an essential part of regulation of cellular gene transcription. HDACs also regulate gene expression in an indirect fashion by mediating the acetylation of non-histone proteins such as DNA-binding proteins, transcription factors, signal transducers, DNA repair and chaperon proteins (Ververis K et al., Biologies: 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)-1 H-pyrrol-3-yl]-N-hydroxy- acrylamide
- HDAC histone-deacetylase
- Phase Ha SHELTER (for further information on clinical trials, a search is available on https://clinicaltrials.gov) evaluated resminostat both as monotherapy and in combination with sorafenib as a second-line treatment of advanced HCC after proven radiological disease progression under first-line sorafenib therapy.
- the study met its primary endpoint both in the monotherapy arm and in the combination therapy.
- Patients receiving the resminosfat/sorafenib combination therapy showed a progression-free survival rate (PFSR) after 12 weeks of 70.0% and a median PFS of 5.4 months, resulting in a median overall survival (OS) of 8.1 months.
- PFSR progression-free survival rate
- OS median overall survival
- resminostat in monotherapy has demonstrated substantial anti-tumor activity, with an overall response rate of 34% and a clinical benefit in 54% of the patients in a heavily pre-treated patient population together with very good safety and tolerability. Furthermore, resminostat was studied in a Phase 1 dose escalation approach in advanced colorectal cancer (CRC) patients, evaluating resminostat in combination with the standard chemotherapeutic FOLFIRI regimen.
- CRC colorectal cancer
- HCC liver cancer
- NSCLC non-smaii-ceil lung cancer
- Sorafenib (4-[4-[[4-chloro-3-(thfluoromethyl)phenyl]carbamoylarnino]phenoxy]-/V-rnethyl- pyridine-2-carboxamide; brand name Nexavar®), https://en.wikipedia.org/wiki/Sorafenib is an orally available protein kinase inhibitor from the group of multi-kinase inhibitors. It has been evaluated in a number of clinical studies and so far been approved for the treatment of advanced renal cell carcinoma, advanced hepatocellular carcinoma, and radioactive iodine resistant advanced thyroid carcinoma. HDAC inhibitors have been described to cause growth arrest with subsequent differentiation or apoptosis of tumor cells, whereas normal cells are not affected.
- HDAC inhibitors cause cell-cycle arrest in G1 and/or G2 phase. Growth-inhibitory effects have been documented in vitro in virtually ali transformed ceil types, including cell lines that arise from both hematological and epithelial tumors. The growth inhibitory cellular mechanism of the HDAC inhibitors has been described as a specific induction of expression of the cell cycle inhibitor CDKN1A (p21 ). Additionally, this review article summarizes the induction of growth arrest in tumor-bearing mice by HDAC inhibitors. Efficacy of HDAC inhibitors has been demonstrated in animal models of diverse cancer types such as breast, prostate, lung and stomach cancers, neuroblastoma and leukemias.
- HDAC inhibition has an effect on the expression of a number of proteins playing pivotal roles in tumor-relevant processes, such as HER2/neu, VEGF, raf-1 , cyclin A and B, Bax, Bad, p53, c-myc, Caspase 3, p21 and ERo. According to a review by Villar-Garea et ai.
- cancer is understood to be an epigenetic as well as a genetic disease and the main goal using HDAC inhibitors would be restoration of gene expression of those tumor-suppressor genes that have been transcriptionally silenced by promotor-associated histone deacetylation.
- Drummond et al. (Annu. Rev, Pharmacol. Toxicol. 2005. 45:495-528) review the molecular mechanism and outcome of histone and non-histone substrates in cancer cells, which are effectors of HDAC, while HDAC also facilitates the acetylation of several key proteins other than histones.
- acetylation is a key posttra relational modification of many proteins responsible for regulating critical intracellular pathways, and many of these substrates are tissue/development specific (EKLF, GATA-1 , ERct, MyoD), oncogenic (c-Myb), tumor-suppressing (p53), or even rather ubiquitous (TFIIE, TFIIF, TCF, HNF-4) transcription factors. Modulation of those proteins can lead to induction of cell cycle arrest, differentiation and apoptosis, all of which are desirable mechanisms for treatment of cancer.
- Kelly et al. (Expert Opin Invest Drugs, 1 1 (12), 2002) provides a further review on HDAC inhibitors in general and their application in cancer therapy.
- WO 2005/087724 A2 describes certain N-sulphonylpyrrole derivatives, which are described to be used in the pharmaceutical industry for the production of pharmaceutical compositions.
- WO 2007/39404 A1 describes novel N-sulphonylpyrrole derivatives and certain salts of these N-suiphonylpyrrole derivatives, which are described to be used in the pharmaceutical industry for the production of pharmaceutical compositions.
- WO 2009/1 12529 A1 describes a specific production method of N-sulphonylpyrrole derivatives and salts thereof, which are described to be used in the pharmaceutical industry for the production of pharmaceutical compositions. Brief descri tion of the figures
- Figure 1 shows a Comparison of AUC0-6h of the 800mg cohort of the Western and Asian Phase I studies, or Phase I part of these studies (cf. examples section).
- the invention thus relates to medical applications of the HDAC inhibitor resminostat ((E)-3-[1- (4-Dimethyiaminomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylamlde) or a salt or solvate thereof in the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg, and administering at least one further chemotherapeutic agent to said human subject.
- HDAC inhibitor resminostat ((E)-3-[1- (4-Dimethyiaminomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylamlde) or a salt or solvate thereof in the treatment of benign or malignant neoplasia in a human subject
- resminostat or a salt or solvate thereof for the manufacture of a medicament for use in the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and wherein said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg resminostat, and administering at least one further chemotherapeutic agent to said human subject.
- resminostat or a salt or solvate thereof for the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and wherein said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg resminostat, and administering at least one further chemotherapeutic agent to said human subject.
- Resminostat or a salt or solvate thereof for use in the treatment of benign or malignant neoplasia in a human subject, wherein said human subject is an Asian, and wherein said treatment comprises administering resminostat or a salt or solvate thereof to said human subject in a daily dose of less than 600 mg resminostat, and administering at least one further chemotherapeutic agent to said human subject.
- Resminostat or a salt or solvate thereof for the use the use or method according to claim 8, wherein said treatment comprises administering resminostat or a salt or solvate thereof and sorafenib with following biweekly dosing regimen: a : administering a daily dose of about 400mg resminostat for 5 days, followed by a period of 9 days drug withdrawal, and b : administering a daily dose of about 800mg of sorafenib.
- the daily dose of resminostat is less than 600 mg, particularly 550 mg or less, more particularly 500 mg or less, even more particularly 500 mg or less, even more particularly 450 mg or less, even more particularly 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 which is an International Non-proprietary Name, i.e. INN
- E -3-[1-(4-Dimethylaminomethyl-benzenesulfonyl)-1 H-pyrrol-3-yl]-N-hydroxy-acrylamide (its chemical name) are used interchangeably and both refer to a compound of the following formula:
- said further chemotherapeutic agent is a kinase inhibitor, particularly a class 3 kinase inhibitor, a RAF inhibitor, a VEGFR inhibitor, particularly a VEGFR inhibitor from the group of multikinase inhibitors or tyrosine kinase inhibitors, even more particularly a VEGFR inhibitor selected from the group consisting of Sunitinib, Sorafenib, Ramucirumab und Vatalanib, yet even more particularly Sorafenib.
- a kinase inhibitor particularly a class 3 kinase inhibitor, a RAF inhibitor, a VEGFR inhibitor, particularly a VEGFR inhibitor from the group of multikinase inhibitors or tyrosine kinase inhibitors, even more particularly a VEGFR inhibitor selected from the group consisting of Sunitinib, Sorafenib, Ramucirumab und Vatalanib, yet even more particularly Sorafenib.
- a molecular targeted agent is a chemotherapeutic agent that acts through specific interactions with one or more molecular targets, e.g. proteins in the patient. This is opposed to agents that act through non-specific interactions, such e.g. genera! cytotoxic agents that act through DNA intercalation or DNA modifications such as alkylation or DNA crosslinking.
- sorafenib which is an International Non-proprietar Name
- Sorafenib is also known under its trade name Nexavar®.
- Suitable salts for resminostat are acid addition salts or salts with bases. Particular mention may be made of the pharmacologically tolerable inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-insoluble and, particularly, water-soluble acid addition salts, the acids being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom, particularly in an equimolar quantitative ratio. On the other hand, salts with bases are - depending on substitution - also suitable, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
- resminostat as well as its salts may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore all solvates and in particular all hydrates of resminostat as well as all solvates and in particular all hydrates of resminostat, in particular such solvates or hydrates comprising about 0,5, 1 or 2 solvate or water molecules per molecule of resminostat or salts thereof.
- Particular salts in the context of the present invention are the salts of resminostat with methanesulfonic acid, in particular in a molar ratio of about 1 :1.
- Resminostat and salts thereof can be prepared, for example, as described in detail in WO 2005/087724 A2, WO 2007/39404 A1 and WO 2009/1 12529 A1 , respectively. Sorafenib is commercially available and methods of its preparation are well-known.
- Asian is herein particularly defined to be a person having aboriginal origins or having ancestors, e.g. at least one parent with aboriginal origins in the Far East or Southeast Asia, including in particular for example, China, Mongolia, Taiwan, Singapore, Korea, Japan, Vietnam, Cambodia, Laos, Burma, Thailand, Malaysia, Indonesia and Philippines, but more particularly excluding the Indian subcontinent.
- subjects can also be specified as Asians, or any of the specific groups included of the definition of Asians as defined herein, by self-identification ⁇ e.g. by a questionnaire) or by assignment by a physician on the basis of their somatic traits and/or their country of origin or the country of origin of their ancestors.
- Asian descent can also be determined by microsatellite markers as described in the known literature.
- Cancer as used herein, and also known as malignant neoplasia, is a medical condition characterized by tumor cells metastasizing into distinct organs or tissues.
- malignant neoplasia treated with the embodiments of the present invention include solid and hematological tumors. Solid tumors are exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands (e.g.
- Malignant neoplasia includes inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasia includes primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases").
- Hematological tumors are exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgklns disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkin's disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers of unknown primary site, as well as AIDS related malignancies.
- non-Hodgklns disease chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkin's disease, multiple myeloma and T-cell lymphoma.
- myelodysplastic syndrome plasma cell neoplasia
- paraneoplastic syndromes cancers of unknown primary site, as well as AIDS related malignancies.
- HCC hepatocellular cancer
- NSCLC non-small cell lung cancer
- CTCL cutaneous T-cell lymphoma
- malignant tumors differ from benign tumors in four biological properties: structure, rate of growth, invasive growth, and disseminated growth by metastasis. Common for both benign and malignant tumors is the abnormal proliferation of ceils. Since HDAC inhibitors can inhibit proliferation by regulation of cell cycle dependent genes and proteins or induce cell cycle arrest, which has been demonstrated for malignant tumors, it is apparent that HDAC inhibitors can also be used for the treatment of benign neoplasia.
- benign neoplasia in the context of the present invention are colonic polyps, adenoma, papilloma, cystadenoma, liver cell adenoma, hydatiform moles, renal tubular adenoma, squamous cell papilloma, gastric polyps, hemangioma, osteoma, chondroma, lipoma, fibroma, lymphangioma, leiomyoma, rhabdomyoma, astrocytoma, nevi, meningioma, ganglioneuroma, and endometriosis.
- endometriosis and HDAC see Reprod Sci. 2012 ay; 19(5):483-92.
- Drug resistance is of particular importance for the frequent failure of standard cancer therapeutics. This drug resistance is caused by various cellular and molecular mechanisms like overexpression of drug efflux pumps, mutation within the cellular target protein or fusion proteins formed by chromosomal translocations.
- the commercial applicability of resminostat is not limited to 1 st line treatment of patients. Patients with resistance to cancer chemotherapeutics or target specific anti-cancer drugs can be also amenable for treatment with resminostat for e.g. 2 nd or 3 rd line treatment cycles.
- a prominent example is given by acute promyelocytic leukemia patients with the PML-RARa fusion protein, resistant to standard therapy with retinoids.
- resminostat and the at least one further chemotherapeutic agent may be administered, simultaneously, sequentially or separately.
- active agents refers to a compound exerting a medical effect on a disease or medical condition (e.g. an amelioration thereof) and said term in particular includes resminostat and sorafenib.
- the active agents may be provided in pharmaceutical compositions comprising one or more of said active agents and a pharmaceutically acceptable carrier or diluent.
- resminostat and sorafenib may be provided in the same pharmaceutical composition (also known as a fixed combination) or in separate pharmaceutical compositions (e.g. in two separate tablets).
- Such pharmaceutical compositions may be provided in the context of pharmaceutical products, comprising e.g. one or more pharmaceutical compositions and packaging material.
- Said packaging material typically comprises a label or package insert which indicates that the active agent(s) is/are useful for treating the diseases detailed herein.
- the packaging material, label and package insert otherwise parallel or resemble what is generally regarded as standard packaging material, labels and package inserts for pharmaceuticals having related utilities.
- compositions according to this invention are prepared by processes which are known per se and familiar to the person skilled in the art.
- the active agents are either employed as such, or preferably in combination with suitable pharmaceutical auxiliaries and/or excipients, e.g. in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active agent content advantageously being between 0.1 and 95% and where, by the appropriate choice of the auxiliaries and/or excipients, a pharmaceutical administration form (e.g. a delayed release form or an enteric form) exactly suited to the active agent and/or to the desired onset of action can be achieved.
- suitable pharmaceutical auxiliaries and/or excipients e.g. in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active agent content advantageously being between
- auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulations, preparations or compositions on account of his/her expert knowledge.
- solvents for example antioxidants, dispersants, emulsifiers, preservatives, soiubiiizers, colorants, complexing agents or permeation promoters, can be used.
- additional therapeutically active agents which are normally administered to treat said benign or malignant neoplasia, may optionally be co-administered with resminostat and sorafenib.
- chemotherapeutic anticancer agents used in cancer therapy, including, but not are limited to (i) alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®), Ifosfamid (Holoxan®), Thiotepa (ThiotehpaLederle®), elphalan (Alkeran®), or chloroethylnitrosourea
- alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®), Ifosfamid (Holoxan®), Thiotepa (ThiotehpaLederle®), elphalan (Alkeran®), or chloroethylnitrosourea
- BCNU platinum derivatives like cis-platin
- Platinum derivatives like cis-platin platinum derivatives like cis-platin (Platinex® BMS), oxaliplatin or carboplatin (Cabroplat® BMS);
- antimitotic agents / tubulin inhibitors such as vinca alkaloids (vincristine, vinblastine, vinorelbine), taxanes such as Taxol (Paclitaxel®), Taxotere (Docetaxel®) and analogs as well as new formulations and conjugates thereof;
- topoisomerase inhibitors such as anthracyclines (exemplified by Doxorubicin / Adriblastin®), epipodophyllotoxines (examplified by Etoposide / Etopophos®) and camptothecin analogs (exemplified by Topotecan / Hycamtin®);
- pyrimidine antagonists such as 5-fluorouracil (5- FU), Capecitabine (
- target specific anti-cancer drug classes used in experimental or standard cancer therapy include but are not limited to (i) kinase inhibitors such as e.g. Glivec (Imatinib®), ZD- 1839 / Iressa (Gefitinib®), SU 1 1248 (Sutent®) or OSI-774 / Tarceva (Erlotinib®); (ii) proteasome inhibitors such as PS-341 (Velcade®); (iii) heat shock protein 90 inhibitors like 17-allylaminogeldanamycin (17-AAG): (iv) vascular targeting agents (VTAs) and anti- angiogenic drugs like the VEGF antibody Avastin (Bevacizumab®) or the KDR tyrosine kinase inhibitor PTK787 / ZK222584 (Vatalanib®); (v) monoclonal antibodies such as Herceptin (Trastuzumab®) or MabThera / Ritux
- Tamoxifen anti-androgens (e.g. Flutamide or Casodex), LHRH analogs (e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors.
- Other known anti-cancer agents which can be used for combination therapy include bleomycin, retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as the 2-deoxycytidine derivative Decitabine (Docagen®), alanosine, cytokines such as interleukin-2, interferons such as interferon «2 or interferon--,-, TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists and finally histone deacetylase inhibitors different to sulphonylpyrrole derivatives as described in the present invention such as SAHA, PXD101 , MS275, GCD0103, Depsipeptide / FK228, NVP
- the following drugs may be mentioned, without being restricted thereto, 5 FU, actinomycin D, abarelix, abciximab, aclarubicin, adapalene, alemtuzumab, altretamine, aminoglutethimide, amiprilose, amrubicin, anastrozole, ancitabine, artemisinin, azaihioprine, basiliximab, bendamustine, bicalutamide, bleomycin, broxuridine, busulfan, capecitabine, carboplatin, carboquone, carmustine, cetrorelix, chlorambucil, chlormethine, cisplatin, cladribine, clomifene, cyclophosphamide, dacarbazine, daclizumab, dactinomycin, daunorubicin, deslore
- agents commonly known as immune checkpoint inhibitors or short checkpoint inhibitors i.e. agents that inhibit inhibitory checkpoint molecules, such as the inhibitory checkpoint molecules Adenosine A2A receptor (A2AR), B7-H3 (also called CD276), B7-H4 (also called VTCN1 ), B and T Lymphocyte Attenuator (BTLA, also called CD272), short for Cytotoxic T-Lymphocyte- Associated protein 4 (CTLA-4, also called CD152), Indoleamine 2,3-dioxygenase (IDO), Killer-cell Immunoglobulin-iike Receptor (KIR), Lymphocyte Activation Gene-3 (LAGS), Programmed Death 1 receptor (PD-1 ), as well as Programmed Death 1 receptor Ligand (PD- L1 ), T-cell Immunoglobulin domain and Mucin domain 3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA, also called C10orf
- checkpoint inhibitors examples include MGA271 (by acroGenics), Ipilimumab (Yervoy*), Tremelimumab (formerly CP-675,206), Lirilumab, B S-986016 (by BMS), BMS-936559/MDX-1 105 (by BMS), Pembroiizumab (Keytruda ® ), Nivolumab (Opdivo ® ), Ga!iximab, IMP321 (by Immuntep), BMS-663513 (by BMS), PF-05082566 (by Pfizer), IPH2101 (by Innate Pharma / BMS), KW-0761 (by Kyowa Kirin), CDX-1 127 (by CellDex Therapeutics), MEDI-6469 (by Medlmmune/ AstraZeneca), MEDI4736 (by AstraZeneca),CP-870,893 (by Genentech), Pidiiizumab, MPDL32
- the active agents according to the present invention may be administered in combination therapy separately, sequentially, simultaneously or chronologically staggered (e.g. as combined unit dosage forms, as separate unit dosage forms or adjacent discrete unit dosage forms, as fixed or non-fixed combinations, as kit-of- parts or as admixtures).
- a “fixed combination” is defined as a combination wherein a first active ingredient (e.g. resminostat) and at least one further active ingredient (e.g. sorafenib) are present together in one unit dosage or in a single entity.
- a first active ingredient e.g. resminostat
- at least one further active ingredient e.g. sorafenib
- a pharmaceutical composition wherein the said first active ingredient and said further active ingredient are present in admixture for simultaneous administration, such as in a single formulation.
- Another example of a "fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said further active ingredient are present in one unit without being in admixture.
- kits-of-parts is defined as a combination wherein the said first active ingredient and the said further active ingredient are present in more than one unit.
- a “kit-of-parts” is a combination wherein the said first active ingredient and the said further active ingredient are present separately.
- the components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered.
- the first and further active ingredient of a combination or kit-of-parts according to this invention may be provided as separate formulations ⁇ i.e. independently of one another), which are subsequently brought together for simultaneous, sequential, separate or chronologically staggered use in combination therapy; or packaged and presented together as separate components of a combination pack for simultaneous, sequential, separate or chronologically staggered use in combination therapy.
- the type of pharmaceutical formulation of the first and further active ingredient of a combination or kit-of-parts according to this invention can be similar, i.e. both ingredients are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. one active ingredient is formulated as tablet or capsule and the other is formulated for e.g. intravenous administration.
- a further aspect of the present invention is a combination comprising, in non-fixed form, resminostat or a salt thereof, in particular resminostat mesylate (i.e. methanesuifonate), and one or more art-known standard therapeutic, in particular art-known chemotherapeutic or target specific anti-cancer agents, such as those mentioned above, in particular sorafenib, for sequential, separate, simultaneous or chronologically staggered use in therapy in any order.
- said combination comprises instructions for its use in therapy.
- a further aspect of the present invention is a combined preparation, such as e.g. a kit of parts, comprising a preparation of resminostat or a salt thereof and a pharmaceutically acceptable carrier or diluent; a preparation of a further active ingredient, in particular sorafenib, and a pharmaceutically acceptable carrier or diluent; and optionally instructions for simultaneous, sequential, separate or chronologically staggered use in therapy.
- a kit of parts comprising a preparation of resminostat or a salt thereof and a pharmaceutically acceptable carrier or diluent; a preparation of a further active ingredient, in particular sorafenib, and a pharmaceutically acceptable carrier or diluent; and optionally instructions for simultaneous, sequential, separate or chronologically staggered use in therapy.
- a further aspect of the present invention is a kit of parts comprising a dosage unit of resminostat or a salt thereof, a dosage unit of a further active ingredient, in particular sorafenib, and optionally instructions for simultaneous, sequential or separate use in therapy.
- a further aspect of the present invention is a pharmaceutical product comprising resminostat, or one or more pharmaceutical compositions comprising said compounds; and one or more art-known therapeutic agents, in particular sorafenib, or one or more pharmaceutical compositions comprising said therapeutic agents, for simultaneous, sequential or separate use in therapy.
- this pharmaceutical product comprises instructions for use in said therapy.
- a further aspect of the present invention is a pharmaceutical composition as unitary dosage form comprising, in admixture, resminostat or a salt thereof, a further active ingredient, which is an art-known standard therapeutic, in particular sorafenib, and optionally a pharmacologically acceptable carrier, diluent or excipient.
- a further aspect of the present invention is a commercial package comprising resminostat or a salt thereof together with instructions for simultaneous, sequential or separate use with one or more art-known standard therapeutic, in particular sorafenib.
- the combination according to the present invention can be used in the pre- or post-surgical treatment of benign or malignant neoplasia.
- the combination according to the present invention can be used in combination with radiation therapy, in particular in sensitization of patients towards standard radiation therapy.
- compositions according to the invention may be performed in any of the generally accepted modes of administration available in the art.
- suitable modes of administration include intravenous, oral, nasal, parenteral, topical, transdermal and rectal delivery. Oral and intravenous delivery are preferred.
- doses refer to the amount of compound with respect to the free form of said compound, i.e. the free acid or free base form of said compound. Consequently, adducts, salts, etc. of such free acid or free base form are actually to be administered in a correspondingly higher dose in order to account for the weight of the counter-ion or adduct partner.
- the administration of active agents may follow a certain schedule, which may include periods of daily administration of active agents and periods wherein no active agents are administered.
- a schedule may consist of repeating cycles of 5 days of active agents (or resminostat) administration followed by 9 days wherein no active agents are administered ("rest period") (14-day cycle), 5 days of active agents (or resminostat) administration followed by 18 days of rest period (21 -day cycle), or 14 days of active agents (or resminostat) administration followed by 7 days of rest period (21 -day cycle).
- FIM First-in-Man study
- patients were to have good performance status (ECOG 0-1 ), adequate hepatic, renal, cardiac and bone marrow function and an estimated life expectancy of greater than 12 weeks.
- Treatment with resminostat consisted of once daily oral administration on Days 1 to 5 followed by 9 days of rest during 14-day treatment cycles. Sequential cohorts of patients were treated with escalating doses of resminostat, including 7 patients at 800 mg.
- SAPHIRE SC-201 -2-2009
- IWG International Working Group
- SHORE This was an open-label phase l/l I study of orally administered resminostat in patients with advanced colorectal carcinoma (CRC). Resminostat was administered in combination with the standard FOLFIRI regimen. The phase I dose escalation part of the study was conducted at 2 centers in Germany. Patients with histologically or cytologically confirmed advanced stage CRC were included in this study. Patients should have received previous treatment for advanced CRC and been foreseen for chemotherapy with FOLFIRI in second or third line therapy. The main eligibility criteria included a performance status of ECOG 0-2, adequate hepatic, renal, cardiac and bone marrow function and a life expectancy ⁇ 12 weeks.
- Treatment consisted of once or twice daily oral administration of resminostat on Days 1 to 5 followed by 9 days of rest during 14-day treatment cycles.
- FOLFIRI was administered on Days 3 and 4 of each resminostat treatment cycle.
- sequential cohorts of 3-8 patients were treated with escalating doses, of which 8 patients received 2x 400 mg resminostat + FOLFIRI daily.
- Study YHI-1001 -ST-01 This was an open-label phase I study of orally administered resminostat in Asian patients with advanced solid tumors.
- the primary objectives of the study were to determine the maximum tolerated dose (MTD) of resminostat in the Asian patient population based on dose-limiting toxicities (DLTs) and safety. Secondary objectives were to evaluate pharmacokinetics, pharmacodynamics and efficacy of repeated oral doses of resminostat.
- the study was conducted at a single center in Japan. Patients with histologically or cytologically confirmed advanced solid tumors who have failed standard therapies or for whom no treatment options were available were included in this study.
- the main eligibility criteria included a performance status of ECOG 0-1 , adequate hepatic, renal, cardiac and bone marrow function and a life expectancy of more than 12 weeks.
- Study YHI-1001-HCC-02 This is an open-label, multi-center Phase l/l I study in patients with advanced HCC previously untreated with systemic chemotherapy (first-line therapy) to determine the MTD and to evaluate safety and efficacy of resminostat in combination with sorafenib in the Asian patient population.
- the study is conducted in Japan and Korea.
- the main eligibility criteria included a performance status of ECOG 0-1 , adequate hepatic, renal, cardiac and bone marrow function and a life expectancy of more than 12 weeks.
- Venous blood samples (2 ml) were collected in 3 ml K 2 EDTA vacutainers (Becton Dickinson 13x75 mm), then carefully swiveled 8-10 times and put on ice. Within 15 minutes after blood collection, samples were centrifuged for 10 min at 2700 x g and +4°C. The supernatant (plasma) was transferred into a polypropylene tube and immediately frozen at -80°C,
- Mobile phase A 5 mM ammonium formate (315.3 mg/L) in water containing 0.2% formic acid, v/v;
- Mobile phase B 5 mM ammonium formate (315.3 mg/L) in acetonitrile/water 95/5 (v/v) containing 0.2% formic acid, v/v;
- Mass spectrometry was performed on an API 3000 (MDS Sciex) triple quadrupole mass spectrometer in the MRM-mode (multiple reaction monitoring) with the TurbolonSpray® interface.
- the mass spectrometer was operated in the positive ion mode using a linear gradient from 4.75% to 95% acetonitrile in 5 mM aqueous ammonium formate.
- the selected precursor- and product-ions for Resminostat were at m/z 350.0 and m/z 317.0, respectively.
- the selected precursor- and product-ions for the interna! standard were at m/z 356.2 and m/z 323.0, respectively.
- LLOQ lower limit of quantification
- UEOQ upper limit of quantification
- the standard curves were linear using weighted linear regression analysis (1/x2; concentration- squared weighting).
- the coefficients of correlation (r) for the calibration curves ranged from 0.9965 to 0.9988.
- Table 1 Study FIM; 7341/EM-001 - Western / Caucasian Patients
- Leucopenia 1 3 1 2 1 Tabie 3 Study YHI-1001-HCC-02 - Japanese Patients
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