CN109069647A

CN109069647A - Medical applications of the Rui meter Si Ta (Resminostat) in asian patients

Info

Publication number: CN109069647A
Application number: CN201780023078.7A
Authority: CN
Inventors: 曼夫莱德·格罗佩尔
Original assignee: 4SC AG
Current assignee: 4SC AG
Priority date: 2016-04-14
Filing date: 2017-04-13
Publication date: 2018-12-21
Also published as: WO2017178577A1; TW201801723A; JP2019511544A; KR20180130565A

Abstract

The present invention relates to hdac inhibitor Rui meter Si Ta ((E) -3- [1- (4- dimethylaminomethyl-benzenesulfonyl) -1H- pyrroles -3- base]-N- hydroxy-acrylamide) or its salt or solvate, and the medical applications that benign or malignant tumor becomes are treated in human experimenter; wherein the human experimenter is Asian; and wherein the treatment includes giving Rui meter Si Ta or its salt or solvate to the human experimenter with the daily dosage less than 600mg Rui meter Si Ta, and give at least one other chemotherapeutant of the human experimenter.

Description

Medical applications of the Rui meter Si Ta (Resminostat) in asian patients

Technical field

The present invention relates to hdac inhibitor Rui meter Si Ta ((E) -3- [1- (4- dimethylaminomethyl-benzenesulfonyl) -1H- Pyrroles -3- base]-N- hydroxy-acrylamide) or its salt or solvate treat what benign or malignant tumor became in human experimenter Medical applications, wherein the human experimenter is Asian, and the treatment includes by Rui meter Si Ta or its salt or solvation Object gives the human experimenter with the daily dosage less than 600mg, and gives human experimenter's at least one in addition Chemotherapeutant.

Background technique

Histone deacetylase (HDAC) is catalysis from specific group protein loci, especially in promoter region and enhancer Area removes the enzyme of Acetyl Groups, which is the necessary part for adjusting cytogene transcription.HDAC also passes through Jie in an indirect way Lead the acetyl of nonhistone proteins (e.g., DNA binding protein, transcription factor, signal transducer, DNA reparation and chaperone) Be turned into for adjust gene expression (Wo Weiruisi K (Ververis K) et al., biological agent: target and therapy (Biologics: Targets and Therapy)7:47-60,2013；Spy D (Vitt D) et al. is tieed up, acetylation of histone (Targeting is targeted Histone acetylation), in RSC drug discovery serial 48th phase: epigenetics (the In:RSC Drug of drug discovery Discovery Series No.48:Epigenetics for Drug Discovery), editor: Nei Sakairui (Nessa Carey), Royal Institute of Chemistry (The Royal Society of Chemistry), 2016).

Rui meter Si Ta ((E) -3- [1- (4- dimethylaminomethyl-benzenesulfonyl) -1H- pyrroles -3- base]-N- hydroxyl-the third Acrylamide) it is that one kind takes orally available hdac inhibitor histone deacetylase (HDAC) inhibitor.

IIa phase SHELTER research (for the other information about clinical test, it can be in https: // Searched on clinicaltrials.gov) it is combined using Rui meter Si Ta as monotherapy and with Sorafenib as in a clue The second line treatment of advanced stage HCC under La Feini therapy after attested radiation disease progress is assessed.The research is in single treatment Meet its Primary Endpoint in method branch and conjoint therapy.Receive Rui meter Si Ta/Sorafenib conjoint therapy patient to show Progresson free survival rate (PFSR) after 12 weeks is that 70.0% and middle position PFS is 5.4 months, causes the middle position Overall survival (OS) to be 8.1 months.

In the II phase SAPHIRE test with advanced stage SAPHIRE Hodgkin lymphoma (HL) patient, in monotherapy Rui meter Si Ta shown significant anti-tumor activity, and in the PATIENT POPULATION of a large amount of pretreatments, overall reaction rate is 34%, 54% patient clinical is benefited, and very good safety and tolerance.

In addition, late having studied Rui meter Si Ta in I phase dosage escalation method in colorectal cancer (CRC) patient, commenting The Rui meter Si Ta combined with standard chemotherapeutic regimens FOLFIRI scheme is estimated.

Recently, I/ of the investigation Rui meter Si Ta in liver cancer (HCC) and the indication of non-small cell lung cancer (NSCLC) is completed II second phase trial.Compared with the monotherapy of corresponding cancer drug, these research test in asian patients with routine The Rui meter Si Ta of cancer drug Sorafenib (in HCC) and docetaxel (in NSCLC) combination therapy.Equally, in Asia Phase I clinical trial is carried out in the cancer of bile ducts and cancer of pancreas of patient.

Sorafenib (4- [4- [[4- chloro- 3- (trifluoromethyl) phenyl] carbamoyl ammonia] phenoxy group]-N- methyl-pyrrole Pyridine -2- formamide；Trade (brand) name), https: //en.wikipedia.org/wiki/Sorafenib, it is a kind of Available protein kinase inhibitors are taken orally from multi-kinase inhibitor group.Assessed in many clinical researches, And the treatment for advanced renal cell carcinoma, advanced liver cancer and radioresistens iodine patients with late-stage thyroid carcinoma is had been approved by so far.

Hdac inhibitor has been described and causes growth retardation, subsequent tumor cell differentiation or apoptosis, however normal cell It is unaffected.Such as by Marx (Marks) et al. (cancer is commented on (Nature Reviews Cancer) naturally, the 2001, the 1st Volume, the 194-202 pages) comment summarized in, hdac inhibitor causes cell cycle arrest in G1 the and/or G2 phase. In the cell type (cell line including being originated from blood disease and epithelial tumor) of nearly all conversion, growth suppression is had recorded in vitro Production is used.The growth inhibition celelular mechanism of hdac inhibitor is described as cell cycle inhibitor CDKN1A (p21) expression Specificity induction.In addition, this comment summarizes the growth retardation induced in tumor-bearing mice by hdac inhibitor.HDAC The effect of inhibitor various cancer types (such as breast cancer, prostate cancer, lung cancer and gastric cancer, neuroblastoma and Leukaemia) animal model in prove.

Many cancer types are treated by hdac inhibitor to be described in obtainable document.HDAC inhibition pair Play a crucial role in tumour correlated process many protein (e.g., HER2/neu, VEGF, raf-1, cyclin A and B, Bax, Bad, p53, c-myc, caspase 3, p21 and ER α) expression have influence.According to by Wella-Gai Rui (Villar-Garea) et al. the summary of (international journal of cancer (Int.J.Cancer): 112,171-178 (2004)), cancer are answered It is considered as epigenetic and genetic disease, and the use of the main target of hdac inhibitor will restore to pass through promoter Relevant histone deacetylation acts on the gene expression of those of Transcriptional Silencing tumor suppressor gene.Drummond (Drummond) et al. (Ann. Rev.Pharmacol. Toxicol (Annu.Rev.Pharmacol.Toxicol.) 2005.45:495- 528) molecular mechanism and as a result, the histone and nonhistones of the histone and nonhistones substrate in cancer cell are reviewed Substrate is the effect protein of HDAC, however HDAC also promotes the acetyl of several key protein matter other than histone to be turned into With.According to the summary, acetylation is responsible for adjusting in key cells after the crucial translation of many protein of approach Modification, and many in these substrates is tissue/development special (EKLF, GATA-1, ER α, MyoD), carcinogenic (c- Myb), (p53) of tumor-inhibitory or even generally existing (TFIIE, TFIIF, TCF, HNF-4) transcription factor.Those eggs The adjustment of white matter will lead to induction of cell cycle arrest, differentiation and apoptosis, all these to contribute to the desired for the treatment of cancer Mechanism.Kai Li (Kelly) et al. (investigation drug comment of experts (Expert Opin Invest Drugs), 11 (12), 2002) the further summary about general hdac inhibitor, and its application in cancer therapy are provided.

The website official US NIH http://clinicaltrials.gov lists (state: 2 months 2016) for use 545 clinical test lists of the cancer indication of hdac inhibitor treatment, except other things, various forms of leukaemia (examples Such as, CML, CLL, AML), myelodysplastic syndrome, the lymthoma including non Hodgkin lymphom, Huppert's disease, Plasma cell tumor, general solid tumor, carcinoma of small intestine, celiothelioma, prostate cancer, breast cancer (male and female), lung cancer are (including non-small Cell and cellule), neuroendocrine tumor, carcinoma, cancer of pancreas, cutaneum carcinoma (including melanoma), multiple bone Myeloma, cervical carcinoma, clear-cell carcinoma, head and neck cancer, gastric cancer, oophoroma, liver cancer, colon and rectum carcinoma, thymoma, carcinoma of fallopian tube, abdomen Film cancer, nasopharyngeal carcinoma, vestibular schwannomas, meningioma, acoustic neurinoma, 2 type of neurofibromatosis, thyroid cancer, bladder transitional cell carcinoma, Glioma, the cancer of the brain, the cancer of the esophagus, neuroastrocytoma, denaturation Oligodendroglioma, megaloblastic collagen Cytoma, spongioblastoma, atypical hyloma, mixed type glioma, brain tumor and oophoroma.

2005/087724 A2 of WO describes certain N- sulphonylpyrroles derivatives, is described in pharmaceuticals industry, For producing pharmaceutical composition.

2007/39404 A1 of WO describes novel N- sulphonylpyrroles derivative and these N- sulphonylpyrroles are derivative Certain salt of object, are described in pharmaceuticals industry, for producing pharmaceutical composition.

2009/112529 A1 of WO describes the specific production method of N- sulphonylpyrroles derivative and its salt, their quilts Description is used in pharmaceuticals industry, for producing pharmaceutical composition.

Brief Description Of Drawings

Fig. 1 is shown in the phase part I that the I phase is studied or these are studied, westerner and Asian 800mg group AUC0-6h comparison (referring to instance section).

Specific embodiment

It has now been found that it is surprising that compared to those of previously for example being given to west/caucasian patient, Asian patients under Rui meter Si Ta treatment can benefit from different dosage.

Therefore, the present invention relates to hdac inhibitor Rui meter Si Ta ((E) -3- [1- (4- dimethylaminomethyls-benzene sulfonyl Base) -1H- pyrroles -3- base]-N- hydroxy-acrylamide) or its salt or solvate treat benign or dislike in human experimenter Property the medical applications that become of tumor, wherein the human experimenter is Asian, and the treatment includes by Rui meter Si Ta or its salt Or solvate gives the human experimenter with the daily dosage less than 600mg, and gives the human experimenter at least A kind of other chemotherapeutant.

Certain embodiments of the present invention is listed in following items:

1. Rui meter Si Ta or its salt or solvate are for manufacturing for treating benign or malignant tumor in human experimenter Purposes in the drug of change, wherein the human experimenter is Asian, and wherein the treatment include by Rui meter Si Ta or Its salt or solvate give the human experimenter with the daily dosage less than 600mg Rui meter Si Ta, and give the people At least one other chemotherapeutant of class subject.

2. Rui meter Si Ta or its salt or solvate are used to treat the purposes that benign or malignant tumor becomes in human experimenter, Wherein the human experimenter is Asian, and wherein the treatment includes by Rui meter Si Ta or its salt or solvate with few The human experimenter is given in the daily dosage of 600mg Rui meter Si Ta, and it is at least one another to give the human experimenter Outer chemotherapeutant.

3. for treating the Rui meter Si Ta or its salt or solvate that benign or malignant tumor becomes in human experimenter, wherein The human experimenter is Asian, and wherein the treatment includes by Rui meter Si Ta or its salt or solvate to be less than The daily dosage of 600mg Rui meter Si Ta gives the human experimenter, and gives human experimenter's at least one in addition Chemotherapeutant.

4. a kind of method treating benign or malignant tumor in human experimenter in need thereof and becoming, wherein the mankind Subject is Asian, and wherein the method includes by Rui meter Si Ta or its salt or solvate to be less than the auspicious rice of 600mg The daily dosage for taking charge of him gives the human experimenter, and at least one for giving human experimenter's therapeutically effective amount is another Outer chemotherapeutant.

5. purposes according to any one of claim 1 to 5, for the Rui meter Si Ta of the purposes or its salt or solvent Compound or method, wherein the other chemotherapeutant is molecular targeted dose.

6. the purposes according to any one of project 1 to 5, for the Rui meter Si Ta of the purposes or its salt or solvation Object or method, wherein the other chemotherapeutant is VEGFR inhibitor.

7. for the Rui meter Si Ta of the purposes or its salt or solvate, purposes according to any one of project 1 to 6 Or method, wherein the other chemotherapeutant is Sorafenib.

8. for the Rui meter Si Ta of the purposes or its salt or solvate, purposes according to any one of project 1 to 7 Or method, wherein giving Sorafenib to the human experimenter with the daily dosage of about 800mg.

9. according to claim 8 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes or side Method, wherein the treatment includes coming Rui meter Si Ta or its salt or solvate and Sorafenib by following dosage regimen every two weeks It gives:

A: the daily dosage for giving about 400mg Rui meter Si Ta continues 5 days, is then discontinued 9 days, and

B: the about 800mg daily dosage of Sorafenib is given.

10. according to claim 9 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes or side Method, it is characterised in that the reduction of the toxicity of Rui meter Si Ta and/or Sorafenib and the holding of anti-tumor activity.

11. for the Rui meter Si Ta of the purposes or its salt or solvate, use according to any one of project 1 to 10 Way or method, wherein the human experimenter is the member of Southeast Asian or Northeast Asia people's genetic group.

12. for the Rui meter Si Ta of the purposes or its salt or solvate, use according to any one of project 1 to 10 Way or method, wherein the human experimenter be Samoyed, Mongolian, Tibetans, Korean, Japanese, Ainu, South Chinese, Cambodia clansman, Thailander, Indonesian, Filipino or Malaysian's genetic group member.

13. for the Rui meter Si Ta of the purposes or its salt or solvate, use according to any one of project 1 to 10 Way or method, wherein the human experimenter is the member of Northeast Asia people's genetic group.

14. for the Rui meter Si Ta of the purposes or its salt or solvate, use according to any one of project 1 to 10 Way or method, wherein the human experimenter is Samoyed, Mongolian, Tibetans, Korean, Japanese or A Yinu The member of people's genetic group.

15. for the Rui meter Si Ta of the purposes or its salt or solvate, use according to any one of project 1 to 10 Way or method, wherein the human experimenter is the member of Korean or Japanese's genetic group.

16. for the Rui meter Si Ta of the purposes or its salt or solvate, use according to any one of project 1 to 15 Way or method, the salt of Qi Zhong Suo Shu Rui meter Si Ta are Rui meter Si Ta mesylates.

17. for the Rui meter Si Ta of the purposes or its salt or solvate, use according to any one of project 1 to 16 Way or method, wherein benign or malignant tumor change is cancer, especially hepatocellular carcinoma.

In the present invention, the daily dosage of Rui meter Si Ta is less than 600mg, in particular 550mg or less, more particularly 500mg less, is even more particularly 500mg or less, is even more particularly 450mg or less, even more particularly It is 400mg or less, is even more particularly 350mg or less, is even more particularly 300mg or less, even particularly Ground is 250mg or less, is even more particularly 200mg or less.

As used herein, Rui meter Si Ta (it is international nonproprietary name, i.e. INN) and (E) -3- [1- (4- dimethylamino Ylmethyl-benzenesulfonyl) -1H- pyrroles -3- base]-N- hydroxy-acrylamide (its chemical name) is interchangeably used, and two Person refers to the compound with following below formula:

In specific embodiment of the invention, the other chemotherapeutant is kinase inhibitor, in particular 3 class Kinase inhibitor, RAF inhibitor, VEGFR inhibitor come from multi-kinase inhibitor or tyrosine kinase inhibitor group in particular VEGFR inhibitor, be even more particularly VEGFR inhibitor selected from the group below, the group consisting of: relax Buddhist nun replace Buddhist nun, Sorafenib, thunder not Lu Dankang (ramucirumab) and vatarani (Vatalanib), and be even more particularly rope La Feini.

As used herein, molecular targeted dose be by with one or more molecular targets (for example, the albumen in patient Matter) specificity interaction and the chemotherapeutant that plays a role.This plays a role with by non-specific interaction Reagent on the contrary, such as, by DNA insertion or DNA modification (such as alkylation or DNA crosslinking) play a role cell Toxin agent.

As used herein, Sorafenib (it is international nonproprietary name) and 4- [4- [[4- chloro- 3- (trifluoromethyl) benzene Base] carbamoyl ammonia] phenoxy group]-N- methvl-pyridinium -2- formamide (its chemical name) is interchangeably used, and the two Refer to the compound with following below formula.Sorafenib is also with its trade (brand) nameAnd it is known.

The suitable salt of Rui meter Si Ta is acid-addition salts or the salt with alkali.Can pharmacologically be resistant to The inorganic acid and organic acid received, and pharmaceutically usually used alkali.Those suitable salt are on the one hand water-insolubles Also, in particular, water-soluble acid addition salts, these acid are used for salt with equimolar quantitative ratio or the ratio being different from In preparation, especially with the use of equimolar quantitative ratio.On the other hand, the salt with alkali is, and-depending on replacing-is equally suitable It closes, these alkali are with the quantitative ratio of equimolar or the ratio being different from salt pref.Pass through the common skill in this field Method known to art personnel will pharmacologically (it can for example make during commercial scale prepares Rui meter Si Ta not tolerable salt Obtained for process products) it is converted into the salt of pharmacologic tolerable.According to the present invention, such as when separating in crystalline form, Rui meter Si Ta and its salt may include different amounts of solvent.It therefore, within the scope of the invention include all solvates, and The particularly all hydrates and all solvates of Rui meter Si Ta, and particularly all hydrates of Rui meter Si Ta, it is special Other ground per molecule Rui meter Si Ta or its salt include such solvate or the hydration of about 0.5,1 or 2 solvate or hydrone Object.

Specific salt is the salt with the Rui meter Si Ta of methanesulfonic acid in the context of the present invention, is in about 1 in particular: 1 molar ratio.

Rui meter Si Ta and its salt can be prepared, for example, as respectively in 2005/087724 A2, WO 2007/39404 of WO It is described in detail in 2009/112529 A1 of A1 and WO.

Sorafenib is commercially available, and preparation method is well known.

Genetic group " Asian " " Southeast Asian, people from Northeast Asia, Samoyed, the Mongolian, Tibet being mentioned above People, Korean, Japanese, Ainu, South Chinese, Cambodia clansman, Thailander, Indonesian, Filipino or Malaysia People from West Asia " is interpreted as such as in Caralier-Si Fuzha (Cavalli-Sforza), Mai Nuozi (Menozzi) and skin Sa (Piazza), the history of human gene and geography (" The History and Geography of Human Genes "), 1994, Princeton University Press (Princeton University Press) (ISBN:9780691087504) is middle to be divided Class.

It is particularly defined as having aboriginal to originate from or people with ancestors term " Asian " herein, for example, tool There is at least one parent with aboriginal origin in the Far East or Southeast Asia, particularly including, such as China, Mongolia, Taiwan, newly Add slope, South Korea, Japan, Vietnam, Cambodia, Laos, Burma, Thailand, Malaysia, Indonesia and Philippine, but more special Not being does not include the Indian subcontinent.

In the present invention, subject is also based on the country of origin of its physical trait and/or its country of origin or its ancestors, leads to It crosses self identification (such as by questionnaire survey) or Asian is designated as by doctor's distribution, or including as defined herein Any specific group that Asian defines.

Asian descent can also be determined by the microsatellite marker described in known references.

Rui meter Si Ta and its corresponding salt are described in detail in the prior art (being included in references cited herein) And Sorafenib biology and pharmaceutical properties.

Cancer that is as used herein and being also known as malignant tumor change, is to be characterized in that Nasopharyngeal neoplasms to not With the medical conditions of organ or tissue.The example that the malignant tumor treated with the embodiment of the present invention becomes includes that solid tumor and blood are swollen Tumor.Solid tumor example be mammary gland, bladder, bone, brain, maincenter and peripheral neverous system, colon, endocrine gland (for example, thyroid gland and Adrenal cortex), esophagus, endometrium, reproduction cell, incidence, kidney, liver, lung, larynx and hypopharynx, celiothelioma, ovum The tumour of nest, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva.It dislikes Property tumor become include example into the hereditary cancer of retinoblastoma and nephroblastoma.In addition, it includes the device that malignant tumor, which becomes, Corresponding secondary tumors (" metastases ") in primary tumor and remote organ in official.Neoplastic hematologic disorder example is invasion With the leukaemia and lymthoma of painless form, i.e. non-Hodgkin lymphoma, chronic and acute myelocytic leukemia (CML/AML), urgency Property lymphoblastic leukemia (ALL), Hodgkin's disease, Huppert's disease and t cell lymphoma.It further include myelosis Abnormal syndrome, plasmacytoma change, paraneoplastic syndrome, the cancer of unknown original site and the relevant malignant tumour of AIDS.

In the context of the present invention specific cancer types be hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), Cancer of pancreas, cancer of bile ducts and skin T cell lymphoma (CTCL), more specifically HCC, CTCL and NSCLC.

In general, malignant tumour and carcinoid difference are four biological characteristics: structure, growth rate, invasive It grows and is grown by the dissemination of transfer.The abnormal of cell, which increases, to be had in common that for both benign and malignant tumours It grows.Because hdac inhibitor can be by the adjusting of cell cycle dependant gene and protein come Inhibit proliferaton or inducing cell Cycle arrest has confirmed malignant tumour, it is clear that hdac inhibitor can be also used for treatment benign tumor and become.

The concrete form that benign tumor in the context of the present invention becomes is polyp of colon, adenoma, papilloma, capsule gland Tumor, adenoma, vesicular mole (hydatiform moles), renal tubule adenoma, squamous cell papilloma, polyp of stomach, blood Tuberculation, osteoma, chondroma, lipoma, fibroma, lymphangioma, liomyoma, rhabdomyoma, neuroastrocytoma, mole, Meningioma, ganglioma and mullerianosis.For the information about mullerianosis and HDAC, referring to reproductive science (Reprod Sci.) in May, 2012；19(5):483-92.

Drug resistance is unsuccessfully especially important for the frequent of cancer therapy of standard.The drug resistance is by various cells And molecular mechanism, for example the overexpressions of multi-efflux pumps, the mutation in cell target protein or melted by what chromosome translocation was formed Caused by hop protein.The commercial suitability of Rui meter Si Ta is not limited to the First Line treatment of patient.To cancer chemotherapy or target The resistant patient of anticancer drug of specificity can also be subjected to reinstating Rui meter Si Ta continue such as second or third line control Treat the treatment in period.By the acute promyelocytic leukemia patient with PML-RAR alpha fusion protein, (it is yellow to being regarded with class The standard treatment of alcohol is resistant) give an example outstanding.By being treated with HDAC suppressive drug, such as Rui meter Si Ta, These patients can be made sensitive again to retinoids.

In the present invention, Rui meter Si Ta and at least one other chemistry can simultaneously, sequentially or individually be given Therapeutic agent.

In further context of the invention, term " activating agent ", which refers to, applies medical effect to disease or medical symptom The compound of (for example, it is alleviated), and the term particularly includes Rui meter Si Ta and Sorafenib.

In an embodiment of the present invention, which can be provided in include one or more activating agents and pharmacy In the pharmaceutical composition of upper acceptable carrier or diluent.Particularly, Rui meter Si Ta and Sorafenib can be provided in phase In same pharmaceutical composition (also known as fixed Combination) or individual pharmaceutical composition (for example, with two kinds of individual tablets).

Such pharmaceutical composition can be provided under the background of drug products, the background of the drug products includes for example a kind of Or a variety of pharmaceutical compositions and packaging material.The packaging material generally includes label or package insert, points out a kind of or more Kind activating agent can be used for treating disease detailed in this article.The packaging material, label and package insert are similar in other cases Or similar to the standard packaging material of the drug with related practicability being typically considered to, the article of label and package insert.

Pharmaceutical composition according to the present invention is prepared by method known per se and well known within the skill of those ordinarily skilled Object.As pharmaceutical composition, these activating agents use as it is, or preferably with suitable pharmaceutical auxiliary agent and/or excipient, Such as with tablet, coated tablet, capsule, caplet, suppository, patch (such as TTS), emulsion, suspension, gel or solution Form is applied in combination, which is advantageously between 0.1% and 95%, and wherein by proper choice of auxiliary agent And/or excipient, it may be implemented to fit entirely into the activating agent and/or be suitable for the drug administration form of desired role (for example, sustained release forms or enteric form).

Those of ordinary skill in the art are familiar with being suitable for desired medicament preparation due to his/her professional knowledge, The auxiliary agent of preparation or composition, medium, excipient, diluent, carrier or adjuvant.In addition to the solvent, gel can be used Forming agent, ointment bases and other excipient (such as antioxidant, dispersing agent, emulsifier, preservative, solubilizer, colorant, Complexing agent or penetrating agent).

Depending on the specific type of the benign or malignant tumor change up for treatment, can will optionally be generally given to control The other therapeutically active agent that the benign or malignant tumor becomes is treated, is given jointly with Rui meter Si Ta and Sorafenib.

The example of such other therapeutically active agent is the known chemotherapy anticancer agent for cancer therapy, these changes Learning therapy anticancer agent includes but is not limited to: (i) alkylating agent/carbamyl agent, such as cyclophosphamideDifferent ring phosphorus AmideThiotepaMelphalanOr chlorethylnitrosourea (BCNU)；(ii) platinum derivatives, as cis-platinum (BMS), oxaliplatin or carboplatin (BMS)；(iii) Antimitotic agent/Antitubulin, such as vinca alkaloids (vincristine, vinblastine, Vinorelbine), taxane Class, such as taxolTaxotereAnd analog, and new preparation and its conjugate；(iv) Topoisomerase enzyme inhibitor, as (example is Doxorubicin/Ehrlichin injection to anthracene nucleus medicament), table (example is Etoposide/Etopophos to podophyllotoxin) and camptothecin analogues (example be topotecan/and It is U.S. new)；(v) Pyrimidine antagonists, such as 5-fluor-uracil (5-FU), capecitabine (Xeloda), arabinosylcytosine/cytarabin (A Liekesang) or gemcitabine (gemzar)；(vi) purine antagonist, such as Ismipur6- thioguanine or fludarabine (Fuda China ) and last (vii) antifol, such as methotrexate (MTX)

For testing or the example of the target specificity anticancer drug classification of standard cancer therapies includes but is not limited to: (i) Kinase inhibitor, such as GleevecZD-1839/ IressaSU11248Or OSI-774/ Erlotinib(ii) proteasome inhibitor, such as PS-341 (iii) inhibitor of heat shock protein 90, such as 17-AAG (17-AAG)；(iv) blood-vessels target agent (VTA) With anti-angiogenetic therapy drug, such as VEGF antibody AvastinOr KDR tyrosine kinase inhibitor PTK787/ ZK222584 (vatarani)；(v) monoclonal antibodies, such as TrastuzumabOr must not Tumor/MabtheraThe conjugate of mutant and monoclonal antibody and antibody fragment；(vi) based on few core The therapy of thuja acid is received such as G-3139/ root and is thought carefully (vii) protease inhibitors (viii) hormonotherapy, such as Anti-estrogens (such as tamosifen), anti-androgens (such as Flutamide or Casodex), p-GLU-HIS-TRP-SER-TYR-D-TRP-LEU-ARG-PRO-GLY-NH2 are (such as bright third auspicious Woods, Goserelin or Triptorelin) and aromatase inhibitor.

The other known anticancer agent that can be used for conjoint therapy includes bleomycin, retinoids (such as total trans dimension first Sour (ATRA)), dnmt rna inhibitor (such as 2- '-deoxycytidine derivatives), Decitabine (Di Kagen ), Alanosine, cell factor (such as interleukin 2), interferons (such as interferon-' alpha ' 2 or interferon-γ), TRAIL, DR4/5 agonistic antibody, FasL and TNF-R agonist, and the last such as sulphonylpyrroles described in the present invention that are different from spread out The histone deacetylase inhibitor of biology, such as SAHA, PXD101, MS275, MGCD0103, depsipeptide/FK228, NVP- LBH589, valproic acid (VPA) and butyrate.

As the exemplary anticancer agent used in the complementary therapy being mentioned above with compound combination according to the present invention, It can be mentioned that following drug, and without being limited thereto: 5FU, actinomycin D, abarelix, Abciximab, Aclarubicin, A Dapa Woods, alemtuzumab, hemel, aminoglutethimide, amiprilose, Amrubicin, Anastrozole, ancitabine, qinghaosu, sulphur azoles Purine, basiliximab, bendamustine, Bicalutamide, bleomycin, Broxuridine, busulfan, capecitabine, carboplatin, card wave Quinone, Carmustine, Cetrorelix, Chlorambucil, mustargen, cis-platinum, Cladribine, Clomifene, cyclophosphamide, Dacarbazine, Daclizumab, dactinomycin D, daunorubicin, Deslorelin, dexrazoxane, docetaxel, deoxyfluorouridine, Doxorubicin, Droloxifene, dromostanolone, Edelfosine, Eflornithine, Emitefur, epirubicin, epithioandrostanol, eptaplatin, love must Appropriate, Estramustine, Etoposide, Exemestane, Fadrozole, Finasteride, floxuridine, Flucytosine, fludarabine, fluorine urine are phonetic Pyridine, Flutamide, Formestane, phosphonic acid, Fosfestrol, Fotemustine, fulvestrant, Gefitinib, gemcitabine, Gleevec, Goserelin, Gusperimus, Trastuzumab, darubicin, iodoxuridine, ifosfamide, Imatinib, Improsulfan, English sharp former times are single Anti-, Irinotecan, Lanreotide, Letrozole, Leuprorelin, lobaplatin, lomustine, melphalan, mercaptopurine, methotrexate (MTX), U.S. are appropriate TEPA, Miboplatin (miboplatin), mifepristone, Miltefosine, Mirimostim, mitoguazone, mitolactol, mitogen are mould Element, mitoxantrone, mizoribine, motexafin, Nartograstim, how to pull out pearl monoclonal antibody (nebazumab), Nedaplatin, Nilutamide, Nimustine, Octreotide, Ormeloxifene, oxaliplatin, taxol, palivizumab, Pegaspargase, training Filgrastim, spray are bent Peptide, Pentostatin, Perfosfamide, piposulfan, pirarubicin, plicamycin, prednimustine, procarbazine, Propagermanium, third Spiral shell oronain, Raltitrexed, Ranimustine, ranpirnase (ranpirnase), rasburicase, razoxane, Rituximab, Li Fu Flat, Ritrosulfan, Romurtide, Lu Baisita, Sargramostim, Satraplatin, rapamycin, Sobuzoxane, spiromustine, chain urea are mould Element, tamoxifen, tasonermin, tegafur, Temoporfin, Temozolomide, Teniposide, Testolactone, thiotepa, thymus gland method Newly, thiapurine, topotecan, Toremifene, Herceptin, Treosulfan, triethyleneiminobenzoquinone, Trimetrexate, Triptorelin, Trofosfamide, uredepa, valrubicin, Verteporfin, vinblastine, vincristine, eldisine, Vinorelbine and volt chlorine Azoles.

The other known anticancer agent that can be used for conjoint therapy includes being commonly referred to as immunologic test point inhibitor or short inspection The medicament of inhibitor is made an inventory of, that is, inhibits the medicament of inhibition checkpoint molecule, such as inhibition checkpoint molecule adenosine A 2 A receptor (A2AR), B7-H3 (also referred to as CD276), B7-H4 (also referred to as VTCN1), B and T lymphocyte attenuator (BTLA, also referred to as CD272), abbreviation (CTLA-4, also referred to as CD152), the indoleamine 2 of the relevant albumen 4 of cytotoxic t-lymphocyte, 3- is bis- to be added Oxygenase (IDO), killer cell immunoglobulin-like receptors (KIR), lymphocyte activation gene -3 (LAG3), programmed death 1 Receptor (PD-1) and 1 receptors ligand of programmed death (PD-L1), T cell immunoglobulin domains and mucoprotein structure Domain 3 (TIM-3), T cell activation V structure domain Ig inhibitor (VISTA, also referred to as C10 or f54).Such checkpoint inhibits The example of agent includes MGA271 (by macro genome company (MacroGenics)), her wooden monoclonal antibodySibutramine Hydrochloride wood monoclonal antibody (being Cp-675,206 in the past), Li Ruilu monoclonal antibody (Lirilumab), BMS-986016 (by BMS), BMS-936559/MDX- 1105 (by BMS), pyridine aldoxime methyliodide (PAM) monoclonal antibodyReceive military monoclonal antibodyGaliximab, IMP321 are (by immune Thailand General company (Immuntep)), BMS-663513 (by BMS), PF-05082566 (by Pfizer), IPH2101 is (by Ying Neite Drugmaker (Innate Pharma)/BMS), KW-0761 (by coordinate kylin company (Kyowa Kirin)), CDX-1127 (by Avant Immunotherapeutics Inc. (CellDex Therapeutics)), MEDI-6469 is (by Medimmune Inc. (Medimmune)/Astrazeneca AB (AstraZeneca)), MEDI4736 (by Astrazeneca AB), CP-870,893 (by Genentech corp (Genentech)), skin stand pearl monoclonal antibody (Pidilizumab), MPDL3280A (by genentech corp), AMP-514 (by Medimmune Inc./AZ), MEDI4736 (by Medimmune Inc./AZ), 12 peptide of AUNP are (by Australia Rui Jiyin (Aurigene) and Pierre's method C Compaq (Pierre Fabre)), MSB0010718C is (by Merck Xue Lannuo company (Merck Serono))。

In the practice of the present invention, and depend on it is above-mentioned they purposes details, feature or purpose, can be with Activating agent according to the present invention is pressed individually, sequentially, simultaneously or in chronological order across (for example, with combined list Position dosage form is tried with individual unit dosage forms or close to discrete unit dosage forms, with fixed or revocable combination, with multi-section point Agent box or with mixture) given with conjoint therapy.

" fixed Combination " is defined as a kind of combination, wherein the first active constituent (such as Rui meter Si Ta) and at least one are another Outer active constituent (such as Sorafenib) exists with a unit dose or with single entity together.One of " fixed Combination " Example is a kind of pharmaceutical composition, wherein first active constituent and the other active constituent exists with mixture For giving simultaneously, such as with single preparation.Another example of " fixed Combination " is a kind of pharmaceutical composition, wherein described the One active constituent and the other active constituent exist with a unit rather than with mixture.

" more part kits " is defined as a kind of combination, wherein first active constituent and the other work Property ingredient exists with more than one unit.One example of " more part kits " is a kind of combination, wherein the first described Active constituent and the other active constituent are individualisms.Can by the component of more part kits by individually, Sequentially, simultaneously or in chronological order give across.

The first active constituent and other active constituent of combination according to the present invention or more part kits can be by following Form is provided: as individual preparation (i.e. independently of one another), being subsequently put on and is used in conjoint therapy together together When, sequence, individually or cross-reference in chronological order；Or packed and presented together by the individual component of combination packet, it is used for In conjoint therapy simultaneously, sequence, individually or cross-reference in chronological order.

Combination according to the present invention or the first active constituent of more part kits and the drug of other active constituent are matched The type of product can be similar, i.e., two kinds of ingredients are all formulated in independent tablet or capsule, or can be different, i.e., suitable Different administration forms is closed, such as, a kind of active constituent is configured to tablet or capsule, and another kind is configured to be used for Such as vein is given.

Another aspect of the present invention is a kind of combination, which includes Rui meter Si Ta or its salt in the form of revocable, spy It is not standard treatment, especially technology known to Rui meter Si Ta mesylate (namely for methane sulfonate) and one or more technologies Known chemotherapy or target specificity anticancer agent, those of as alluded to above, especially Sorafenib is used in therapy In any order, sequence, individually, simultaneously or in chronological order cross-reference.Optionally, the combination includes it in therapy In purposes specification.

Another aspect of the present invention is a kind of combination formulations, such as more part kits comprising Rui meter Si Ta or its The preparation of salt and pharmaceutically acceptable carrier or diluent；Other active constituent, especially Sorafenib, and pharmaceutically may be used The carrier of receiving or the preparation of diluent；And intersection makes simultaneously, sequentially, individually or in chronological order optionally in therapy Specification.

Another aspect of the present invention is a kind of more part kits comprising the Rui meter Si Ta of dosage unit or its Salt, dosage unit ground other active constituent, especially Sorafenib, and optionally in therapy by simultaneously, sequence, Or the specification being used alone.

Another aspect of the present invention is a kind of drug products comprising Rui meter Si Ta, or one kind including the compound Or a variety of pharmaceutical compositions；With it is a kind of or more in therapeutic agent, especially Sorafenib known to technologies, or including the therapeutic agent One or more pharmaceutical compositions, in therapy by simultaneously, sequence or be used alone.Optionally, this drug products packet Include the specification used in the therapy.

Another aspect of the present invention is a kind of pharmaceutical composition as single formulation, includes Rui meter Si Ta with mixture Or its salt, active constituent in addition, the other active constituent are therapeutic agent known to technology, especially Sorafenib, and Optional pharmacologically acceptable carrier, diluent or excipient.

Another aspect of the present invention is a kind of commercial packing comprising Rui meter Si Ta or its salt together with one or more skills Standard care agent known to art, especially Sorafenib simultaneously, sequence or the specification that is used separately.

In addition, combination according to the present invention can be used for the preoperative or aftertreatment that benign or malignant tumor becomes.

It is further supplementing, combination according to the present invention can be applied in combination with radiotherapy, particularly make to suffer from Person is to the sensitive aspect of Standard radiometric therapy.

Combination according to the present invention and giving for pharmaceutical composition according to the present invention can be available by any this field It is generally accepted to give mode progress.The suitable illustrative examples for giving mode include intravenous, mouth, nose, parenteral, office Portion, percutaneous and rectal delivery.It is preferred that oral and intravenous delivery.

In an embodiment of the present invention, dosage refers to the free form (trip of the i.e. described compound about the compound From sour form or free alkali form) compound amount.Therefore, the adduction object of this free acid or free alkali form, salt etc. are real Border will be given with corresponding higher doses, in order to illustrate the weight of counter ion or addition gametophyte.For example, about Rui meter Si Ta Mesylate, " dosage of 400mg Rui meter Si Ta " are related to the 510mg Rui meter Si Ta mesylate-include (by what is rounded up) 400mg Rui meter Si Ta free alkali and 110mg methanesulfonic acid (molecular weight=349,4 of Rui meter Si Ta；Point of Rui meter Si Ta mesylate Son amount=445,5；Therefore 400:349,4*445,5=510).

The present invention is described in detail, the scope of the present invention is not limited only to described those of feature or embodiment. Such as those of ordinary skill in the art will be apparent that, can on the basis of knowledge known to technology and/or, specifically, On the basis of disclosure content (for example, specific, implicit or intrinsic disclosure content) of the invention, without departing from such as appended In the case where the spirit or scope of the present invention defined in the scope of the claims, the described present invention is modified, class Than, variation, derive, assimilation and reorganization.

In the present invention, giving for activating agent can follow certain scheme, may include giving activating agent daily Period and the period for not giving activating agent.For example, such scheme can be made of the following repetition period: giving work within 5 days Activating agent (" rest period ") (14 day period) is not given in property agent (or Rui meter Si Ta) for subsequent 9 days, gives within 5 days activating agent (or auspicious rice Take charge of him) subsequent 16 days rest periods (21 day period) or give within 14 days activating agent (or Rui meter Si Ta) subsequent 7 days rest periods (21 day period).

Example

Following embodiment is for further illustrating the present invention without limiting the present invention.

Clinical research:

First research (the FIM in the mankind；7341/EM-001): this is one in the patient for suffering from late malignant tumour In take orally that giving the open-label of Rui meter Si Ta, dosage escalation, the I phase studies.This research is carried out in Britain.Including with pair In the primary or metastatic solid tumors that standard treatment is refractory or records without histology existing for standard treatment or cytology Patient.Tumour is progressive (new or progressive lesion or the PSA of rising).In addition, patient will have good behavior State (ECOG 0-1), enough livers, kidney, heart and marrow function, and there is the life expectancy of the estimation greater than 12 weeks.With The treatment of Rui meter Si Ta is made up of: taken orally once a day to the 5th day on day 1 during 14- days treatment cycles to It gives, is followed by rest 9 days.The sequence group of patient, including 7 patients are treated with the Rui meter Si Ta of ascending-dose with 800mg.

SAPHIRE (4SC-201-2-2009): this is one in the patient with advanced stage hodgkin's lymphomas (HL) The oral open-label for giving Rui meter Si Ta, the II phase is studied.The main purpose of the research is the repetition mouth of determining Rui meter Si Ta Take the objective reactivity (ORR) of dosage.Secondary objective is safety and tolerance, effect, the medicine assessed with Rui meter Si Ta treatment For dynamics and pharmacodynamics.Terminal includes OS, PFS, TTP and reaction phase (DOR).The research is in Czech Republic, Poland It is carried out with Rumanian 5 centers.This research include based on international working group (IWG) reaction normal, with through histology or The patient of recurrent or intractable HL that cytology confirms.Patient should have good behavior state (ECOG 0-1) and enough Liver, kidney, heart and marrow function.During the major part of this research, during 14- days treatment cycles, on day 1 extremely Patient is treated once a day with 600mg or 800mg Rui meter Si Ta 5th day, then rest 9 days.Treatment patient at least 12 weeks (6 A treatment cycle) or until tumour progression.After 12 weeks, the patient of no progressive disease be can choose in the subsequent portion of the research Continue to be treated with Rui meter Si Ta up to 1 year in point.

SHORE (4SC-201-3-2010): this be one with advanced colorectal cancer (CRC) patient in take orally to The open-label I/II phase for giving Rui meter Si Ta is studied.It combines Rui meter Si Ta with standard FOLFIRI scheme and gives.The I of the research Phase dosage escalation part carries out at 2 centers of Germany.This research includes with the advanced stage CRC confirmed through histology or cytology Patient.Patient should receive the treatment for being previously directed to advanced stage CRC, and it is contemplated that the second line or third gamma therapy It is middle to carry out chemotherapy with FOLFIRI.Main eligibility criteria includes the behavior state of ECOG0-2, enough livers, kidney, heart And marrow function, and >=12 weeks life expectancies.Treatment is by being made up of: the 1st day during 14- days treatment cycles It was taken orally once-or twice-a-day to the 5th day and gives Rui meter Si Ta, then rest 9 days.The 3rd of each Rui meter Si Ta treatment cycle the It and give FOLFIRI within the 4th day.During dosage escalation, with the 3-8 name patient of ascending-dose treatment sequence group, therein 8 Name patient receives 2x 400mg Rui meter Si Ta+FOLFIRI daily.

Research YHI-1001-ST-01: this be one with advanced solid tumor asian patients in take orally give Rui meter Si His open-label I phase is studied.The main purpose of the research is determined based on dose-limiting toxicity (DLT) and safety The maximum tolerated dose (MTD) of Rui meter Si Ta in asian patients group.Secondary objective is that the repetition of assessment Rui meter Si Ta is oral Pharmacokinetics, pharmacodynamics and the effect of dosage.This research carries out at a single center of Japan.This research includes Patient with the advanced solid tumor through histology or cytology confirmation, the standard treatment of these patient experiences failure or to it There is no available therapeutic choice.Main eligibility criteria includes the behavior state of ECOG 0-1, enough livers, kidney, heart and bone Marrow function, and the life expectancy greater than 12 weeks.During 14 days treatment cycles, used once a day to the 5th day on day 1 The 3-6 name of the Rui meter Si Ta treatment sequence group of the ascending-dose of 400mg (N=3), 600mg (N=3) or 800mg (N=6) Patient then rests 9 days.It amounts to, 12 patients is treated at least two treatment cycle, or until tumour progression or patient are discontinued.

Research YHI-1001-HCC-02: this is a chemotherapy in the previous virgin system with advanced stage HCC (the first gamma therapy) treatment patient in open-label, the multicenter I/II phase study, with determine MTD and with assessment in Asia The safety and effect of the Rui meter Si Ta combined in the PATIENT POPULATION of continent with Sorafenib.The research is carried out in Japan and South Korea.It is main The eligibility criteria wanted included the behavior state of ECOG 0-1, enough livers, kidney, heart and marrow function, and greater than 12 weeks Life expectancy.

In the phase part I, with Rui meter Si Ta and the 800mg Suo Lafei of the ascending-dose of 400mg (N=3) or 600mg (N=6) Buddhist nun combines to treat the 3-6 name patient of sequence group.Treatment is made up of: during 14 days treatment cycles, being given 5 days The Rui meter Si Ta of 400mg daily dosage is then discontinued 9 days, and gives the Sorafenib of 800mg daily dosage.It amounts to, by 9 Name patient treats at least two treatment cycle, or until tumour progression or patient are discontinued.Under the dosage of 400mg Rui meter Si Ta, 2 Name patient realizes part reaction (PR), and 1 patient suffers from stable disease (SD).In the dosage of 600mg Rui meter Si Ta Under, PR is realized without patient, and 4 patients suffer from SD.Under the dosage of 600mg Rui meter Si Ta, a kind of only dosage is observed Restricted toxicity is 4 grades of thrombopenias.It shows being observed during preceding 2 periods and is related to auspicious in the following table 3 The major toxicity that meter Si Ta gives.

The collection and preparation of plasma sample:

Venous blood sample (2ml) is collected in 3ml K₂EDTA vacuum blood collection tube (BD company (Becton Dickinson) 13x 75mm) in, then careful rotation 8-10 times, and be placed on ice.After blood collection in 15 minutes, by sample in 2700x 10min is centrifuged at g and+4 DEG C.Supernatant (blood plasma) is transferred in PA tube, and is freezed at -80 DEG C immediately.

PK measurement:

Each PK is measured, the human plasma sample of 200 μ L is added to the internal standard work of the 50 μ L in 96 hole deep hole blocks Make solution (the 20 μ g/L D in human plasma₆- Rui meter Si Ta [two (three-deuterated-methyl)-amino methyl-derivatives]) in.With Afterwards, diisopropyl ether/isoamyl alcohol (80/20v/v) of 600 μ L is drawn into each chamber.It is acutely automatic mixed after the sealing of deep hole block It closes (5min), is then centrifuged (5min, 3000rpm).The organic layer (upper layer) of the 500 μ L from each hole is transferred to In two deep-well plates.After evaporating under nitrogen flowing, by the residue water rehydration of the DMSO and 30 μ L of 30 μ L.10 μ L are injected into 2 μ In the sample loop of L, analyzed for HPLC-MS/MS.In LunaC18、5μm、50mm x 2mm On analytical column, chromatography is carried out using column switching technique under biserial mode with the flow velocity of 0.5mL/min.Mobile phase A: it is wrapping 5mM ammonium formate (315.3mg/L) in water containing 0.2% formic acid, v/v；Mobile phase B: in the acetonitrile/water comprising 0.2% formic acid 5mM ammonium formate (315.3mg/L) in 95/5 (v/v), v/v；

It is used under MRM mode (multiple-reaction monitoring) in three pole quadrupole mass spectrometer of API 3000 (MDS Sciex)Interface is analyzed by mass spectrometry.The mass spectrograph in positive ion mode use in the aqueous ammonium formate of 5mM from The linear gradient of 4.75% to 95% acetonitrile is operated.Seleced precursor and product ion for Rui meter Si Ta are respectively In m/z 350.0 and m/z 317.0.It is in m/z 356.2 respectively for the seleced precursor of interior target and product ion With m/z 323.0.Based on 200 μ L human plasmas, the lower limit of quantitation (LLOQ) for BYK409578 is 0.100 μ g/L, and quantitative The upper limit (ULOQ) is 100 μ g/L.(1/x2 is analyzed using weighted linear regression；Concentration square weighting), which is linear 's.Related coefficient (r) range from 0.9965 to 0.9988 of the calibration curve.

Adverse events

It studies in FIM Dosage and is studied in the two in YHI-1001-ST-01 Dosage, have recorded and be related to auspicious rice Take charge of the adverse events that he gives.Result about cytopenia is shown in the following table.

Table 1: research FIM；The west 7341/EM-001-/caucasian patient

Table 2: research YHI-1001-ST-01- Japanese patients

Table 3: research YHI-1001-HCC-02- Japanese patients

According to the phase part I as a result, the dosage of the 400mg Rui meter Si Ta combined with Sorafenib shows rice more auspicious than 600mg Take charge of his the higher validity of dosage and tolerance.

However an example cytopenia only occurs in Western patients, more asian patients when being treated with Rui meter Si Ta Such event occurs.

Particularly, 600mg/ days dosage shows the increase of cytopenia in asian patients, and the disease is in Western patients In be not observed, and however be within 400mg/ days well-tolerated in asian patients.

Westerner/Asian PK compares

Exploratory data analysis and the determination of AUC value are to be based on carrying out following research using software program WinNonLin Non- room between analysis (NCA) carry out.From in the period 1, the 1st day Asia and west I phase patient (combined FIM, SAPHIRE and SHORE comparative study YHI-1001-ST-01) corresponding 800mg group AUC_0-6hComparison result be Average AUC westerner compares between Asian without significant difference (double tail t are examined).As a result it is illustrated in Fig. 1.

These results show the influence to asian patients tolerance independently of Pharmacokinetic effect.

Claims (according to the 19th article of modification of treaty)

1. Rui meter Si Ta or its salt or solvate are used to manufacture for treating benign or malignant tumor change in human experimenter Purposes in drug, wherein the human experimenter is Asian, and wherein the treatment includes by Rui meter Si Ta or its salt Or solvate to be to give the human experimenter less than the daily dosage of 600mg Rui meter Si Ta, and give the mankind by At least one other chemotherapeutant of examination person.

2. Rui meter Si Ta or its salt or solvate are used to treat the purposes that benign or malignant tumor becomes in human experimenter, wherein The human experimenter is Asian, and wherein the treatment includes by Rui meter Si Ta or its salt or solvate to be less than The daily dosage of 600mg Rui meter Si Ta gives the human experimenter, and gives human experimenter's at least one in addition Chemotherapeutant.

3. for treating the Rui meter Si Ta or its salt or solvate that benign or malignant tumor becomes in human experimenter, wherein described Human experimenter is Asian, and wherein the treatment includes by Rui meter Si Ta or its salt or solvate less than 600mg The daily dosage of Rui meter Si Ta gives the human experimenter, and gives at least one other chemistry of the human experimenter Therapeutic agent.

4. a kind of method treating benign or malignant tumor in human experimenter in need thereof and becoming, wherein the human subjects Person is Asian, and wherein the method includes by Rui meter Si Ta or its salt or solvate to be less than 600mg Rui meter Si Ta Daily dosage give the human experimenter, and give at least one other of human experimenter's therapeutically effective amount Chemotherapeutant.

5. purposes according to any one of claim 1 to 4, for the Rui meter Si Ta of the purposes or its salt or solvation Object or method, wherein the other chemotherapeutant is molecular targeted dose.

6. purposes according to any one of claim 1 to 5, for the Rui meter Si Ta of the purposes or its salt or solvation Object or method, wherein the other chemotherapeutant is VEGFR inhibitor.

7. according to any one of claim 1 to 6 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes Or method, wherein the other chemotherapeutant is Sorafenib.

8. according to any one of claim 1 to 7 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes Or method, wherein giving Sorafenib to the human experimenter with the daily dosage of about 800mg.

9. it is according to claim 8 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes or method, Described in treatment include giving Rui meter Si Ta or its salt or solvate and Sorafenib by following dosage regimen every two weeks: A: the daily dosage for giving about 400mg Rui meter Si Ta continues 5 days, is then discontinued 9 days and b: giving about 800mg Sorafenib Daily dosage.

10. it is according to claim 9 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes or method, It is characterized in that the reduction of the toxicity of Rui meter Si Ta and/or Sorafenib and the holding of anti-tumor activity.

11. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter is the member of Southeast Asian or Northeast Asia people's genetic group.

12. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter be Samoyed, Mongolian, Tibetans, Korean, Japanese, Ainu, South Chinese, Cambodia clansman, Thailander, Indonesian, Filipino or Malaysian's genetic group member.

13. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter is the member of Northeast Asia people's genetic group.

14. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter is Samoyed, Mongolian, Tibetans, Korean, Japanese or A Yinu The member of people's genetic group.

15. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter is the member of Korean or Japanese's genetic group.

16. according to claim 1 to the Rui meter Si Ta or its salt or solvate, use for being used for the purposes described in any one of 15 Way or method, the salt of Qi Zhong Suo Shu Rui meter Si Ta are Rui meter Si Ta mesylates.

17. according to claim 1 to the Rui meter Si Ta or its salt or solvate, use for being used for the purposes described in any one of 16 Way or method, wherein benign or malignant tumor change is cancer, especially hepatocellular carcinoma.

18. according to claim 1 to the Rui meter Si Ta or its salt or solvate, use for being used for the purposes described in any one of 17 Way or method, wherein treatment malignant tumor becomes, it includes solid tumor and neoplastic hematologic disorder that the malignant tumor, which becomes, and the solid tumor is selected from: cream Gland, bladder, bone, brain, maincenter and peripheral neverous system, colon, endocrine gland (for example, thyroid gland and adrenal cortex), esophagus, It is endometrium, reproduction cell, incidence, kidney, liver, lung, larynx and hypopharynx, celiothelioma, ovary, pancreas, prostate, straight Intestines, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva solid tumor；The malignant tumor change can be selected It is corresponding secondary swollen in the primary tumor and remote organ in retinoblastoma and nephroblastoma, organ from example The cancer of tumor (" metastases ")；The neoplastic hematologic disorder be selected from invasion and painless form leukaemia and lymthoma, i.e., it is non-suddenly Odd gold sick, chronic and acute myelocytic leukemia (CML/AML), acute lymphoblastic leukemia (ALL), Huo Qijin Disease, Huppert's disease and t cell lymphoma, myelodysplastic syndrome, plasmacytoma become, paraneoplastic syndrome, not Know the cancer and the relevant malignant tumour of AIDS of original site.

19. according to claim 1 to the Rui meter Si Ta or its salt or solvate, use for being used for the purposes described in any one of 17 Way or method, wherein the benign or malignant tumor become selected from hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), cancer of pancreas, Cancer of bile ducts and skin T cell lymphoma (CTCL), more specifically HCC, CTCL and NSCLC.

Claims

1. Rui meter Si Ta or.

2. its salt or solvate are used to manufacture for treating the use in the drug that benign or malignant tumor becomes in human experimenter On the way, wherein the human experimenter is Asian, and wherein the treatment includes by Rui meter Si Ta or its salt or solvate The human experimenter is given with the daily dosage less than 600mg Rui meter Si Ta, and gives the human experimenter at least one The other chemotherapeutant of kind.

3. Rui meter Si Ta or its salt or solvate are used to treat the purposes that benign or malignant tumor becomes in human experimenter, wherein The human experimenter is Asian, and wherein the treatment includes by Rui meter Si Ta or its salt or solvate to be less than The daily dosage of 600mg Rui meter Si Ta gives the human experimenter, and gives human experimenter's at least one in addition Chemotherapeutant.

4. for treating the Rui meter Si Ta or its salt or solvate that benign or malignant tumor becomes in human experimenter, wherein described Human experimenter is Asian, and wherein the treatment includes by Rui meter Si Ta or its salt or solvate less than 600mg The daily dosage of Rui meter Si Ta gives the human experimenter, and gives at least one other chemistry of the human experimenter Therapeutic agent.

5. a kind of method treating benign or malignant tumor in human experimenter in need thereof and becoming, wherein the human subjects Person is Asian, and wherein the method includes by Rui meter Si Ta or its salt or solvate to be less than 600mg Rui meter Si Ta Daily dosage give the human experimenter, and give at least one other of human experimenter's therapeutically effective amount Chemotherapeutant.

6. purposes according to any one of claim 1 to 4, for the Rui meter Si Ta of the purposes or its salt or solvation Object or method, wherein the other chemotherapeutant is molecular targeted dose.

7. purposes according to any one of claim 1 to 5, for the Rui meter Si Ta of the purposes or its salt or solvation Object or method, wherein the other chemotherapeutant is VEGFR inhibitor.

8. according to any one of claim 1 to 6 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes Or method, wherein the other chemotherapeutant is Sorafenib.

9. according to any one of claim 1 to 7 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes Or method, wherein giving Sorafenib to the human experimenter with the daily dosage of about 800mg.

10. it is according to claim 8 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes or method, Wherein the treatment include by Rui meter Si Ta or its salt or solvate and Sorafenib by following dosage regimen every two weeks come to Give: a: the daily dosage for giving about 400mg Rui meter Si Ta continues 5 days, is then discontinued 9 days and b: giving about 800mg Sorafenib Daily dosage.

11. it is according to claim 9 for the Rui meter Si Ta of the purposes or its salt or solvate, purposes or method, It is characterized in that the reduction of the toxicity of Rui meter Si Ta and/or Sorafenib and the holding of anti-tumor activity.

12. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter is the member of Southeast Asian or Northeast Asia people's genetic group.

13. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter be Samoyed, Mongolian, Tibetans, Korean, Japanese, Ainu, South Chinese, Cambodia clansman, Thailander, Indonesian, Filipino or Malaysian's genetic group member.

14. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter is the member of Northeast Asia people's genetic group.

15. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter is Samoyed, Mongolian, Tibetans, Korean, Japanese or A Yinu The member of people's genetic group.

16. according to any one of claim 1 to 10 for the Rui meter Si Ta of the purposes or its salt or solvate, use Way or method, wherein the human experimenter is the member of Korean or Japanese's genetic group.

17. according to claim 1 to the Rui meter Si Ta or its salt or solvate, use for being used for the purposes described in any one of 15 Way or method, the salt of Qi Zhong Suo Shu Rui meter Si Ta are Rui meter Si Ta mesylates.

18. according to claim 1 to the Rui meter Si Ta or its salt or solvate, use for being used for the purposes described in any one of 16 Way or method, wherein benign or malignant tumor change is cancer, especially hepatocellular carcinoma.