CN109985039A - For treating the combination medicine of leukaemia and its preparing the purposes in the drug for treating acute myeloid leukaemia - Google Patents
For treating the combination medicine of leukaemia and its preparing the purposes in the drug for treating acute myeloid leukaemia Download PDFInfo
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- CN109985039A CN109985039A CN201810892420.3A CN201810892420A CN109985039A CN 109985039 A CN109985039 A CN 109985039A CN 201810892420 A CN201810892420 A CN 201810892420A CN 109985039 A CN109985039 A CN 109985039A
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- chidamide
- leukaemia
- dcag
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- 208000031261 Acute myeloid leukaemia Diseases 0.000 title claims abstract description 50
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Classifications
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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
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A—HUMAN NECESSITIES
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The present invention relates to field of medicaments, more particularly to it is a kind of for treating the combination medicine of leukaemia, including the chidamide and DCAG drug with effective dose for simultaneously, respectively or being successively administered, the DCAG drug is the composition of medicine of Decitabine, cytarabine, aclacinomycin and granulocyte colony stimulating factor.The present invention provides chidamide joint DCAG to prepare the purposes in the drug for treating acute myeloid leukaemia, the beneficial effect is that: solve the problems, such as that the recurrence of existing AML Combination chemotherapy is refractory, its complete remission rate (CR) for treating the refractory patients with acute myeloid leukemia of recurrence has reached 43.6%, and objective remission rate (ORR) has reached 58.2%.
Description
This application claims in submission on December 29th, 2017 Patent Office of the People's Republic of China, application No. is 201711485562.X, invention
Entitled " combination medicine for treating leukaemia and its use in drug of the preparation for treating acute myeloid leukaemia
The priority of Chinese patent application on the way ", entire contents are hereby incorporated by reference in the application.
Technical field
It is used the present invention relates to field of medicaments more particularly to a kind of combination medicine for treating leukaemia and its in preparation
Purposes in the drug for the treatment of acute myeloid leukaemia, specifically chidamide joint other drugs are in preparation for treating urgency
Purposes and combination medicine in the drug of property myelogenous leukemia.
Background technique
Leukaemia (being commonly called as leukemia) is a kind of candidate stem cell malignant clone disease, by the emergency of onset can be divided into it is anxious,
Chronic leukemia;By sick cell series classification, the T and B cell of grain, single, red, macronucleus system including medullary system and Lymphatic System
System;Leukaemia is often clinically divided into lymphocytic leukemia, myelocytic leukemia, cell mixing leukaemia etc..Wherein, acute
Myelocytic leukemia (acute myelocytic leukemia, AML) or acute non lymphocytic leukemia (ANLL), including
The acute leukemia in all non-lymphocyte sources.It is that multipotential stem cell or the precursor caryogram slightly broken up occur to dash forward
Change is formed by a kind of disease, is the Clonal malignant disease of hemopoietic system.Crowd receives large dosage of radioactive ray or Long Term Contact
The chemical substances such as benzene and its derivative can increase the disease incidence of this kind of disease.Acute myelocytic leukemia, which is one, has height
Heterogeneous disease group, it can be turned by the pernicious change of hematopoietic progenitor cells of different phase during normal myeloid cell differentiation and development
Change, the AML originating from different phase progenitor cells has different biological properties.
Currently, the treatment for AML, in addition to acute promyelocytic leukemia, still based on joint chemotherapy.
The classical induction chemother of acute myeloid leukaemia (AML) is DA scheme, comprising: daunorubicin (DNR) 45~60mg/ (m2·d)
(the 1st~3 day)+cytarabine (Ara-C) 100mg/ (m2D) (the 1st~5 day or the 1st~7 day);First course for the treatment of complete incidence graph
Rate (CR) is 40%~50%;Second course for the treatment of is up to 60%~75%.
Other induction chemother schemes include: 1. AID scheme: cytarabine (Ara-C)+idarubicin (goes methoxy soft red mould
Element, IDA) or cytarabine (Ara-C)+idarubicin (IDA)+Etoposide (VP-16) (ICE);2. cytarabine (Ara-
C)+daunorubicin (DNR)+thioguanine (6-TG);3. mitoxantrone (NVT)+Etoposide (VP-16) (ME) etc..
Using above-mentioned induction chemother scheme, the total complete remission rate of AML patient only 50%~70%, long-term disease-free survival rate
It is 25%~30%.With the continuous improvement of combined chemotherapy mode, the remission rate of AML and life cycle increase.But with
Upper AML therapeutic scheme can not still overcome the recurrent and refractory of AML, for current therapeutic modality, if it is 1 year after alleviating for the first time
The AML patient of interior recurrence, CR rate is down to 10~15% (Felicitas Thol, Richard F.Schlenk, Michael
Heuser,and Arnold Ganser.How I treat refractory and early relapsed acute
myeloid leukemia:《Blood》,2015,126(3):319)。
Recurrent AML is defined as: complete incidence graph (CR) afterwards peripheral blood reappear leukaemia cell or bone marrow blast >
There is leukemiacell infiltration outside 0.05 (removing marrow-reconstitution after other reasons, such as strengthening measures) or marrow.Intractable AML
Is defined as: (1) 2 courses for the treatment of of standard scheme induction chemother do not obtain CR;Recidivist in 6 months after (2) the 1st CR;(3) the 1st CR
Afterwards recurrence after 6 months, through former scheme induction chemother loser again;(4) 2 times or 2 times or more recidivists;(5) Extramedullary leukemia is held
It renews.Therefore, it is necessary to explore novel, effective, safe drugs therapeutic scheme.
Summary of the invention
In view of this, the combination medicine that the purpose of the present invention is to provide a kind of new for treating leukaemia and its
The purposes for treating the drug of acute myeloid leukaemia is prepared, combination medicine provided by the invention can solve existing AML connection
Close the refractory problem of recurrence of chemotherapy regimen.
The present invention provides a kind of for treating the combination medicine of leukaemia, comprising: chidamide and DCAG drug, it is described
DCAG drug is the composition of medicine of Decitabine, cytarabine, aclacinomycin and granulocyte colony stimulating factor.
Combination medicine provided by the present invention for treating leukaemia includes chidamide;(English is entitled for chidamide
Chidamide, trade name love spectrum are husky), it is a kind of subtype-selective histon deacetylase (HDAC) (HDAC) inhibitor, is 1.1
Kind new medicine.The chemical name of chidamide is N- (2- amino -4- fluorophenyl) -4- (N- (3- pyridine acryloyl group) aminomethyl) benzene
Formamide, chemical structure is as shown in structural formula 1:
The first indication of chidamide --- single therapy relapsed or stubborn lymphoma peripheral T cell (PTCL), in
Obtain state food pharmaceuticals administration general bureau (CFDA) listing approval on December 23rd, 2014.Currently, chidamide there is no through infusing
Other indications of volume approval.
Combination medicine provided by the present invention for treating leukaemia includes DCAG drug, and the DCAG drug is ground west
His shore, cytarabine, aclacinomycin and granulocyte colony stimulating factor composition of medicine (combination medicine, DCAG scheme),
It is represented by Decitabine+cytarabine+aclacinomycin+granulocyte colony stimulating factor.Wherein:
Decitabine (English name Decitabine), its chemical name is 5- azepine-deoxycytidine,
It is a kind of chemotherapeutics, clinical report shows that it has broad-spectrum anti-tumor activity to blood borne pernicious canceration and solid tumor.
It is anxious to be mainly used for acute myeloblastic leukemia etc. for anti-pyrimidine drug for cytarabine (Ara-C, Cytarabine)
Property leukaemia, generally merges application with other drugs.
Aclacinomycin (English alias: Aclarubicin), also known as Aclarubicin are anthracyclines, are mainly used for
Acute granulocytic leukemia, acute lymphatic leukemia, malignant lymphoma are treated, to gastric cancer, lung cancer, breast cancer, ovum
Nest cancer is also effective.
Granulocyte colony stimulating factor (G-CSF), is a kind of glycoprotein, mainly acts on neutrophil series
(lineage) proliferation of hematopoietic cell, differentiation and activation.
The embodiment of the invention provides for treat leukaemia, particularly for treat acute myeloid leukaemia drug combination
Object includes: the chidamide with effective dose, Decitabine, cytarabine for simultaneously, respectively or being successively administered, Ah
Clarithromycin and granulocyte colony stimulating factor.Chidamide is combined above-mentioned DCAG drug by the present invention, is applied to acute myelogenous
The therapeutic agent of leukaemia can play synergistic effect, can solve the problems, such as that the recurrence of existing AML Combination chemotherapy is refractory.
In a preferred embodiment of the invention, described white for treating for the different subjects of 35~90 kg body weights
The combination medicine of blood disease includes the active constituent of following effective dose:
The chidamide of 180mg;20mg/m2Decitabine;10mg/m2Aclacinomycin;50~100mg/m2Ah
Sugared cytidine;With 300 g/ days granulocyte colony stimulating factors of μ.
Wherein, the X-ray powder diffraction figure of the crystal form of the chidamide 2 θ of angle of reflection be 4.18 °, 6.61 °,
8.42°、12.69°、17.85°、18.34°、19.27°、20.10°、20.59°、21.58°、23.70°、23.96°、25.52°、
There is characteristic peak at 27.00 °, 27.90 °, 29.59 ° and 29.94 °;Its infrared spectroscopy 3412,3282,3199,3043,1654,
1615,1524,1514,1497,1442,1418,1332,1296,1234,1198,1183,1166 and 1027cm-1There is feature at place
Absorption peak;Its differential scanning calorimetric analysis curve has endothermic peak at 239.4 DEG C, referring to Chinese patent CN103833626B text
It offers;The granulocyte colony stimulating factor can be recombined human granulocyte stimulating factors.
In a preferred embodiment of the invention, described for treating the connection of leukaemia in addition to above-mentioned active pharmaceutical ingredient
Combination with medication further includes pharmaceutically acceptable carrier, i.e., also includes pharmaceutical acceptable carrier.Pharmaceutical acceptable carrier includes: " acceptable excipients
Agent handbook " " pharmaceutic adjuvant handbook " (Handbook for publishing of (American Pharmaceutical Association, in October, 1986) or Chemical Industry Press
Of Pharmaceutical Excipients, original work fourth edition) listed by carrier auxiliary material, be preferred for the medicinal of tablet formulation
Auxiliary material, but it is not limited to these pharmaceutic adjuvants.
In a specific embodiment of the present invention, the chidamide uses dosage form, as chidamide preparation, including
Active constituent chidamide and pharmaceutically acceptable carrier;Common pharmaceutical formulation can be made, such as tablet, capsule, liquid
The common carriers object such as fragrance, sweetener, liquid, solid packing or diluent can also be added in agent, pulvis, injection, suspending agent
Matter, the present invention are not particularly limited.Specifically, said preparation usually contains the effective component of 1~70wt%, and preferable content is 5~
50%, remaining group is divided into carrier filler, diluent or solvent.In the present invention, the chidamide preferably uses oral preparation
Form, more preferably tablet formulation.
In a specific embodiment of the present invention, the DCAG drug uses dosage form, it is preferred to use ejection preparation is adopted
It is injection Decitabine, cytarabine for injection, injection aclacinomycin and granulocyte with the DCAG drug of ejection preparation
Colony stimulating factor injection.The present invention is also not particularly limited pharmaceutical acceptable carrier in ejection preparation, using corresponding normal
Advise marketed drugs injection.
The present invention also provides combination medicines as described above in the drug that preparation is used for acute myeloid leukaemia
Purposes, i.e., the present invention provides chidamide joint DCAG to prepare the use in the drug for treating acute myeloid leukaemia
On the way, the DCAG is the combination medicine of Decitabine, cytarabine, aclacinomycin and granulocyte colony stimulating factor.
In a preferred embodiment of the invention, the acute myeloid leukaemia is to recur refractory acute myeloid leukaemia.
For different subjects, 67 ± 20 kilograms of male's weight (47-87 kilograms), 55 ± 20 kilograms of women weight (35-75 kilograms),
Specifically application scheme includes:
Chidamide 180mg, d1 starts to take orally, 2 weeks oral;
Decitabine 20mg/m2, intravenously administrable, d1-d5;
Aclacinomycin 10mg/m2, intravenously administrable, d3-d7;
50~100mg/m of cytarabine2, intravenously administrable, q12h;
300 μ of granulocyte colony stimulating factor g/ days, subcutaneous injection, d2- neutrophil leucocyte restore (WBC > 20 × 109/L
When suspend).
By clinical test show chidamide provided by the invention, Decitabine, cytarabine, aclacinomycin and
Granulocyte colony stimulating factor, for treating purposes and its pharmaceutical composition in acute myeloid leukaemia, solves existing in preparation
There is the refractory problem of the recurrence of AML Combination chemotherapy, the complete incidence graph of refractory patients with acute myeloid leukemia is recurred in treatment
Rate (CR) has reached 43.6%, and objective remission rate (ORR) has reached 58.2%.
Detailed description of the invention
Fig. 1 is the embodiment of the present invention 2 total life span (OS) figure.
Specific embodiment
The present invention provides the new application of chidamide joint DCAG, those skilled in the art can use for reference present disclosure,
It is suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications carry out those skilled in the art
Say it is it will be apparent that they are considered as being included in the present invention.Method and application of the invention has passed through preferred embodiment
It is described, related personnel can obviously not depart from the content of present invention, in spirit and scope to method described herein and answer
With being modified or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
The raw material that the present invention uses is all common commercially available product, is all available on the market.
Below with reference to embodiment, the present invention is further explained:
Embodiment 1: chidamide combines DCAG and treats acute myeloid leukaemia clinical test
1.1 trial drug
Chidamide piece (being produced by Shenzhen Weixin Biological Science and Technology Co., Ltd), injection Decitabine are (by Shandong
The production of southern pharmacy Group Plc), injection aclacinomycin, cytarabine for injection and recombinant humangranulocyte stimulation
Factor injection (is purchased from hospital pharmacy, no regular supply producer).
1.2 test method
Case load: totally 100;
Inclusion criteria:
1) between 18-59 years old age, male, female are unlimited;
2) AML patient (the non-AML- made a definite diagnosis is examined according to 2008 World Health Organization (WHO) medullary system malignant disease diagnosis mark
M3);
3) previously multiple after systemic therapy at least once (including chemotherapy, hematopoietic stem cell transplantation etc.) is without alleviation or alleviation
The patient of hair;
4) ECOG KPS scale is 0-3 points;
5) expected life span >=3 month;
6) without severe cardiac, lung, liver, kidney diaseases;
7) weight: 67 ± 20 kilograms of male (47-87 kilograms), 55 ± 20 kilograms of women (35-75 kilograms);
8) enter and do not received the treatment such as radiotherapy, chemotherapy, targeted therapy or hematopoietic stem cell transplantation in group first 4 weeks;
9) it has the ability to understand and is ready to sign this test informed consent form.
Exclusion criteria:
(1) drug included to experimental program in the past, or to drug allergy person similar with test medicine chemical structure;
Gestation, lactating female and be reluctant to take the reproduction age patient of contraceptives;
(3) the person that has Active infection;
(4) it takes drugs, chronic alcoholism is so that influence the patient of evaluation of test result;
(5) informed consent can not be obtained with mental disease or other state of an illness, not be able to cooperate research treatment and human observer;
(6) the patient (male > 450ms, women > 470ms) with clinical meaning QTc interval prolongation medical history, room property mistake aroused in interest
Fast (VT), auricular fibrillation (AF), II degree or more atrioventricular block, myocardial infarction breaks out in (MI) 1 year, congestive heart failure
(CHF), symptom needs the patient of coronary heart disease of drug therapy;
(7) Heart Brightness Mode shows diastasis cavum pericardiale opaque dark area of fluid width >=10mm patient;
(8) the patient of organ transplant is received;
(9) the patient of active hemorrhage is had;
(10) the patient of the diseases such as new hair thrombus, embolism, cerebral hemorrhage or medical history is had for nearly 1 year;
(11) the less than 6 weeks persons of main organs surgical site infections;
(12) myelosis is low and leucocyte < 2.0 × 109/L;
Dysfunction of liver (1.5 times of total bilirubin > Upper Limit of Normal Value, 2.5 times of ALT/AST > Upper Limit of Normal Value or liver
By invading 5 times of patient ALT/AST > Upper Limit of Normal Value), renal dysfunction (1.5 times of serum creatinine > Upper Limit of Normal Value);
(14) researcher determines to be not suitable for participating in this experimenter.
Therapeutic scheme:
The entire totally 8 weeks test of cure phase, every 4 weeks are a treatment cycles.
Chidamide: d1 starts to take orally, and takes medicine 30mg (6), takes medicine weekly twice, dosing interval should not lack twice every time
It in 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday and Saturday), early takes within postprandial 30 minutes, takes orally 2 weeks, withdraw 2 weeks.
Decitabine: 20mg/m2Intravenously administrable d1-d5;
Aclacinomycin: 10mg/m2Intravenously administrable d3-d7;
Cytarabine: 100mg/m2Infusion Time > 3 hour intravenously administrable q12h;
WBC≥20×109/ L, d1-d7;
WBC < 20 × 109/ L, d3-d7;
Subcutaneous injection d2-- neutrophil leucocyte restores (WBC > 20 × 10 within G-CSF:300ug/ days9Suspend when/L).
28d is 1 treatment cycle, treats 2 periods altogether.
Note: such as the 1st period d28 myelosis is low, and WBC < 2 × 109/ L, the 2nd period can delay to carry out, and such as delay super
Spend 4 weeks then patient need exit test.
Evaluation index:
Curative effect index: objective remission rate, the sum of the patient numbers for alleviating (PR) including complete incidence graph (CR), part account for
Percentage, the total effective rate of all subject populations for participating in efficacy analysis.
Secondary efficacy index: including alleviating duration (DOR), progression free survival phase (PFS) and total life span (OS).
Safety indexes: adverse events;Laboratory checks abnormal;3-4 grades of clinical adverse events and laboratory check abnormal
Incidence.
Therapeutic evaluation:
(1) it therapeutic evaluation interval: is evaluated after each cycle treatment;
(2) therapeutic evaluation means: peripheral blood and bone marrow smear, immunophenotyping, chromosome;
(3) the standard of curative effect evaluation:
1) complete incidence graph (CR):
1. clinical without sings and symptoms caused by leukemiacell infiltration, life is normal or close to normally;
2. blood picture: Hb≤100g/L (male) Huo≤90g/L (female and children), neutrophil leucocyte absolute value >=1.5 × 109/
L, blood platelet >=100 × 109/L.Without leukaemia cell in peripheral white blood cells classification;
3. bone marrow smear: (original monocytic+naivety monocyte or primitive lymphoid+naivety lymph are thin for myeloblast I type+II type
Born of the same parents')≤5%, red blood cell and macronucleus system are normal.
2) (PR) is alleviated in part: (original monocytic+naivety monocyte or primitive lymphoid are thin for marrow myeloblast I type+II type
Born of the same parents+immature lymphocytes) > 5% Er≤20%;Or there is a Xiang Weida complete incidence graph standard person in clinic, blood picture, bone marrow smear.
Statistical analysis:
1) safety analysis:
The case scenario of blood or non-blood toxic reaction occurs for detailed description, calculates the incidence of different event, calculates
The composition ratio of each event severity.
2) efficacy analysis:
All statistical analysis are completed using SAS9.2, and continuous data uses mean, standard deviation, median, maximum value, minimum
Value description, enumeration data are described using frequency, percentage.
3) curative effect index --- objective remission rate need to calculate 95%CI.
4) secondary efficacy index alleviates duration (DOR), Progression free survival time using the estimation of Kaplan-Meier method
(PFS) and survival rate, median survival time and its 95%CI of the total life span (OS) on each time point.
It is as follows that 1.3 chidamides combine DCAG treatment acute myeloid leukaemia clinical test efficacy result:
This clinical test enters 62 patients of group altogether, and patient in group's overall situation and baseline information are shown in Table 1.
Table 1: patient in group's overall situation and baseline information table
The treatment condition of patient in group is shown in Table 2, and totally 62.
Table 2: the treatment condition of patient in group
Curative effect and chromatographic analysis are shown in Table the 3:12 month above recurrence 4 people of AML patient (7.2%), intractable 51 people of AML patient
(92.7%).
Table 3: curative effect and chromatographic analysis table
Clinical test results: it is overall to comment number (n=55), obtain 1 30 people of estimator;Obtain 2 25 people of estimator;
Complete remission rate CR 24/55 (43.6%), objective remission rate ORR are 29/55 (58.2%), and clinical test results are shown in Table 4.
Table 4: clinical test results
The above clinical test results can be seen that chidamide provided in this embodiment, Decitabine, cytarabine, Ah
The complete remission rate (CR) of refractory patients with acute myeloid leukemia is recurred in clarithromycin and granulocyte colony stimulating factor, treatment
Reach 43.6%, objective remission rate (ORR) has reached 58.2%, and the recurrence for solving existing AML Combination chemotherapy is refractory
Problem, and it is significant in efficacy.
Embodiment 2: chidamide combines DCAG and treats acute myeloid leukaemia clinical test
2.1 trial drugs, 2.2 test methods are the same as corresponding contents in embodiment 1.
It is as follows that 2.3 chidamides combine DCAG treatment acute myeloid leukaemia clinical test efficacy result:
Case number can be evaluated on the basis of embodiment 1 and increased to 93 for this clinical test, and result is as follows:
Clinical test results: overall to comment number (n=93), wherein 24 acquisition complete incidence graphs, CR rate are 26% (24/
93,95%confidence interval [CI]: 16.9-34.7%), 19 acquisition complete incidence graphs are not completely extensive with peripheral blood
Multiple (abbreviation CRi), CRi rate are 20% (19/93,95%CI:12.2-28.4%), objective total effective rate be 46% (95%CI:
36.1-56.4%), clinical test results are shown in Table 5.
Table 5: clinical test results*
*Therapeutic effect is according to IWG criterion evaluation.
Remarks: CR, complete incidence graph;CRi, complete incidence graph do not restore completely with peripheral blood;RP, part are alleviated;NR, without slow
Solution;ED, Deaths.
Also, according to total life span of Fig. 1 as a result, 6 months survival rates are 52% (95%CI:41.5-61.8%),
Median survival interval is 266 days (95%CI:235-398).
Embodiment 3: drug combination compositions
The drug combination compositions of the present embodiment include the active constituent of following effective dose:
Chidamide 180mg, Decitabine 20mg/m2, aclacinomycin 10mg/m2, cytarabine 100mg/m2It is thin with grain
Born of the same parents' colony stimulating factor 300ug/ days.
Embodiment 4: drug combination compositions
The drug combination compositions of the present embodiment include the active constituent of following effective dose:
Chidamide 180mg, Decitabine 20mg/m2, aclacinomycin 10mg/m2, cytarabine 50mg/m2It is thin with grain
Born of the same parents' colony stimulating factor 300ug/ days.
Embodiment 5: combination medicine composite preparation
The combination medicine composite preparation of the present embodiment includes active constituent below with effective dose: Xi Daben
Amine, Decitabine, aclacinomycin, cytarabine and granulocyte colony stimulating factor;And pharmaceutical acceptable carrier.It is described pharmaceutically acceptable
Carrier is the pharmaceutic adjuvant of tablet formulation, selects " pharmaceutic adjuvant the handbook " (Handbook published with reference to Chemical Industry Press
Of Pharmaceutical Excipients, original work fourth edition) listed by carrier auxiliary material.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (9)
1. a kind of for treating the combination medicine of leukaemia, comprising: chidamide and DCAG drug, the DCAG drug are ground
His shore of west, cytarabine, aclacinomycin and granulocyte colony stimulating factor composition of medicine.
2. combination medicine according to claim 1, which is characterized in that the combination medicine further includes that can pharmaceutically connect
The carrier received.
3. combination medicine according to claim 1, which is characterized in that the chidamide and DCAG drug are all made of system
Dosage form formula.
4. combination medicine according to claim 3, which is characterized in that the chidamide uses oral preparation, uses
The DCAG drug of ejection preparation is injection Decitabine, cytarabine for injection, injection aclacinomycin and granulocyte collection
G-CSF injection.
5. combination medicine according to claim 4, which is characterized in that the chidamide uses tablet formulation.
6. described in any item combination medicines according to claim 1~5, which is characterized in that the crystal form of the chidamide
X-ray powder diffraction figure 2 θ of angle of reflection be 4.18 °, 6.61 °, 8.42 °, 12.69 °, 17.85 °, 18.34 °, 19.27 °,
There is spy at 20.10 °, 20.59 °, 21.58 °, 23.70 °, 23.96 °, 25.52 °, 27.00 °, 27.90 °, 29.59 ° and 29.94 °
Levy peak;Its infrared spectroscopy 3412,3282,3199,3043,1654,1615,1524,1514,1497,1442,1418,1332,
1296,1234,1198,1183,1166 and 1027cm-1There is characteristic absorption peak at place;Its differential scanning calorimetric analysis curve is 239.4
There is endothermic peak at DEG C.
7. described in any item combination medicines according to claim 1~5, which is characterized in that the work including following effective dose
Property ingredient:
The chidamide of 180mg;20mg/m2Decitabine;10mg/m2Aclacinomycin;50~100mg/m2Arabinose born of the same parents
Glycosides;With 300 g/ days granulocyte colony stimulating factors of μ.
8. if combination medicine according to any one of claims 1 to 7 is in the drug that preparation is used for acute myeloid leukaemia
Purposes.
9. purposes according to claim 8, which is characterized in that the acute myeloid leukaemia is that recurrence is refractory acute myelogenous
Leukaemia.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101397295A (en) * | 2008-11-12 | 2009-04-01 | 深圳微芯生物科技有限责任公司 | 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof |
CN101906076A (en) * | 2009-06-04 | 2010-12-08 | 深圳微芯生物科技有限责任公司 | Naphthaline amide derivative serving as protein kinase inhibitor and histone deacetylase inhibitor and preparation method and application thereof |
CN103833626A (en) * | 2012-11-27 | 2014-06-04 | 深圳微芯生物科技有限责任公司 | Crystal form of chidamide and preparation method and application thereof |
CN105451750A (en) * | 2013-03-29 | 2016-03-30 | 生物医学谷探索股份有限公司 | C. novyi for the treatment of solid tumors in humans |
-
2018
- 2018-08-07 CN CN201810892420.3A patent/CN109985039A/en active Pending
- 2018-12-25 TW TW107147044A patent/TWI702949B/en active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101397295A (en) * | 2008-11-12 | 2009-04-01 | 深圳微芯生物科技有限责任公司 | 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof |
CN101906076A (en) * | 2009-06-04 | 2010-12-08 | 深圳微芯生物科技有限责任公司 | Naphthaline amide derivative serving as protein kinase inhibitor and histone deacetylase inhibitor and preparation method and application thereof |
CN103833626A (en) * | 2012-11-27 | 2014-06-04 | 深圳微芯生物科技有限责任公司 | Crystal form of chidamide and preparation method and application thereof |
CN105451750A (en) * | 2013-03-29 | 2016-03-30 | 生物医学谷探索股份有限公司 | C. novyi for the treatment of solid tumors in humans |
Non-Patent Citations (6)
Title |
---|
CHINESE PLA GENERAL HOSPITAL: "Chidamide Plus DCAG for Relapsed/Refractory AML", 《HTTPS://CLINICALTRIALS.GOV/CT2/SHOW/RECORD/NCT02886559》 * |
丁洁: "清华长庚血液内科:招募复发_难治急性髓系白血病患者志愿者", 《HTTP://WWW.BTCH.EDU.CN/KSDH/NKB/XYZLK/KSDT_XYNK/22930.HTM》 * |
刘强: "地西他滨联合CAG方案治疗AML1-ETO+ AML的临床效果", 《中国实验血液学杂志》 * |
朱成英: "地西他滨联合改良CAG方案治疗复发、难治型急性髓系白血病的临床研究", 《中国实验血液学杂志》 * |
王继芳: "地西他滨联合CAG方案治疗难治复发急性髓系白血病的疗效观察", 《中国医药指南》 * |
郭智: "DCAG方案治疗初次诱导失败的急性髓系白血病的临床研究", 《实用癌症杂志》 * |
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