TWI702949B - Pharmaceutical combination for treating leukemia and use thereof in the preparation of a medicament for treating acute myeloid leukemia - Google Patents

Abstract

The present invention relates to the field of medicine, and in particular to a pharmaceutical combination for treating leukemia, comprising an effective dose of chidamide and DCAG drug administered simultaneously, separately or sequentially, the DCAG drug being the combination of decitabine, cytarabine, aclarubicin and granulocyte colony stimulating factor. The invention provides the use of chidamide combined with DCAG in the preparation of a medicament for treating acute myeloid leukemia. Its beneficial effect is solving the relapsed and refractory problem of the existing AML combined chemotherapy regimen. The complete remission rate (CR) in treating patients with acute myeloid leukemia which is relapsed and refractory reached 43.6%, and the objective remission rate (ORR) reached 58.2%.

Description

Combination medicine for treating leukemia and its use in preparing medicine for treating acute myeloid leukemia

The present invention is required to be submitted to the Chinese Patent Office on December 29, 2017, the application number is 201711485562.X, the name of the invention is "a combination drug for the treatment of leukemia and its use in the preparation of a drug for the treatment of acute myeloid leukemia "The priority of the Chinese patent application, the entire content of which is incorporated into the present invention by reference.

The present invention relates to the field of medicine, in particular to a combination drug for the treatment of leukemia and its use in the preparation of a drug for the treatment of acute myeloid leukemia, in particular to the preparation of chidamide combined with other drugs for the treatment of acute myeloid leukemia Use in drugs for sexual leukemia and combined drugs.

Leukemia (commonly known as blood cancer) is a type of malignant clonal disease of hematopoietic stem cells, which can be divided into acute and chronic leukemia according to the onset of the disease; according to the series of diseased cells, it includes myeloid, mononuclear, red, megakaryotic, and lymphoid T and B cell lines; clinically, leukemia is often divided into lymphocytic leukemia, myeloid leukemia, mixed cell leukemia and so on. Among them, acute myelocytic leukemia (AML) or acute nonlymphocytic leukemia (ANLL) includes all acute leukemias of non-lymphocytic origin. It is a type of disease caused by mutations in the karyotype of pluripotent stem cells or slightly differentiated precursor cells. It is a clonal malignant disease of the hematopoietic system. People receiving large doses of radiation or long-term exposure to chemicals such as benzene and its derivatives can increase the incidence of such diseases. Acute myeloid leukemia is a highly heterogeneous disease group. It can be transformed from the malignant transformation of hematopoietic progenitor cells at different stages during the differentiation and development of normal myeloid cells. AML derived from progenitor cells at different stages has different biology feature.

At present, for the treatment of AML, in addition to acute promyelocytic leukemia, combined chemotherapy is still the main treatment. The classic induction chemotherapy for acute myeloid leukemia (AML) is the DA regimen, including: Daunorubicin (DNR, Daunorubicin) 45~60mg/(m ² .d) (Day 1~3) + Cytarabine (Ara) -C, Cytarabine) 100mg/(m ² .d) (1~5 days or 1~7 days); the first course of treatment complete response rate (CR, complete response) is 40%~50%; the second course of treatment reaches 60%~75%.

Other induction chemotherapy regimens include: ①AID regimen: cytarabine (Ara-C) + idarubicin (demethoxydaunorubicin, IDA, idarubicin), or cytarabine (Ara-C) + idarubicin Star (IDA) + Etoposide (VP-16, Etoposide) (ICE); ② Cytarabine (Ara-C) + Daunorubicin (DNR) + Thioguanine (6-TG, 6-Thioguanine) ③ Mitoxantrone (NVT, Mitoxantrone) + Etoposide (VP-16) (ME) and so on.

With the above-mentioned induction chemotherapy regimen, the total complete remission rate of AML patients is only 50% to 70%, and the long-term disease-free survival rate is 25% to 30%. With the continuous improvement of combined chemotherapy, the remission rate and survival time of AML have improved. However, the above AML treatment regimens still cannot overcome the relapse and refractory of AML. For current treatment methods, if the AML patients who relapse within 1 year after the first remission, the CR rate is as low as 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).

Relapsing AML is defined as: the reappearance of leukemia cells or bone marrow blasts in peripheral blood after complete remission (CR)>0.05 (excluding other reasons, such as bone marrow reconstruction after consolidation chemotherapy, etc.), or extramedullary leukemia cell infiltration. Refractory AML is defined as: (1) Standard regimen of induction chemotherapy without CR after 2 courses; (2) Relapse within 6 months after the first CR; (3) Relapse and after 6 months after the first CR Those who failed the original regimen and re-induction chemotherapy; (4) Relapsed twice or more; (5) Extramedullary leukemia persisted. Therefore, it is necessary to explore novel, effective and safe drug treatment programs.

In view of this, the purpose of the present invention is to provide a new combination drug for the treatment of leukemia and its use in the preparation of a drug for the treatment of acute myeloid leukemia. The combination drug provided by the present invention can solve the existing AML combined chemotherapy The relapse and refractory problem of the program.

The present invention provides a combined drug for the treatment of leukemia, comprising: chidamide and DCAG drug, the DCAG drug is a combination of decitabine, cytarabine, aclamycin and granulocyte colony stimulating factor drug.

The combination medicine for the treatment of leukemia provided by the present invention contains chidamide; chidamide (English name is Chidamide, trade name is Aipusha), which is a subtype selective histone deacetylase ( HDAC) inhibitor is a 1.1 new drug. The chemical name of chidamide is N-(2-amino-4-fluorophenyl)-4-(N-(3-pyridinepropenyl)aminomethyl)benzamide, and its chemical structure is as structural formula 1 shows:

Chidamide's first indication-monotherapy for relapsed or refractory peripheral T cell lymphoma (PTCL, peripheral T cell lymphoma), was listed on December 23, 2014 by the China Food and Drug Administration (CFDA) Approved. Currently, Chidamide has no other indications approved by registration.

The combination drug for the treatment of leukemia provided by the present invention includes a DCAG drug, and the DCAG drug is a combination drug of decitabine, cytarabine, aclarithromycin and granulocyte colony stimulating factor (combination drug, DCAG) Protocol), which can be expressed as Decitabine + Cytarabine + Aclarithromycin + granulocyte colony stimulating factor. Among them: Decitabine (English name Decitabine), its chemical name is 5-aza-2'-deoxycytosine nucleoside, is a chemotherapeutic drug, clinical reports show that it has the effect of hematological malignant carcinogenesis and solid tumors Broad-spectrum anti-tumor activity.

Cytarabine (Ara-C, Cytarabine), an antipyrimidine drug, is mainly used for acute leukemia such as acute myeloid leukemia, and is generally combined with other drugs.

Aclarubicin (English alias: Aclarubicin), also known as arubicin, is an anthracycline anticancer drug, mainly used for the treatment of acute myeloid leukemia, acute lymphocytic leukemia, malignant lymphoma, gastric cancer, lung cancer , Breast cancer and ovarian cancer are also effective.

Granulocyte colony-stimulating factor (G-CSF, granulocyte colony-stimulating factor) is a glycoprotein that mainly acts on the proliferation, differentiation and activation of neutrophil lineage hematopoietic cells.

The embodiment of the present invention provides a combination medicine for the treatment of leukemia, especially for the treatment of acute myeloid leukemia, comprising: an effective dose of chidamide, decitabine, Cytarabine, aclarithromycin and granulocyte colony stimulating factor. In the present invention, chidamide combined with the above-mentioned DCAG drug is applied to the treatment drug of acute myeloid leukemia, which can exert a synergistic effect and can solve the relapse and refractory problem of the existing AML combined chemotherapy scheme.

In a preferred embodiment of the present invention, for different subjects weighing 35 to 90 kg, the combination drug for treating leukemia includes the following effective dose of active ingredient: 180 mg of chidamide; 20 mg/m ² Decitabine; 10mg/m ² of aclamycin; 50~100mg/m ² of cytarabine; and 300μg/day of granulocyte colony stimulating factor.

Wherein, the X-ray powder diffraction pattern of the crystalline form of chidamide has reflection angles 2θ of 4.18°, 6.61°, 8.42°, 12.69°, 17.85°, 18.34°, 19.27°, 20.10°, 20.59°, There are characteristic peaks at 21.58°, 23.70°, 23.96°, 25.52°, 27.00°, 27.90°, 29.59° and 29.94°; its infrared spectrum is at 3412, 3282, 3199, 3043, 1654, 1615, 1524, 1514, 1497, There are characteristic absorption peaks at 1442, 1418, 1332, 1296, 1234, 1198, 1183, 1166, and 1027 cm ^-1 ; the differential scanning calorimetry curve has an endothermic peak at 239.4°C, see Chinese patent CN103833626B document; The cell colony stimulating factor may be recombinant human granulocyte stimulating factor.

In a preferred embodiment of the present invention, in addition to the above-mentioned pharmaceutical active ingredients, the combination drug for treating leukemia further includes a pharmaceutically acceptable carrier, that is, it also includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include: "Handbook of Pharmaceutical Excipients" (American Pharmaceutical Association, October 1986) or "Handbook of Pharmaceutical Excipients" (Handbook of Pharmaceutical Excipients, fourth edition of the original) published by Chemical Industry Press The carrier excipients are preferably pharmaceutical excipients for tablet formulations, but are not limited to these pharmaceutical excipients.

In the specific embodiment of the present invention, the chidamide takes the form of a preparation, that is, a chidamide preparation, which includes the active ingredient chidamide and a pharmaceutically acceptable carrier; it can be made into a common pharmaceutical preparation For example, tablets, capsules, liquids, powders, injections, suspensions, and common carrier materials such as flavors, sweeteners, liquids, solid fillers or diluents can also be added, and the present invention is not particularly limited. Specifically, the preparation usually contains 1 to 70 wt% of active ingredients, preferably 5 to 50%, and the remaining components are carrier fillers, diluents or solvents. In the present invention, the chidamide is preferably in the form of an oral preparation, more preferably a tablet preparation.

In a specific embodiment of the present invention, the DCAG drug is in the form of a preparation, preferably an injection preparation, that is, the DCAG drug used in the injection preparation is decitabine for injection, cytarabine for injection, aclamycin for injection and Granulocyte colony stimulating factor injection. In the present invention, there is no special restriction on the pharmaceutically acceptable carrier in the injection preparation, and the corresponding conventional commercial drug injection solution can be used.

The present invention also provides the use of the combination drug as described above in the preparation of a drug for acute myeloid leukemia, that is, the present invention provides the use of chidamide combined with DCAG in the preparation of a drug for the treatment of acute myeloid leukemia Purpose: The DCAG is a combined drug of decitabine, cytarabine, aclamycin and granulocyte colony stimulating factor.

In a preferred embodiment of the present invention, the acute myeloid leukemia is relapsed and refractory acute myeloid leukemia. For different subjects, male weight 67±20 kg (47-87 kg), female weight 55±20 kg (35-75 kg), the specific application plan includes: Chidamine 180mg, oral administration on d1, oral administration 2 weeks; Decitabine 20mg/m ² , intravenously administered, d1-d5; Aclarithromycin 10mg/m ² , intravenously administered, d3-d7; Cytarabine 50-100mg/m ² , intravenously administered Medicine, q12h; granulocyte colony stimulating factor 300μg/day, subcutaneous injection, d2-neutrophil recovery (pause when WBC>20×10 ⁹ /L).

Clinical trials have shown that the use of the chidamide, decitabine, cytarabine, aclarithromycin and granulocyte colony stimulating factor provided by the present invention in the preparation for the treatment of acute myeloid leukemia and the drug combination thereof It solves the relapse and refractory problem of the existing AML combined chemotherapy regimen. The complete remission rate (CR) of the treatment of relapsed and refractory acute myeloid leukemia patients reached 43.6%, and the objective response rate (ORR, Objective Response Rate) reached 58.2% .

The present invention provides a new use of quinolizidine alkaloids, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention. The method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant personnel can modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.

The raw materials used in the present invention are all common commercially available products, and all are available on the market.

The following examples further illustrate the present invention:

Example 1: Clinical trial of Chidamide combined with DCAG in the treatment of acute myeloid leukemia

1.1 Test drug

Cidabenamide tablets (produced by Shenzhen Microchip Biotechnology Co., Ltd.), decitabine for injection (produced by Lunan Pharmaceutical Group Co., Ltd.), aclamycin for injection, cytarabine for injection and Recombinant human granulocyte stimulating factor injection (purchased from a hospital pharmacy, no fixed supplier).

1.2 Test method

Number of cases: 100 cases in total;

3個月；6)無嚴重心、肺、肝、腎疾病；7)體重：男性67±20公斤(47-87公斤)，女性55±20公斤(35-75公斤)；8)入組前4週內未接受過放療、化療、靶向治療或造血幹細胞移植等治療；9)有能力理解並願意簽署本試驗知情同意書。 Inclusion criteria: 1) 18-59 years old, male or female; 2) AML patients (non-AML-M3) diagnosed according to the 2008 World Health Organization (WHO) diagnostic criteria for myeloid malignancies; 3) past Patients who have undergone at least one systemic treatment (including chemotherapy, hematopoietic stem cell transplantation, etc.) without remission or relapse after remission; 4) ECOG behavioral status score is 0-3; 5) Expected survival time

3 months; 6) No serious heart, lung, liver, or kidney disease; 7) Weight: 67±20 kg (47-87 kg) for men, 55±20 kg (35-75 kg) for women; 8) Before enrollment Have not received radiotherapy, chemotherapy, targeted therapy or hematopoietic stem cell transplantation within 4 weeks; 9) have the ability to understand and are willing to sign the informed consent for this trial.

10mm的患者；(8)接受器官移植的患者；(9)有活動性出血的患者；(10)近1年有新發血栓、栓塞、腦出血等疾病或病史的患者；(11)主要臟器外科手術後未滿6週者；(12)骨髓增生低下且白細胞<2.0×10⁹/L；(13)肝功能異常(總膽紅素>正常值上限的1.5倍，ALT/AST>正常值上限的2.5倍或肝受侵患者ALT/AST>正常值上限的5倍)、腎功能異常(血清肌酐>正常值上限的1.5倍)；(14)研究者判定不適合參加本試驗者。 Exclusion criteria: (1) People who were allergic to the drugs included in the experimental protocol or to drugs with similar chemical structure to the tested drugs in the past; (2) Pregnant and lactating women and patients of childbearing age who are unwilling to take contraceptive measures; (3) Yes Actively infected patients; (4) Drugs or long-term alcohol abuse that affect the evaluation of the test results; (5) Patients with mental illness or other conditions who cannot obtain informed consent and cannot cooperate with research treatment and monitoring; (6) QTc with clinical significance Patients with a history of prolonged interval (male>450ms, female>470ms), ventricular tachycardia (VT, ventricular tachycardia), atrial fibrillation (AF, atrial fibrillation), atrioventricular block of degree Ⅱ or higher, myocardial infarction ( MI, Myocardial infarction) within 1 year, congestive heart failure (CHF, Congestive Heart Failure), patients with symptomatic coronary heart disease requiring medical treatment; (7) Cardiac B-ultrasound shows the width of the end-diastolic pericardial cavity fluid dark space

10mm patients; (8) patients receiving organ transplantation; (9) patients with active bleeding; (10) patients with new thrombosis, embolism, cerebral hemorrhage and other diseases or medical history in the past year; (11) major organs Less than 6 weeks after organ surgery; (12) hypoplasia of bone marrow and white blood cell <2.0×10 ⁹ /L; (13) abnormal liver function (total bilirubin>1.5 times the upper limit of normal, ALT/AST> normal 2.5 times the upper limit of the value or ALT/AST>5 times the upper limit of normal in patients with liver invasion), abnormal renal function (serum creatinine>1.5 times the upper limit of normal); (14) The investigator judged those who are not suitable to participate in this trial.

Treatment plan: The entire trial treatment period is 8 weeks, and every 4 weeks is a treatment cycle.

Chidamide: Begin oral administration on d1, 30mg (6 tablets) each time, twice a week, the interval between the two doses should not be less than 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday And Saturday, etc.), take 30 minutes after breakfast, orally for 2 weeks, stop taking it for 2 weeks.

20×10⁹/L，d1-d7；WBC<20×10⁹/L，d3-d7； G-CSF：300ug/日皮下注射d2--中性粒細胞恢復(WBC>20×10⁹/L時暫停)。 Decitabine: 20mg/m ² intravenously administered d1-d5; Aclamycin: 10mg/m ² intravenously administered d3-d7; Cytarabine: 100mg/m ² intravenously administered q12h Infusion time> 3 hours ; WBC

20×10 ⁹ /L, d1-d7; WBC<20×10 ⁹ /L, d3-d7; G-CSF: 300ug/day subcutaneous injection d2--neutrophil recovery (WBC>20×10 ⁹ /L Time out).

28d is 1 treatment cycle, 2 cycles in total.

Note: If the first cycle d28 is hypomyeloproliferation, and WBC<2×10 ⁹ /L, the second cycle can be postponed. If the postponement exceeds 4 weeks, the patient needs to withdraw from the trial.

Evaluation indicators: main efficacy indicators: objective remission rate, including the total number of patients with complete remission (CR) and partial remission (PR) as a percentage of the total number of patients participating in the efficacy analysis, and the total effective rate.

Secondary efficacy indicators: including duration of response (DOR, Duration of Response), progression-free survival (PFS, Progression-free survival) and overall survival (OS, Overall Survival).

Safety indicators: adverse events; abnormal laboratory examinations; incidence of grade 3-4 clinical adverse events and abnormal laboratory examinations.

Efficacy evaluation: (1) Efficacy evaluation interval: evaluation after each cycle of treatment; (2) Efficacy evaluation methods: peripheral blood and bone marrow smears, immune typing, chromosome; (3) Efficacy evaluation criteria:

1.5×10⁹/L，血小板

100×10⁹/L。外周血白細胞分類中無白血病細胞；③骨髓象：原粒細胞I型+II型(原始單核+幼稚單核細胞或原始淋巴+幼稚淋巴細胞)≦5%，紅細胞及巨核系正常。 1) Complete remission (CR): ①There are no clinical symptoms and signs caused by leukemia cell infiltration, and life is normal or close to normal; ②Blood picture: Hb≧100g/L (male) or ≧90g/L (female and children), medium Absolute value of neutrophil

1.5×10 ⁹ /L, platelets

100×10 ⁹ /L. There are no leukemia cells in the classification of peripheral blood leukocytes; ③Bone marrow phenomenon: Myelocytic type I + II (primordial mononuclear + naive monocytes or primitive lymph + naive lymphocytes) ≦5%, red blood cells and megakaryocytes are normal.

2) Partial response (PR, Partial response): bone marrow myelomyelocytic type I + type II (primordial monocytes + naive monocytes or primordial lymphocytes + naive lymphocytes)> 5% and ≤ 20%; or clinical and blood picture One of the bone marrow findings is for complete remission.

Statistical Analysis:

1) Safety analysis: describe in detail the cases of blood or non-blood toxic reactions, calculate the incidence of different events, and calculate the composition ratio of the severity of each event.

2) Efficacy analysis: All statistical analysis is completed by SAS9.2, measurement data is described by mean, standard deviation, median, maximum and minimum, and count data is described by frequency and percentage.

3) The main curative effect index──The objective response rate needs to be calculated with 95% CI.

4) Kaplan-Meier method is used to estimate the survival rate, median survival time and 95% of the duration of remission (DOR), progression-free survival time (PFS) and overall survival time (OS) at each time point for secondary efficacy indicators. CI.

1.3 The clinical trial results of chidamide combined with DCAG in the treatment of acute myeloid leukemia are as follows:

A total of 62 patients were enrolled in this clinical trial. The overall status and baseline information of the enrolled patients are shown in Table 1.

The treatment status of the enrolled patients is shown in Table 2, a total of 62 cases.

The curative effect and stratified analysis are shown in Table 3: 4 patients (7.2%) with relapsed AML over 12 months, 51 patients with refractory AML (92.7%).

Clinical trial results: the overall number of evaluable persons (n=55), 30 persons were evaluated once; 25 persons were evaluated twice; the complete remission rate was CR 24/55 (43.6%), and the objective remission rate ORR was 29/55 (58.2%). The clinical trial results are shown in Table 4.

It can be seen from the above clinical test results that the chidamide, decitabine, cytarabine, aclarithromycin and granulocyte colony stimulating factor provided in this example can treat patients with relapsed and refractory acute myeloid leukemia. The remission rate (CR) reached 43.6%, and the objective remission rate (ORR) reached 58.2%, which solved the relapse and refractory problem of the existing AML combined chemotherapy regimen, and the effect was significant.

Example 2: Combined pharmaceutical composition

The combination pharmaceutical composition of this embodiment contains the following effective doses of active ingredients: Chidamide 180 mg, Decitabine 20 mg/m ² , Aclarithromycin 10 mg/m ² , Cytarabine 100 mg/m ² and Granulocyte colony stimulating factor 300ug/day.

Example 3: Combined pharmaceutical composition

The combination pharmaceutical composition of this embodiment contains the following effective doses of active ingredients: Chidamide 180 mg, Decitabine 20 mg/m ² , Aclarithromycin 10 mg/m ² , Cytarabine 50 mg/m ² and Granulocyte colony stimulating factor 300ug/day.

Example 4: Combined pharmaceutical composition preparation

The combination pharmaceutical composition preparation of this embodiment contains the following active ingredients with effective doses: chidamide, decitabine, aclarithromycin, cytarabine and granulocyte colony stimulating factor; and a pharmaceutically acceptable carrier . The pharmaceutically acceptable carrier is the pharmaceutical excipient of the tablet preparation, and the carrier excipients listed in the "Handbook of Pharmaceutical Excipients" (Handbook of Pharmaceutical Excipients, original fourth edition) published by Chemical Industry Press are selected.

The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications are also It should be regarded as the protection scope of the present invention.

Claims (8)

A combined drug for the treatment of leukemia, comprising: Chidamide and DCAG drug, the DCAG drug is a combination drug of decitabine, cytarabine, aclamycin and granulocyte colony stimulating factor; wherein The combination drug contains the following effective doses of active ingredients: 30 mg of chidamide; 20 mg/m ² of decitabine; 10 mg/m ² of aclamycin; 100 mg/m ² of cytarabine ; And 300μg/day granulocyte colony stimulating factor. The combination drug according to item 1 of the scope of patent application, wherein the combination drug further includes a pharmaceutically acceptable carrier. The combination drug according to item 1 of the scope of patent application, wherein the chidamide and DCAG drugs are both in the form of preparations. The combination drug according to item 3 of the scope of patent application, wherein the chidamide is in an oral preparation, and the DCAG drug in the injection preparation is decitabine for injection, cytarabine for injection, and accra for injection Mycin and granulocyte colony stimulating factor injection. The combination drug according to item 4 of the scope of patent application, wherein the chidamide is in a tablet formulation. The combination drug according to any one of items 1 to 5 in the scope of the patent application, wherein the X-ray powder diffraction pattern of the crystal form of chidamide has reflection angles 2θ of 4.18°, 6.61°, There are characteristic peaks at 8.42°, 12.69°, 17.85°, 18.34°, 19.27°, 20.10°, 20.59°, 21.58°, 23.70°, 23.96°, 25.52°, 27.00°, 27.90°, 29.59° and 29.94°; its The infrared spectrum has characteristic absorption peaks at 3412, 3282, 3199, 3043, 1654, ¹⁶¹⁵ , 1524, 1514, 1497, 1442, 1418, 1332, 1296, 1234, 1198, 1183, 1166 and 1027 cm ^-1 ; its differential scanning The calorimetric analysis curve has an endothermic peak at 239.4℃. The use of a combination drug as described in any one of items 1 to 6 of the scope of patent application in the preparation of a drug for acute myeloid leukemia. The use according to item 7 of the scope of patent application, wherein the acute myeloid leukemia is relapsed and refractory acute myeloid leukemia.