TW201929852A - 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

   Combined medicine for treating leukemia and use thereof in preparing medicine for treating acute myeloid leukemia   

The present invention requires that the Chinese Patent Office be filed on December 29, 2017, with the application number 201711485562.X, and the invention name be "combined medicine for treating leukemia and its use in the preparation of a medicine for treating acute myeloid leukemia. The priority of a Chinese patent application is incorporated herein by reference in its entirety.

The present invention relates to the field of medicine, in particular to a combined medicine for treating leukemia and its use in preparing a medicine for treating acute myeloid leukemia, in particular, Cedarbenzamine in combination with other medicines for preparing and treating acute myeloid leukemia. Use of medicine for combined leukemia and combined medicine.

Leukemia (commonly known as blood cancer) is a type of malignant clonal disease of hematopoietic stem cells. It can be divided into acute and chronic leukemia according to the onset of its onset; it is classified according to the series of diseased cells, including myeloid granules, single, red, megakaryotic, and lymphoid T and B cell lines; clinically, leukemia is often divided into lymphocytic leukemia, myeloid leukemia, and mixed cell leukemia. 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 lightly differentiated precursor cells, and 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 these diseases. Acute myeloid leukemia is a highly heterogeneous disease group. It can be transformed from malignant transformation of hematopoietic progenitor cells at different stages of the normal myeloid cell differentiation and development process. AML originating from different stages of progenitor cells has different biology. feature.

Currently, 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, which includes: daunorubicin (DNR, Daunorubicin) 45 ~ 60mg / (m ² .d) (days 1-3) + cytarabine (Ara -C, Cytarabine) 100mg / (m ² .d) (Days 1 to 5 or Days 1 to 7); Complete response rate (CR, complete response) for the first course of treatment is 40% to 50%; 60% ~ 75%.

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

With the above induction chemotherapy regimen, the total complete response 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 of AML have improved. However, the above AML treatment schemes still cannot overcome the refractory AML recurrence. For the current treatment, if the AML patients 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).

Recurrent AML is defined as the recurrence of leukemia cells or bone marrow blasts> 0.05 in peripheral blood after complete remission (CR) (excluding other causes, such as bone marrow reconstruction after consolidation chemotherapy), or leukemia cell infiltration in extramedullary cells. Refractory AML is defined as: (1) CR was not obtained for 2 courses of standard chemotherapy induction chemotherapy; (2) those who relapsed within 6 months after the first CR; (3) those who relapsed after 6 months after the first CR Those who failed chemotherapy induced by the original protocol; (4) those who relapsed 2 or more times; (5) extramedullary leukemia persisted. Therefore, it is necessary to explore new, effective and safe drug treatment programs.

In view of this, the object of the present invention is to provide a new combination drug for treating leukemia and its use in preparing a drug for treating acute myeloid leukemia. The combination drug provided by the present invention can solve the existing AML combined chemotherapy Relapse of the program is refractory.

The present invention provides a combination drug for treating leukemia, which includes: cedaramide and DCAG drug, the DCAG drug is a combination of decitabine, cytarabine, aclanomycin, and granulocyte colony-stimulating factor drug.

The combination drug for treating leukemia provided by the present invention comprises cidabenzide; cidabenzamide (English name: Chidamide, trade name: Albizar) is a subtype selective histone deacetylase ( HDAC) inhibitors are new drugs of class 1.1. The chemical name of Sidabenzylamine is N- (2-amino-4-fluorophenyl) -4- (N- (3-pyridylpropenyl) aminomethyl) benzidine. Its chemical structure is as follows: Shown as 1:

The first indication of Cedaramide-monotherapy for relapsed or refractory peripheral T cell lymphoma (PTCL), was listed on December 23, 2014 by the State Food and Drug Administration (CFDA) Approved. At present, there are no other registered indications for Cestabenamide.

The combination drug for treating leukemia provided by the present invention comprises a DCAG drug, which is a combination drug of decitabine, cytarabine, aclamycin, and granulocyte colony-stimulating factor (combined drug, DCAG Protocol) can be expressed as decitabine + cytarabine + aclamycin + granulocyte colony stimulating factor. Among them: Decitabine (English name Decitabine), its chemical name is 5-aza-2'-deoxycytosine riboside, is a chemotherapeutic drug, clinical reports show that it has effects on hematological malignant cancer and solid tumors. Broad-spectrum antitumor activity.

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

Aclarubicin (English alias: Aclarubicin), also known as Arububicin, 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, ovarian cancer are also effective.

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

The embodiments of the present invention provide a combination drug for treating leukemia, especially for treating acute myeloid leukemia, comprising: effective doses of sitabine, decitabine, Cytarabine, Aclamycin and Granulocyte Colony Stimulating Factor. The present invention uses cidabenzamide in combination with the above-mentioned DCAG drugs for the treatment of acute myeloid leukemia, can exert a synergistic effect, and can solve the problem of refractory recurrence of the existing AML combined chemotherapy scheme.

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

Wherein, the X-ray powder diffraction pattern of the crystal form of Cestabenamide at the reflection angle 2θ is 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 °; their infrared spectra are 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 1027cm ^-1 ; their differential scanning calorimetry analysis curves have endothermic peaks at 239.4 ° C, see the Chinese patent CN103833626B document; the particles The colony-stimulating factor may be a recombinant human granulocyte-stimulating factor.

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

In a specific embodiment of the present invention, the cidabenzamide is in the form of a formulation, that is, a cidabenzamide formulation, which includes the active ingredient cidabenzamide and a pharmaceutically acceptable carrier; common pharmaceutical preparations can be made. For example, tablets, capsules, liquids, powders, injections, suspensions, and commonly used carrier materials such as flavors, sweeteners, liquids, solid fillers or diluents can also be added. The present invention is not particularly limited. Specifically, the preparation usually contains 1 to 70% by weight of active ingredients, preferably 5 to 50%, and the remaining components are carrier fillers, diluents or solvents. In the present invention, the cidabenzamine 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 using 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 particular limitation 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 a combination drug as described above in the preparation of a medicament for acute myeloid leukemia, that is, the present invention provides the use of cidabenzamide in combination with DCAG in the preparation of a medicament for the treatment of acute myeloid leukemia. The DCAG is a combination drug of decitabine, cytarabine, aclanomycin, and granulocyte colony-stimulating factor.

In a preferred embodiment of the present invention, the acute myeloid leukemia is a relapsed refractory acute myeloid leukemia. For different subjects, men weighed 67 ± 20 kg (47-87 kg) and women weighed 55 ± 20 kg (35-75 kg). Specific application schemes include: Cedarbenzine 180 mg, d1 started orally, orally 2 weeks; decitabine 20mg / m ² , intravenous administration, d1-d5; aclamycin 10mg / m ² , intravenous administration, d3-d7; cytarabine 50 ~ 100mg / m ² , intravenous administration Drug, q12h; granulocyte colony-stimulating factor 300 μg / day, subcutaneous injection, d2-neutrophil recovery (pause when WBC> 20 × 10 ⁹ / L).

Clinical trials have shown that the use of Cedarbenzamine, Decitabine, Cytarabine, Aclanomycin, and Granulocyte Colony Stimulating Factor provided by the present invention in the preparation of a drug for treating acute myeloid leukemia and a pharmaceutical combination thereof It solves the problem of relapse and refractory of the existing AML combined with chemotherapy. The complete response rate (CR) of patients with relapsed and refractory acute myeloid leukemia 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 noted that all similar replacements and modifications will be apparent to those skilled in the art, and they are all considered 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 persons can modify or appropriately modify 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 commercially available products, and all are commercially available.

The following further describes the present invention in combination with the embodiments:

Example 1: A clinical trial on the treatment of acute myeloid leukemia

1.1 Test drugs

Xidabenamide 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 hospital pharmacy, no fixed supplier).

1.2 Test method

Number of cases: a total of 100 cases;

Inclusion criteria: 1) between 18 and 59 years old, male and female are not limited; 2) AML patients (non-AML-M3) diagnosed according to the 2008 World Health Organization (WHO) diagnosis of myeloid malignant diseases; 3) previous Patients who have no remission or relapse after at least one systemic treatment (including chemotherapy, hematopoietic stem cell transplantation, etc.); 4) ECOG behavior status score is 0-3 points; 5) Expected survival time 3 months; 6) no serious heart, lung, liver, kidney disease; 7) weight: 67 ± 20 kg (47-87 kg) for males, 55 ± 20 kg (35-75 kg) for females; 8) before enrollment Have not received any treatment such as radiotherapy, chemotherapy, targeted therapy or hematopoietic stem cell transplantation within 4 weeks; 9) have the ability to understand and be willing to sign the informed consent of this trial.

Exclusion criteria: (1) People who are allergic to the drugs included in the experimental protocol or drugs similar to the chemical structure of the test drug; (2) Pregnant and lactating women and patients of reproductive age who are unwilling to take contraceptive measures; (3) Yes People with active infections; (4) Patients who use drugs and long-term alcoholism that affect the evaluation of the test results; (5) People with mental illness or other conditions who cannot obtain informed consent and cannot cooperate with research treatment and monitoring; (6) Clinically significant QTc Patients with prolonged medical history (male> 450ms, female> 470ms), ventricular tachycardia (VT), atrial fibrillation (AF), atrial fibrillation (AF), atrioventricular block above grade Ⅱ, and myocardial infarction ( MI, Myocardial infarction) Patients with congestive heart failure (CHF) and symptomatic coronary heart disease within 1 year; (7) Ultrasound of pericardial pericardial cavity dark space in the end of diastole 10mm patients; (8) patients receiving organ transplants; (9) patients with active bleeding; (10) patients with new-onset 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) hypomyeloplasia and white blood cells <2.0 × 10 ⁹ / L; (13) abnormal liver function (total bilirubin> 1.5 times the upper limit of normal value, ALT / AST> normal) 2.5 times the upper limit or ALT / AST> 5 times the upper limit of normal values in patients with liver invasion), renal dysfunction (serum creatinine> 1.5 times the upper limit of normal values); (14) The investigator determines that it is not appropriate to participate in this trial.

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

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

Decitabine: 20 mg / m ² intravenously administered d1-d5; Aclamycin: 10 mg / m ² intravenously administered d3-d7; Cytarabine: 100 mg / 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 of d2--neutrophil recovery (WBC> 20 × 10 ⁹ / L When paused).

28d is a treatment cycle, and a total of 2 cycles are treated.

Note: If myelodysplasia is low at d28 in the first cycle and WBC <2 × 10 ⁹ / L, the second cycle can be postponed. If the extension is more than 4 weeks, the patient needs to withdraw from the test.

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

Secondary efficacy indicators include duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

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

Efficacy evaluation: (1) Efficacy evaluation interval: evaluation after each cycle of treatment; (2) Efficacy evaluation means: peripheral blood and bone marrow smears, immunotyping, chromosomes; (3) Efficacy evaluation standards:

1) Complete remission (CR): ① clinically free of symptoms and signs caused by leukemia cell infiltration, life is normal or close to normal; ② blood: Hb ≧ 100g / L (male) or ≧ 90g / L (female and children), medium Neutrophil absolute value 1.5 × 10 ⁹ / L, platelets 100 × 10 ⁹ / L. There are no leukemia cells in the classification of peripheral blood leukocytes; ③ Bone marrow image: blastocyte type I + type II (primitive monocytes + naive monocytes or primitive lymphocytes + naive lymphocytes) ≦ 5%, red blood cells and megakaryocytes are normal.

2) Partial response (PR, Partial response): bone marrow blasts type I + type II (primary monocytes + naive monocytes or primordial lymphocytes + naive lymphocytes)> 5% and ≦ 20%; or clinical, haematological There is one item in the bone marrow to reach the standard of complete remission.

Statistical Analysis:

1) Safety analysis: Describe in detail the cases of blood or non-hematological 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 was completed using SAS9.2. Measurement data were described by mean, standard deviation, median, maximum, and minimum values, and count data were described by frequency and percentage.

3) The main efficacy index ——the objective response rate needs to calculate 95% CI.

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

1.3 The results of the clinical trials of Cestabenamide and DCAG in the treatment of acute myeloid leukemia are as follows:

A total of 62 patients were enrolled in this clinical trial. The overall situation 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.

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

Clinical trial results: overall evaluable number (n = 55), 30 persons who obtained 1 evaluation; 25 persons who obtained 2 evaluations; complete response rate CR 24/55 (43.6%), and objective response rate ORR was 29/55 (58.2%), and the results of the clinical trials are shown in Table 4.

It can be seen from the results of the above clinical trials that the cedarbenzamide, decitabine, cytarabine, aclamycin, and granulocyte colony-stimulating factor provided by this embodiment can completely The response rate (CR) reached 43.6%, and the objective response rate (ORR) reached 58.2%, which solved the problem of refractory recurrence of the existing AML combined chemotherapy regimen, and the effect was significant.

Example 2: Combination pharmaceutical composition

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

Example 3: Combination pharmaceutical composition

Combined pharmaceutical composition according to the present embodiment comprising an effective dose of active ingredient: Chidamide 180mg, decitabine 20mg / m ^2, aclarubicin 10mg / m ^2, cytarabine 50mg / m ^2, and Granulocyte colony-stimulating factor 300 ug / day.

Example 4: Formulation of combined pharmaceutical composition

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

The above is only a preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principles of the present invention, several improvements and retouches can be made. These improvements and retouches also It should be regarded as the protection scope of the present invention.

Claims (9)

    A combination drug for treating leukemia, which includes: sitabine and DCAG drug, the DCAG drug is a combination drug of decitabine, cytarabine, aclamycin, and granulocyte colony-stimulating factor.         The combination drug according to item 1 of the scope of patent application, wherein the combination drug further comprises a pharmaceutically acceptable carrier.         The combination drug according to item 1 of the scope of the patent application, wherein both the cidabenzamine and the DCAG drug are in the form of a preparation.         The combination drug according to item 3 of the scope of the patent application, wherein the sitagamide is an oral preparation, and the DCAG drug using an 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 cidabenzamine is in a tablet preparation.     The combination drug according to any one of claims 1 to 5 of the scope of the patent application, wherein the X-ray powder diffraction pattern of the crystal form of the Cedarbenzamine at the reflection angle 2θ is 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 °; their characteristic peaks are: Infrared spectra have characteristic absorption peaks at 3412, 3282, 3199, 3043, 1654, ¹⁶¹⁵ , 1524, 1514, 1497, 1442, 1418, 1332, 1296, 1234, 1198, 1183, 1166, and 1027cm ^-1 ; their differential scanning The calorimetric analysis curve has an endothermic peak at 239.4 ° C. The combination drug according to any one of claims 1 to 5 of the scope of the patent application, which comprises the following effective dose of the active ingredient: 180 mg of cidabenzamine; 20 mg / m ² of decitabine; 10 mg / m ² of aclamycin; 50 to 100 mg / m ² of cytarabine; and 300 μg / day of granulocyte colony-stimulating factor.     The use of the combination medicament according to any one of claims 1 to 7 of the scope of patent application for the preparation of a medicament for acute myeloid leukemia.         The use according to item 8 of the scope of patent application, wherein the acute myeloid leukemia is relapsed refractory acute myeloid leukemia.