RU2802620C2 - Use of chidamide in combination with r-chop and drug combination - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a method of the treatment of B-cell lymphoma using chidamide in combination with R-CHOP. The proposed method for the treatment of B-cell lymphoma is characterized by the fact that hidamide is administered on days 1, 4, 8 and 11 orally, rituximab is administered on day 1 by an intravenous bolus, cyclophosphamide is administered on day 2 by an intravenous bolus, epirubicin is administered on day 2 by an intravenous bolus, vincristine is administered on day 2 by intravenous bolus and prednisone is administered on days 2–6 orally, while rituximab is administered at a dosage of 375 mg/m², cyclophosphamide is administered at a dosage of 750 mg/m², epirubicin is administered at a dosage of 70 mg/m², vincristine is administered at dosage of 1.4 mg/m², prednisone is administered at a dosage of 60 mg/m², chidamide is administered at a dosage of 20 mg/day.

EFFECT: use of the method shows high efficiency, especially for the patients that have a disease for the first time and are at high risk and elderly patients with diffuse large B-cell lymphoma.

5 cl, 1 tbl, 1 ex

Description

This application claims the priority of a Chinese patent application which was registered by the Chinese Patent Office on November 20, 2018 and has application number 201811394614.7 and the invention title “Use of chidamide in combination with R-CHOP and combination drug thereof,” the entire contents of which are included in this application via link.

Field of technology

The present invention relates to the field of medicine, in particular to the use of chidamide in combination with R-CHOP and their combination drug.

Prior Art

B-cell lymphoma mainly includes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone B-cell lymphoma (MCL), mantle cell lymphoma (MCZ) and so on. Currently, the R-CHOP regimen, consisting of rituximab (R) in combination with cyclophosphamide (CTX), adriamycin (ADR), vincristine (VCR) and prednisone (Pred), is used as the standard first-line regimen for the treatment of diffuse large B-cell disease. cell lymphoma (DLBCL), and good long-term survival was achieved. With current conventional immunochemotherapy, 1/3 of patients still fail to respond or relapse, and there is still room for improvement in efficacy, such as changing the combination of conventional chemotherapy or adding targeted agents. High-risk elderly patients with DLBCL have poor response to R-CHOP, with a complete response rate of only approximately 70% and poor long-term survival, and efficacy needs to be improved urgently.

Contents of the invention

In light of the above, an object of the present invention is to provide the use of chidamide in combination with R-CHOP in the manufacture of a medicament for the treatment of B cell lymphoma and/or for the treatment of B cell lymphoma. R-CHOP refers to a combination drug regimen R-CHOP in this field, namely a combination drug regimen comprising rituximab (R) in combination with cyclophosphamide (CTX), adriamycin or epirubicin (ADR/EPI), vincristine (VCR) and prednisone (Pred); in specific embodiments of the present invention, clinical studies were performed on diffuse large B-cell lymphoma as the specific disease being treated.

Chidamide (epidase) is a selective histone deacetylase (HDAC) subtype inhibitor independently studied and developed in China and is a class 1.1 new drug. Chidamide for its first indication, monotherapy for relapsed or refractory peripheral T-cell lymphoma (PTCL), was approved by the Chinese Food and Drug Administration (CFDA) on December 23, 2014, and is thus the world's first oral a selective HDAC subtype inhibitor approved for marketing for this indication. Chidamide mainly targets class I subtypes 1, 2 and 3 and class IIb subtype 10 HDACs and has regulatory effects on abnormal epigenetic functions of tumors. It induces chromatin remodeling by inhibiting cognate HDAC subtypes with increasing levels of histone acetylation in chromatin, and thus leading to changes in gene expression of several signaling pathways (i.e., epigenetic changes), thereby inhibiting the tumor cell cycle and inducing apoptosis of tumor cells and, having general regulatory activity on the body's cellular immunity, inducing and enhancing the tumor killing effect mediated by natural killer cells (NK) and antigen-specific cytotoxic T cells (CTL). Chidamide also has functions such as inducing tumor stem cell differentiation and reversing epithelial-mesenchymal transition (EMT) of tumor cells through epigenetic regulatory mechanisms, thus playing a potential role in restoring drug sensitivity of drug-resistant tumor cells and in inhibiting tumor metastasis and relapses, and so on.

The results of the phase I clinical trial of chidamide showed that the effective remission rate in chidamide monotherapy for T-cell non-Hodgkin lymphoma is 80%, but for 3 cases of B-cell non-Hodgkin lymphoma in patients included in the study, one case showed disease progression after treatment with chidamide , and the other two showed stable disease without curative effect, so the above results meant that chidamide alone did not show efficacy in the treatment of B-cell lymphoma.

However, in the present invention, it has surprisingly been found that chidamide in combination with R-CHOP shows a synergistic effect in the treatment of diffuse large B-cell lymphoma, and has better efficacy, especially for newly diagnosed, high-risk patients and elderly patients with DLBCL. In a mid-term evaluation following administration of the combination drug strategy of the present invention in a total of 31 clinically evaluable patients, the complete response rate was 90.3% and the partial response rate was 6.5%. At the final evaluation of a total of 23 clinically evaluable patients, the complete response rate was 87% and the objective response rate was 100%. The results of this clinical trial showed that R-CHOP in combination with chidamide had significantly improved efficacy in the treatment of new, elderly, high-risk patients with diffuse large B-cell lymphoma compared with the R-CHOP regimen.

As follows from the technical effects, the present invention specifically provides a combination drug in accordance with the intended use, which contains chidamide, rituximab, cyclophosphamide, Adriamycin or epirubicin, vincristine and prednisone in effective doses for simultaneous, separate or sequential administration.

In addition, the present invention also provides a drug for the treatment of B cell lymphoma that uses the above combination drug as the main active ingredient and is supplemented with other active ingredients and/or excipients for the drug that do not interfere with each other. Other active ingredients that do not interfere with each other may be an active ingredient for treating B-cell lymphoma, or an active ingredient for treating other diseases, or a combination of the two.

In addition, the present invention also provides a method for treating B-cell lymphoma, comprising simultaneous, separate or sequential administration of chidamide, rituximab, cyclophosphamide, adriamycin or epirubicin, vincristine and prednisone in effective doses.

From the above technical solutions, it can be seen that the present invention proposes the use of a therapeutic regimen comprising chidamide in combination with R-CHOP, which has a synergistic therapeutic effect on B cell lymphoma, and through clinical studies it is confirmed that the treatment regimen comprising chidamide in combination with R-CHOP, shows better effect in the treatment of diffuse large B-cell lymphoma compared with the R-CHOP treatment regimen, and such use can treat patients with B-cell lymphoma more effectively.

Specific embodiments of the invention

The present invention discloses the use of chidamide in combination with R-CHOP and a combination drug thereof, and a person skilled in the art can learn from the contents of this document the process parameters for producing the above and improve them accordingly. It is especially noted that all such substitutions and modifications will be obvious to one skilled in the art, and all are considered to be included in the present invention. The use of the present invention has been described by way of preferred examples, and one skilled in the art can obviously make substitutions or appropriate changes and combinations for the use described herein without departing from the content, spirit and scope of the present invention in order to carry out and apply the technology of the present invention.

The following is a description of the use of chidamide in combination with R-CHOP and the combination drug thereof provided by the present invention.

Example 1: Prospective, single-arm, open-label, phase II study of chidamide in combination with R-CHOP in the treatment of new-onset, older, high-risk patients with diffuse large B-cell lymphoma.

Drugs tested: Chidamide tablets: off-white tablets, 5 mg/tablet. Manufactured by Shenzhen Chipscreen Biosciences Co., Ltd. Chemotherapy drugs combined with R-CHOP: rituximab (R) in combination with cyclophosphamide (CTX), adriamycin or epirubicin (ADR/EPI), vincristine (VCR), prednisone (Pred).

Number of Cases: It was planned that this clinical trial could enroll a total of 49 patients.

Eligibility Criteria: To be included in the study, patients must meet all of the following criteria.

1. Histopathologically diagnosed diffuse large B-cell lymphoma and CD20-positive lymphocytes;

2. Age: equal to or older than 61 years, equal to or less than 75 years old;

3. Physical condition assessment according to ECOG (five-point scale for assessing the general condition of a cancer patient 0-4 Eastern Cooperative Oncology Group): 0, 1 or 2 points;

4. No history of malignant tumor; and at the same time other tumors that arose;

5. Patients with a life expectancy of at least 6 months as assessed by the investigators;

6. Patients or their legal representatives must provide written informed consent before being involved in any special examinations or research procedures.

7. International Prognostic Index (IPI): more than 1 point. Therapeutic treatment regimen, including:

1. The names and dosages of the drugs to be studied are listed in the table below, and the administration routes in the table below were applied to the patients:

Patients subsequently received 6 courses of the R-CHOP treatment regimen in combination with chidamide every 21 days. Patients were continuously assessed after completion of treatment (patients recorded the described follow-up period in the Intervention Chart) until the end of the specified follow-up period (total study duration of 3 years) or until patients met exclusion criteria.

The necessary conditions for continuous treatment are as follows, and if the following conditions are met, then the following course of treatment is carried out as planned:

1) After myelosuppression, the numbers of neutrophils and platelets were at an increasing stage;

2) On the first day of the next course of treatment, the number of neutrophils in the blood was more than or equal to 1.0×10 ⁹ /l, leukocytes (WBC) was more than or equal to 3.0×10 ⁹ /l;

3) On the first day of the next course of treatment, the platelet count was more than or equal to 75×10 ⁹ /l;

If not, the next course of treatment should be postponed for 3-4 days and the blood cell test should be repeated. If the above indicators have not yet been achieved, treatment is postponed for the next 3-4 days until the above chemotherapy standards are met. If treatment was delayed more than 14 days and standards were still not met, the patient was excluded from treatment and recorded as an adverse event. The patient is monitored continuously as required by protocol.

Cytotoxic drug reduction standard: 1. For agents with grade 2 or higher neurotoxicity, reduce VCR to 1 mg, 2. When neutrophil or platelet counts were insufficient, chemotherapy drug reduction should be considered. This can be done with reference to the following standards:

1. When the delay time for the next course of treatment was from 0 to 7 days: the original dosage should be maintained;

2. When the delay in the next course of treatment ranged from 8 to 14 days or the myelosuppression observed in the last course of treatment was grade 4, the dosage should be adjusted to:

STX 75% EPI 75% VCR 100% Pred 100% Chidamide 100%

Chidamide: If the disease did not progress or there was no intolerable adverse reaction, continued administration was recommended. Throughout the entire treatment process, if grade 3-4 myelosuppression was observed, administration should be suspended until the absolute value of neutrophils is greater than or equal to 1.5 × 10 ⁹ / L and platelets greater than or equal to 75.0 ×10 ⁹ /l, and then treatment with this drug can be continued.

3. Combination drug and treatment

In the first course of chemotherapy for patients with a large tumor burden (substantial mass or LDH greater than or equal to 500 U/L) or a partial response of 2 or gastrointestinal non-Hodgkin's lymphoma (prevention of gastrointestinal perforation), allopurinol and baking soda should be administered first Oral prednisone may be administered, and if necessary, chemotherapy may be administered for 2 days to prevent tumor collapse syndrome.

Granulocyte colony-stimulating factor (G-CSF): This should only be used when the physician has determined that it is necessary based on clinical guidelines. The use of G-CSF should be noted on the CRF Table.

Concomitant treatments prescribed because of adverse events, if they meet the reporting standards, should also be reported and the contents should be populated on the adverse events page of the CRF form. If necessary, patients should be given appropriate supportive treatment, including intravenous infusion of whole blood and blood products, antibiotic treatment, antiemetic treatment, and so on. The rationale for the treatment and its dosage and date of initiation of treatment should also be noted in the CRF table.

The decision whether to administer radiation therapy to patients with significant mass was made by the investigator.

Clinical Study Results: At mid-term evaluation, all 31 clinically evaluable patients had a complete response rate of 90.3% and a partial response rate of 6.5%. At end point, for all 23 clinically evaluable patients, the complete response rate was 87% and the objective response rate was 100%.

The results of this clinical trial showed that R-CHOP in combination with chidamide had significantly improved efficacy in the treatment of new-onset, older, high-risk patients with diffuse large B-cell lymphoma compared with the R-CHOP regimen.

The above are merely preferred embodiments of the present invention. It should be noted that certain improvements and modifications may be made by one of ordinary skill in the art without departing from the principles of the present invention, and such improvements and modifications should also be considered within the scope of the present invention.

Claims (5)

1. A method of treating B-cell lymphoma, which is characterized by administering chidamide on days 1, 4, 8 and 11 orally, administering rituximab on day 1 as an intravenous bolus, administering cyclophosphamide on day 2 as an intravenous bolus, administering epirubicin on day 2 as an intravenous bolus , vincristine is administered on day 2 by intravenous bolus and prednisone is administered orally on days 2-6, while rituximab is administered at a dosage of 375 mg/ ^m2 , cyclophosphamide is administered at a dosage of 750 mg/ ^m2 , epirubicin is administered at a dosage of 70 mg/ ^m2 , vincristine is administered at a dosage of 1.4 mg/ ^m2 , prednisone is administered at a dosage of 60 mg/ ^m2 , chidamide is administered at a dosage of 20 mg/day. 2. The method according to claim 1, wherein the B-cell lymphoma is a diffuse large B-cell lymphoma. 3. The method according to claim 2, wherein the diffuse large B-cell lymphoma is CD20 positive. 4. The method according to claim 1, where the administration of chidamide and R-CHOP is repeated every 21 days for 6 courses. 5. The method according to claim 4, where when repeating the course of treatment, the dosage of cyclophosphamide is reduced to 75%, the dosage of epirubicin is reduced to 75%, and/or the dosage of vincristine is reduced to 1 mg/ ^m2 .