WO2021129616A1 - Pharmaceutical combination of anti-pd-1 antibody and histone deaceylase inhibitor, use thereof, and usage method therefor - Google Patents

Abstract

The present invention relates to a pharmaceutical combination of an anti-PD-1 antibody targeting programmed death protein-1 (PD-1) and a HDAC inhibitor, which combination is used for treating cancers, especially extranodal NK/T cell lymphoma. The present invention also relates to a use of and method for using the combination to prevent or treat cancers, especially extranodal NK/T cell lymphoma.

Description

Drug combination of anti-PD-1 antibody and histone deacetylase inhibitor and its use and use method Technical field

The present invention relates to a pharmaceutical combination of an anti-PD-1 antibody or an antigen binding fragment thereof and a histone deacetylase inhibitor, which is used for the prevention or treatment of cancer, especially extranodal NK/T cell lymphoma. The present invention also relates to the use of the drug combination in the preparation of a drug for preventing or treating cancer, especially extranodal NK/T cell lymphoma, and a method for applying the drug combination to prevent or treat cancer, especially extranodal NK/T cell lymphoma .

Background technique

Extranodal NK/T-cell lymphoma, nasal type (extranodal natural killer/T-cell lymphoma, nasal type, ENKTL) is a rare subtype of non-Hodgkin’s lymphoma, in all non-Hodgkin’s lymphoma subtypes in my country Among them, it accounts for up to 6%. It is highly invasive, and the prognosis of patients with newly-treated late stage and refractory relapsed patients is poor. ENKTL mainly occurs in the nasal cavity, followed by the skin and gastrointestinal tract. The main pathological manifestations of this disease are vascular invasion and tissue destruction. Specific markers and specific genetic changes on the surface of ENKTL cells can also help diagnose the disease. ENKTL is closely related to Epstein-Barr virus (EBV) infection, and the level of EBV-DNA has important significance for its prognosis and auxiliary diagnosis. At present, the treatment of ENKTL lacks prospective, randomized, controlled clinical research, and there is no standard treatment method. Its main treatment methods include radiotherapy, chemotherapy and hematopoietic stem cell transplantation. In the early stage of initial treatment, radiotherapy ± L-asparaginase-based chemotherapy combined treatment mode is adopted, and the 5-year overall survival (OS) of the patient can exceed 80%. However, patients with newly diagnosed advanced and refractory relapses who are treated with L-asparaginase-based chemotherapy and/or hematopoietic stem cell transplantation, the 5-year OS of the patients is only 30-50%. At present, the National Comprehensive Cancer Network (NCCN) recommends SMILE (Japan), AspaMetDe (France) and P-Gemox (Sun Yat-sen University Cancer Hospital) as a combination chemotherapy regimen. In 2011, Japanese scholars first used SMILE regimen (dexamethasone, high-dose methotrexate, ifosfamide, L-asparaginase, etoposide) to treat 38 patients with newly-treated stage IV, relapsed or refractory ENKTL The objective response rate (ORR) and complete response rate (CRR) were 79% and 45%, respectively, and the 1-year OS rate was 55%. However, 92% of patients had grade 4 neutropenia, and 61% of patients had grade 3/4 infection [1]. The Hong Kong Queen Mary Hospital subsequently reported the results of the SMILE program to expand the sample size, including 43 cases of newly diagnosed late stage and 44 cases of refractory relapsed patients. After treatment, the ORR and CRR were 81% and 66%, respectively, the 5-year OS rate was 50%, and the 4-year progression-free survival (PFS) rate was 64%; 57 patients had grade 3/4 neutropenia , 36 patients had grade 3/4 thrombocytopenia, and 15 patients had nephrotoxicity. Among them, 5 patients died of treatment-related sepsis; 1 patient died of acute renal failure caused by high-dose methotrexate [2]. In addition, the GELA and GOELAMS collaborative group reported the results of AspaMetDex (L-asparaginase, high-dose methotrexate, and dexamethasone) in the treatment of 19 patients with refractory and relapsed ENKTL. The ORR and CRR were 78% and 61%, respectively. The median OS was 1 year, and the median duration of response was 12 months. The main adverse events were hepatitis, cytopenias and allergies, but there were still 5 patients with high-dose methotrexate-related transient renal insufficiency, and grade 3/4 agranular fever [3]. In 2018, Professor Huang Huiqiang from the Cancer Center of Sun Yat-sen University and other researchers reported on the P-Gemox regimen (peaspartase, gemcitabine, oxaliplatin) in the treatment of 267 patients with newly treated and refractory relapsed ENKTL at the American Hematology Annual Meeting. As a result, the P-Gemox regimen is safer than SMILE and AspaMetDex regimens, and the survival of newly-treated stage I/II patients is satisfactory, but the survival of newly-treated stage III/IV and refractory relapsed patients is still poor [4]. In recent years, domestic and foreign scholars have tried to further improve the prognosis of ENKTL in the late stage and refractory relapsed ENKTL through different cytotoxic drug combinations, but they have not achieved a breakthrough, and traditional cytotoxic drug treatment has encountered a bottleneck in curative effect. Therefore, how to improve the survival of newly treated stage III/IV and refractory relapsed patients is the direction of the next treatment.

Histone deacytelase (HDAC) is involved in the biological processes of a variety of tumors. When tumors occur, their activity is significantly increased, which makes the histones in the nucleosomes in a state of hypoacetylation, leading to tumor suppressor genes. Transcription activity is inhibited, and the abnormal expression of a variety of genes that regulate cell proliferation and cell cycle causes malignant transformation of cells [5]. HDAC inhibitors are a new type of small-molecule targeted drugs that play an anti-tumor effect by regulating epigenetics. By blocking the deacetylation of HDAC, DNA maintains transcriptional activity and causes changes in multiple downstream signaling pathways. , Can cause tumor cell apoptosis, induce cell differentiation and inhibit angiogenesis [5-7]. At the same time, it also has a regulatory effect on the body's immune cells, and can induce and enhance the tumor killing effect mediated by NK cells and cytotoxic T lymphocytes (CTL). Chidamide is a subtype-selective oral HDAC inhibitor. Its main target is type I and type II HDAC. It has been approved for the treatment of refractory and relapsed peripheral T-cell lymphoma in my country. In the pivotal phase II clinical trial (registered clinical trial), a total of 83 patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) were enrolled, and all received 30 mg/time, twice/week of chidamide Treatment until the disease progresses or untolerable adverse reactions occur. The main efficacy index is ORR. The efficacy of 79 patients was evaluated, and the results showed that: ORR was 28%, median PFS and median OS were 2.1 months and 21.4 months, respectively; the most common grade 3/4 adverse reactions were thrombocytopenia (22%), white blood cells Decrease (13%) and neutropenia (10%). The study included 16 patients with refractory and relapsed ENKTL. The ORR of chidamide was only 25%, and the CRR was 6% [8]. In the reports of real-world studies in my country, the ORR, CRR and disease control rate (DCR) of chidamide monotherapy in patients with refractory and relapsed ENKTL were 15%, 6% and 42%, respectively [9]. The efficacy of Chidamide in the real world is not ideal. The team of Professor Huang Huiqiang from Sun Yat-sen University Cancer Hospital also conducted a study of chidamine monotherapy in 22 patients with refractory relapsed ENKTL. The results of the study showed that the ORR reached 50%, the CR rate was 31.3%, and the survival of patients who could obtain CR exceeded 2 year. Although Chidamide may be an effective drug for potential treatment of ENKTL, its efficacy still has great limitations.

Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis is a powerful signaling pathway to inhibit immune activation, and it is also a tumor to achieve immune escape One of the important mechanisms [10,11]. Tumor infiltrating lymphocytes highly express PD-1. These PD-1 combine with PD-L1 on the surface of tumor cells or immune cells to inhibit the initial activation of T cells, and inhibit the production and function of effector T cells (including cytokine production and Cytotoxicity) [12,13]. Many types of tumors, including Hodgkin’s lymphoma [14], diffuse large B-cell lymphoma [15], ENKTL [16], etc., express PD-L1 and inhibit anti-tumor T cell responses through PD-L1 [ 17]. Blocking the PD-L1/PD-1 axis can restore the function of T cells to kill tumors and obtain a lasting clinical response [10,11,18]. There have been many studies at home and abroad that have confirmed the efficacy of PD-1 monoclonal antibody in patients with refractory and relapsed ENKTL. The First Affiliated Hospital of Zhengzhou University reported in the Journal of Hematology&Oncology the results of Pembrolizumab monotherapy in 7 patients with refractory and relapsed ENKTL. After a median of 4 (2-18) courses of treatment, the ORR was 57% and the CR rate was 28.6. % (2 cases of CR, 2 cases of PR), the side effects were mild. This study once again confirmed the potential therapeutic value of PD-1 inhibitors in refractory and relapsed ENKTL [19]. Cinda Biopharmaceuticals (Suzhou) Co., Ltd., a well-known national medical center in the United Nations, carried out a multi-center, single-arm Phase II clinical study (ORIENT-4) of Sintilimab as a single agent in refractory and relapsed ENKTL in 2017. , The patient received Sintilizumab (200mg IV Q3W) monotherapy until the disease progressed, died, the toxicity was intolerable or the study was withdrawn. In the study, PET-CT and enhanced CT/MRI were used to evaluate tumor response. The main study endpoint is ORR based on the LUGANO 2014 efficacy evaluation criteria for malignant lymphoma. As of February 2, 2019, a total of 28 patients were enrolled, 60.7% of them were male, and the median age was 37 years. 68% of patients had stage IV, and 89.3% had ECOG score ≥1. All patients received asparaginase-containing regimens that failed. The median number of previous treatment regimens was 3, 78.6% of patients had received radiotherapy, and 7.1% of patients had received hematopoietic stem cell transplantation. Preliminary results showed that the median duration of treatment was 14 months, and 19 patients were still receiving sintilizumab. The ORR was 68%, and the CR rate was 7.1%. With a median follow-up of 15.4 months, the 1-year OS rate was 82.1%, and the median OS has not yet been reached. ORR subgroup analysis showed that patients with EBV negative, no B symptoms, normal LDH levels, and bone marrow unaffected patients were more effective [20]. Although Sintilimab is effective against ENKTL, how to improve the effectiveness of tumor treatment is still an urgent problem that needs to be solved in the current tumor treatment field.

The biological behavior of most tumors is not dominated by a single signal transduction pathway, but multiple signal transduction pathways work together. In some cases, drugs with different mechanisms of action can be used in combination. However, any combination form of drugs that have different mechanisms of action but work in similar fields does not necessarily produce a combination form with beneficial effects. Therefore, although there is indeed a demand for combination medication schemes and products for different signal transduction pathways in the prior art, in view of the complexity of tumorigenesis and the unpredictability of interactions between different drugs, it has been found to be feasible and capable of bringing about Compared with a single drug, a combination drug that has a better effect (reduce the dose of a single drug, improve the incidence and/or severity of adverse events (AE) during treatment, and/or act in a synergistic manner, etc.) Solutions and products are still a major challenge in the field of medicine.

Summary of the invention

The inventors surprisingly found that the drug combination of the present application can treat cancer, especially extranodal NK/T cells in a way that synergistically acts and/or improves the incidence and/or severity of adverse events (AE) during treatment. Lymphoma plays a preventive and/or therapeutic effect.

In the first aspect, the present invention provides a pharmaceutical combination comprising a PD-1 antibody or an antigen-binding fragment thereof and an HDAC inhibitor,

The anti-PD-1 antibody contains 6 CDRs, and LCDR1, LCDR2, and LCDR3 are composed of the amino acid sequences RASQGISSWLA (SEQ ID NO: 9), SAASSLQS (SEQ ID NO: 10) and QQANHLPFT (SEQ ID NO: 11), respectively, and Wherein HCDR1, HCDR2 and HCDR3 are respectively composed of amino acid sequences KASGGTFSSYAIS (SEQ ID NO: 2), LIIPMFDTAGYAQKFQG (SEQ ID NO: 5) and ARAEHSSTGTFDY (SEQ ID NO: 8); or

The anti-PD-1 antibody is selected from Sintilimab, Pembrolizumab, Nivolumab, Teriplizumab and Carrelizumab;

Wherein the HDAC inhibitor is selected from the following compounds of formula I or pharmaceutically acceptable salts thereof:

Among them, A is a benzene ring or heterocyclic ring, which can contain 1 to 4 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, 1 to 4 Carbon atom alkoxy group, 1 to 4 carbon atom aminoalkyl group, 1 to 4 carbon atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acyl group, 1 to 4 A thioalkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a perfluoroalkoxy group of 1 to 4 carbon atoms, a carboxyl group of 1 to 4 carbon atoms, and a perfluoroalkyl group of 1 to 4 carbon atoms Alkoxycarbonyl, phenyl or heterocyclic substituents;

B is a benzene ring or heterocyclic ring, which can contain 1 to 3 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, and 1 to 4 carbon atoms Alkoxy, aminoalkyl of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, acyl of 2 to 4 carbon atoms, acylamino of 2 to 4 carbon atoms, 1 to 4 carbons Atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 carbon atom perfluoroalkoxy group, 1 to 4 carbon atom carboxyl group, 1 to 4 carbon atom alkoxy group Carbonyl, phenyl or heterocyclic substituents:

Z is a covalent bond, an alkylene of 1 to 4 carbon atoms, or a linear structure or a ring _{containing -O-, -S-, -NH, -CO-, -CS-, -SO-, -SO 2-} Structure or a combination of linear structure and cyclic structure;

Y is a linear structure, a cyclic structure or a combination of a linear structure and a cyclic structure containing -CO-, -CS-, -SO-, -SO ₂ -, wherein the center point (W1) of ring A and the center of ring B The distance between the point (W2) and the O atom or S atom (W3) contained in Y as the hydrogen bond acceptor satisfies the following conditions:

The better distance between them is

R ¹ and R ² are respectively hydrogen or an alkyl group containing 1 to 4 carbon atoms, and R ¹ and R ² can also form a covalent bond together;

R ³ is hydrogen or an alkyl group containing 1 to 4 carbon atoms;

R ⁴ is hydrogen, halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 Alkylamino of to 4 carbon atoms, acyl of 2 to 4 carbon atoms, amido of 2 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, perfluoroalkane of 1 to 4 carbon atoms Group, perfluoroalkoxy group of 1 to 4 carbon atoms, carboxyl group of 1 to 4 carbon atoms, alkoxycarbonyl group of 1 to 4 carbon atoms;

One of X ¹ , X ² , X ³ , and X ⁴ is halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, 1 to Aminoalkyl groups of 4 carbon atoms, alkylamino groups of 1 to 4 carbon atoms, acyl groups of 2 to 4 carbon atoms, acylamino groups of 2 to 4 carbon atoms, thioalkyl groups of 1 to 4 carbon atoms, Perfluoroalkyl groups of 1 to 4 carbon atoms, perfluoroalkoxy groups of 1 to 4 carbon atoms, carboxyl groups of 1 to 4 carbon atoms, alkoxycarbonyl groups of 1 to 4 carbon atoms; the rest are hydrogen , Halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 to 4 carbons Atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acid amino group, 1 to 4 carbon atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 Perfluoroalkoxy with 4 carbon atoms, carboxyl with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms;

Or wherein the HDAC inhibitor is selected from Vorinostat, Romidepsin, Belinostat, Panobinostat, Chidamide, Entinol Special (Entinostat) and Mocetinostat (MGCD0103).

In a preferred embodiment, preferably, the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 13 or has at least 90% of the sequence of SEQ ID NO: 13 , 95%, 98%, or 99% identical sequences, and/or the light chain variable region comprising the sequence of SEQ ID NO: 15 or a sequence having at least 90%, 95%, 98% or 99% identity therewith;

Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 17 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and/or SEQ ID NO: 22 or has A light chain sequence that is at least 90%, 95%, 98%, or 99% identical.

In a preferred embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from Sintilimab, Pembrolizumab, Nivolumab, and Trepre Lizumab and Carrelizumab; preferably, the anti-PD-1 antibody is Sintilizumab.

In a preferred embodiment of the present invention, the HDAC inhibitor is selected from the group consisting of Vorinostat, Romidepsin, Belinostat, Panobinostat, and Panobinostat. Chidamide, Entinostat and Mocetinostat (MGCD0103) or a pharmaceutically acceptable salt thereof, more preferably, the HDAC inhibitor is Chidamide.

In a preferred embodiment, the drug combination is used to prevent or treat cancer, preferably non-Hodgkin's lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably late or refractory extranodal NK/T Cell lymphoma.

In a preferred embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is in the form of a dosage unit of 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, more preferably 200 mg, Preferably it is a parenteral, more preferably an intravenous administration form; and/or

The HDAC inhibitor is in the form of a dosage unit of 10 to 50 mg, preferably 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, preferably in a dosage form for oral administration.

In a preferred embodiment, the single administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from 100-300 mg, such as 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, preferably once every two to four weeks, preferably It is administered by intravenous infusion.

In a preferred embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is intravenously infused once every three weeks, and the single infusion dose is 200 mg.

In a preferred embodiment, the single administration dose of the HDAC inhibitor is selected from 10mg-50mg, preferably 1-4 times per week, preferably by oral administration;

In a preferred embodiment, the oral dose of the HDAC inhibitor is selected from 20 mg, 25 mg and 30 mg.

In a preferred embodiment, the HDAC inhibitor is taken orally twice a week, and each oral dose is 30 mg.

In a preferred embodiment, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the HDAC inhibitor are administered separately, simultaneously or sequentially.

In a preferred embodiment, after the anti-PD-1 antibody and the HDAC inhibitor combined treatment cycle is over, the anti-PD-1 antibody or its binding fragment can be continuously administered for treatment.

In the second aspect, the present invention provides the use of the drug combination of the anti-PD-1 antibody or its antigen-binding fragment and HDAC inhibitor as defined in the first aspect in the preparation of a drug for the prevention or treatment of cancer, and the cancer is preferably selected From non-Hodgkin's lymphoma, extranodal NK/T cell lymphoma is more preferred, and extranodal NK/T cell lymphoma that is advanced or refractory to relapse is most preferred.

In the third aspect, the present invention provides a method for preventing or treating cancer, the method comprising administering to a patient in need a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof defined in the first aspect and HDAC inhibition The cancer is preferably selected from non-Hodgkin’s lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably advanced or refractory and relapsed extranodal NK/T cell lymphoma.

In the fourth aspect, the present invention also provides a single drug dosage unit, which includes a therapeutically effective amount of the drug combination of the anti-PD-1 antibody or antigen-binding fragment thereof as defined in the first aspect and an HDAC inhibitor.

In the fifth aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof as defined in the first aspect and a pharmaceutical combination of an HDAC inhibitor and pharmaceutically acceptable excipients Agent.

In the sixth aspect, the present invention also provides a kit of medicines comprising a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof defined in the first aspect and a drug combination of an HDAC inhibitor.

In a seventh aspect, the present invention also provides the use of the above-mentioned single drug dosage unit, pharmaceutical composition or kit in the preparation of a drug for preventing or treating cancer. The cancer is preferably selected from non-Hodgkin’s lymphoma, more preferably nodal. Extranodal NK/T cell lymphoma, most preferably advanced or refractory and relapsed extranodal NK/T cell lymphoma.

definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. For the purpose of the present invention, the following terms are defined below.

The term "about" when used in conjunction with a numerical value means to encompass a numerical value within a range having a lower limit that is 5% smaller than the specified numerical value and an upper limit that is 5% larger than the specified numerical value.

The term "and/or" should be understood to mean any one of the alternatives or a combination of any two or more of the alternatives.

As used herein, the term "comprising" or "including" means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps. In this document, when the term "comprises" or "includes" is used, unless otherwise specified, it also encompasses the situation consisting of the stated elements, integers or steps. For example, when referring to an antibody variable region that "comprises" a specific sequence, it is also intended to encompass the antibody variable region composed of the specific sequence.

As used herein, the term "antibody" refers to a polypeptide comprising at least a light chain or heavy chain immunoglobulin variable region, which specifically recognizes and binds to an antigen. The term encompasses various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, single-chain or multi-chain antibodies, monospecific or multispecific antibodies (such as bispecific antibodies), fully human antibodies, or Chimeric antibodies or humanized antibodies, full-length antibodies, and antibody fragments, as long as they exhibit the desired antigen-binding activity.

The term "antigen-binding fragment" of an antibody (which can be used interchangeably with "antibody fragment" and "antigen-binding portion" herein) refers to a molecule that is not an intact antibody, which includes the intact antibody used to bind the intact antibody. Part of the antigen. As understood by those skilled in the art, the antigen-binding portion of an antibody usually contains amino acid residues from the "complementarity determining region" or "CDR". The antigen-binding fragment can be prepared by recombinant DNA technology, or by enzymatic or chemical cleavage of the intact antibody. Antigen-binding fragments include but are not limited to Fab, scFab, Fab', F(ab')2, Fab'-SH, Fv, single-chain Fv, double-chain antibody (diabody), triabody (triabody), four-chain antibody ( tetrabody), minibody (minibody), single domain antibody (sdAb). For a more detailed description of antibody fragments, please refer to: Fundamental Immunology, edited by WEPaul, Raven Press, NY (1993); Shao Rongguang et al. (ed.), Research and Application of Antibody Drugs, People's Medical Publishing House (2013); Hollinger et al., PNAS USA 90:6444-6448 (1993); Hudson et al., Nat. Med. 9:129-134 (2003).

The term "prevention" includes the suppression or delay of the occurrence or frequency of the occurrence or occurrence of a disease or disorder or its symptoms, and it generally refers to the administration of drugs before the occurrence or occurrence of the symptoms or symptoms, especially before the occurrence of the symptoms or symptoms in individuals at risk.

The term "treatment" as used herein refers to the slowing, prevention or reversal of the progression of a subject's cancer (for example, extranodal NK/T cell lymphoma) as evidenced by the reduction or elimination of clinical or diagnostic symptoms of the disease. Treatment may include, for example, reducing the severity of symptoms, the number of symptoms, or the frequency of recurrence, for example, tumor growth inhibition, tumor growth arrest, or regression of existing tumors.

The term "single drug dosage unit" as used herein refers to a single drug dosage form administered to a patient at the time of the dosing schedule, including injections, tablets, and freeze-dried powders.

The term "drug combination" refers to a non-fixed combination product or a fixed combination product, such as a kit. The term "non-fixed combination" means that the active ingredients (for example, (i) anti-PD-1 antibodies or antigen-binding fragments thereof, and (ii) HDAC inhibitors as separate entities are simultaneously, without a specific time limit, or in the same or different The two agents are administered to the patient sequentially at intervals of time, wherein such administration provides prophylactic or therapeutically effective levels of the two active agents in the patient. In some embodiments, the anti-PD-1 antibody molecule and HDAC used in the drug combination The two molecules of the inhibitor are administered at a level not exceeding the level when they are used alone. The term "fixed combination" means that the two active agents are administered to the patient simultaneously in the form of a single entity. The dosage and/or of the two active agents are preferred. The time interval is selected so that the combined use of each part can produce an effect greater than that achieved by using any single component in the treatment of diseases or conditions. Each component can be in the form of a separate preparation, and the preparation form can be the same or different.

When it comes to combination therapy, the term "therapeutically effective amount" as used herein refers to the combined effect that triggers the desired biological or medical response when administered in combination, that is, one or more cancers that are inhibited or improved include extranodal NK/T cell lymph The combined dose for the clinical or diagnostic symptoms of tumors. For example, when referring to combination therapy, the term "therapeutically effective amount" as used herein refers to antibodies that produce a therapeutically effective and/or synergistic combination when administered together (sequentially or simultaneously) on the same day or on different days in the treatment cycle. Dosage and dosage of chemotherapy drugs. Moreover, those skilled in the art should recognize that in the case of combined treatment with a therapeutically effective amount (as in the above example), the amount of individual antibodies and/or chemicals may or may not be therapeutically effective.

The term "period" refers to a specific period of time expressed in days or weeks that repeats on a regular schedule. For example, each treatment cycle is 15 to 30 days, such as 15 to 24 days, and preferably each treatment cycle is three weeks (ie, 21 days). In one embodiment, one treatment cycle is four weeks (ie, 28 days).

The term "administration" refers to the physical introduction of each active ingredient of the pharmaceutical composition of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art. The route of administration of each active ingredient in the pharmaceutical combination of the present invention includes oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other parenteral routes of administration . As used herein, the phrase "parenteral administration" refers to methods of administration other than gastrointestinal and topical administration, usually via intravenous, and without limitation includes intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrasaccular , Intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injection and infusion, and in vivo electroporation. Correspondingly, each active ingredient in the pharmaceutical combination of the present invention can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, etc.

The term "dose" is the amount of a drug that induces a therapeutic effect. Unless otherwise stated, the dosage is related to the amount of the free form of the drug. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased in proportion to the amount of the drug in the free form. For example, the dosage will be stated on the product packaging or product information sheet.

The term "pharmaceutically acceptable salt" includes but is not limited to acid addition salts or base addition salts, for example: HADC inhibitors (including compounds of formula (I)) formed with inorganic acids, such as hydrochloride, hydrogen Bromate, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts formed by HADC inhibitors (including compounds of formula (I)) and organic acids, such as methyl Acid salt, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxy Ethyl sulfonate, benzoate, salicylate, stearate, and _{salt formed with alkane dicarboxylic acid of the formula HOOC-(CH 2} ) _n -COOH (wherein n is 0-4), etc. "Pharmaceutically acceptable salts" also include base addition salts of compounds of formula (I) with acidic groups and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

The term "pharmaceutically acceptable" refers to those compounds and materials that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and commensurate with a reasonable benefit/risk ratio , Composition and/or dosage form.

The term "adverse event" (AE) is any unfavorable and often unexpected or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of medical treatment. For example, an adverse event may be related to the activation of the immune system in response to treatment or the expansion of immune system cells (e.g., T cells) in response to treatment. Medical treatments can have one or more related AEs, and each AE can have the same or different levels of severity.

The "anti-PD-1 antibody" used herein includes the anti-PD-1 antibodies described in WO2017025016, CN108473977B and WO2017133540, the entire contents of which are incorporated herein by reference. Wherein, the anti-PD-1 antibody is preferably the anti-PD-1 antibody D-S228P IgG4 disclosed in WO2017025016A1, which is also referred to as sintilimab in this application. The numbering of the sequence used herein directly corresponds to the numbering in WO2017025016A1, and has not been renumbered.

"HDAC inhibitor" as used herein includes the compound described in Chinese application 03139760.3 (publication number CN1513839A), the entire content of which is incorporated herein by reference. For the definition of the terms in the compound of formula I above, please refer to Chinese Application 03139760.3 (Publication No. CN1513839A). The HDAC inhibitor is preferably Chidamide

Or its pharmaceutically acceptable salt.

Use of the drug combination of the present invention and treatment method using the drug combination of the present invention

The present invention provides the aforementioned pharmaceutical combination of the present invention for preventing and/or treating the severity of at least one symptom or indication of cancer in an individual or inhibiting the growth of cancer cells.

The present invention provides a method of preventing or treating cancer, which comprises administering an effective amount of the pharmaceutical combination of the present invention to an individual in need. The effective amount includes a preventive effective amount and a therapeutically effective amount.

The present invention provides the use of the aforementioned pharmaceutical combination of the present invention in the preparation of drugs for the prevention or treatment of cancer.

The cancer of the present invention includes solid tumors and hematological malignancies, such as non-Hodgkin’s lymphoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, lung cancer, such as non-small cell lung cancer, thymic cancer, kidney cancer, melanoma Tumors, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors, such as stomach cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma, brain cancer, and bone cancer. The cancer is preferably advanced cancer, refractory cancer and/or cancer resistant to chemotherapy, more preferably advanced solid tumor, unresectable or metastatic advanced solid tumor (confirmed by histology or cytology). The cancer is preferably extranodal NK/T cell lymphoma, bowel cancer (including colorectal cancer), lung cancer (including non-small cell lung cancer). The cancer is preferably late-stage recurrent or metastatic cancer (advanced malignant tumor), preferably late-stage or refractory extranodal NK/T cell lymphoma.

The drug combination of the present invention can be administered to individuals who have been treated with one or more previous therapies but subsequently relapsed or metastasized.

The drug combination of the present invention is administered to display one or more cancer-related biomarkers [e.g., programmed death ligand 1 (PD-L1), CA125, CA19-9, prostate specific antigen (PSA), lactate Individuals with elevated levels of hydrogenase, KIT, carcinoembryonic antigen, vascular endothelial growth factor (VEGF)]. For example, a prophylactically effective amount or a therapeutically effective amount of the pharmaceutical combination of the present invention is administered to an individual with an elevated PD-L1 level and/or an elevated VEGF level.

The anti-PD-1 antibody in the pharmaceutical combination of the present invention can be administered to an individual in need in one or more doses, where in the case of administering multiple doses, after the previous dose 1, 2, 3, 4, 5, The next dose is administered at 6, 7, 8, 9 or 10 weeks. A dose of anti-PD-1 antibody may be selected from 0.1-10 mg/kg of the individual's body weight (for example, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg). In some other embodiments, each dose contains 50-500 mg of anti-PD-1 antibody, such as 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of anti-PD-1 antibody.

The HDAC inhibitor (for example, chidamide or its pharmaceutically acceptable salt) in the pharmaceutical combination of the present invention is administered approximately once a day, once every two days, once every three days, once every four days, twice a week, and weekly One time, once every two weeks for continuous administration, or two times a week for three weeks and one week off every three weeks, two times a week for two weeks and two weeks off for one week. The dosage of the HDAC inhibitor is 10 to 50 mg/time, for example, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 45 mg/time, or 50 mg/time.

In one embodiment, the pharmaceutical combination of the present invention can be administered for at least one cycle, for example 2-12 or more treatment cycles, preferably wherein the one cycle is administered 1-2 doses of anti-PD-1 antibody, and at least The HDAC inhibitor is administered on days 1 to 10 of each cycle, preferably on days 1 to 14 or on days 1 to 21, preferably twice a week, and preferably at least 15 per cycle To 30 days, more preferably 21 days or 28 days.

Preferably, the HDAC inhibitor in the pharmaceutical combination of the present invention is at a dose of 10 to 50 mg/time, for example, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 45 mg A dose of 50 mg/time or 50 mg/time is taken orally twice a week, continuously administered for 2, 3 or 4 weeks and stopped for 1 week or continuously administered during the use cycle, and the anti-PD-1 antibody is administered intravenously at 100-300 mg, such as 200 mg, Once every 3, 4, or 5 weeks, every 3, 4, or 5 weeks is a cycle.

Preferably, the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally at a dose of 20 mg twice a week for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks.

Preferably, the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally at a dose of 25 mg twice a week for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks.

Preferably, the HDAC inhibitor in the pharmaceutical combination of the present invention is taken orally twice a week at a dose of 30 mg for continuous administration, and the anti-PD-1 antibody is infused intravenously at 200 mg, once every 3 weeks, once every 3 weeks.

Preferably, the anti-PD-1 antibody in the pharmaceutical combination of the present invention may be administered before, at the same time, or after the start of administration of the HDAC inhibitor. When the anti-PD-1 antibody is administered "before" the start of the HDAC inhibitor, the anti-PD-1 antibody may be greater than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours before the start of the HDAC inhibitor. , About 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes, about 15 minutes or Approximately 10 minutes to apply. When administered after the HDAC inhibitor starts to be administered, the anti-PD-1 antibody may be about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 minutes after the start of administration of the HDAC inhibitor. Hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours. Administration "simultaneously" with the start of administration of the HDAC inhibitor means that the anti-PD-1 antibody is administered to the individual within less than 10 minutes (before, after, or simultaneously) of the start of administration of the HDAC inhibitor. Preferably, the anti-PD-1 antibody in the pharmaceutical combination of the present invention is administered after the HDAC inhibitor starts to be administered, for example, the anti-PD-1 antibody is administered about 1 hour, about 3 hours, about 6 hours after the start of the HDAC inhibitor administration. About 12 hours, about 15 hours administration.

Preferably, the anti-PD-1 antibody in the pharmaceutical combination of the present invention is an injection, and if it is administered by intravenous infusion, the administration time may be about 15-60 minutes.

In some embodiments, the administration of at least one cycle of the drug combination of the present invention results in an increased, preferably synergistically increased, ORR of the patient compared to a patient administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy ( Objective response rate), CRR (complete response rate), progression-free survival (PFS) or overall survival (OS). In some embodiments, the administration of at least one cycle of the drug combination of the present invention results in an increase in the patient's PFS by at least about 1 month, compared to a patient administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy. About 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, About 1 year, about 2 years or more. In some embodiments, the administration of at least one cycle of the drug combination of the present invention results in an increase in the patient's OS by at least about 1 month, compared to patients who are administered anti-PD-1 antibody monotherapy or HDAC inhibitor monotherapy. About 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, About 1 year, about 2 years or more.

Compared with monotherapy with the administration of anti-PD-1 antibodies or monotherapy with the administration of HDAC inhibitors, the drug combination of the present invention results in an improved, preferably synergistically improved, therapeutic effect on cancer. In some embodiments, compared with the administration of anti-PD-1 antibody monotherapy or the administration of HDAC inhibitor monotherapy, the drug combination of the present invention results in a patient's ORR (objective response rate) increased by about 10%, about 20%, About 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150 %, about 200%, or about 300%. In some embodiments, compared with the administration of anti-PD-1 antibody monotherapy or the administration of HDAC inhibitor monotherapy, the drug combination of the present invention results in a patient's CRR (complete remission rate) increased by about 10%, about 20%, About 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150 %, about 200%, or about 300%.

Compared with the monotherapy of administration of anti-PD-1 antibodies or monotherapy of administration of HDAC inhibitors, the drug combination of the present invention results in an increase, preferably a synergistic increase in the inhibitory effect on tumor growth. In some embodiments, the drug combination of the present invention results in tumor growth being inhibited by at least about 10%, about 20%, about 30%, compared with the administration of anti-PD-1 antibody monotherapy or the administration of HDAC inhibitor monotherapy. About 40%, about 50%, about 60%, about 70%, or about 80%. In some embodiments, administration of the drug combination of the invention results in increased tumor regression, tumor shrinkage and/or disappearance. In some embodiments, the drug combination of the present invention prevents tumor recurrence and/or increases the duration of survival in an individual compared with an untreated individual or with a monotherapy with an anti-PD-1 antibody or a monotherapy with an HDAC inhibitor For example, increase the duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more Within 36 months, or more than 48 months. In some embodiments, the drug combination of the present invention can increase progression-free survival or overall survival.

In some embodiments, administration of the drug combination of the invention to an individual suffering from cancer results in the complete disappearance of the tumor ("complete response"). In some embodiments, administration of the drug combination of the invention to an individual suffering from cancer results in a reduction in tumor cells or tumor size by at least 30% or more ("partial response"). The tumor reduction can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computer tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetics analysis.

In some embodiments, the pharmaceutical combination of the present invention can reduce adverse events caused by the administration of anti-PD-1 antibodies and/or HDAC inhibitors, such as hematological toxic reactions, non-hematological toxic reactions or other toxic reactions, such as pneumonia, Diarrhea, enterocolitis, renal insufficiency, skin rash, hepatitis, endocrine disease and peripheral or central neuritis, liver function abnormalities, etc.

The kit of the present invention

Another object of the present invention is to provide a kit of medicines comprising the drug combination of the present invention, preferably the kit is in the form of a single drug dosage unit.

In one embodiment, the kit of the present invention contains in the same package:

-A first container containing a pharmaceutical composition for parenteral administration, the pharmaceutical composition comprising the anti-PD-1 antibody described above;

-A second container containing a pharmaceutical composition for oral administration, said pharmaceutical composition containing the HDAC inhibitor described above.

The various embodiments/technical solutions described in the present invention and the features in the various embodiments/technical solutions should be understood to be arbitrarily combined with each other, and the various solutions obtained by these mutual combinations are all included in the scope of the present invention, just like in This article specifically and one by one lists the solutions obtained by combining these mutually, unless the context clearly shows otherwise.

The following examples are described to assist the understanding of the present invention. It is not intended and should not be construed in any way to limit the scope of protection of the present invention.

Description of the drawings

Figure 1.14 Changes in lesions in patients with evaluable efficacy

Figure 2. Changes in the lesions of subject 0101

Figure 3. Changes in the lesions of subject 0103

Detailed ways

The present invention is further illustrated by the following non-limiting examples, which are not intended to limit the scope of the present invention.

Example 1

1. Test drug

Sintilimab Injection: Specification 10ml:100mg, Xinda Biopharmaceutical (Suzhou) Co., Ltd.

Chidamide: Specification 5mg, Shenzhen Chipset Biotechnology Co., Ltd.

2. Criteria for enrolled subjects

standard constrain:

1) Volunteer to participate in clinical research; fully understand and know the research and sign the Informed Consent Form (ICF); willing to follow and have the ability to complete all trial procedures.

2) The age at the time of signing the ICF is ≥18 years old and ≤75 years old.

3) ENKTL confirmed by research center histopathology.

4) Available tumor tissue samples (10-15 unstained, fresh-frozen, paraffin-embedded [FFPE] glass slides) obtained from past or fresh coarse needle puncture or excision.

5) Refractory and relapsed ENKTL that has failed the treatment of asparaginase-based chemotherapy or radiotherapy and chemotherapy.

Definition of refractory: i) The curative effect did not reach PR after chemotherapy with asparaginase-containing regimen; or ii) the disease progressed within 6 months of the last asparaginase-containing regimen.

6) The ECOG score is 0 to 1.

7) Expected survival is greater than 3 months.

8) There must be at least 1 evaluable or measurable lesion that meets the RECIL 2017 lymphoma standard [evaluable lesion: 18F-Fluorodeoxyglucose/Positron Emission Tomography, 18FDG/PET) examination Shows increased local uptake in lymph nodes or extranodal areas (higher than liver) and PET and/or Computed Tomography (CT) features are consistent with lymphoma; measurable lesions: nodular lesions longer than 15mm or extranodal lesions longer diameter >10mm (if the only measurable lesion has received radiotherapy in the past, there must be evidence of imaging progression after radiotherapy) and accompanied by increased 18FDG uptake]. It is necessary to exclude the case where there is no measurable lesion and the diffuse 18FDG uptake in the liver is increased.

9) Sufficient organ and bone marrow function, no serious hematopoietic dysfunction, abnormal heart, lung, liver, kidney, thyroid dysfunction and immunodeficiency (without receiving blood transfusion, granulocyte colony stimulating factor or other within 14 days before using the study drug) Related medical support):

a) The absolute value of neutrophils ≥1.0×10 ⁹ /L;

b) Platelets ≥75×10 ⁹ /L;

c) Hemoglobin ≥9g/dL;

d) Serum creatinine ≤ 1.5 times the upper limit of normal (Upper Limit Normal, ULN), or creatinine clearance ≥ 40 mL/min (estimated based on the Cockcroft-Gault formula);

e) Serum total bilirubin ≤ 1.5 times ULN;

f) Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) ≤2.5 times ULN;

g) Coagulation function: International Normalized Ratio (INR) ≤ 1.5 times ULN; Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN ( Unless the subject is receiving anticoagulant therapy, and PT and APTT are within the expected range of anticoagulant therapy at the time of screening).

h) Thyroid-stimulating hormone (TSH) or free thyroxine (FT4) or free triiodothyronine (FT3) are all within ±10% of the normal value.

10) There is no evidence that the subject has difficulty breathing at rest, and the pulse oximetry value at rest is >92%.

11) Subjects must pass pulmonary function tests (PFT) to confirm that forced expiratory volume (FEV1)/forced vital capacity (FVC)> 60% in the first second, unless it is caused by a large mediastinal mass caused by Hodgkin’s lymphoma This standard cannot be met; the diffusion of carbon monoxide (DLCO), FEV1 and FVC are more than 50% above the predicted value; all PFT results must be obtained within 4 weeks before the first administration of Sintilimab.

12) Subjects who have received anti-tumor therapy in the past should return to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grade score ≤ level 1 or baseline level after the toxicity of the previous treatment has returned to the evaluation criteria for common adverse events (CTCAE) Entry into the group; Grade 2 toxicity (such as thrombocytopenia, anemia, neurotoxicity, alopecia, and hearing loss) caused by previous anti-tumor therapy that is irreversible and is not expected to worsen during the study treatment period, with the consent of the investigator, you can Join the group.

13) Women of Childbearing Potential (WOBCP) must undergo a serum pregnancy test within 7 days before the first medication, and the result is negative; WOBCP or men and their WOBCP partners should agree from signing the ICF to the last dose Take effective contraceptive measures within 6 months after the study drug.

3. Administration method and process

This study is a phase Ib/II clinical study, divided into two parts. In phase Ib, subjects received chidamide and sintilizumab, and the dose of chidamide was explored in this phase. The initial dose of chidamide: 3 dose groups (20mg, 25mg, 30mg) are set up, with 3-6 subjects in each group. Starting dose: 20 mg/time, 2 times/week, for continuous oral administration. If DLT (Dose-Limiting Toxicities) does not appear, follow the established dose escalation plan to continue the next dose level test. If there is 1 case of DLT, add 3 subjects to this dose level. When no new DLT appears, continue to the next dose level test. If there are ≥ 2 cases of DLT, the previous dose level of this dose level is defined as MTD (Maximum Tolerated Dose). Sintilimab dose: 200mg/time (fixed dose), 1 time/3 weeks, intravenous infusion.

The administration method of the phase II study: the dose of chidamide is RP2D dose (Recommended Phase II Dose, the recommended phase II clinical study dose), 2 times a week, continuous oral; Sintilizumab dose: 200 mg/time (fixed Dose), 1 time/3 weeks, intravenous infusion.

DLT definition: The subject has the following graded toxicity related to the study drug (according to the NCI CTCAE v5.0 toxicity evaluation standard, including but not limited to) within 2 consecutive courses of treatment (6 weeks): grade IV blood Toxicity, including but not limited to the following: febrile neutropenia (ANC<1.0×10 ⁹ /L with a single body temperature >38.3℃, or continuous body temperature ≥38℃ for more than 1h); non-hematology of grade Ⅲ or above Toxicity (excluding hair loss and electrolyte imbalance that can be corrected within 3 days); despite symptomatic treatment, nausea, vomiting or diarrhea of grade ≥ III still occurs.

4. Test results

Phase Ib study:

From March 29, 2019 to June 21, 2019, the Sun Yat-sen University Cancer Center enrolled a total of 9 subjects. The 9 subjects were divided into 3 groups, and 3 patients in each group were subjected to a study of chidamide dose climbing. The three dosage levels are 20mg, 25mg, 30mg, biw (twice a week). Except for subjects 0106 and 0107 who failed to complete 6 courses of treatment due to disease progression (received 5 and 3 courses of treatment respectively) among the 9 subjects, the remaining 7 subjects all completed more than 6 courses of combined treatment. Subjects in the three dose groups did not have MTD or DLT, so the recommended dose of RP2D is 30 mg biw.

9 subjects in stage Ib can be evaluated for efficacy, of which 7 subjects (0101, 0102, 0103, 0104, 0105, 0108, 0109) obtained CR (Complete Response), and 1 subject ( 0106) After obtaining PR (Partial Response), it progressed again, and 1 subject (0107) had the effect of PD (Progressive Disease, disease progression). In the phase Ib study, ORR (Objective Response Rate, objective response rate) was 88.9% (8/9), and CRR (Complete Response Rate, complete response rate) was 77.8% (7/9).

Phase II study:

The phase II study adopted the simon two-phase optimal design method. In the first phase, 7 patients were enrolled. If only 4 or fewer patients are effective, the trial will be terminated. Otherwise, enter the second phase, and 21 patients will be enrolled in the second phase, that is, a total of 28 patients will be enrolled in the phase II study. After the end of the Phase Ib study, a Phase II clinical study was conducted. As of November 4, 2019, 11 subjects have been enrolled in the Phase II study. Subject 0117-0120 received only one course of treatment, and the efficacy has not been evaluated yet. Among them, 5 of the 0110-0116 subjects can be evaluated for efficacy, 2 cases of CR, 2 cases of SD (stable disease), and 1 case of PD.

Based on the current enrollment status of Phase Ib and II studies, 20 subjects have been enrolled (see Table 1 for general clinical characteristics), 14 of which can be evaluated for efficacy, ORR 71.4% (10/14), CR rate 64.3% ( 9/14), the PR rate was 7.1% (1/14). The CR rate was significantly higher than that of previous PD-1 monoclonal antibody treatment of refractory and relapsed ENKTL (Figure 1), and the combined treatment produced a significant synergistic effect.

safety:

The overall safety of this study was relatively high, and there were no treatment-related deaths.

Example 2

Subject 0101, male, 52 years old.

NK/T cell lymphoma recurred in the right lung more than 2 years after radiotherapy and chemotherapy.

In November 2016, the patient was diagnosed with nasal cavity NK/T cell lymphoma stage I, and received 4 cycles of P-Gemox chemotherapy, local radiotherapy 50Gy, and the curative effect was CR. In March 2019, a lump in the right lower lung was found due to "cough", the size of which was about 4.9×5.8×6.0cm. 2019.3.22 The pathology of lung tumor puncture in our hospital was NK/T cell lymphoma. The patient was enrolled in this study on March 29, 2019. The cough symptoms disappeared 7 days after 1 course of treatment, and the PET/CT curative effect CR was rechecked after 2 courses (Figure 2). At present, 11 courses of treatment have been completed and the CR continues.

Example 3

Subject 0103, female, 20 years old.

NK/T cell lymphoma complicated with hematopoietic syndrome, recurrence after chemotherapy and maintenance of anti-PD-1 antibody injection.

The patient was diagnosed with NK/T-cell lymphoma with hemophagocytic syndrome in March 2018. After treatment with HLH2004 regimen, the bloodthirsty phenomenon was corrected, and then the P-Gemox regimen was given 3 cycles of chemotherapy, and the curative effect was PR. From 2018.6-2018.8, Pembrolizumab was treated for 4 courses, and the effect was CR. Later, the treatment was stopped due to economic reasons. In April 2019, the patient went to the doctor due to "continuous high fever". On April 28, 2019, PET/CT in our hospital showed: right supraclavicular, bilateral subclavian, mediastinum, right hilum, hepatic hilum, portal space, right kidney posterior Multiple enlarged lymph nodes. Multiple nodules in both lungs have concentrated metabolism, multiple low-density shadows in the liver, and active metabolism. 2019-5-6 Liver biopsy was NK/T cell lymphoma. The patient combined with three lines at the same time slightly decreased, EBV-DNA=3.6×10 ⁴ copy/ml. After the diagnosis, the patient was enrolled in the study on May 2019. At present, he has completed 10 courses of treatment, and the curative effect is CR after 2 courses (Figure 3). The fever disappeared after 1 cycle, and the EBV-DNA dropped to zero.

references

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2.Kwong, Y.L., et al., SMILE for natural killer/T-cell lymphoma: analysis of safety and efficiency from the Asia Lymphoma Study Group.Blood, 2012.120(15): p.2973-80.

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14.Green, MR, et al., Integrative analysis reveals selective 9p24.1 amplification, increased PD-1ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary (mediastinal) large. 116. B-cell ly, 2010. :p.3268-77.

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Although certain representative embodiments and details have been shown for the purpose of illustrating the present invention, it will be obvious to those skilled in the art that various changes and modifications can be made to them without departing from the scope of the subject invention. In this regard, the scope of the invention is limited only by the following claims.

Claims (14)

1. A pharmaceutical combination comprising a PD-1 antibody or an antigen-binding fragment thereof and an HDAC inhibitor,

   The anti-PD-1 antibody contains 6 CDRs, and LCDR1, LCDR2, and LCDR3 are composed of the amino acid sequences RASQGISSWLA (SEQ ID NO: 9), SAASSLQS (SEQ ID NO: 10) and QQANHLPFT (SEQ ID NO: 11), respectively, and Wherein HCDR1, HCDR2 and HCDR3 are respectively composed of amino acid sequences KASGGTFSSYAIS (SEQ ID NO: 2), LIIPMFDTAGYAQKFQG (SEQ ID NO: 5) and ARAEHSSTGTFDY (SEQ ID NO: 8); or

   The anti-PD-1 antibody is selected from sintilizumab, pembrolizumab, nivolizumab, teriprizumab and carrelizumab;

   Wherein the HDAC inhibitor is selected from the following compounds of formula I or pharmaceutically acceptable salts thereof:

   

   Among them, A is a benzene ring or heterocyclic ring, which can contain 1 to 4 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, 1 to 4 Carbon atom alkoxy group, 1 to 4 carbon atom aminoalkyl group, 1 to 4 carbon atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acyl group, 1 to 4 A thioalkyl group of 1 to 4 carbon atoms, a perfluoroalkyl group of 1 to 4 carbon atoms, a perfluoroalkoxy group of 1 to 4 carbon atoms, a carboxyl group of 1 to 4 carbon atoms, and a perfluoroalkyl group of 1 to 4 carbon atoms Alkoxycarbonyl, phenyl or heterocyclic substituents;

   B is a benzene ring or heterocyclic ring, which can contain 1 to 3 substituents, and its substituents can be halogen, amino, hydroxyl, nitro, cyano, alkyl with 1 to 4 carbon atoms, and 1 to 4 carbon atoms Alkoxy, aminoalkyl of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, acyl of 2 to 4 carbon atoms, acylamino of 2 to 4 carbon atoms, 1 to 4 carbons Atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 carbon atom perfluoroalkoxy group, 1 to 4 carbon atom carboxyl group, 1 to 4 carbon atom alkoxy group Carbonyl, phenyl or heterocyclic substituents:

   Z is a covalent bond, an alkylene of 1 to 4 carbon atoms, or a linear structure or a ring _{containing -O-, -S-, -NH, -CO-, -CS-, -SO-, -SO 2-} Structure or a combination of linear structure and cyclic structure;

   Y is a linear structure, a cyclic structure or a combination of a linear structure and a cyclic structure containing -CO-, -CS-, -SO-, -SO ₂ -, wherein the center point (W1) of ring A and the center of ring B The distance between the point (W2) and the O atom or S atom (W3) contained in Y as the hydrogen bond acceptor satisfies the following conditions:

   

   

   The better distance between them is

   

   R ¹ and R ² are respectively hydrogen or an alkyl group containing 1 to 4 carbon atoms, and R ¹ and R ² can also form a covalent bond together;

   R ³ is hydrogen or an alkyl group containing 1 to 4 carbon atoms;

   R ⁴ is hydrogen, halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 Alkylamino of to 4 carbon atoms, acyl of 2 to 4 carbon atoms, amido of 2 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms, perfluoroalkane of 1 to 4 carbon atoms Group, perfluoroalkoxy group of 1 to 4 carbon atoms, carboxyl group of 1 to 4 carbon atoms, alkoxycarbonyl group of 1 to 4 carbon atoms;

   One of X ¹ , X ² , X ³ , and X ⁴ is halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, 1 to Aminoalkyl groups of 4 carbon atoms, alkylamino groups of 1 to 4 carbon atoms, acyl groups of 2 to 4 carbon atoms, acylamino groups of 2 to 4 carbon atoms, thioalkyl groups of 1 to 4 carbon atoms, Perfluoroalkyl groups of 1 to 4 carbon atoms, perfluoroalkoxy groups of 1 to 4 carbon atoms, carboxyl groups of 1 to 4 carbon atoms, alkoxycarbonyl groups of 1 to 4 carbon atoms; the rest are hydrogen , Halogen, amino, hydroxyl, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, 1 to 4 carbons Atom alkylamino group, 2 to 4 carbon atom acyl group, 2 to 4 carbon atom acid amino group, 1 to 4 carbon atom thioalkyl group, 1 to 4 carbon atom perfluoroalkyl group, 1 to 4 Perfluoroalkoxy with 4 carbon atoms, carboxyl with 1 to 4 carbon atoms, alkoxycarbonyl with 1 to 4 carbon atoms;

   Or selected from vorinostat, romidepsin, belisstat, pabirestat, chidamide, entinostat and Mocetinostat or a pharmaceutically acceptable salt thereof.
2. The drug combination according to claim 1, wherein

   The anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 13 or is at least 90%, 95%, 98% or 99% identical to it Sexual sequence, and/or the variable region of the light chain comprises the sequence of SEQ ID NO: 15 or a sequence that is at least 90%, 95%, 98% or 99% identical to it;

   Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 17 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and/or SEQ ID NO: 22 or has A light chain sequence that is at least 90%, 95%, 98%, or 99% identical.
3. The pharmaceutical combination according to claim 1 or 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of sintilizumab, pembrolizumab, nivolizumab, and teriprizumab And carrelizumab; preferably, the anti-PD-1 antibody is sintilizumab; and/or

   The HDAC inhibitor is selected from the group consisting of vorinostat, romidepsin, belisstat, pabisstat, chidamide, entinostat and Mocetinostat or a pharmaceutically acceptable salt thereof, more preferably, The HDAC inhibitor is Chidamide.
4. The pharmaceutical combination according to any one of claims 1 to 3, which is used for the prevention or treatment of cancer, preferably non-Hodgkin’s lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably advanced or Refractory and relapsed extranodal NK/T cell lymphoma.
5. The pharmaceutical combination according to any one of claims 1 to 4, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, more preferably In the form of a 200 mg dosage unit, preferably a parenteral, more preferably intravenous administration form; and/or

   The HDAC inhibitor is in the form of a dosage unit of 10 to 50 mg, preferably 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, preferably in a dosage form for oral administration.
6. The pharmaceutical combination according to any one of claims 1-5, wherein the single administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from 100-300 mg, such as 100 mg, 150 mg, 200 mg, 250 mg or 300 mg , Preferably once every two to four weeks, preferably by intravenous infusion;

   Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is intravenously infused once every three weeks, and the single infusion dose is 200 mg.
7. The pharmaceutical combination according to any one of claims 1-6, wherein the single administration dose of the HDAC inhibitor is selected from 10mg-50mg, preferably 1-4 times a week, preferably by oral administration;

   Preferably, the oral dose of the HDAC inhibitor is selected from 20 mg, 25 mg and 30 mg;

   More preferably, the HDAC inhibitor is taken orally twice a week, and each oral dose is 30 mg.
8. The pharmaceutical combination according to any one of claims 1-7, wherein the anti-PD-1 antibody or antigen-binding fragment thereof and the HDAC inhibitor are administered separately, simultaneously or sequentially.
9. The use of the pharmaceutical combination according to any one of claims 1 to 8 in the preparation of a medicament for the prevention or treatment of cancer, the cancer is preferably selected from non-Hodgkin's lymphoma, more preferably extranodal NK/T cells Lymphoma, most preferably extranodal NK/T cell lymphoma that is advanced or refractory to relapse.
10. A method for preventing or treating cancer, the method comprising administering a therapeutically effective amount of the drug combination according to any one of claims 1 to 8 to a patient in need, and the cancer is preferably selected from non-Hodgkin's lymph Tumor, more preferably extranodal NK/T cell lymphoma, most preferably late or refractory extranodal NK/T cell lymphoma.
11. A single drug dosage unit comprising a therapeutically effective amount of the drug combination according to any one of claims 1-8.
12. A pharmaceutical composition comprising a therapeutically effective amount of the pharmaceutical combination according to any one of claims 1-8 and pharmaceutically acceptable excipients.
13. A kit of medicines comprising a therapeutically effective amount of the drug combination according to any one of claims 1-8.
14. The use of the single drug dosage unit according to claim 11, the pharmaceutical composition according to claim 12, or the kit according to claim 13 in the preparation of drugs for preventing or treating cancer, the cancer is preferably It is selected from non-Hodgkin's lymphoma, more preferably extranodal NK/T cell lymphoma, most preferably late or refractory extranodal NK/T cell lymphoma.

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