CN112955148B

CN112955148B - Use of CDK4/6 inhibitors in combination with immunotherapy for the preparation of a medicament for the treatment of lymphoma

Info

Publication number: CN112955148B
Application number: CN201980072280.8A
Authority: CN
Inventors: 江瑶; 王泉人; 李华军
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Suzhou Suncadia Biopharmaceuticals Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Suzhou Suncadia Biopharmaceuticals Co Ltd
Priority date: 2018-12-13
Filing date: 2019-12-12
Publication date: 2022-11-22
Anticipated expiration: 2039-12-12
Also published as: CN112955148A; TW202034925A; WO2020119757A1

Abstract

The application of a CDK4/6 inhibitor combined immunotherapy in preparing a medicament for treating lymph, in particular to the application of a compound shown as I or a pharmaceutically acceptable salt thereof combined with an anti-PD-1 antibody or an antigen binding fragment thereof in preparing a medicament for treating lymphoma. The method has good tolerance, controllable toxicity, and enhanced antitumor effect.

Description

Use of CDK4/6 inhibitors in combination with immunotherapy for the preparation of a medicament for the treatment of lymphoma

Technical Field

The disclosure belongs to the field of pharmacy, and relates to application of CDK4/6 inhibitor combined immunotherapy in preparation of a medicine for treating lymphoma.

Background

Immunotherapy is a new treatment method for refractory or recurrent tumors, and the tumor immunotherapy represented by anti-PD-l/PD-Ll monoclonal antibody represents the research direction of tumor therapy. The immune checkpoint inhibitory receptor for programmed cell death protein-1 (PD-1) is predominantly expressed in activated T cells. The PD-1 signaling cascade negatively regulates T cell receptor activation while also attenuating T cell proliferation and function, with the end result being T cell depletion. In tumor-infiltrating lymphocytes, PD-1 expression is markedly upregulated. While the expression of PD-1 ligand (PD-L1) is also markedly elevated in tumor cells and tumor-associated immune cells when stimulatory cytokines such as IFN- α and IFN- γ are present in the tumor microenvironment. These data provide a basis for using antagonists of PD-1 as cancer immunotherapeutics.

The effectiveness of this therapeutic approach to block the interaction of PD-1 and PD-L1 has recently been demonstrated in a number of tumor types. Monoclonal antibodies to PD-1, such as nivolumab and pembrolizumab, have the ability to bind to PD-1, thereby disrupting the interaction between the PD-1 protein and its ligands (PD-L1 and PD-L2) and preventing inhibitory signals in the T-cell microenvironment. These monoclonal antibodies are now approved for the treatment of a variety of cancers, including bladder, lung, head and neck squamous cell carcinoma, and are approved for the treatment of melanoma in the united states, europe, and other regions. Meanwhile, the use of anti-PD-1 monoclonal antibodies (mabs) to achieve PD-1 blocking has been shown to be effective against relapsed/refractory classical hodgkin lymphomas, and also to show some efficacy against non-hodgkin lymphomas, with gain rates of 44% and 25% for EBV positive NK/T lymphomas and mediastinal B-cell lymphomas, respectively. Clinical remission was also observed with anti-PD-1 antibody treatment of relapsing T-cell lymphoma in phase 1 study. Previous studies have shown that EBV infection may enhance PD-L1 expression in tumor cells, and that some EBV-associated non-hodgkin lymphomas, such as mature T-cell and NK-cell lymphomas, express high levels of PD-L1, indicating that EBV-associated mature T-cell and NK-cell lymphomas may be more susceptible to PD-1 blockade. However, many patients with non-hodgkin lymphoma do not obtain good curative effect by using the anti-PD-l/PD-Ll monoclonal antibody alone, so that a combined drug for enhancing the anti-PD-l/PD-Ll monoclonal antibody still needs to be continuously searched.

Studies by Zhang et al (Nature vol 553, pages 91-95) have found that PD-L1 protein abundance is regulated by cyclin D-CDK4 kinase and Cullin 3-SPOP E3 ligase, and that the regulation process belongs to a classical proteasome mediated degradation pathway. In vivo studies found that CDK4/6 inhibitors promote FZR1 degradation of SPOP and increase PD-L1 expression by blocking cyclin D-CDK4 mediated phosphorylation of speckle-type POZ (SPOP) proteins. This article lays the theoretical foundation for the enhancement of anti-tumor immunotherapy by the combination of a PD-L1 antibody with a CDK4/6 inhibitor.

Known CDK4/6 inhibitors are abemaciclib, ribociclib or palbociclib, W02014183520 provides a potent CDK4/6 inhibitor, the structure of which is shown in formula I, WO2016124067 discloses a isethionate salt of a CDK4/6 inhibitor compound of formula I,

the above studies have generated interest in the use of drugs for the treatment of lymphomas, particularly non-hodgkin's lymphoma, in combination with novel CDK4/6 inhibitors.

Disclosure of Invention

The disclosure provides an application of a compound shown in a formula I or a medicinal salt thereof in combination with an anti-PD-1 antibody or an antigen binding fragment thereof in preparing a medicament for treating golden lymphoma,

in some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure is selected from the group consisting of AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, pidilizumab, PF-06801591, genolimzumab, CA-170, MEDI-0680, JS-001, TSR-042, camrelizumab, pembrolizumab, LZM-009, AK-103, and Nivolumab.

In other embodiments, the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region as set forth in SEQ ID NOs: 4. SEQ ID NO:5 and SEQ ID NO: LCDR1, LCDR2 and LCDR3 as shown in 6; the heavy chain variable region comprises the amino acid sequences shown as SEQ ID NO: 1. SEQ ID NO:2 and SEQ ID NO:3 HCDR1, HCDR2 and HCDR3.

In some embodiments, each CDR sequence of the PD-1 antibody or antigen-binding fragment thereof is as set forth in the following table:

name (R)	Sequence of	Numbering
			HCDR1	SYMMS	SEQID NO：1
HCDR2	TISGGGANTYYPDSVKG	SEQID NO：2
			HCDR3	QLYYFDY	SEQID NO：3
LCDR1	LASQTIGTWLT	SEQID NO：4
			LCDR2	TATSLAD	SEQID NO：5
LCDR3	QQVYSIPWT	SEQID NO：6

In other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from a humanized antibody or fragment thereof.

In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described in this disclosure is an antibody fragment selected from the group consisting of Fab, fab '-SH, fv, scFv, and (Fab') 2 fragments.

The immunoglobulin may be derived from any commonly known isotype, including, but not limited to, igA, secretory IgA, igG, and IgM. IgG subclasses are also well known to those of skill in the art, including but not limited to IgG1, igG2, igG3, and IgG4. "isotype" refers to the heavy chain constant region gene encoding Ab class or subclass (e.g., igM or IgG 1).

In some alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure comprises a heavy chain constant region of a human IgG1, igG2, igG3, or IgG4 isotype, preferably of an IgG1 or IgG4 isotype.

In other alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain constant region that is a kappa or lambda light chain constant region.

Further, the humanized antibody comprises SEQ ID NO:10 or a variant thereof, preferably a light chain variable region as set forth in SEQ ID NO:10, more preferably a43S, with amino acid changes from 0-10; the humanized antibody comprises SEQ ID NO:9 or a variant thereof, preferably a heavy chain variable region as set forth in SEQ ID NO: the heavy chain variable region shown in FIG. 9 has amino acid changes of 0 to 10, more preferably G44R.

The sequences of the heavy and light chain variable regions of the humanized antibody are shown below:

heavy chain variable region

Light chain variable region

In other alternative embodiments, the humanized antibody comprises SEQ ID NO:8, or a variant thereof, said variant preferably having 0-10 amino acid changes in the light chain variable region, more preferably a43S amino acid change; the humanized antibody comprises SEQ ID NO:7 or a variant thereof, said variant preferably having 0-10 amino acid changes in the heavy chain variable region, more preferably the amino acid change of G44R.

In another embodiment, the humanized antibody comprises the amino acid sequence set forth in SEQ ID NO:8, and the light chain as set forth in SEQ ID NO:7, or a heavy chain as shown in figure 7.

The sequences of the heavy chain and the light chain of the humanized antibody are shown as follows:

heavy chain

Light chain

In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described in this disclosure is administered to a human subject at a dose of 0.1 to 10.0mg/kg, may be 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.8mg/kg, 8.0mg/kg, 8.2mg/kg, 8.4mg/kg, 8.6mg/kg, 8.8mg/kg, 9.0mg/kg, 9.2mg/kg, 9.4mg/kg, 9.6mg/kg, 9.8mg/kg or 10.0mg/kg.

The anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered at a frequency selected from once a week, once a three weeks, once a four weeks, or once a month; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, once in two days, once in three days or once a week, and further the compound shown in the formula I or the pharmaceutically acceptable salt thereof is continuously administered for three weeks and is stopped for 1 week.

In other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in combination with the compound of formula I, or pharmaceutically acceptable salt thereof, is 1 cycle every 4 weeks.

The compounds represented by formula I or pharmaceutically acceptable salts thereof and the anti-PD-1 antibody or antigen-binding fragment thereof in the present disclosure have synergistic pharmacodynamic effects in combination.

In alternative embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof as described in the present disclosure is administered at a dose selected from 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg or any value therebetween, preferably 100mg or 150mg, in a human subject.

In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 1 to 600mg in a human subject, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose selected from the group consisting of 20 to 500mg in a human subject.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the human subject at a dose selected from the group consisting of 1 to 600mg once every 1 to 4 weeks, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the human subject at a dose selected from the group consisting of 20 to 500mg once a day.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the human subject at a dose selected from 200mg once every 2 weeks, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the human subject at a dose selected from 150mg once a day.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose selected from 200mg, once every 2 weeks, intravenously in the human subject, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose selected from 150mg, once daily, orally in the human subject.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose selected from 200mg, once every 2 weeks, intravenously, and the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose selected from 150mg, once daily, orally, once every three weeks on continuous dosing.

In other embodiments, an induction regimen (loading) of a treatment with a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient prior to administration of an anti-PD-1 antibody or antigen-binding fragment thereof in combination with a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the induction regimen is a monotherapy administering a compound of formula I or a pharmaceutically acceptable salt thereof at the beginning of the treatment.

In some embodiments, the induction regimen cycle may be 1 week (or 7 days), 2 weeks (or 14 days), 3 weeks or longer, preferably 3 weeks (or 21 days); the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose selected from 50mg, 100mg or 150mg, at a frequency selected from once a day, once in two days or once in three days.

The route of administration described in the present disclosure may be oral, parenteral, including but not limited to intravenous, subcutaneous, intramuscular, transdermal.

In an alternative embodiment, the PD-1 antibody or antigen-binding fragment thereof is administered by injection, e.g., subcutaneously or intravenously, formulated in an injectable form prior to injection. Particularly preferred injectable forms of the PD-1 antibody or antigen-binding fragment thereof are injectable solutions or lyophilized powders, for example injectable forms of the PD-1 antibody comprising the PD-1 antibody, a buffer, a stabilizer, optionally further comprising a surfactant. The buffer may be selected from one or more of acetate, citrate, succinate, and phosphate. The stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, maltose. The surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80, most preferably polysorbate 20.

The pharmaceutically acceptable salts of the drugs described in this disclosure may be the hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate. Malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate salts, and the like.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is selected from isethionate.

In some embodiments, the isethionate salt of the compound of formula I is administered in combination with the PD-1 antibody or antigen-binding fragment thereof, thereby enhancing anti-lymphoma activity and improving the therapeutic effect of lymphoma disease.

Further, the lymphoma in the present disclosure is a non-hodgkin lymphoma, preferably relapsed and/or refractory. The recurrence refers to a patient who presents with a new lesion at the primary site or other sites after being fully treated to achieve complete or partial remission.

In other embodiments, the refractory is any one of: currently, the combination chemotherapy regimen of common choice in the clinic is used, with efficacy assessed after 2 cycles as disease Progression (PD), or efficacy assessed after 4 cycles as not achieving Partial Remission (PR), or efficacy assessed after 6 cycles as not achieving Complete Remission (CR).

In an alternative embodiment, the lymphoma patient in the present disclosure has been treated with lymphoma, the tumor treatment selected from one or more of chemotherapy, immunotherapy, surgery or vaccine, preferably from chemotherapy.

In some alternative embodiments, the lymphoma patients described in this disclosure are at least treated with a ≧ 1-line regimen (excluding radiation therapy) following relapse.

In some embodiments, the lymphoma patient has previously received a combination chemotherapy with CHOP, R-CHOP, IMVP-I6, EPOCH, DHAP, or similar regimens.

The CHOP scheme: cyclophosphamide, 750mg/m ² Intravenous, day one; adriamycin, 50mg/m ² Intravenous, day one; vincristine, 1.4mg/m ² Intravenous, day one; prednisone, 100mg/m ² Orally daily for the first to five days; the administration period was 21 days.

R-CHOP scheme: rituximab 375mg/m ² Intravenous injection, first day 6 cycle; cyclophosphamide, 750mg/m ² Intravenous, day one; adriamycin, 50mg/m ² Intravenous, day one; vincristine, 1.4mg/m ² Intravenous, day one; prednisone, 100mg/m ² Orally daily for the first to five days; the administration period was 21 days.

E-CHOP protocol: etoposide, 50mg/m ² Intravenous injection, day one to four; vincristine, 1.4mg/m ² Intravenous injection, day one to four; adriamycin, 50mg/m ² Intravenous injection, day one to four; prednisone, 60mg/m ² Orally daily for the first to six days; cyclophosphamide, 750mg/m ² Intravenous injection, day six; the dosing cycle was 21 days.

The DHAP scheme: cisplatin, 1000mg/m ² Intravenous, day one; cytarabine, 2mg/m ² Intravenous injection twice a day; dexamethasone, 40mg/d, orally administered orIntravenous injection, first to four days; the dosing cycle was 21 days.

IMVP-I6 protocol: ifosfamide, 1000mg/m ² Intravenous injection, day one to five; 60 percent of the total amount of mesna and ifosfamide, intravenous injection is carried out for 4h and 8h, and intravenous injection is carried out for the first day to the fifth day; methotrexate, 30mg/m ² On days three and 10, etoposide, 100mg/m ² Intravenous injection, day one to three; the administration period is 21 to 28 days.

In some embodiments, the lymphoma patient is previously receiving treatment based on L-asparaginase.

In other embodiments, the lymphoma patient has been previously treated (either alone or in combination with a chemotherapeutic agent) with a regimen comprising rituximab or an analog thereof.

The combination optionally further comprises other components as described in the present disclosure, including but not limited to other drugs for treating lymphoma and the like.

Also provided in the present disclosure is a method of treating lymphoma comprising: administering to a patient having lymphoma an effective dose of an anti-PD-1 antibody or an antigen-binding fragment thereof and a compound of formula I or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of treating a lymphoma as described herein comprises administering to a patient 1 to 600mg of an anti-PD-1 antibody or antigen-binding fragment thereof and 20 to 500mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of treating a lymphoma as described herein comprises administering to a patient 200mg of an anti-PD-1 antibody or antigen-binding fragment thereof once every 2 weeks and 150mg of a compound of formula I or a pharmaceutically acceptable salt thereof once a day.

In other embodiments, the methods of lymphoma of the present disclosure comprise: an induction regimen (loading) of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient prior to administration of an anti-PD-1 antibody or an antigen-binding fragment thereof in combination with a compound of formula I or a pharmaceutically acceptable salt thereof, said induction regimen being a monotherapy in which a compound of formula I or a pharmaceutically acceptable salt thereof is administered during the initial phase of treatment.

In other embodiments, the induction regimen cycle may be 1 week (or 7 days), 2 weeks (or 14 days), 3 weeks or longer, preferably 3 weeks (or 21 days); the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose selected from 50mg, 100mg or 150mg, at a frequency selected from once a day, once in two days or once in three days.

The present disclosure also provides a method of reducing adverse effects caused by an anti-PD-1 antibody or an antigen-binding fragment thereof, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising administering to a lymphoma patient an effective dose of an anti-PD-1 antibody or an antigen-binding fragment thereof and a compound of formula I, or a pharmaceutically acceptable salt thereof, simultaneously.

Also provided in the present disclosure is a method of reducing the separate administered doses of a PD-1 antibody or an antigen-binding fragment thereof, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising administering to a lymphoma patient an effective dose of an anti-PD-1 antibody or an antigen-binding fragment thereof and a compound of formula I, or a pharmaceutically acceptable salt thereof, simultaneously.

In another aspect, the present disclosure also provides a pharmaceutical combination comprising a pharmaceutical composition comprising the PD-1 antibody or antigen-binding fragment thereof and a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

In some embodiments, the PD-1 antibody or antigen-binding fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO:8, and the light chain as set forth in SEQ ID NO:7, or a heavy chain as shown in figure 7.

Unless otherwise defined, terms in this disclosure have the following meanings:

the term "humanized antibody" (also referred to as CDR-grafted antibody) in the present disclosure refers to an antibody produced by grafting mouse CDR sequences into a human antibody variable region framework, i.e., a different type of human germline antibody framework sequence. Can overcome the strong antibody variable antibody reaction induced by the chimeric antibody because of carrying a large amount of mouse protein components. Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. Germline DNA Sequences of genes such as the human heavy and light chain variable regions can be found in the "VBase" human germline sequence database (available at the Internet www.mrccpe.com.ac.uk/VBase), and in Kabat, E.A. et al, 1991 Sequences of Proteins of Immunological Interest, 5 th edition. In a preferred embodiment of the present disclosure, the CDR sequences of the PD-1 humanized antibody are selected from the group consisting of SEQ ID NO:1,2,3,4,5,6.

The term "antigen-binding fragment" as used in this disclosure refers to Fab fragments, fab 'fragments, F (ab') 2 fragments, and Fv fragments, sFv fragments, which bind to human PD-1, having antigen-binding activity; an antibody selected from the group consisting of SEQ ID NOs: 1 to SEQ ID NO: 6. The Fv fragment contains the variable regions of the antibody heavy and light chains, but no constant regions, and has the smallest antibody fragment of the entire antigen-binding site. Generally, fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the structures required for antigen binding. Two antibody variable regions can also be joined together with different linkers into a single polypeptide chain, known as single chain antibodies (scFv) or single chain Fv (sFv). The term "binds to PD-1" in the present disclosure means capable of interacting with human PD-1. The term "antigen binding site" in the present disclosure refers to a three-dimensional spatial site that is not contiguous on an antigen and is recognized by an antibody or antigen binding fragment in the present disclosure.

The "immunotherapy" in the present disclosure refers to the immunotherapy of diseases by using immune system, and in the present disclosure, mainly refers to the stimulation and enhancement of the anti-tumor immune response of the organism by increasing the immunogenicity of tumor cells and the sensitivity to killing of effector cells, and the infusion of immune cells and effector molecules into the host body, in coordination with the killing of tumor and inhibition of tumor growth by the immune system of the organism.

In the present disclosure, "combination or association" is an administration mode, which means that at least one dose of a compound of formula I or a pharmaceutically acceptable salt thereof and at least one dose of a PD-1 antibody or antigen-binding fragment thereof, wherein both drugs show pharmacological effects, are administered over a period of time. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The compound of formula I or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment may be administered simultaneously or sequentially. Such term includes treatments wherein the compound of formula I or a pharmaceutically acceptable salt thereof and the PD-1 antibody or antigen-binding fragment thereof are administered by the same route of administration or different routes of administration. The mode of administration of the combinations of the invention is selected from simultaneous administration, separate formulation and co-administration or separate formulation and sequential administration.

An "effective amount or dose" as described in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount or effective dose also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount or dose may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

As used in this disclosure, "treatment failure" refers to a subject at baseline with measurable tumor lesions, either disease Progression (PD) or intolerance according to RECIST 1.1 efficacy assessment criteria.

The term "intolerant" in this disclosure means that adverse effects due to the drug are not amenable to further treatment.

Overall Survival (OS) refers to the period from random to death for any cause. Subjects who survived the last follow-up had OS data loss on the last follow-up time basis. Subjects who were missed their OS were data loss as the last confirmed survival time before the missed visit. The OS of data erasure is defined as the time from random grouping to erasure.

Objective Response Rate (ORR) refers to the proportion of patients with a certain tumor shrinkage and a certain time, including CR and PR cases. Objective tumor remission was assessed using the criteria for tumor remission assessment (RECIST 1.1 criteria). Subjects must be accompanied by measurable tumor lesions at baseline, and the criteria for efficacy assessment are divided into Complete Remission (CR), partial Remission (PR), stable (SD), progression (PD) according to RECIST 1.1 criteria.

The Disease Control Rate (DCR) refers to the percentage of confirmed complete remission, partial remission and stable Disease (≧ 8 weeks) cases among patients whose efficacy can be evaluated.

Complete Remission (CR): all target lesions disappeared and the short diameter of all pathological lymph nodes (including target and non-target nodes) had to be reduced to < 10mm.

Partial Remission (PR): the sum of the target lesion diameters is reduced by at least 30% from baseline levels.

Disease Progression (PD): the diameter and relative increase is at least 20% with respect to the minimum of the sum of all measured target lesion diameters throughout the experimental study (baseline values are referenced if the baseline measurement is minimal); in addition to this, it must be satisfied that the absolute value of the sum of the diameters increases by at least 5mm (the appearance of one or more new lesions is also considered as disease progression).

Disease Stability (SD): the target lesion was decreased to a degree that did not reach PR and increased to a degree that did not reach PD levels, between which the minimum of the sum of the diameters was considered for the study.

Isethionates of compounds of formula I of the present disclosure may be prepared according to the method described in WO2016124067, and other equipment or reagents used are commercially available.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Example 1:

grouping standard:

1) Recurrent mature T cell and NK cell or B cell lymphoma confirmed by histopathology. Recurrence is defined as a patient who presents with new lesions at the primary site or elsewhere after being adequately treated to achieve complete or partial remission. Treatment with at least a 1-line regimen (excluding radiation therapy) following recurrence of B cell lymphoma was performed. Refractory is defined as any one of the following: currently, the combination chemotherapy regimen of choice is clinically used with 2 cycles followed by efficacy assessment for disease Progression (PD), or 4 cycles followed by efficacy assessment for Partial Remission (PR), or 6 cycles followed by efficacy assessment for Complete Remission (CR)

T-NHL: has previously received combination chemotherapy such as CHOP, EPOCH or similar regimens.

NKTL: it has previously received L-asparaginase-based therapy.

B-NHL: CD20 positive B-NHL has previously been treated with a regimen comprising rituximab or an analog thereof (either alone or in combination with a chemotherapeutic agent).

2) With at least one two-dimensional measurable lesion as an assessment basis: for intra-nodal lesions, the definition is: the long diameter is more than or equal to 1.5cm and the short diameter is more than or equal to 1.0cm; for extranodal lesions, the major diameter should be greater than or equal to 1.0cm.

The administration scheme is as follows:

drug a (PD-1, prepared according to the method in patent application WO2017054646 a): the dosage is 200mg, and the preparation is administered by intravenous injection for 30min (not less than 20min, not more than 60 min) every time, 1 time for 2 weeks, and 1 cycle for 4 weeks;

drug B (isethionate tablet of the compound of formula I, prepared according to the method disclosed in WO 2017133542): 125 mg/tablet or 150mg, orally administered 1 time a day, 1 time each time, continuously administered for 3 weeks and 1 week, 4 weeks are 1 cycle.

And (4) conclusion: of the 4 evaluable subjects in the group of 200mg of drug a and 150mg of drug B, 4 subjects showed Stable Disease (SD) and 100% Disease Control Rate (DCR).

Claims

1. The application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen binding fragment thereof in preparing a medicament for treating lymphoma,

the light chain variable region of the anti-PD-1 antibody or an antigen-binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6 respectively, and the heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3 respectively; the lymphoma is non-hodgkin lymphoma.

2. The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is isethionate.

3. The use of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is selected from a humanized antibody or fragment thereof.

4. The use of claim 3, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of human IgG1, igG2, igG3, or IgG4 isotype.

5. The use of claim 4, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of a human IgG4 isotype.

6. The use of claim 4, wherein the humanized antibody comprises a light chain as set forth in SEQ ID NO 8 or a variant thereof having 0 to 10 amino acid changes in the light chain variable region; the humanized antibody comprises the heavy chain of SEQ ID NO. 7 or a variant thereof having 0-10 amino acid changes in the heavy chain variable region.

7. The use of claim 6, wherein the humanized antibody comprises the light chain of SEQ ID NO 8 or a variant thereof having an amino acid change of A43S in the light chain variable region; the humanized antibody comprises the heavy chain of SEQ ID NO. 7 or a variant thereof having an amino acid change of G44R in the heavy chain variable region.

8. The use of claim 6, wherein the humanized antibody comprises a light chain as set forth in SEQ ID NO 8 and a heavy chain as set forth in SEQ ID NO 7.

9. The use of claim 1, wherein the lymphoma is relapsed and/or refractory.

10. The use of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 0.1-10.0 mg/kg in a human subject.

11. The use according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose selected from 1 to 1000mg in a human subject.

12. The use according to claim 11, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose selected from 100mg or 150mg in a human subject.

13. The use of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose in the range of 1 to 600mg in a human subject.

14. The use of claim 13, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200mg in a human subject.

15. The use of any one of claims 1-14, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered prior to an induction regimen of treatment with a compound of formula I, or a pharmaceutically acceptable salt thereof, prior to administration of the compound of formula I, or a pharmaceutically acceptable salt thereof.

16. The use of claim 15, wherein the induction regimen is a monotherapy administering a compound of formula I or a pharmaceutically acceptable salt thereof during the initial phase of treatment.

17. The use according to claim 15, wherein the induction regimen is administered to the patient at a dose of 50mg, 100mg or 150mg of the compound of formula I or a pharmaceutically acceptable salt thereof, daily or every 2 days or every 3 days from day zero.