CN113750096A - Quinoline derivatives for the treatment of peripheral T cell lymphoma - Google Patents

Abstract

The application belongs to the technical field of medicines, and relates to an antitumor application of a quinoline derivative. In particular, the present application relates to quinoline derivatives represented by compound I for the treatment of peripheral T-cell lymphoma, as well as pharmaceutical compositions thereof in combination with a second therapeutic agent and their use for the treatment of peripheral T-cell lymphoma. Wherein, the chemical name of the compound I is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine.

Description

Quinoline derivatives for the treatment of peripheral T cell lymphoma

Technical Field

The invention belongs to the field of medicines, and particularly relates to application of a quinoline derivative in treating peripheral T cell lymphoma.

Background

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of diseases that originate from post-thymic mature T cells. Normal lymphoid structures are destroyed and endothelial proliferation small vessels are often accompanied by an inflammatory background. With regional differences, asian countries are more common, and the incidence of PTCL accounts for about 21.4% of all lymphomas.

At present, the first-line treatment mainly adopts a CHOP scheme (cyclophosphamide, doxorubicine, vincristine and prednisone), the complete remission rate is 50-70%, and the 5-year total survival rate is 20-30%, but compared with ALK positive anaplastic cell lymphoma, the prognosis of other types of peripheral T cell lymphoma is poor, the first-line treatment has low response rate and high recurrence rate. Peripheral T cell lymphoma is highly malignant and there is no gold standard treatment regimen, so that the current treatment for PTCL is far from being met, and a new treatment regimen is urgently needed.

Summary of The Invention

In a first part, the present application provides the use of compound I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of peripheral T cell lymphoma. The present application also provides a method of treating peripheral T cell lymphoma comprising administering compound I or a pharmaceutically acceptable salt thereof to a subject. The present application also provides the use of compound I or a pharmaceutically acceptable salt thereof for the treatment of peripheral T cell lymphoma.

In a second part, the present application provides a combination pharmaceutical composition for the treatment of peripheral T-cell lymphoma comprising (I) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent.

In a third aspect, the present application also provides the use of a combination pharmaceutical composition for the manufacture of a medicament for the treatment of peripheral T cell lymphoma. The application also provides the use of the combination pharmaceutical composition for the treatment of peripheral T cell lymphoma.

In a fourth aspect, the present application also provides a method of treating peripheral T cell lymphoma comprising administering to a subject the combination pharmaceutical composition of the present application. The pharmaceutical composition comprises (I) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent.

Disclosure of Invention

In a first part, the present application provides the use of compound I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of peripheral T cell lymphoma.

In some embodiments, the peripheral T cell lymphoma is a heterogeneous lymphoma derived from post-thymic mature T cells.

In some embodiments, the peripheral T-cell lymphoma includes, but is not limited to, non-specific peripheral T-cell lymphoma (PTCL, NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large-cell lymphoma (ALCL, including ALK-positive anaplastic large-cell lymphoma, ALK-negative anaplastic large-cell lymphoma), enteropathy-associated T-cell lymphoma (EATL), monomorphic epithelial T-cell lymphoma (MEITL), nodal peripheral T-cell lymphoma with TFH phenotype (PTCL, TFH), follicular T-cell lymphoma (FTCL), primary cutaneous T-cell lymphoma, unclassified peripheral T-cell lymphoma.

In some embodiments, the peripheral T-cell lymphoma is non-finger peripheral T-cell lymphoma.

In some embodiments, the peripheral T-cell lymphoma is angioimmunoblastic T-cell lymphoma.

In some embodiments, the peripheral T cell lymphoma is anaplastic large cell lymphoma. In some specific embodiments, the peripheral T cell lymphoma is an ALK-positive anaplastic large cell lymphoma or an ALK-negative anaplastic large cell lymphoma. In some specific embodiments, the peripheral T-cell lymphoma is cutaneous anaplastic large-cell lymphoma, systemic anaplastic large-cell lymphoma, or breast graft-associated (BIA) anaplastic large-cell lymphoma.

In a second part, the present application provides a combination pharmaceutical composition for the treatment of peripheral T-cell lymphoma comprising (I) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent.

In some embodiments, there is provided a pharmaceutical combination for treating peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one chemotherapeutic agent, optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one small molecule targeted antineoplastic drug, optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one immunotherapeutic drug, optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one macromolecular antibody drug, optionally in combination with radiotherapy.

In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) vinblastines, optionally in combination with radiotherapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) platinum, optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) an anthracycline, optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) etoposide, optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) ifosfamide and/or cyclophosphamide, optionally in combination with radiotherapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) one, two, three or four of cyclophosphamide, doxorubicine, vincristine, prednisone, and optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) one, two, three, four or five of cyclophosphamide, vincristine, doxorubicine, etoposide, prednisone, and optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) a "CHOP" regimen, optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) a "CHOEP" regimen, optionally in combination with radiation therapy. In some embodiments, there is provided a pharmaceutical combination for the treatment of peripheral T cell lymphoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) a "DA-EPOCH" regimen, optionally in combination with radiation therapy.

In a third aspect, the present application also provides the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of peripheral T cell lymphoma.

In a fourth aspect, the present application also provides a method of treating peripheral T cell lymphoma comprising administering to a subject the pharmaceutical composition of the present application. The pharmaceutical composition comprises (I) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic agent.

The present application provides a method for treating a patient having peripheral T cell lymphoma. In some aspects of the present application, the patient has previously received chemotherapy and/or radiation therapy. In some embodiments, the patient is treated with chemotherapy and/or radiation before the patient has achieved complete remission before disease progression occurs. In some embodiments, the patient has failed to complete remission or failed to partial remission following chemotherapy and/or radiation therapy.

The present application provides a method of treating peripheral T cell lymphoma comprising administering to a patient in need of treatment compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent. In some embodiments, the present application provides a method of treating peripheral T cell lymphoma not receiving a chemotherapeutic agent, comprising administering to a patient in need thereof compound I, or a pharmaceutically acceptable salt thereof, and at least one second therapeutic agent. In some embodiments, the present application provides a method of treating peripheral T cell lymphoma previously treated with at least one chemotherapeutic agent, comprising administering to a patient in need thereof compound I, or a pharmaceutically acceptable salt thereof, and at least one second therapeutic agent. In some embodiments, the present application provides a method of treating second-and beyond-second-line treatment-failed peripheral T-cell lymphoma comprising administering to a patient in need thereof compound I, or a pharmaceutically acceptable salt thereof, and at least one second therapeutic agent. In one embodiment, the present application provides a method of treating refractory relapsed peripheral T-cell lymphoma comprising administering to a patient in need thereof compound I, or a pharmaceutically acceptable salt thereof, and at least one second therapeutic agent. In some embodiments, the compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent are used in combination to treat primary peripheral T cell lymphoma or secondary peripheral T cell lymphoma. In some embodiments, the peripheral T cell lymphoma is a peripheral T cell lymphoma that is intolerant to chemotherapy.

In some embodiments of the present application, the patient has not previously received systemic chemotherapy. In some embodiments, the patient has previously received radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the patient has not previously received systemic chemotherapy, but has received radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the patient experiences complete remission followed by radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy before disease progression occurs. In some embodiments, the patient has failed to complete remission or partial remission following radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the cancer metastasizes after the patient has undergone radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.

The method of administration can be determined comprehensively on the basis of the activity, toxicity of the drug, tolerance of the subject, and the like. In some embodiments of the present application, the use or method of treatment, including but not limited to, the second therapeutic agent may be administered once, twice, three times, or four times daily (qd), every other day (qod), every 3 days (q3d), every 4 days (q4d), every 5 days (q5d), weekly (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w), e.g., twice daily (bid), twice weekly (biw), three times daily (tid), four times daily (qid), etc. In some embodiments of the present application, the second therapeutic agent may also be administered in an intermittent manner for use or method of treatment. The intermittent administration includes a dosing period and a rest period, for example, a second therapeutic agent is administered daily during the dosing period, then the administration is stopped for a period of time during the rest period, followed by the dosing period, then the rest period, and so on, which may be repeated multiple times.

In some embodiments of the present application, the use or method of treatment, including but not limited to the administration of compound I or a pharmaceutically acceptable salt thereof, may be administered at a dose of 6mg, 8mg, 10mg or 12mg once daily for 2 weeks, with a dosing regimen of 1 week off; and/or, in a dosing regimen of 2 weeks on continuous dosing, and 2 weeks off.

In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each cycle, with one cycle of administration every 21 days.

In some embodiments, the second therapeutic agent and compound I, or a pharmaceutically acceptable salt thereof, each have the same or different treatment cycles. In some specific embodiments, the second therapeutic agent and compound I or a pharmaceutically acceptable salt thereof have the same treatment cycle, e.g., one treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some specific embodiments, the second therapeutic agent and compound I, or a pharmaceutically acceptable salt thereof, are each one treatment cycle every 3 weeks.

In some embodiments, the present application provides a combination pharmaceutical composition which is a formulation suitable for administration within a single treatment cycle (e.g. one treatment cycle of 3 weeks) comprising 84 to 168mg, preferably 112 to 168mg of compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent. Wherein, compound I or a pharmaceutically acceptable salt thereof can be packaged separately in multiple aliquots (e.g., 2 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, or more).

In addition, the present application provides a kit for treating peripheral T cell lymphoma comprising compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent, each packaged separately, and optionally instructions.

In some specific embodiments of the present application, the objective remission rate of the compound I or a pharmaceutically acceptable salt thereof and the pharmaceutical composition for combination use containing the compound I or a pharmaceutically acceptable salt thereof in clinical trials for human patients with peripheral T cell lymphoma reaches more than about 10%, preferably more than about 15%, further preferably more than about 20%, more preferably more than about 30%, especially more than 35%; the disease control rate is 50% or more, preferably about 60% or more, more preferably about 70% or more, still more preferably about 80% or more, particularly 90% or more.

Peripheral T cell lymphoma

In embodiments of the present application, the peripheral T-cell lymphoma is pathohistologically classified and refers to heterogeneous lymphomas derived from post-thymic mature T cells, including but not limited to non-specific peripheral T-cell lymphomas (PTCL, NOS), angioimmunoblastic T-cell lymphomas (AITL), anaplastic large-cell lymphomas (ALCL, including ALK-positive anaplastic large-cell lymphomas, ALK-negative anaplastic large-cell lymphomas), enteropathy-associated T-cell lymphomas (EATL), monomorphic epithelial T-cell lymphomas (MEITL), nodal peripheral T-cell lymphomas with TFH phenotypes (PTCL, TFH), follicular T-cell lymphomas (FTCL), primary cutaneous T-cell lymphomas, non-classifiable peripheral T-cell lymphomas.

In some embodiments, the peripheral T cell lymphoma is primary peripheral T cell lymphoma and/or secondary peripheral T cell lymphoma; in some embodiments, the peripheral T cell lymphoma is clinically staged including, but not limited to, locally advanced, and/or advanced (e.g., stage III/IV) peripheral T cell lymphoma. In some embodiments, the peripheral T cell lymphoma is a peripheral T cell lymphoma that affects different organs, including, but not limited to, oropharynx, stomach, lung, pleura, bone, brain, pericardium, kidney, liver. In some embodiments, the peripheral T cell lymphoma is brain metastatic peripheral T cell lymphoma.

In some embodiments of the present application, the peripheral T cell lymphoma is relapsed; in certain embodiments, the peripheral T cell lymphoma is refractory. In some embodiments, the peripheral T-cell lymphoma is relapsed and/or refractory peripheral T-cell lymphoma. In some embodiments, the peripheral T-cell lymphoma is non-operable peripheral T-cell lymphoma. In some embodiments, the peripheral T-cell lymphoma is a peripheral T-cell lymphoma that has failed radiation therapy.

In some embodiments, the peripheral T cell lymphoma is a peripheral T cell lymphoma that has failed prior therapy. In some embodiments, the peripheral T cell lymphoma is a chemotherapy drug and/or targeted drug therapy-failed peripheral T cell lymphoma. In some embodiments, the peripheral T cell lymphoma is a peripheral T cell lymphoma that has been subjected to at least two chemotherapeutic regimens. In some embodiments, the peripheral T cell lymphoma is a peripheral T cell lymphoma that fails second-and beyond-second-line chemotherapy. In some embodiments, the peripheral T cell lymphoma is peripheral T cell lymphoma that has failed therapy with surgery and/or radiation and/or chemotherapeutic drugs, more preferably, the peripheral T cell lymphoma is peripheral T cell lymphoma that has failed therapy with one or more of cyclophosphamide, doxorubicine, vincristine, prednisone, etoposide.

In some embodiments, the chemotherapeutic agent includes, but is not limited to, one or more of platinum-based agents, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, podophyllums, antineoplastic agents, and antimetabolites. In some embodiments, the chemotherapy comprises first-line chemotherapy and second-line chemotherapy; the chemotherapeutic drug includes but is not limited to one or more of cyclophosphamide, vincristine, doxorubicin, etoposide and prednisone. It will be appreciated by those skilled in the art that the patient may also receive radiation therapy either simultaneously with or subsequent to the described chemotherapy.

A second therapeutic agent

The second therapeutic drug described herein includes, but is not limited to, chemotherapeutic drugs, small molecule targeted antineoplastic drugs, immunotherapeutic drugs, macromolecular antibody drugs.

In some embodiments, the second therapeutic agent is a chemotherapeutic agent, including but not limited to one or more of platinum-based drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, podophylls, antineoplastic, antimetabolites, and examples that may be cited include, but are not limited to, platinum-based drugs (e.g., oxaliplatin, miriplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin (dicycloproxiltin), leplatin (Lobaplatin), triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, difurofluorouracil, floxuridine, tegafur, carmofur, trifluridine), taxanes (e.g., paclitaxel, albumin-conjugated paclitaxel, and docetaxel), camptothecins (e.g., camptothecin, hydroxycamptothecin, 9-amino base, camptothecin, etc.) 7-ethylcamptothecin, irinotecan, topotecan), vinblastines (vinorelbine, vinblastine, vincristine, vindesine, vinflunine (vinflunine), catharanthine), anthracyclines (epirubicin, doxorubicin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, doxorubicin, valrubicin, zorubicin, pixantrone, pyradoxin, cytarabine, thioguanine, pemetrexed, carmustine, melphalan, etoposide (etoposide), teniposide, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, pentostatin, liposomal doxorubicin, actinomycin D (dactinomycin), bleomycin, pingomycin, temozolomide, climbamide, lomycin, eribulin, pranobufin (plinabulin), One or more of Sapacitabine, troosulfan (treosulfan), 153Sm-EDTMP, tegafur, l-asparaginase, pemetrexed, harringtonine, and encequidar.

In certain embodiments, the second therapeutic agent is one or more of platinum group antineoplastic agents including, but not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, miriplatin, triplatin tetranitrate, phenanthroline, picoplatin, satraplatin, leplatin, and the like.

Optionally, the second therapeutic agent is used in combination with chemotherapeutic adjuvants, including but not limited to leucovorin (CF), aldehydo acid, mesna, bisphosphonates, amifostine, hematopoietic cell Colony Stimulating Factors (CSFs), dexamethasone, prednisone, methylprednisolone, cyclosporine. In some embodiments, the chemotherapeutic adjuvant is dexamethasone, prednisone, methylprednisolone.

In some embodiments, the second therapeutic agent is an immunotherapeutic agent including, but not limited to, one or more of interferon (interferon alpha, interferon alpha-1 b, interferon alpha-2 b), interleukin, sirolimus (temsirolimus), everolimus (everolimus), ridaforolimus (ridaforolimus), temsirolimus.

In some embodiments, the second therapeutic agent is a small molecule targeted anti-tumor agent, including but not limited to protein kinase inhibitors. Wherein, the protein kinase inhibitor includes but is not limited to tyrosine kinase inhibitor, serine and/or threonine kinase inhibitor, Poly ADP Ribose Polymerase (PARP), poly ADP-ribose polymerase inhibitor, the target of the inhibitor includes but is not limited to Fascin-1 protein, HDAC (histone deacetylase), Proteasome, CD38, SLAMF7(CS1/CD319/CRACC), Proteasome, RANKL, EGFR (epidermal growth factor receptor), Anaplastic Lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signal channel, DDR2 (discoid death receptor 2) gene, FGFR1 (vitamin fibroblast receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene; the target of the small molecule targeted antitumor drug also comprises COX-2 (cyclooxygenase-2), APE1 (depurination and depyrimidinization endonuclease), VEGFR (vascular endothelial growth factor receptor), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), Ezrin, PEDF (pigment epithelium derived factor), AS, ES, OPG (bone protective factor), Src, IFN, ALCAM (leukocyte activated adhesion factor), HSP, JIP1, GSK-3 (glycogen synthesis kinase 3 sugar), CyclinD1 (cell cycle regulatory protein), CDK4 (cyclin dependent kinase), TIMP1 (histometalloproteinase inhibitor), THBS3, PTHR1 (parathyroid hormone related protein receptor 1), TEM7 (human tumor vascular endothelial marker 7), COPS3, cathepsin K, and alpha-beta-glucosidase, T cell surface antigen (CD4), Aurora a kinase, fusion protein, PNP, cyclic depsipeptide, DHFR. Examples of small molecule targeted antineoplastic agents include, but are not limited to, Imatinib (Imatinib), Sunitinib (Sunitinib), Nilotinib (Nilotinib), bosutinib (bosutinib), saratinib (Saracatinib), Pazopanib (Pazopanib), trabectedidin (Trabectedin), Regorafenib (Regorafenib), Cediranib (Cediranib), Bortezomib (Bortezomib), Panobinostat (Panobinostat), Carfilzomib (Carfilzomib), ixazomide (Ixazomib), apatinib (trapatitinib), Erlotinib (Erlotinib), Afatinib (Afatinib), Crizotinib (critinib), Ceritinib (ceratinib), Erlotinib (veitinib), Erlotinib (grittinib), Ceritinib (grittinib), Erlotinib (grittinib), Gefitinib (grittib), Gefitinib (grittinib), Gefitinib (grittib), or a), Gefitinib (grittib), or a), a (grittib), a (Gefitinib (grittib), a (Gefitinib (grittib), a (Gefitinib (grittib), a (Gefitinib (ge, Lapatinib (Lapatinib), Vandetanib (Vandetinib), serentinib (Selumetinib), Sorafenib (Sorafenib), ormotinib (Olmutinib), Wolinitinib (Savoltinib), furolinib (Fruquintinib), Entrotinib (Entretinib), Dasatinib (Dasatinib), Ensaratinib (Ensartinib), Lenvatinib (Lenvatinib), itacetinib, piritinib (Pyratinib), bimetinib (Binimitinib), Erdasatinib (Erdasatinib), Asitinib (Axitinib), lenatinib (Neratinib), Cobimitinib (Cobimitinib), acartinib (Acastatinib), Falitatinib (Valentinib) (L803-Lpini), Lpini-1205, Lpini-L), Lpinotinib (Lvcitinib, Lpinnitorinib, Lvi-1205, Lvcitinib, Lvi-L, Lvi-PC, Lvi-libertinib, Lvi-292, Lvi-L (Lvi-PC-E), Lvi-libertinib, Lvi-PC-E, L-libertinib, L (L-R-II, L-II, L-II-III, L-III, L-L, L-III, L-III, L, metformin, seliciclib, OSE-2101, APL-101, berzosertib, idelalisib, lerociclib, ceralasertib, PLB-1003, tomivosertib, AST-2818, SKLB-1028, D-0316, LY-3023414, allitinib, MRTX-849, AP-32788, AZD-4205, lifrafenib, vactor, mivebresib, napabucasin, stravatinib, TAS-114, molibrisib, CC-223, rivoranib, CK-101, LXH-254, simotinib, GSK-3368715, TAS-0728, masitinib, tepotib, HS-10296, AZD-4547, zestinestib, SAF-1, SAF-43, ASL-3727, ASL-077, SCC-3727, AST-077, SCC-3, SANTI-379, SANTI-53, SANTB-53, SANTI-3639, SANTI-7, SANTI-3, SANTI-379, SANTI-3, SANTI-3, SANTI, SAC-3, SANTI-3, SANTI-3, SANTI-1, SANTI-3, SANTI, SAC-3, SANTI, SAC-3, SAC, SANTI, SAID, SAC-3, SAID, SANTI, SAID, SA, epitinib succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosynalate, DV-281, Siremaddin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, reminiostat, epacadostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, KML-001, Bellistat, Pralatrexate, Ropidexin (Roepsin), Semidemide (Chidamide), Alweisib, Piletisindin, Piletisindine, or a plurality of them. In some embodiments, the small molecule targeted antineoplastic agent is one or more of romidepsin, pralatrexate, sidaribamine, belinostat, sorafenib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozitinib, gefitinib, dacomitinib, ocitinib, erlotinib, brigatinib, lorartinib, tretinib, larotinib, erlotinib, lapatinib, vandetanib, sematinib, tematinib, wallitinib, furlitinib, emtricitinib, dasatinib, emtinib, lenvatinib, lucatinib, itatinib, pyrrole-tinib, erlotinib, acitinib, lenatinib, benitinib, bicartitinib, acatinib, famitinib, masitinib, imatinib, and isertinib.

In some embodiments, the second therapeutic agent is a macromolecular antibody agent. Wherein, the target point includes any one or more of PD-1, PD-L1, cytotoxic T lymphocyte antigen 4 (cytoxic T-lymphocyte antigen 4, CTLA-4), platelet derived growth factor receptor alpha (PDGFR-alpha), Vascular Endothelial Growth Factor (VEGF), human epidermal growth factor receptor-2 (HER2), Epidermal Growth Factor Receptor (EGFR), ganglioside GD2, B cell surface protein CD20, B cell surface protein CD52, B cell surface protein CD38, B cell surface protein CD319, B cell surface protein CD30, and B cell surface protein CD19/CD 3.

In some embodiments, the antibody drug is an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1; in some embodiments, the antibody agent is a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor. In some embodiments, the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR-alpha) inhibitor.

In some embodiments, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-1) and/or inhibits PD-1 activity, or an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-L1) and/or inhibits PD-L1 activity, such as an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, the antibody or antigen-binding portion thereof is (a) a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; or (b) a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

In some embodiments, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

In some embodiments, the anti-PD-1 or PD-L1 antibody is a human or murine antibody.

In some embodiments, the anti-PD-1 antibody can be selected from any one or more of Nivolumab, bebolizumab (Pembrolizumab), debarville mab (Durvalumab), teriepril mab (torelizumab, JS-001), Cendilizumab (IBI308), Carelizumab (Camrelizumab), Cetirelizumab (BGB-A317), Jennuzumab (GB226), Lilizumab (LZM009), HLX-10, BAT-1306, AK103(HX008), AK104 (Combo organism), CS1003, SCT-I10A, F520, SG001, GLS-010.

In some embodiments, the anti-PD-L1 antibody can be selected from any one or more of Atezolizumab, Avelumab, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014(ZKAB0011), KN035, MSB2311, HLX-20, CS-1001, and SGN-35.

In some specific embodiments, the anti-PD-1 antibody is tereprimab.

In some specific embodiments, the anti-PD-1 antibody is pabollizumab.

In some embodiments, the inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

In some embodiments, the anti-CTLA-4 antibody may be selected from any one or more of Ipilimumab (Iplimumab), Tremelimumab (Tremelimumab), AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI 310.

In some specific embodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the platelet-derived growth factor receptor alpha (PDGFR-alpha) inhibitor is an anti-PDGFR alpha antibody. In some embodiments, the anti-PDGFR α antibody is an anti-PDGFR α monoclonal antibody.

In some specific embodiments, the anti-PDGFR α antibody is Olaratumab (olarataumab).

In some specific embodiments, the antibody drug may further include, but is not limited to, Bevacizumab (Bevacizumab), Ramucirumab (Ramucirumab), Pertuzumab (Pertuzumab), trastuzumab (trastuzumab), cetuximab (Cotuximab), Nimotuzumab (Nimotuzumab), Panitumumab (Panitumumab), Nimotuzumab (Necitumumab), dinuximab (Necitumumab), dinitumumab, Rituximab (Rituximab), Ibritumomab (Ibritumomab), ofazumab ozitumomab (ofamab), Alemtuzumab (Alemtuzumab), daratuzumab (Daratumumab), Gemtuzumab (Gemtuzumab), rituzumab (Rituximab), present antibody (brentuzumab), Rituximab (Rituximab), or adomtuzumab (Rituximab), or any of them.

In some embodiments, the second therapeutic agent is one or more of etoposide, cyclophosphamide, doxorubicin, vincristine, methotrexate, cisplatin, carboplatin, paclitaxel, docetaxel fluorouracil, catharanthine, bleomycin, ifosfamide, mesna, aldehydofylic acid, mitoxantrone, doxorubicin, daunorubicin, cytarabine, thioguanine, cephalotaxine, gemcitabine, alemtuzumab, epirubicin.

In some embodiments, the second therapeutic agent is one or both of carboplatin and 5-fluorouracil.

In some embodiments, the second therapeutic agent is one or both of cisplatin and alemtuzumab.

In some embodiments, the second therapeutic agent is one or both of carboplatin and alemtuzumab.

In some embodiments, the second therapeutic agent is one or both of gemcitabine and vinorelbine.

In some embodiments, the second therapeutic agent is one or both of gemcitabine and paclitaxel.

In some embodiments, the second therapeutic agent is one, two, or three of docetaxel, cisplatin, and 5-fluorouracil.

In some embodiments, the second therapeutic agent is one, two, or three of cisplatin, epirubicin, and paclitaxel.

In some embodiments, the second therapeutic agent is one, two, or three of cisplatin, 5-fluorouracil, and alemtuzumab.

In some embodiments, the second therapeutic agent is one, two, or three of carboplatin, 5-fluorouracil, and alemtuzumab.

In some embodiments, the second therapeutic agent is one, two, or three of cisplatin, docetaxel, and paclitaxel.

In some embodiments, the second therapeutic agent is one, two, or three of carboplatin, docetaxel, and paclitaxel.

In some embodiments, the second therapeutic agent is one, two, or three of carboplatin, paclitaxel, and gemcitabine.

In some embodiments, the second therapeutic agent is one, two, three, or four of cyclophosphamide, doxorubicine, vincristine, prednisone. In some embodiments, the second therapeutic agent is a "CHOP" regimen.

In some embodiments, the second therapeutic agent is one, two, three, four, or five of cyclophosphamide, vincristine, doxorubicine, etoposide, prednisone. In some embodiments, the second therapeutic agent is a "CHOEP" regimen. In some embodiments, the second therapeutic agent is a "DA-EPOCH" regimen.

In some embodiments, the second therapeutic agent is one, two, or three of gemcitabine, oxaliplatin, and a pemetrexed. In some embodiments, the second therapeutic agent is a "P-GemOx" regimen.

In some embodiments, the second therapeutic agent is one or both of cytarabine and etoposide. In some embodiments, the second therapeutic agent is an "EA" regimen.

In some embodiments, the second therapeutic agent is one or both of capecitabine and docetaxel. In some embodiments, the second therapeutic agent is a "DX" regimen.

In some embodiments, the second therapeutic agent is one, two, three, or four of mitoxantrone, cytarabine, etoposide, and dexamethasone. In some embodiments, the second therapeutic agent is a "MEDA" regimen.

In some embodiments, the second therapeutic agent is one, two, or three of gemcitabine, ifosfamide, and oxaliplatin. In some embodiments, the second therapeutic agent is a "GIFOX" regimen.

In some embodiments, the second therapeutic agent is one or both of bortezomib and dexamethasone. In some embodiments, the second therapeutic agent is a "BD" regimen.

In some embodiments, the second therapeutic agent is one or both of cisplatin and fluorouracil. In some embodiments, the second therapeutic agent is a DF regimen.

In some embodiments, the second therapeutic agent is one or both of paclitaxel and carboplatin. In some embodiments, the second therapeutic agent is a PC regimen.

In some embodiments, the second therapeutic agent is one or both of daunorubicin and cytarabine. In some embodiments, the second therapeutic agent is a DA regimen.

In some embodiments, the second therapeutic agent is one or both of mitoxantrone, etoposide. In some embodiments, the second therapeutic agent is an ME regimen.

In some embodiments, the second therapeutic agent is one or both of gemcitabine and cisplatin. In some embodiments, the second therapeutic agent is a GP regimen.

In some embodiments, the second therapeutic agent is one or both of 5-fluorouracil and cisplatin. In some embodiments, the second therapeutic agent is an FP regimen.

In some embodiments, the second therapeutic agent is one or both of doxorubicin and cisplatin. In some embodiments, the second therapeutic agent is an AP regimen.

In some embodiments, the second therapeutic agent is one, two, or three of ifosfamide, mesna, etoposide. In some embodiments, the second therapeutic agent is an IE regimen.

In certain embodiments, the second therapeutic agent is tegafur.

In some embodiments, the second therapeutic agent is one, two or three of catharanthine, methotrexate, and bleomycin. In some embodiments, the second therapeutic agent is an NMB regimen.

In some embodiments, the second therapeutic agent is one, two, three, or four of paclitaxel, ifosfamide, mesna, cisplatin. In some embodiments, the second therapeutic agent is a PIC regimen.

In some embodiments, the second therapeutic agent is one, two, or three of cisplatin, fluorouracil, and aldehydic acid. In some embodiments, the second therapeutic agent is a DLF regimen.

In some embodiments, the second therapeutic agent is one, two, or three of cisplatin, bleomycin, fluorouracil. In some embodiments, the second therapeutic agent is a PBF regimen.

In some embodiments, the second therapeutic agent is one, two, or three of mitoxantrone, fluorouracil, and carboplatin. In some embodiments, the second therapeutic agent is an MFC protocol.

In some embodiments, the second therapeutic agent is one, two, or three of doxorubicin pyrane, cisplatin, fluorouracil. In some embodiments, the second therapeutic agent is a TPF regimen.

In some embodiments, the second therapeutic agent is one, two, three, or four of daunorubicin, cytarabine, thioguanine, etoposide. In some embodiments, the second therapeutic agent is a DAT regimen.

In some embodiments, the second therapeutic agent is one, two, or three of harringtonine, cytarabine, thioguanine. In some embodiments, the second therapeutic agent is an HA regimen.

In some embodiments, the second therapeutic agent is one, two, three, or four of harringtonine, vincristine, cytarabine, prednisone. In some embodiments, the second therapeutic agent is a HOAP regimen.

Compound I or a pharmaceutically acceptable salt thereof

Compound I has the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the following structural formula:

in the application, all references to erlotinib refer to compound I.

Compound I can be administered in its free base form, as well as in the form of its salts, hydrates, and prodrugs, which convert in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the present application and can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, compound I is administered as the hydrochloride salt of compound I. In some embodiments, compound I is administered as the monohydrochloride salt of compound I. In some embodiments, compound I is administered as the dihydrochloride salt. In some embodiments, the compound I is administered as a crystalline form of the hydrochloride salt of compound I. In a particular embodiment, compound I dihydrochloride is administered as a crystalline form.

Compound I, or a pharmaceutically acceptable salt thereof, the second therapeutic agent can be administered by a variety of routes including, but not limited to, a route selected from: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal. In a particular embodiment, administration is by oral administration.

The amount of compound I or a pharmaceutically acceptable salt thereof, and the second therapeutic agent administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicities, the age and health of the subject. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 3 mg to 30 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 5 mg to 20 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 8mg to 16 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 10mg to 14 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 8 mg. In a particular embodiment, compound I or a pharmaceutically acceptable salt thereof is administered in a daily dose of 10 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 12 mg. In this application, for example, with respect to tablets or capsules, "12 mg of compound I on a unit dose basis" means that each tablet or each capsule ultimately produced contains 12mg of compound I.

Compound I or a pharmaceutically acceptable salt thereof, the second therapeutic agent may be administered one or more times daily. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once daily. In one embodiment, the oral solid formulation is administered once daily.

In the above-mentioned treatment methods, the administration method can be comprehensively determined depending on the activity and toxicity of the drug, the tolerance of the subject, and the like. Preferably, compound I or a pharmaceutically acceptable salt thereof is administered at intervals. The intermittent administration includes a dosing period during which compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per day and a rest period. For example, compound I or a pharmaceutically acceptable salt thereof is administered daily during a dosing period, then the administration is stopped for a period of time during a rest period, followed by a dosing period, then a rest period, and so on, which may be repeated multiple times. Wherein the ratio of the administration period to the withdrawal period in days is 2: 0.5-5, preferably 2: 0.5-3, more preferably 2: 0.5-2, and still more preferably 2: 0.5-1.

In some embodiments, the administration is discontinued for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 14 days off; followed by 1 administration per day for 14 days and then 14 days, so that the administration may be repeated several times at 2-week intervals.

In some embodiments, the administration is discontinued for 1 week for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 7 days of discontinuation; the administration is followed 1 time per day for 14 days and then discontinued for 7 days, so that the administration is repeated multiple times at 1 week intervals for 2 weeks of continuous administration.

In some embodiments, the administration is continued for 5 days and discontinued for 2 days. In some embodiments, administration is 1 time per day for 5 days, followed by 2 days off; the administration is followed 1 time per day for 5 days and then discontinued for 2 days, and the administration may be repeated multiple times at intervals of 5 consecutive days and 2 discontinued days.

In certain particular embodiments, the administration is oral at a dose of 12mg once daily for 2 weeks with 1 week rest.

Combined pharmaceutical composition or pharmaceutical combination

The components of the combination pharmaceutical compositions described herein may optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient. The pharmaceutical compositions for combination use described herein may be formulated separately from each other or some or all of them may be co-formulated. Preferably, the components of the combination pharmaceutical composition are formulated separately or each is formulated as a suitable pharmaceutical composition. In some embodiments, the combination pharmaceutical compositions of the present application may be formulated as a pharmaceutical composition suitable for single or multiple administration. In some particular embodiments, the pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof may be selected from solid pharmaceutical compositions including, but not limited to, tablets or capsules.

The components of the combined pharmaceutical composition of the present application may be administered individually or some or all of them may be co-administered. The components of the combination pharmaceutical compositions of the present application may be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.

The components of the combination pharmaceutical compositions of the present application may be administered independently of each other, or some or all of them together in a suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the combination pharmaceutical compositions of the present application may be administered orally or parenterally, each independently, or some or all of them together, for example intravenously or intraperitoneally.

The components of the combination pharmaceutical compositions of the present application may each independently, or some or all of them together be in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and sustained release formulations for oral or non-oral administration.

In some embodiments of the present application, the combination pharmaceutical composition is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

The present invention provides a kit comprising (a) at least one unit dose of a pharmaceutical composition of compound I or a pharmaceutically acceptable salt thereof and (b) instructions for the treatment of peripheral T cell lymphoma.

The invention also provides a kit comprising (a) at least one unit dose of a formulation suitable for oral administration of compound I or a pharmaceutically acceptable salt thereof and (b) instructions for use in the treatment of peripheral T-cell lymphoma by intermittent administration. In some particular embodiments, a kit is provided comprising (a) at least one unit dose of a tablet or capsule of compound I or a pharmaceutically acceptable salt thereof and (b) instructions for use in the treatment of peripheral T cell lymphoma by intermittent administration. In some more typical embodiments, the peripheral T cell lymphoma is a peripheral T cell lymphoma that has failed treatment with a chemotherapeutic and/or targeted drug. The term "unit dose" refers to a pharmaceutical composition packaged in a single package for ease of administration. Such as tablets or capsules.

In some embodiments of the present application, the combination pharmaceutical composition is a non-fixed combination. In some embodiments, the second therapeutic agent and compound I, or a pharmaceutically acceptable salt thereof, in the non-fixed combination are each in the form of a pharmaceutical composition.

In some embodiments of the present application, compound I or a pharmaceutically acceptable salt thereof is administered simultaneously or sequentially with one or more second therapeutic agents. In certain embodiments, the one or more second therapeutic agents have been administered to the subject prior to administration of compound I, or a pharmaceutically acceptable salt thereof, or prior to combination with compound I, or a pharmaceutically acceptable salt thereof. In certain embodiments, the one or more second therapeutic agents are administered to the subject after administration of compound I or a pharmaceutically acceptable salt thereof or after combination with compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, compound I or a pharmaceutically acceptable salt thereof has been administered to the subject prior to or in combination with the one or more second therapeutic agents. In certain embodiments, compound I or a pharmaceutically acceptable salt thereof is administered to the subject after administration of the one or more second therapeutic agents or after combination with the one or more second therapeutic agents. In some embodiments, when compound I or a pharmaceutically acceptable salt thereof is administered to a subject in combination with one or more second therapeutic agents, compound I or a pharmaceutically acceptable salt thereof and the one or more second therapeutic agents are administered to the subject sequentially. In certain embodiments, the one or more second therapeutic agents are not effective in treating cancer. In some embodiments, the second therapeutic agent is any anti-cancer agent described herein or known in the art.

In some embodiments, there is also provided a kit of parts for a pharmaceutical composition for treating peripheral T cell lymphoma, comprising: (a) a first pharmaceutical composition comprising a chemotherapeutic agent as an active ingredient; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, there is also provided a kit of parts for a pharmaceutical composition for treating peripheral T cell lymphoma, comprising: (a) the first medicine composition contains small molecular targeted antitumor medicine as active component; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, there is also provided a kit of parts for a pharmaceutical composition for treating peripheral T cell lymphoma, comprising: (a) a first pharmaceutical composition comprising an immunotherapeutic agent as an active ingredient; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a kit of pharmaceutical compositions for treating peripheral T cell lymphoma is also provided, comprising (a) a first pharmaceutical composition comprising a macromolecular antibody drug as an active ingredient; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient.

In some embodiments, there is also provided a kit of parts for a pharmaceutical composition for treating peripheral T cell lymphoma, comprising: (a) the first medicine composition contains one, two, three or four of cyclophosphamide, carbendazim, vincristine and prednisone as active ingredients; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a kit for a pharmaceutical composition for treating peripheral T cell lymphoma is also provided, which comprises (a) a first pharmaceutical composition comprising one, two, three, four or five of cyclophosphamide, vincristine, doxorubicine, etoposide and prednisone as active ingredients; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, unless otherwise indicated, the dosages and ranges provided herein are based on the molecular weight of compound I in its free base form.

The crystalline forms of the hydrochloride salt of compound I described herein include, but are not limited to, form A, B and form C crystals as disclosed in chinese patent application CN102344438A, wherein form a and B crystals are crystals substantially free of water of crystallization and other solvents and form C crystals are crystals containing two water of crystallization. In some embodiments, the crystalline form of the dihydrochloride salt of compound I is form a crystalline.

Unless otherwise indicated, the following terms used in the specification and claims shall have the following meanings for the purposes of this application.

In the application, all references to erlotinib refer to compound I.

By "patient" or "subject" is meant a mammal, preferably a human.

By "pharmaceutically acceptable" is meant that it is used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include that they are acceptable for human pharmaceutical use.

"pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic, trifluoroacetic, propionic, hexanoic, heptanoic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, 1, 2-ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-chlorobenzenesulfonic, p-toluenesulfonic, 3-phenylpropionic, trimethylacetic, t-butylacetic, dodecylsulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic acid and the like.

By "treatment" is meant any administration of a therapeutically effective amount of a compound and includes:

(1) inhibiting the disease (i.e., arresting the further development of the pathology and/or symptomatology) in a human experiencing or exhibiting the pathology or symptomatology of the disease, or

(2) Ameliorating the disease (i.e., reversing the pathology and/or symptomatology) in a human experiencing or exhibiting the pathology or symptomatology of the disease.

"treatment failure" refers to intolerance of toxic side effects, disease progression during treatment, or relapse after treatment is complete; wherein intolerance includes, but is not limited to, hematologic toxicity up to grade IV (platelet lowering grade III and above), and non-hematologic toxicity up to grade III or above.

"CR" means complete remission. "PR" refers to partial remission. "PD" refers to disease progression. "SD" refers to stable disease. "ORR" refers to the objective remission rate (ORR ═ CR + PR). "DCR" refers to the rate of disease control (DCR ═ CR + PR + SD).

"late" includes "locally advanced".

The "CHOP" regimen, refers to the combination of cyclophosphamide, doxorubicine, vincristine, prednisone;

the 'CHOEP' scheme refers to the combination of cyclophosphamide, vincristine, doxorubicine, etoposide and prednisone;

the DA-EPOCH scheme is the combination of etoposide, vincristine, carbendazim, cyclophosphamide and prednisone.

The "P-GemOx" regimen refers to a combination of gemcitabine, oxaliplatin and pemetrexed.

The "EA" regimen refers to the combination of cytarabine and etoposide.

The "DX" regimen refers to the combination of capecitabine and docetaxel.

The "MEDA" regimen refers to a combination of mitoxantrone, cytarabine, etoposide and dexamethasone.

The "GIFOX" regimen refers to a combination of gemcitabine, ifosfamide and oxaliplatin.

The "BD" regimen refers to a combination of bortezomib and dexamethasone.

The "CDOP" regimen refers to the combination of liposomal doxorubicin, cyclophosphamide, vindesine, prednisone.

The "B-CDOP" regimen refers to the combination of bleomycin, liposomal doxorubicin, cyclophosphamide, vindesine, prednisone.

"clinical benefit" in the present application includes, but is not limited to: clinical patients have prolonged Progression Free Survival (PFS), prolonged Overall Survival (OS), improved Objective Remission Rate (ORR), improved Disease Control Rate (DCR), reduced number and/or extent of adverse effects, decreased distant metastasis rates, decreased local control rates, and the like. In particular, in some particular embodiments of the present application, especially in particular embodiments of the present application, the objective remission rate in clinical trials for human patients with peripheral T-cell lymphoma is up to about 10% or more, preferably up to about 15% or more, further preferably up to about 20% or more, more preferably up to about 30% or more, especially up to 35% or more; the disease control rate of the patient is 50% or more, preferably about 60% or more, more preferably about 70% or more, still more preferably about 80% or more, and particularly 90% or more.

"about" in this application means within + -5% of the specified numerical range given, preferably within + -2% and more preferably within + -1%.

In this document, unless otherwise indicated, the terms "comprises, comprising and including" or equivalents thereof, are open-ended and mean that elements, components and steps other than those listed may be included.

All patents, patent applications, and other established publications are herein expressly incorporated by reference for the purpose of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date of these documents or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to such publications in this specification does not constitute an admission that the publications form part of the common general knowledge in the art in any country.

Detailed Description

The present application is further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present application.

Example 1 clinical trial protocol

Patients diagnosed pathologically well with graded peripheral T-cell lymphomas (PTCL) including unspecified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), anaplastic large-cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic T-cell lymphoma (MEITL), intranodal peripheral T-cell lymphoma with TFH phenotype (PTCL, TFH), follicular T-cell lymphoma (FTCL), NK/T-cell lymphoma, primary cutaneous T-cell lymphoma and unclassified peripheral T-cell lymphoma WHO received a single oral administration of anitinib, specifically administered as follows:

the erlotinib hydrochloride capsule is orally taken on an empty stomach 1 time a day, 1 granule (12mg) is orally taken each time, and the drug is continuously taken for two weeks and is stopped for one week, namely, every 3 weeks (21 days) is a treatment course.

Dose adjustment: the dosage can be adjusted by the investigator depending on the severity of the adverse reaction. This study designed 2 levels of dose modulation. The first-stage down-regulation dose is 10mg, 1 time per day, and is orally taken before breakfast, and is stopped taking the medicine for one week for two weeks. The second-stage down-regulation dose is 8mg, 1 time per day, and is orally taken before breakfast, and is stopped taking the medicine for one week for two weeks. For subjects who have been downregulated twice (to 8mg), after a period of time, and the investigator determines that there is a likelihood of progression of the disease, the dose may be upregulated once (to 10 mg). At most, only one dose up-regulation was performed per subject.

The observation indexes of the curative effect evaluation comprise: objective Remission Rate (ORR), Progression Free Survival (PFS), Duration of remission (DOR), Overall Survival (OS).

This study showed that the therapeutic regimen of anitinib was clinically beneficial for peripheral T-cell lymphoma patients. The best efficacy of 2 patients in the group were CR (complete remission) and PR (partial remission), respectively, with 100% ORR and 3.15 months PFS in peripheral T cell lymphoma using the solitary capsule of aritinib hydrochloride.

Claims (11)

1. The use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of peripheral T cell lymphoma,

2. the application of the combination of the compound I or the pharmaceutically acceptable salt thereof and a second therapeutic drug in preparing the drugs for treating the peripheral T cell lymphoma, wherein the second therapeutic drug is one or more of chemotherapeutic drugs, small molecule targeted antitumor drugs, immunotherapy drugs and macromolecular antibody drugs,

3. use according to claim 1 or 2, wherein the peripheral T-cell lymphoma is selected from the group consisting of unspecified peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, enteropathy-associated T-cell lymphoma, monomorphic epithelial T-cell lymphoma, nodular peripheral T-cell lymphoma with TFH phenotype, follicular T-cell lymphoma, primary cutaneous T-cell lymphoma, unclassifiable peripheral T-cell lymphoma.

4. The use according to claim 3, wherein the anaplastic large cell lymphoma is ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma or cutaneous anaplastic large cell lymphoma or systemic anaplastic large cell lymphoma or mammary graft-associated anaplastic large cell lymphoma.

5. Use according to any one of claims 1 to 4, wherein the peripheral T-cell lymphoma is primary and/or secondary peripheral T-cell lymphoma, or locally advanced, and/or advanced peripheral T-cell lymphoma, or is metastatic peripheral T-cell lymphoma, or is recurrent, and/or refractory, and/or inoperable peripheral T-cell lymphoma, or is peripheral T-cell lymphoma that has failed treatment with surgery and/or chemotherapeutic and/or targeted drugs.

6. The use of any one of claims 2 to 5, wherein the chemotherapeutic agent is oxaliplatin, miriplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, leplatin, triplatin tetranitrate, phenanthrplatin, picoplatin, satraplatin, gemcitabine, capecitabine, ancitabine, fluorouracil, difurofluorouracil, doxifluridine, tegafur, carmofur, trifluridine, paclitaxel, albumin-bound paclitaxel, docetaxel, camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan, vinorelbine, vinblastine, vincristine, vindesine, vinblastine, epirubicin, doxorubicin, daunorubicin, doxorubicin, pirrubicin, amrubicin, idarubicin, mitoxantrone, doxorubicin, valrubicin, rubicin, cisplatin, or a mixture thereof, One or more of zorubicin, pixantrone, doxorubicin pyrans, cytarabine, thioguanine, pemetrexed, carmustine, melphalan, etoposide, tennixin, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, pentostatin, liposomal doxorubicin, actinomycin D, bleomycin, pingyanomycin, temozolomide, amiloride, pellomycin, eribulin, plinabune, Sapacitabine, trooshusuo, 153Sm-EDTMP, tioxadiol, levansetrexed, pemphigus, cephalotaxin, and encequidar.

7. The use according to any one of claims 2 to 5, wherein the immunotherapeutic agent is one or more of interferons, interleukins, sirolimus, everolimus, ridaforolimus, temsirolimus.

8. The use of any one of claims 2-5, wherein the small molecule targeted antineoplastic agent is imatinib, sunitinib, nilotinib, bosutinib, secatinib, pazopanib, trabectedin, regorafenib, cediranib, bortezomib, panobistat, carfilzomib, isozamide, apatinib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozinib, gefitinib, dacomitinib, oxitinib, orlistatic, ibrutinib, brigatitinib, luracitinib, erlotinib, lapatinib, tretinotinib, erlotinib, lapatinib, vandetatinib, seretinib, sorafenib, temotinib, voritinib, nifitinib, enroflavitinib, tematinib, dasatinib, sunitinib, enratinib, neritinib, acritinib, acitinib, bivatinib, piritinib, gefitinib, erlotinib, gefitinib, erlotinib, acitinib, lenatinib, cobitinib, acatinib, famitinib, masitinib, ibrutinib, rociletinib, nintedib, lenalidomide, LOXO-292, Vorolaniib, bemcentinib, caplatinib, entretinib, TAK-931, ALT-803, palbociclib, famitinib L-malalate, LTT-462, BLU-667, ninetinib, tipifarnib, poziiniib, DS-1205c, capivastrib, SH-1028, metformin, iciclicilib, OSE-2101, APL-101, berzosertib, IDELisiib, lericicliib, ceraralisib, PLB-1003, tomitinib, serast-4208, SKIIB-1028-7, SALX1, SALX-848, SALX-223, SALX-848, SALzoctonib, SALzocatinib, SANYLB-358, SALX-223, SANzocitabine, SAC-358, SALzoctonib, SALTS-358, SALTS-IB, SALTS-351, SALTS-IB, SALTS-150, SALTS-IB, SAL-150, SALTS-IBA, SAL-IBI, SAL-IBA, SAL-3, SAL-1, SALTS-IBA, SAL-IBC, SAL-IBA, SALTS-IBA, SAL-IBA, SAL-3, SAL-IBA, SALTS-IBA, SAL-3, SALTS-IBA, SAL-III, SAL-3, SAL-IBA, SAL-III, SALTS-III, SAL-III, SALX-III, SAL-III, SA, tepotinib, HS-10296, AZD-4547, merestinib, olapted pegol, galinisertib, ASN-003, gedatolisib, defactinib, lazertiniib, CKI-27, S-49076, BPI-9016M, RF-A-089, RMC-4630, AZD-3759, antroquinolol, SAF-189S, AT-101, TTI-101, naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, epitinib succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate, DV-281, Siremaddin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, remininostat, epacadostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, KML-001, belinostat, pralatrexate, romidepsin, cidentamine, aliertib, Duvelisib, Deniletin-diftox, Forodesine, and Pitidepsin.

9. The use of any one of claims 2-5, wherein the macromolecular antibody drug is bevacizumab, ramucirumab, pertuzumab, trastuzumab, cetuximab, nimotuzumab, panitumumab, nixituzumab, dinutuzumab, rituximab, tiitumumab, ofatumumab, Obinutuzumab, alemtuzumab, daratuzumab, gemtuzumab, erlotintuzumab, bentuximab, inotuzumab, obizumab ozotan, bortuzumab ozogamicin, nivolumitumumab, palbocepritumumab, delaviruzumab, terlipizumab, belimumab, chariluzumab, gravelizumab, jirituximab, jirituzumab, HLX-10, BAT-1306, AK103, AK104, CS1003, SCT-I10A, F, SG001, GLSs-520, atezumab ozolizumab, shx 167, shruzumab, avr-1316, avr-l-r-g, Any one or more of BGB-333, JS003, STI-A1014, KN035, MSB2311, HLX-20, CS-1001, ipilimumab, tiximumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI310, Mogamulizumab, aleurizumab, and Zanolimumab.

10. The use according to any one of claims 2 to 5, wherein the second therapeutic agent is any one or more of the following (1) to (38):

(1) one or both of carboplatin and 5-fluorouracil; (2) one or both of cisplatin and alemtuzumab; (3) one or both of carboplatin and alemtuzumab; (4) one or both of gemcitabine and vinorelbine; (5) one or both of gemcitabine and paclitaxel; (6) one, two or three of docetaxel, cisplatin and 5-fluorouracil; (7) one, two or three of cisplatin, epirubicin and paclitaxel; (8) one, two or three of cisplatin, 5-fluorouracil and alemtuzumab; (9) one, two or three of carboplatin, 5-fluorouracil and alemtuzumab; (10) one, two or three of cisplatin, docetaxel and paclitaxel; (11) one, two or three of carboplatin, docetaxel and paclitaxel; (12) one, two or three of carboplatin, paclitaxel and gemcitabine; (13) one, two, three or four of cyclophosphamide, doxorubicine, vincristine and prednisone; (14) one, two, three, four or five of cyclophosphamide, vincristine, doxorubicin, etoposide and prednisone; (15) one, two or three of gemcitabine, oxaliplatin and pemetrexed; (16) one or two of cytarabine and etoposide; (17) one or both of capecitabine and docetaxel; (18) one, two, three or four of mitoxantrone, cytarabine, etoposide and dexamethasone; (19) one, two or three of gemcitabine, ifosfamide and oxaliplatin; (20) one or both of bortezomib and dexamethasone; (21) one or both of cisplatin and fluorouracil; (22) one or both of paclitaxel and carboplatin; (23) one or two of daunorubicin and cytarabine; (24) one or two of mitoxantrone and etoposide; (25) one or both of gemcitabine and cisplatin; (26) one or both of 5-fluorouracil and cisplatin; (27) one or two of adriamycin and cisplatin; (28) one, two or three of ifosfamide, mesna and etoposide; (29) tegafur; (30) one, two or three of catharanthine, methotrexate and bleomycin; (31) one, two, three or four of paclitaxel, ifosfamide, mesna and cisplatin; (32) one, two or three of cisplatin, fluorouracil and aldehyde hydrofoil; (33) one, two or three of cisplatin, bleomycin and fluorouracil; (34) one, two or three of mitoxantrone, fluorouracil and carboplatin; (35) one, two or three of pyran doxorubicin, cisplatin and fluorouracil; (36) one, two, three or four of daunorubicin, cytarabine, thioguanine and etoposide; (37) one, two or three of harringtonine, cytarabine and thioguanine; (38) one, two, three or four of harringtonine, vincristine, cytarabine and prednisone.

11. The use according to any one of claims 1 to 10, wherein the compound I or the pharmaceutically acceptable salt thereof is administered in a daily dose of 3 mg to 30 mg, preferably 5 mg to 20 mg, more preferably 8mg to 16 mg, even more preferably 8mg to 14 mg, most preferably 8mg, 10mg or 12 mg.