CN112439061A - New application of famitinib or pharmaceutically acceptable salt thereof in combination with PD-1 antibody - Google Patents

Abstract

The present disclosure relates to a novel use of famitinib or a pharmaceutically acceptable salt thereof in combination with a PD-1 antibody. In particular to application of anti-PD-1 antibody combined with famitinib or pharmaceutically acceptable salt thereof in preparing a medicament for treating osteosarcoma. The scheme shows better disease control rate and objective response rate, and embodies the synergistic effect of the drug combination.

Description

New application of famitinib or pharmaceutically acceptable salt thereof in combination with PD-1 antibody

Technical Field

The disclosure relates to a new application of famitinib or a pharmaceutically acceptable salt thereof in combination with a PD-1 antibody.

Background

Osteosarcoma (Osteosarcoma) is the most common primary malignant bone tumor, has the incidence rate of about 3-4/100 ten thousand, mainly occurs in children and adolescents, the median incidence age is 20 years old, and the proportion of male and female is about 1.5: 1. About 800-900 new osteosarcoma patients in the United states annually die about 300. The incidence rate of Chinese osteosarcoma is equivalent to that of Chinese osteosarcoma, and about 4000-5000 new patients are estimated to be sent every year.

At present, the osteosarcoma is treated by a comprehensive treatment mode of preoperative chemotherapy, surgical operation and postoperative chemotherapy, and the 5-year survival rate of a patient reaches 50% -80%. The three-drug combination (MAP) of high-dose methotrexate (high-dose ethetrexate), cisplatin (cisclin) and doxorubicin (doxorubicin/adriamycin) or the four-drug combination (MAPI) of re-combination ifosfamide (ifosfamide) have become the standard first-line chemotherapeutic regimen for osteosarcoma (as well as for neoadjuvant and adjuvant chemotherapy). Osteosarcoma has been treated only by radical surgery more than forty years ago, however, even with standard destructive amputation, local recurrence and distant metastasis are still difficult to avoid, 5-year survival rate after surgery is less than 20%, and the main cause of death is lung metastasis.

With the increasing knowledge of the pathogenesis and carcinogenic pathway of osteosarcoma and the rapid development of targeted therapy, a plurality of small molecule kinase inhibitors and monoclonal antibodies are studied and used for patients with advanced osteosarcoma who fail chemotherapy, such as imatinib and the like. Among osteosarcoma treatments, anti-angiogenic therapies have a strong biological principle. Previous studies have shown that levels of VEGF and VEGFR in circulating blood are closely related to the extent of osteosarcoma disease and patient prognosis. Preclinical data in vivo and in vitro indicate that inhibition of the angiogenic pathway can effectively slow the growth of osteosarcoma. Early clinical data also suggested the activity of VEGFR kinase inhibitors such as sorafenib and sunitinib in osteosarcoma patients.

In a phase II clinical study (NCT02711007) of apatinib mesylate monotherapy in the advanced osteosarcoma that failed previous standard chemotherapy, 41 subjects with advanced osteosarcoma were enrolled from 3 months to 6 months of 2017 in 2016. By a 30-day follow-up of 12 months and 2017, 16 (43.24%) subjects reached PR, 8 (21.62%) subjects reached SD, PFS rates at 4 months and 6 months were 56.76% (95% CI 39.43% -70.84%) and 36.77% (95% CI 21.48% -52.16%), respectively, while mPFS and mOS reached 4.50 months (95% CI 3.47% -6.27) and 9.87 months (95% CI 7.97% -18.93), respectively.

Recently, it has been found that anti-angiogenic therapy can enhance the efficacy of tumor immunotherapy by increasing the infiltration of immune effector cells into tumor tissue through normalization of tumor blood vessels, and by blocking the immunosuppressive effects induced by VEGF or other hematopoietic factors themselves. A phase II clinical study of carlixizumab in combination with apatinib mesylate in the treatment of advanced osteosarcoma that failed previous standard chemotherapy (NCT03359018), with an objective response rate of 21.95% (9/41), an Objective Remission Rate (ORR) of 30.3%, and a Disease Control Rate (DCR) of 87.9% by last follow-up. The rates of progression-free survival time (PFS) at 6 months and 4 months were 54.32% (95% CI: 37.62%, 68.33%), 70.00% (95% CI: 53.24%, 81.73%), respectively. Median PFS was 6.50 months (95% CI:4.23,7.50), median OS had not been achieved. Apatinib in combination with carleizuzumab prolonged progression-free survival (PFS) in advanced osteosarcoma patients after chemotherapy compared to apatinib single drug, however there was no statistically significant difference in ORR or PFS among different PD-L1 expressing populations (P ═ 0.153, P ═ 0.231) and the Objective Remission Rate (ORR) was 30.3%, the combination was not superior to apatinib alone.

Famirtinib, chemical name 5- (2-diethylamino-ethyl) -2- (5-fluoro-2-oxo-1, 2-dihydro-indol-3-ylidene-methyl) -3-methyl-1, 5,6, 7-tetrahydro-pyrrolo [3,2-c ] pyridin-4-one malate, has obvious inhibitory effect on kinases such as c-Kit, VEGFR2, VEGFR3, PDGFR, Flt1, Flt3, Ret, c-Src and the like, and belongs to a multi-target kinase inhibitor. In a multicenter randomized, double-blind placebo-controlled phase II trial of advanced/metastatic colorectal adenocarcinoma with failure of two or more lines of standard chemotherapy in famitinib, famitinib group (25mg, 1 day/time, 42 days for one cycle) improved progression-free survival (PFS) for advanced/metastatic colorectal cancer patients by 1.3 months (HR 0.596, P0.0053) over placebo group. Objective Remission Rate (ORR) of 2.2%, Disease Control Rate (DCR) of 59.8%, median survival (mOS) of 7.5 months, placebo of 7.6 months, and controlled adverse events,

the objective slow-release rate of the apatinib mesylate combined with the cabrayleigh monoclonal antibody is low, the combined use is not superior to that of apatinib singly, and meanwhile, the report of the combined use of famitinib or pharmaceutically acceptable salt thereof and PD-1 antibody is not available, so that the famitinib or pharmaceutically acceptable salt thereof combined with the anti-PD-1 antibody deserves further research

Disclosure of Invention

The disclosure provides an application of famitinib or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody in preparation of a medicament for treating osteosarcoma.

PD-1 antibodies are known, preferably the PD-1 antibody light chain variable region contains the shown in SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6 LCDR1, LCDR2 and LCDR 3.

The heavy chain variable region of the PD-1 antibody comprises HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3 respectively.

Wherein, the CDR sequences are shown in the following table:

preferably, the anti-PD-1 antibody is a humanized antibody.

In some embodiments, the humanized antibody comprises the light chain variable region set forth in SEQ ID NO. 10 or a variant thereof, preferably having an amino acid change of 0 to 10, more preferably the amino acid change of A43S in the light chain variable region set forth in SEQ ID NO. 10; the humanized antibody comprises the heavy chain variable region of SEQ ID NO. 9 or a variant thereof, preferably having 0-10 amino acid changes, more preferably G44R amino acid changes, in the heavy chain variable region of SEQ ID NO. 9.

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

heavy chain variable region

EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS

SEQID NO：9

Light chain variable region

DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK

SEQID NO：10

In other embodiments, the humanized antibody comprises the light chain of SEQ ID NO. 8 or a variant thereof, preferably having 0-10 amino acid changes in the light chain variable region, more preferably the amino acid change of A43S; the humanized antibody comprises the heavy chain of SEQ ID NO. 7 or a variant thereof, 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 a light chain as set forth in SEQ ID NO. 8 and a heavy chain as set forth in SEQ ID NO. 7.

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

heavy chain

EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

SEQID NO：7

Light chain

DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQID NO：8

The combination of an anti-PD-1 antibody and famitinib or a pharmaceutically acceptable salt thereof disclosed by the disclosure has a synergistic pharmacodynamic effect.

The anti-PD-1 antibody or an antigen-binding fragment thereof can be administered at a dose of 0.1 to 10.0mg/kg, and 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, 4.6mg/kg, 4.0mg/kg, 4mg/kg, 4.6mg, 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, 10.0 mg/kg.

In alternative embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 1-1000 mg, and may be 1.0mg, 1.2mg, 1.4mg, 1.6mg, 1.8mg, 2.0mg, 2.2mg, 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.120 mg, 6.6mg, 6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8mg, 8.0mg, 8mg, 8.120 mg, 8mg, 9.120 mg, 9.15 mg, 9.95 mg, 9.45 mg, 9.95 mg, 9.55 mg, 9.6mg, 10mg, 10.95 mg, 15mg, 15.6, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 505mg, 520mg, 535mg, 525mg, 530mg, 525mg, 530mg, 520mg, 525mg, 530mg, 260mg, 240mg, 440mg, 260mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 695mg, 700mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg, 800mg, 915mg, 810mg, 815mg, 820mg, 825mg, 830mg, 835mg, 840mg, 845mg, 850mg, 855mg, 860mg, 865mg, 870mg, 875mg, 880mg, 925mg, 890mg, 900mg, 895mg, 905mg, 910mg, 930mg, 920mg, 935mg, 980mg, 945mg, 980mg, 965mg, 975mg, 980mg, 965mg, 980mg, 950mg, 980mg, 970mg, 945mg, 980mg, 970mg, 965mg, 975mg, 950mg, 995mg and 1000mg, preferably 50-600 mg, and most preferably 200 mg.

The anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered at a frequency of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, preferably once every two weeks.

In alternative embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present disclosure is administered in a dose of 50-600 mg/2-3 weeks, preferably 200mg/2-3 weeks, once in a human subject.

The famitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 0.1-10.0 mg/kg, which 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, 4.6mg/kg, 4mg/kg, 4.6mg/kg, 4.4mg/kg, 4mg/kg, 4.6mg/kg, 4mg/kg, 4.8mg/kg, 4mg, 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, 10.0 mg/kg.

In alternative embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 0.1-100 mg, and may be 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 51mg, 54mg, 62mg, 54mg, 62mg, 54mg, 52mg, 62mg, 52mg, 55mg, 25mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, preferably 1 to 20 mg.

The administration frequency of the famitinib or a pharmaceutically acceptable salt thereof in the use disclosed by the disclosure is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every three days and once every day for administration, once every four days and once every day for administration, and once every five days and once every day for administration.

In some embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered in a dose of 0.1-100 mg once daily in a human subject.

In other embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered orally once daily; the anti-PD-1 antibody or antigen-binding fragment thereof is administered intravenously at a frequency of once every two weeks.

In other embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered orally in a human subject at a dose of 0.1-100 mg once daily; the anti-PD-1 antibody or an antigen-binding fragment thereof is administered to a human subject at a dose (administered per patient body weight) of 0.1 to 10.0mg/kg at a frequency of once every 2 to 3 weeks by intravenous injection.

In other embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered in a human subject at a dose of 10mg once daily, orally; the anti-PD-1 antibody or an antigen-binding fragment thereof is administered to a human subject at a dose (administered per patient body weight) of 0.1 to 10.0mg/kg at a frequency of once every 2 to 3 weeks by intravenous injection.

In some embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered in a human subject at a dose of 15mg once daily, orally; the anti-PD-1 antibody or an antigen-binding fragment thereof is administered to a human subject at a dose (administered per patient body weight) of 0.1 to 10.0mg/kg at a frequency of once every 2 to 3 weeks by intravenous injection.

In some embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered in a human subject at a dose of 20mg once daily, orally; the anti-PD-1 antibody or an antigen-binding fragment thereof is administered to a human subject at a dose (administered per patient body weight) of 0.1 to 10.0mg/kg at a frequency of once every 2 to 3 weeks by intravenous injection.

In some embodiments, the famitinib or a pharmaceutically acceptable salt thereof is administered in a human subject at a dose of 5mg, at a frequency of once daily, orally; the anti-PD-1 antibody or an antigen-binding fragment thereof is administered to a human subject at a dose (administered per patient body weight) of 0.1 to 10.0mg/kg at a frequency of once every 2 to 3 weeks by intravenous injection. The disclosure also provides the use of a PD-1 antibody in combination with nilotinib, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of osteosarcoma.

The administration frequency of the aritinib or the pharmaceutically acceptable salt thereof in the application disclosed by the disclosure is once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every three days and once a day for administration, once every four days and once a day for administration, and once every five days and once a day for administration.

In some embodiments, the administration frequency of said anirtinib or pharmaceutically acceptable salt thereof is once a day with discontinuation once every two weeks of continuous administration.

In some embodiments, the administration dose of said nilotinib or a pharmaceutically acceptable salt thereof in a human subject is 1-20 mg, with a dosing frequency of once daily, orally; the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200mg at a frequency of once every 2-3 weeks, by intravenous injection.

In some embodiments, the aritinib, or a pharmaceutically acceptable salt thereof, is administered to the human subject at a dose of 10mg, at a frequency of once daily, orally; the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200mg at a frequency of once every 2-3 weeks, by intravenous injection.

In some embodiments, the aritinib, or a pharmaceutically acceptable salt thereof, is administered to the human subject at a dose of 15mg, at a frequency of once daily, orally; the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200mg at a frequency of once every 2-3 weeks, by intravenous injection.

In some embodiments, the aritinib, or a pharmaceutically acceptable salt thereof, is administered to the human subject at a dose of 5mg, at a frequency of once daily, orally; the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200mg at a frequency of once every 2-3 weeks, by intravenous injection.

In another aspect, the patient described in this disclosure has been treated for osteosarcoma. In some embodiments, the patient receives an osteosarcoma treatment regimen selected from, but not limited to, methotrexate, doxorubicin and cisplatin in combination or methotrexate, doxorubicin, cisplatin and ifosfamide in combination.

In another embodiment, the osteosarcoma patient has failed therapy.

In some embodiments, the osteosarcoma patient is an advanced osteosarcoma patient.

In the disclosed embodiments, the PD-1 antibody is administered by injection, for example, subcutaneously or intravenously, and the PD-1 antibody is formulated in an injectable form prior to injection. A particularly preferred injectable form of the PD-1 antibody is an injection solution or a lyophilized powder injection, which comprises the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffer can be one or more selected from 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 most preferred injectable form of the PD-1 antibody comprises the PD-1 antibody, acetate buffer, trehalose, and polysorbate 20.

The pharmaceutically acceptable salts of famitinib described in this disclosure are selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate, preferably malate or hydrochloride.

In some embodiments, the pharmaceutically acceptable salt of famitinib is famitinib malate.

In some embodiments, the pharmaceutically acceptable salt of angutinib is angutinib hydrochloride.

The present disclosure also provides a method of treating osteosarcoma comprising administering to a patient with osteosarcoma a therapeutically effective amount of an anti-PD-1 antibody and said famitinib, angutinib or a pharmaceutically acceptable salt thereof.

In another aspect of the present disclosure there is provided a pharmaceutical combination for use in the treatment of osteosarcoma comprising a therapeutically effective amount of an anti-PD-1 antibody and/or famitinib, or a pharmaceutically acceptable salt thereof.

In another aspect of the present disclosure there is provided a pharmaceutical combination for use in the treatment of osteosarcoma comprising a therapeutically effective amount of an anti-PD-1 antibody and/or nilotinib or a pharmaceutically acceptable salt thereof.

The combination of the anti-PD-1 antibody and the famitinib or the pharmaceutically acceptable salt thereof in the medicament for reducing the adverse drug reaction is disclosed, and preferably the adverse drug reaction is selected from the group consisting of the anti-PD-1 antibody and the famitinib or the pharmaceutically acceptable salt thereof.

The drug for reducing adverse drug reactions in combination of the anti-PD-1 antibody and the nilotinib or a pharmaceutically acceptable salt thereof disclosed by the disclosure is preferably a drug for reducing adverse drug reactions, wherein the adverse drug reactions are selected from the group consisting of those caused by the anti-PD-1 antibody and those caused by the nilotinib or a pharmaceutically acceptable salt thereof.

The anti-PD-1 antibody of the present disclosure in combination with famitinib or a pharmaceutically acceptable salt thereof as a medicament for reducing the dose of anti-PD-1 antibody administered alone and/or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

The anti-PD-1 antibody combined with Falatinib or a pharmaceutically acceptable salt thereof as disclosed in the present disclosure is used as a medicament for reducing the dose of anti-PD-1 antibody administered alone and/or the dose of Falitinib or a pharmaceutically acceptable salt thereof administered alone.

In some embodiments, the famitinib or a pharmaceutically acceptable salt thereof, or apratinib or a pharmaceutically acceptable salt thereof, when used in combination with an anti-PD-1 antibody, is administered at a dose in a human subject that is 10% to 100%, preferably 10% to 75%, more preferably 75%, 50%, 25%, 12.5% of the dose administered alone.

In other embodiments, the anti-PD-1 antibody dose, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, is 10% to 100%, preferably 10% to 50% of the dose of anti-PD-1 antibody administered alone.

In some embodiments, when the PD-1 antibody is used in combination with famitinib or a pharmaceutically acceptable salt thereof, or angutinib or a pharmaceutically acceptable salt thereof, adverse drug reactions mediated by the anti-PD-1 antibody and/or immunity may be reduced; preferably, the adverse reaction is selected from vascular-related adverse reactions, preferably hemangiomas.

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

the tolerance to the same drug varies widely between humans and animals, and animals are generally more tolerant than humans. It can be converted in the following proportions: the medicine is 1 for human, 25-50 for mice and rats, 15-20 for rabbits and guinea pigs, and 5-10 for dogs and cats. In addition, human and animal surface area calculations can be used for scaling, 1) human surface area calculations, generally known as the Schen's formula (J. Physiol., China 12,327,1937), Mech-Rubner's formula. The above method is applicable to the conversion of drug dosage between humans and animals of different species in the present disclosure.

The present disclosure with respect to "combination" or "combination" is a mode of administration, and refers to the administration of at least one dose of a VEGFR inhibitor, such as famitinib or a pharmaceutically acceptable salt thereof, and at least one dose of an additional therapeutic agent over a period of time, wherein both substances exhibit pharmacological effects. 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 VEGFR inhibitor, such as famitinib or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent may be administered simultaneously or sequentially. Such terms include treatments wherein the VEGFR inhibitor, such as famitinib or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered by the same route of administration or different routes of administration. The mode of administration of the combinations described herein is selected from simultaneous administration, separate formulation and co-administration or separate formulation and sequential administration.

An "effective amount" or "therapeutically effective amount" as referred to in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount 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 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 previous lesions of adenocarcinoma, disease Progression (PD), intolerance of toxicity or failure of the subject to continue clinical benefit as judged by the investigator according to RECIST 1.1 efficacy assessment criteria, or disease Progression (PD) as judged by the prostate cancer assessment criteria PCWG3 for 2 or more new bone lesions.

By "toxicity intolerance" in this disclosure is meant that adverse effects due to the drug are not amenable to further treatment.

Progression Free Survival (PFS): the first-appearing person is the standard from the random start to the first recording of the date of objective progression of the previous adenocarcinoma or the time to death due to any cause.

Overall Survival (OS) refers to the period from random to death due to any cause. Subjects who survived the last visit had OS scored as data loss at the time of the last visit. 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 whose tumors have shrunk to a certain extent and are maintained for a certain period of time, including cases of CR and PR. Solid tumor remission evaluation criteria (RECIST 1.1 criteria) were used to assess objective tumor remission. 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.

Duration of remission (DoR): first PR or CR to first PD or death.

Disease Control Rate (DCR) refers to the percentage of confirmed cases of complete remission, partial remission, and stable Disease (> 8 weeks) among patients with evaluable efficacy.

Target lesion assessment

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 < 10 mm.

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.

Assessment of non-target lesions

Complete Remission (CR): all non-target lesions disappeared and tumor markers returned to normal levels. All lymph nodes were of non-pathological size (minor diameter < 10 mm).

Incomplete remission/non-disease progression: the presence of one or more non-target lesions and/or the continued presence of levels of tumor markers above normal levels.

Disease progression: there is clear progression of existing non-target lesions. Note: the appearance of one or more new lesions is also considered disease progression.

Significant toxicity in this study was defined as any of the following events associated with study drug that occurred during the DLT observation period (grading Standard refer to NCI CTCAE 5.0)

(1) Non-hematologic toxicity: non-hematologic toxicity at level III/IV (gastrointestinal toxicity (e.g., nausea and vomiting) and electrolyte disturbances must persist at level III/IV after optimal treatment, but not including alopecia, fever of established cause, such as tumors or infections, pain from tumor bone metastases, elevated levels of alkaline phosphatase, creatine kinase, lactate dehydrogenase, or lipase without associated significant clinical symptoms, etc.); heart insufficiency of II degree and above, renal dysfunction, neurotoxicity;

(2) hematological toxicity: degree IV hematological toxicity, such as degree IV neutropenia, anemia, thrombocytopenia, etc., or degree III neutropenia with ≧ 38 ℃ fever, and degree III thrombocytopenia with significant clinical bleeding tendency.

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:

histopathologically confirmed high-grade osteosarcoma, with distant metastasis or locally advanced stage, and the investigator judges it to be unsuitable for operative treatment (note: patients with local or isolated lesion in lung after primary operation still need to obtain pathological diagnosis again, but patients with multiple metastasis in lung do not need pathological examination).

The traditional Chinese medicine composition receives standard chemotherapy (comprising three medicines such as methotrexate, doxorubicin and cisplatin or combined ifosfamide) aiming at osteosarcoma in large dose) and fails in treatment (namely the disease progresses in the course of treatment or within 6 months after the treatment is finished)

The administration scheme is as follows:

famitinib malate: 20mg, administered orally on an empty stomach once a day with warm water, fasted 2 hours before and 1 hour after administration; every 4 weeks (28 days) for one treatment cycle;

carayleigh mab (light chain sequence shown in SEQ ID NO:8 and heavy chain sequence shown in SEQ ID NO: 7): 200mg, injection (lyophilized powder), intravenous drip (including flushing time, integral drip time not less than 20 minutes, not more than 60 minutes) in 30 minutes, 1 time every 2 weeks (14 days); up to 2 years.

Of the 5 evaluable patients, 1 patient had Stable Disease (SD), 4 patients had Disease Progression (PD), and the Disease Control Rate (DCR) was 20%.

Sequence listing

<110> Hengrui pharmaceutical Co., Ltd of Jiangsu

<120> novel use of famitinib or pharmaceutically acceptable salt thereof in combination with PD-1 antibody

<160> 10

<170> SIPOSequenceListing 1.0

<210> 1

<211> 5

<212> PRT

<213> mouse source (Mus musculus)

<400> 1

Ser Tyr Met Met Ser

1 5

<210> 2

<211> 17

<212> PRT

<213> mouse source (Mus musculus)

<400> 2

Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 3

<211> 7

<212> PRT

<213> mouse source (Mus musculus)

<400> 3

Gln Leu Tyr Tyr Phe Asp Tyr

1 5

<210> 4

<211> 11

<212> PRT

<213> mouse source (Mus musculus)

<400> 4

Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Thr

1 5 10

<210> 5

<211> 7

<212> PRT

<213> mouse source (Mus musculus)

<400> 5

Thr Ala Thr Ser Leu Ala Asp

1 5

<210> 6

<211> 9

<212> PRT

<213> mouse source (Mus musculus)

<400> 6

Gln Gln Val Tyr Ser Ile Pro Trp Thr

1 5

<210> 7

<211> 443

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> PEPTIDE

<222> (1)..(443)

<223> heavy chain sequence

<400> 7

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro

210 215 220

Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 8

<211> 214

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> PEPTIDE

<222> (1)..(214)

<223> light chain sequence

<400> 8

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp

20 25 30

Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 9

<211> 116

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> PEPTIDE

<222> (1)..(116)

<223> heavy chain variable region

<400> 9

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val

100 105 110

Thr Val Ser Ser

115

<210> 10

<211> 107

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<221> PEPTIDE

<222> (1)..(10)

<223> light chain variable region

<400> 10

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp

20 25 30

Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

Claims (10)

1. Use of an anti-PD-1 antibody, preferably a humanized antibody, in combination with famitinib or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of osteosarcoma.

2. The use according to claim 1, wherein the light chain variable region of the PD-1 antibody comprises LCDR1, LCDR2 and LCDR3 as shown in 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 as shown in SEQ ID NO 1, SEQ ID NO 2 and SEQ ID NO 3, respectively.

3. The use according to claim 1, wherein the humanized antibody comprises a light chain as set forth in SEQ ID No. 8 or a variant thereof, preferably having 0-10 amino acid changes in the light chain variable region, more preferably a43S amino acid change; the humanized antibody comprises the heavy chain of SEQ ID NO. 7 or a variant thereof, preferably having 0-10 amino acid changes in the heavy chain variable region, more preferably the amino acid change of G44R.

4. The use of claim 3, 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.

5. The use according to any one of claims 1-4, wherein the patient has been treated with osteosarcoma, preferably in a regimen selected from the group consisting of methotrexate, doxorubicin and cisplatin in combination or methotrexate, doxorubicin, cisplatin and ifosfamide in combination.

6. The use of any one of claims 1-5, wherein the patient has failed therapy, further wherein the osteosarcoma is advanced.

7. Use according to any one of claims 1 to 6, wherein the famitinib or a pharmaceutically acceptable salt thereof is administered at a dose selected from 0.1-100 mg, preferably 1-20 mg; 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.

8. The use according to any one of claims 1-7, wherein the famitinib or a pharmaceutically acceptable salt thereof is administered once daily, orally; the anti-PD-1 antibody or antigen-binding fragment thereof is administered intravenously at a frequency of once every 2 to 3 weeks.

9. Use according to any one of claims 1 to 8, wherein the pharmaceutically acceptable salt of fametinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate and phosphate, preferably malate.

10. A pharmaceutical combination for the treatment of osteosarcoma comprising a therapeutically effective amount of an anti-PD-1 antibody and/or famitinib or a pharmaceutically acceptable salt thereof.