RU2842665C2 - Pharmaceutical composition for treating tumour - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical industry, namely to methods of treating tumours. Method of treating a tumour, comprising administering nivolumab and a liposomal composition containing eribulin mesylate to a patient in need thereof, where the tumour is breast cancer, stomach cancer, oesophageal cancer, small cell lung cancer, colorectal cancer, kidney cancer, thymic carcinoma or intrahepatic cholangocarcinoma, and wherein eribulin mesylate is administered intravenously at 1.7–2.1 mg/m² of body surface area and nivolumab is administered intravenously at 360 mg on day 1 cycle with duration of 21 day. Method of treating a tumour, comprising administering nivolumab and a liposomal composition containing eribulin mesylate to a patient in need thereof, where the tumour is breast cancer, stomach cancer, oesophageal cancer, small cell lung cancer, colorectal cancer, kidney cancer, thymic carcinoma or intrahepatic cholangocarcinoma and where eribulin mesylate is administered intravenously at dose of 1.1–1.4 mg/m² of body surface area and nivolumab is administered intravenously at dose of 240 mg on days 1 and 15 cycle with duration of 28 days.

EFFECT: use of the group of inventions provides the anticancer effect ensured by the synergistic effect of the combined therapy of the liposomal composition containing eribulin or its pharmaceutically acceptable salt, and the PD-1 antagonist – nivolumab.

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Description

Field of technology

[0001] The present invention relates to a pharmaceutical composition for treating a tumor.

State of the art

[0002] Eribulin represented by formula (I) is used as a therapeutic agent for breast cancer and soft tissue tumors.

[0003] Patent Literature 1 discloses eribulin or a pharmaceutically acceptable salt thereof and a method for producing the same. Patent Literatures 2 and 3 disclose methods for producing eribulin and eribulin mesylate, which is its mesylate (methanesulfonate). Patent Literature 4 discloses a method for inhibiting the growth of cancer in a patient by administering eribulin or a pharmaceutically acceptable salt thereof to the patient. Patent Literature 5 discloses a method for treating cancer in a patient by administering eribulin or a pharmaceutically acceptable salt thereof to the patient in combination with a certain second anticancer agent. Patent Literature 6 discloses a method for treating cancer in a patient by administering eribulin or a pharmaceutically acceptable salt thereof to the patient in combination with a second therapeutic approach. Patent Literatures 7 and 8 disclose liposomal compositions containing eribulin mesylate. Patent literature 9 discloses a method for treating breast cancer, which comprises administering a combination of eribulin or a pharmaceutically acceptable salt thereof and a programmed cell death protein 1 (PD-1) antagonist.

[0004] PD-1 is considered to be an important factor in maintaining immunoregulation and peripheral tolerance. PD-1 is moderately expressed in naive T cells, B cells, and NK T cells, and its expression is increased due to T/B cell receptor signal transduction in lymphocytes, monocytes, and myeloid cells (Non-patent literature 1). However, PD-L1 is expressed in various cancer cells or T/B cells, macrophages, mDCs, plasmacytoid DCs (pDCs), bone marrow mast cells, etc.

[0005] Two known PD-1 ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in a variety of tissues. For example, in a large number of sample sets of ovarian cancer, renal cell cancer, colorectal cancer, pancreatic cancer, liver cancer, and melanoma, PD-L1 expression was found to correlate with poor prognosis and reduced overall survival, independent of subsequent treatment (Non-patent literature 2-13). Similarly, PD-1 expression in tumor-infiltrating lymphocytes was found to be characteristic of dysfunctional T cells in breast cancer and melanoma (Non-patent literature 14-15) and was found to correlate with poor prognosis in renal cell cancer (Non-patent literature 16). Therefore, it has been proposed to block the immunosuppressive mechanism activated by cancer cells, such as the interaction of PD-L1-expressing tumor cells with PD-1-expressing T cells, and thereby induce an immune response to the tumor.

[0006] Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of the PD-1 ligands, PD-L1 and PD-L2, are in clinical development for the treatment of cancer. It has been suggested that the efficacy of such antibodies may be enhanced when used in combination with other approved or experimental cancer therapies, such as radiation therapy, surgery, a chemotherapeutic agent, a targeted therapy, an agent that inhibits another signaling pathway that is dysregulated in the tumor, and another immunostimulant.

List of references

Patent Literature Sources

[0007]

Patent Literature 1: WO 99/65894.

Patent Literature 2: WO 2005/118565.

Patent Literature 3: WO 2011/094339.

Patent Literature Source 4: US Patent No. 6,469,182.

Patent Literature Source 5: US Patent Application Publication No. 2006/104984.

Patent Literature Source 6: US Patent No. 6,653,341.

Patent Literature 7: WO 2010/113984.

Patent Literature 8: WO 2017/188350.

Patent Literature Source 9: WO 2016/141209.

Non-patent literature sources

[0008]

Non-Patent Literature 1: Sharpe, A.H., Wherry, E.J., Ahmed R., and Freeman G.J., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunology (2007); 8: 239-245.

Non-patent literature 2: Dong H et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002 Aug; 8(8): 793-800.

Non-patent literature 3: Yang et al., PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci. 2008 Jun; 49(6 (2008): 49: 2518-2525.

Non-Patent Literature 4: Ghebeh et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia (2006) 8:190–198.

Non-patent literature 5: Hamanishi J et al., Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proceeding of the National Academy of Sciences (2007): 104: 3360-3365.

Non-patent literature 6: Thompson RH et al., Significance of B7-H1 overexpression in kidney cancer. Clinical genitourin Cancer (2006): 5: 206-211.

Non-patent literature 7: Nomi, T. Sho, M., Akahori, T., et al., Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clinical Cancer Research (2007) ;13: 2151–2157.

Non-patent literature 8: Ohigashi Y et al., Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand 2 expression in human esophageal cancer. Clin. Cancer Research (2005): 11: 2947-2953.

Non-patent literature 9: Inman et al., PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer (2007): 109: 1499-1505.

Non-patent literature 10: Shimauchi T et al., Augmented expression of programmed death-1 in both neoplasmatic and nonneoplastic CD4+ T-cells in adult T-cell Leukemia/ Lymphoma. Int. J. Cancer (2007): 121: 2585-2590.

Non-patent literature 11: Gao et al., Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clinical Cancer Research (2009) 15: 971–979.

Non-patent literature reference 12: Nakanishi J., Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. (2007) 56: 1173–1182.

Non-patent literature 13: Hino et al., Tumor cell expression of programmed cell death-1 is a prognostic factor for malignant melanoma. Cancer (2010): 116: 1757-1766.

Non-patent literature 14: Ghebeh H., Foxp3+ tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy. BMC Cancer. 2008 Feb 23; 8:57.

Non-patent literature 15: Ahmadzadeh M. et al., Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood (2009) 114: 1537-1544.

Non-patent literature 16: Thompson RH et al., PD-1 is expressed by tumor infiltrating cells and is associated with poor outcome for patients with renal carcinoma. Clinical Cancer Research (2007) 15: 1757-1761.

Brief description of the invention

Technical task

[0009] The present invention is aimed at obtaining a new pharmaceutical composition for treating a tumor.

Solution to the problem

[0010] The present inventors, through careful study, found that the combined administration of a liposomal composition containing eribulin or a pharmaceutically acceptable salt thereof and a PD-1 antagonist exhibits an unexpected antitumor effect, thereby completing the present invention.

[0011] Accordingly, the present invention is as follows.

[1] A pharmaceutical composition for treating a tumor comprising a liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with a PD-1 antagonist.

[2] A pharmaceutical composition for treating a tumor comprising a PD-1 antagonist, wherein the pharmaceutical composition is administered in combination with a liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof.

[3] The pharmaceutical composition according to [1] or [2] above, wherein the liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, continuously or at intervals.

[4-1] The pharmaceutical composition according to any one of [1] to [3] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[4-2] The pharmaceutical composition according to [4-1] above, wherein eribulin mesylate is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[4-3] The pharmaceutical composition according to [4-1] above, wherein eribulin mesylate is administered at a dose of 0.5-2 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[4-4] The pharmaceutical composition according to [4-1] above, wherein eribulin mesylate is administered at a dose of approximately 1.5 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[4-5] The pharmaceutical composition according to [4-1] above, wherein eribulin mesylate is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on day 1 of a 21-day cycle or is administered intravenously at a dose of 0.5-1.5 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on days 1 and 15 of a 28-day cycle.

[5] The pharmaceutical composition according to any one of [1] to [4-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody.

[6-1] The pharmaceutical composition according to [5] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[6-2] The pharmaceutical composition according to [5] above, wherein the antibody to PD-1 is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

[6-3] The pharmaceutical composition according to [5] above, wherein the anti-PD-1 antibody is nivolumab.

[6-4] The pharmaceutical composition according to [6-3] above, wherein nivolumab is administered at a dose of 3 mg/kg (body weight) every 2 weeks, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks.

[6-5] The pharmaceutical composition according to [5] above, wherein the anti-PD-1 antibody is pembrolizumab.

[6-6] The pharmaceutical composition according to [6-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks.

[6-7] The pharmaceutical composition according to [5] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the antibody to PD-1 is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle.

[6-8] The pharmaceutical composition according to [5] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the antibody to PD-1 is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[7-1] The pharmaceutical composition according to any one of [1] to [6-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma, or intrahepatic cholangiocarcinoma.

[7-2] The pharmaceutical composition according to any one of [1] to [6-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, or kidney cancer.

[7-3] The pharmaceutical composition according to any one of [1] to [6-8] above, wherein the tumor is breast cancer.

[7-4] A pharmaceutical composition according to any of [1] to [6-8] above for patients with advanced, inoperable or recurrent solid tumors without standard therapy or other effective therapy.

[7-5] The pharmaceutical composition according to any of [1] to [6-8] above for a patient with inoperable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and who, according to the physician's judgment, has progressed during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer, wherein the patient is a patient with gastric cancer who has been administered combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine-based drug as primary chemotherapy and chemotherapy comprising a taxane-based drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy that includes a platinum-based drug and a fluorinated pyrimidine drug (but does not include a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

[7-6] The pharmaceutical composition according to any of [1] to [6-8] above for a patient with intrahepatic cholangiocarcinoma who has been administered combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy for pretreatment; or for a patient with thymic carcinoma who has been administered combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy for pretreatment.

[8] A therapeutic agent for treating a tumor comprising a liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof, wherein the therapeutic agent is administered in combination with a PD-1 antagonist.

[9] A therapeutic agent for treating a tumor comprising a PD-1 antagonist, wherein the therapeutic agent is administered in combination with a liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof.

[10] The therapeutic agent according to [8] or [9] above, wherein the liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, continuously or at intervals.

[11-1] The therapeutic agent according to any one of [8] to [10] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[11-2] The therapeutic agent according to [11-1] above, wherein eribulin mesylate is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[11-3] The therapeutic agent according to [11-1] above, wherein eribulin mesylate is administered at a dose of 0.5-2 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[11-4] The therapeutic agent according to [11-1] above, wherein eribulin mesylate is administered at a dose of approximately 1.5 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[11-5] The therapeutic agent according to [11-1] above, wherein eribulin mesylate is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on day 1 of a 21-day cycle or is administered intravenously at a dose of 0.5-1.5 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on days 1 and 15 of a 28-day cycle.

[12] The therapeutic agent according to any one of [8] to [11-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody.

[13-1] The therapeutic agent according to [12] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[13-2] The therapeutic agent according to [12] above, wherein the antibody to PD-1 is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

[13-3] The therapeutic agent according to [12] above, wherein the anti-PD-1 antibody is nivolumab.

[13-4] Therapeutic agent as per [13-3] above, wherein nivolumab is administered at a dose of 3 mg/kg (body weight) every 2 weeks, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks.

[13-5] The therapeutic agent according to [12] above, wherein the anti-PD-1 antibody is pembrolizumab.

[13-6] Therapeutic agent as per [13-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks.

[13-7] The therapeutic agent according to [12] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle.

[13-8] The therapeutic agent according to [12] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[14-1] The therapeutic agent according to any one of [8] to [13-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma, or intrahepatic cholangiocarcinoma.

[14-2] The therapeutic agent according to any one of [8] to [13-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, or kidney cancer.

[14-3] The therapeutic agent according to any one of [8] to [13-8] above, wherein the tumor is breast cancer.

[14-4] A therapeutic agent according to any of [8] to [13-8] above for patients with advanced, unresectable, or recurrent solid tumors without standard therapy or other effective therapy.

[14-5] A therapeutic agent according to any of [8] to [13-8] above for a patient with inoperable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and who, in the opinion of a physician, has shown disease progression during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer, where the patient is a patient with gastric cancer who has received combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine drug as primary chemotherapy and chemotherapy comprising a taxane-based drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy that includes a platinum-based drug and a fluorinated pyrimidine drug (but does not include a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

[14-6] A therapeutic agent according to any of [8] to [13-8] above for a patient with intrahepatic cholangiocarcinoma who was administered combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy for prior treatment; or for a patient with thymic carcinoma who was administered combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy for prior treatment.

[15] A method for treating a tumor, which comprises administering to a patient in need thereof a liposomal composition containing eribulin or a pharmaceutically acceptable salt thereof and a PD-1 antagonist.

[16] The method according to [15] above, wherein the liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, continuously or at intervals.

[17-1] The method according to [15] or [16] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[17-2] The method according to [17-1] above, wherein eribulin mesylate is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[17-3] The method according to [17-1] above, wherein eribulin mesylate is administered at a dose of 0.5-2 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[17-4] The method according to [17-1] above, wherein eribulin mesylate is administered at a dose of approximately 1.5 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[17-5] The method according to [17-1] above, wherein eribulin mesylate is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on day 1 of a 21-day cycle or is administered intravenously at a dose of 0.5-1.5 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on days 1 and 15 of a 28-day cycle.

[18] The method according to any one of [15] to [17-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody.

[19-1] The method according to [18] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[19-2] The method according to [18] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

[19-3] The method according to [18] above, wherein the anti-PD-1 antibody is nivolumab.

[19-4] The method according to [19-3] above, wherein nivolumab is administered at a dose of 3 mg/kg (body weight) every 2 weeks, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks.

[19-5] The method according to [18] above, wherein the anti-PD-1 antibody is pembrolizumab.

[19-6] The method according to [19-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks.

[19-7] The method according to [18] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area), and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle.

[19-8] The method according to [18] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[20-1] The method according to any one of [15] to [19-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma, or intrahepatic cholangiocarcinoma.

[20-2] The method according to any one of [15] to [19-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, or kidney cancer.

[20-3] The method according to any one of [15] to [19-8] above, wherein the tumor is breast cancer.

[20-4] The method according to any of [15] to [19-8] above, comprising administration to a patient with advanced, inoperable or recurrent solid tumors without standard therapy or other effective therapy.

[20-5] The method according to any one of [15] to [19-8] above, comprising administering to a patient with inoperable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and who, in the opinion of a physician, has progressed during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer, wherein the patient is a patient with gastric cancer who has been administered combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine drug as primary chemotherapy and chemotherapy comprising a taxane-based drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy that includes a platinum-based drug and a fluorinated pyrimidine drug (but does not include a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

[20-6] The method according to any one of [15] to [19-8] above, comprising administering to a patient with intrahepatic cholangiocarcinoma who has been administered combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy for pretreatment; or to a patient with thymic carcinoma who has been administered combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy for pretreatment.

[21] Use of eribulin or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for the treatment of a tumor, wherein the pharmaceutical composition is administered in combination with a PD-1 antagonist.

[22] Use of a PD-1 antagonist for the preparation of a pharmaceutical composition for the treatment of a tumor, wherein the pharmaceutical composition is administered in combination with a liposomal composition containing eribulin or a pharmaceutically acceptable salt thereof.

[23] Use according to [21] or [22] above, wherein the liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, continuously or at intervals.

[24-1] The use according to any of [21] to [23] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[24-2] Administration as per [24-1] above, wherein eribulin mesylate is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[24-3] Administration as per [24-1] above, wherein eribulin mesylate is administered at a dose of 0.5-2 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[24-4] Administration as per [24-1] above, wherein eribulin mesylate is administered at a dose of approximately 1.5 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[24-5] Administration as per [24-1] above, wherein eribulin mesylate is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on day 1 of a 21-day cycle or administered intravenously at a dose of 0.5-1.5 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on days 1 and 15 of a 28-day cycle.

[25] The use according to any of [21] to [24-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody.

[26-1] The use according to [25] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[26-2] Use according to [25] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

[26-3] Use as per [25] above, wherein the anti-PD-1 antibody is nivolumab.

[26-4] Administration as per [26-3] above, where nivolumab is administered at a dose of 3 mg/kg (body weight) every 2 weeks, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks.

[26-5] Use as per [25] above, wherein the anti-PD-1 antibody is pembrolizumab.

[26-6] Use as per [26-5] above, where pembrolizumab is administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks.

[26-7] Use according to [25] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle.

[26-8] Use according to [25] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[27-1] Use according to any of [21] to [26-8] above, wherein the tumor is breast cancer, gastric cancer, oesophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma, or intrahepatic cholangiocarcinoma.

[27-2] Use according to any of [21] to [26-8] above, where the tumor is breast cancer, gastric cancer, oesophageal cancer, small cell lung cancer, colorectal cancer or kidney cancer.

[27-3] Use according to any of [21] to [26-8] above, where the tumor is breast cancer.

[27-4] Use according to any of [21] - [26-8] above for patients with advanced, unresectable or recurrent solid tumors without standard therapy or other effective therapy.

[27-5] Use according to any of [21] to [26-8] above for a patient with unresectable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and who, in the opinion of a physician, has disease progression during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer, where the patient is a patient with gastric cancer who has received combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine-based drug as primary chemotherapy and chemotherapy comprising a taxane-based drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy that includes a platinum-based drug and a fluorinated pyrimidine drug (but does not include a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

[27-6] Use according to any of [21] to [26-8] above for a patient with intrahepatic cholangiocarcinoma who was given combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy for upfront treatment; or for a patient with thymic carcinoma who was given combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy for upfront treatment.

[28] A liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof for use in the treatment of tumors, wherein the liposomal composition is administered in combination with a PD-1 antagonist.

[29] A PD-1 antagonist for use in the treatment of tumors, wherein the PD-1 antagonist is administered in combination with a liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof.

[30] A liposomal composition or a PD-1 antagonist for use according to [28] or [29] above, wherein the liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, continuously or at intervals.

[31-1] A liposomal composition or PD-1 antagonist for use according to any of [28] to [30] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[31-2] A liposomal composition or PD-1 antagonist for use according to [31-1] above, wherein eribulin mesylate is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[31-3] A liposomal composition or PD-1 antagonist for use according to [31-1] above, wherein eribulin mesylate is administered at a dose of 0.5-2 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[31-4] A liposomal composition or PD-1 antagonist for use according to [31-1] above, wherein eribulin mesylate is administered at a dose of approximately 1.5 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[31-5] A liposomal formulation or PD-1 antagonist for use according to [31-1] above, wherein eribulin mesylate is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on day 1 of a 21-day cycle or is administered intravenously at a dose of 0.5-1.5 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on days 1 and 15 of a 28-day cycle.

[32] A liposomal composition or PD-1 antagonist for use according to any of [28] to [31-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody.

[33-1] A liposomal composition or PD-1 antagonist for use according to [32] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[33-2] A liposomal composition or PD-1 antagonist for use according to [32] above, wherein the PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

[33-3] A liposomal composition or PD-1 antagonist for use according to [32] above, wherein the PD-1 antibody is nivolumab.

[33-4] A liposomal formulation or PD-1 antagonist for use according to [33-3] above, wherein nivolumab is administered at a dose of 3 mg/kg (body weight) every 2 weeks, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks.

[33-5] A liposomal composition or PD-1 antagonist for use according to [32] above, wherein the PD-1 antibody is pembrolizumab.

[33-6] A liposomal formulation or PD-1 antagonist for use according to [33-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks.

[33-7] A liposomal composition or PD-1 antagonist for use according to [32] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle.

[33-8] A liposomal composition or PD-1 antagonist for use according to [32] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[34-1] A liposomal composition or PD-1 antagonist for use according to [28] to [33-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma or intrahepatic cholangiocarcinoma.

[34-2] A liposomal composition or PD-1 antagonist for use according to [28] - [33-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer or renal cancer.

[34-3] A liposomal composition or PD-1 antagonist for use according to [28] - [33-8] above, wherein the tumor is breast cancer.

[34-4] A liposomal formulation or PD-1 antagonist for use according to any of [28] to [33-8] above for patients with advanced, unresectable or recurrent solid tumors without standard therapy or other effective therapy.

[34-5] A liposomal composition or a PD-1 antagonist for use according to any of [28] to [33-8] above for a patient with inoperable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and who, in the opinion of a physician, has progressed during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer, wherein the patient is a patient with gastric cancer who has received combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine drug as primary chemotherapy and chemotherapy comprising a taxane-based drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy that includes a platinum-based drug and a fluorinated pyrimidine drug (but does not include a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

[34-6] A liposomal composition or a PD-1 antagonist for use according to any of [28] to [33-8] above for a patient with intrahepatic cholangiocarcinoma who has been given combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy for upfront treatment; or for a patient with thymic carcinoma who has been given combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy for upfront treatment.

[35] A kit for treating a tumor, comprising a composition comprising a liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof, and a composition comprising a PD-1 antagonist.

[36] The kit according to [35] above, wherein the liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, continuously or at intervals.

[37-1] The kit according to [35] or [36] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[37-2] Assignment as per [37-1] above, wherein eribulin mesylate is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[37-3] Assignment as per [37-1] above, wherein eribulin mesylate is administered at a dose of 0.5-2 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[37-4] Assay as per [37-1] above wherein eribulin mesylate is administered at a dose of approximately 1.5 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[37-5] Assignment as per [37-1] above wherein eribulin mesylate is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on day 1 of a 21-day cycle or administered intravenously at a dose of 0.5-1.5 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on days 1 and 15 of a 28-day cycle.

[38] The kit according to any one of [35] to [37-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody.

[39-1] The kit according to [38] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[39-2] The kit according to [38] above, wherein the antibody to PD-1 is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

[39-3] The kit according to [38] above, wherein the anti-PD-1 antibody is nivolumab.

[39-4] Assignment as per [39-3] above, where nivolumab is administered at 3 mg/kg (body weight) every 2 weeks, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks.

[39-5] The kit according to [38] above, wherein the anti-PD-1 antibody is pembrolizumab.

[39-6] Assignment as per [39-5] above, where pembrolizumab is administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks.

[39-7] The kit according to [38] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle.

[39-8] The kit according to [38] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[40-1] A kit according to any of [35] to [39-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma, or intrahepatic cholangiocarcinoma.

[40-2] A set according to any of [35] to [39-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, or kidney cancer.

[40-3] A set according to any of [35] to [39-8] above, where the tumor is breast cancer.

[40-4] Recruitment according to any of [35] - [39-8] above for patients with advanced, unresectable or recurrent solid tumors without standard therapy or other effective therapy.

[40-5] An enrollment according to any of [35] to [39-8] above for a patient with inoperable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and who, in the opinion of a physician, has disease progression during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer, wherein the patient is a patient with gastric cancer who has received combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine drug as primary chemotherapy and chemotherapy comprising a taxane-based drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy that includes a platinum-based drug and a fluorinated pyrimidine drug (but does not include a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

[40-6] An enrollment according to any of [35] to [39-8] above for a patient with intrahepatic cholangiocarcinoma who was administered combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy for upfront treatment; or for a patient with thymic carcinoma who was administered combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy for upfront treatment.

[41] A pharmaceutical composition according to any of [1] to [7-6] above or a therapeutic agent according to any of [8] to [14-6] above, further comprising a pharmaceutically acceptable carrier.

[42] A therapeutic agent for treating a tumor, wherein a composition comprising a liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof and a composition comprising a PD-1 antagonist are administered simultaneously, separately, continuously or at intervals.

[43-1] A therapeutic agent for the treatment of a tumor according to [42] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[43-2] The therapeutic agent for the treatment of a tumor according to [43-1] above, wherein eribulin mesylate is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[43-3] A therapeutic agent for the treatment of a tumor according to [43-1] above, wherein eribulin mesylate is administered at a dose of 0.5-2 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[43-4] A therapeutic agent for the treatment of a tumor according to [43-1] above, wherein eribulin mesylate is administered at a dose of approximately 1.5 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[43-5] A therapeutic agent for the treatment of a tumor according to [43-1] above, wherein eribulin mesylate is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on day 1 of a 21-day cycle or is administered intravenously at a dose of 0.5-1.5 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on days 1 and 15 of a 28-day cycle.

[44] The therapeutic agent for treating a tumor according to any one of [42] to [43-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody.

[45-1] The therapeutic agent for the treatment of a tumor according to [44] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[45-2] A therapeutic agent for the treatment of a tumor according to [44] above, wherein the antibody to PD-1 is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

[45-3] A therapeutic agent for the treatment of a tumor according to [44] above, wherein the anti-PD-1 antibody is nivolumab.

[45-4] A therapeutic agent for the treatment of a tumor according to [45-3] above, wherein nivolumab is administered at a dose of 3 mg/kg (body weight) every 2 weeks, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks.

[45-5] A therapeutic agent for the treatment of a tumor according to [44] above, wherein the anti-PD-1 antibody is pembrolizumab.

[45-6] A therapeutic agent for the treatment of a tumor according to [45-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks.

[45-7] The therapeutic agent for the treatment of a tumor according to [44] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate, and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area), and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle.

[45-8] The therapeutic agent for the treatment of a tumor according to [44] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[46-1] A therapeutic agent for treating a tumor according to any one of [42] to [45-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma, or intrahepatic cholangiocarcinoma.

[46-2] A therapeutic agent for treating a tumor according to any one of [42] to [45-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, or kidney cancer.

[46-3] A therapeutic agent for treating a tumor according to any one of [42] to [45-8] above, wherein the tumor is breast cancer.

[46-4] A therapeutic agent for the treatment of a tumor according to any of [42] to [45-8] above for patients with advanced, unresectable, or recurrent solid tumors without standard therapy or other effective therapy.

[46-5] A therapeutic agent for the treatment of a tumor according to any of [42] to [45-8] above for a patient with inoperable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and who, in the opinion of a physician, has shown disease progression during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer, wherein the patient is a patient with gastric cancer who has been administered combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine-based drug as primary chemotherapy and chemotherapy comprising a taxane-based drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy that includes a platinum-based drug and a fluorinated pyrimidine drug (but does not include a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

[46-6] A therapeutic agent for the treatment of a tumor according to any of [42] to [45-8] above for a patient with intrahepatic cholangiocarcinoma who has been administered combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy for upfront treatment; or for a patient with thymic carcinoma who has been administered combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy for upfront treatment.

[47] A combination for the treatment of a tumor, comprising a liposomal composition containing eribulin or a pharmaceutically acceptable salt thereof and a PD-1 antagonist.

[48] The combination according to [47] above, wherein the liposomal composition comprising eribulin or a pharmaceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, continuously or at intervals.

[49-1] The combination according to [48] or [49] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate.

[49-2] Combination according to [49-1] above, wherein eribulin mesylate is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[49-3] Combination according to [49-1] above, wherein eribulin mesylate is administered at a dose of 0.5-2 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[49-4] The combination according to [49-1] above, wherein eribulin mesylate is administered at a dose of approximately 1.5 mg/ ^m2 (body surface area) once every 1 week, 2 weeks or 3 weeks.

[49-5] The combination according to [49-1] above, wherein eribulin mesylate is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on day 1 of a 21-day cycle or administered intravenously at a dose of 0.5-1.5 mg/ ^m2 (body surface area) or 0.5-3.0 mg/ ^m2 (body surface area) on days 1 and 15 of a 28-day cycle.

[50] The combination according to any of [47] to [49-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody.

[51-1] The combination according to [50] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[51-2] The combination according to [50] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

[51-3] The combination according to [50] above, wherein the anti-PD-1 antibody is nivolumab.

[51-4] Combination as per [51-3] above, where nivolumab is administered at a dose of 3 mg/kg (body weight) every 2 weeks, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks.

[51-5] The combination according to [50] above, wherein the anti-PD-1 antibody is pembrolizumab.

[51-6] Combination as per [51-5] above, where pembrolizumab is administered at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks.

[51-7] The combination according to [50] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle.

[51-8] The combination according to [50] above, wherein eribulin or a pharmaceutically acceptable salt thereof is eribulin mesylate and the anti-PD-1 antibody is nivolumab, wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[52-1] The combination according to any of [47] to [51-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma, or intrahepatic cholangiocarcinoma.

[52-2] The combination according to any of [47] to [51-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, or kidney cancer.

[52-3] A combination of any one of [47] to [51-8] above, wherein the tumor is breast cancer.

[52-4] Combination according to any of [47] - [51-8] above for patients with advanced, unresectable or recurrent solid tumors without standard therapy or other effective therapy.

[52-5] The combination according to any of [47] to [51-8] above for a patient with unresectable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and who, in the opinion of a physician, has shown disease progression during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer, wherein the patient is a patient with gastric cancer who has received combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine drug as primary chemotherapy and chemotherapy comprising a taxane-based drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy that includes a platinum-based drug and a fluorinated pyrimidine drug (but does not include a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

[52-6] A combination according to any of [47] to [51-8] above for a patient with intrahepatic cholangiocarcinoma who has received combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy in a previous treatment; or for a patient with thymic carcinoma who has received combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy in a previous treatment.

Beneficial effects of the present invention

[0012] Combined administration of a liposomal composition containing eribulin or a pharmaceutically acceptable salt thereof and a PD-1 antagonist exhibits an unexpected antitumor effect.

Brief description of graphic materials

[0013] Fig. 1 is a graph illustrating the effect of treatment using a combination of a liposomal formulation containing eribulin mesylate at a dose of 0.1 mg/kg and an antibody to PD-1 on tumor growth.

Fig. 2 is a graph illustrating the effect of treatment using a combination of a liposomal formulation containing eribulin mesylate at a dose of 0.1 mg/kg and an anti-PD-1 antibody against Tx5.

Fig. 3 is a graph illustrating the effect of treatment using a combination of a liposomal formulation containing eribulin mesylate at a dose of 0.3 mg/kg and an anti-PD-1 antibody on tumor growth.

Fig. 4 is a graph illustrating the effect of treatment using a combination of a liposomal formulation containing eribulin mesylate at a dose of 0.3 mg/kg and an anti-PD-1 antibody against Tx5.

Description of embodiments

[0014] Embodiments of the present invention will be described below. The following embodiments are illustrations intended to describe the present invention and are not intended to limit the present invention to only these embodiments. The present invention can be implemented in various variations as long as they do not deviate from its spirit.

[0015] The liposomal compositions in the present invention contain eribulin or a pharmaceutically acceptable salt thereof (hereinafter referred to as "eribulin etc.").

[0016] In the present invention, the "pharmaceutically acceptable salt" may be a salt of an inorganic acid or a salt of an organic acid, and is not particularly limited as long as it forms a salt with eribulin; examples of such a salt include hydrochloride, sulfate, citrate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, superphosphate, isonicotinate, acetate, lactate, salicylate, tartrate, pantothenate, ascorbate, succinate, maleate, fumarate, gluconate, saccharinate, formate, benzoate, glutamate, mesylate (methanesulfonate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. In one embodiment, the pharmaceutically acceptable salts are hydrochloride, sulfate, acetate, phosphate, citrate, and mesylate. In a specific embodiment, the pharmaceutically acceptable salt is mesylate.

[0017] The pharmaceutically acceptable salt of eribulin may be a salt of eribulin and aluminum, calcium, lithium, magnesium, sodium, zinc or diethanolamine.

[0018] In the present invention, examples of eribulin or the like include eribulin mesylate.

[0019] Eribulin or the like is a compound or a salt thereof described in Patent Literature 1 or U.S. Patent No. 6,214,865, and has a pharmacological activity including antitumor and antimitotic activities. Patent Literature 1 discloses that eribulin or the like as an antitumor agent has an antitumor activity against melanoma, fibrosarcoma, monocytic leukemia, colon cancer, ovarian cancer, breast cancer, osteosarcoma, prostate cancer, lung cancer, and fibroblasts transformed by ras oncogene. Eribulin or the like is produced by the method described in Patent Literatures 1 to 3.

[0020] In the present invention, "liposome" means a closed microvesicle having an internal phase surrounded by a lipid bilayer. Liposomes include small unilamellar liposomes (SUV: small unilamellar vesicles), large unilamellar liposomes (LUV: large unilamellar vesicles), larger unilamellar liposomes (GUV: giant unilamellar vesicles), multilamellar liposomes having a plurality of concentric membranes (MLV: multilamellar vesicles), liposomes having a plurality of non-concentric irregular membranes (MVV: multivesicular vesicles), and the like.

[0021] In the present invention, the "internal phase of a liposome" means an aqueous portion surrounded by a liposomal lipid bilayer, and is used as a synonym for the "internal aqueous phase" and the "internal aqueous phase of a liposome." The "external phase of a liposome" means a portion that is not surrounded by a liposomal bilayer (that is, a portion other than the internal phase and the lipid bilayer) when the liposome is dispersed in a liquid.

[0022] In the present invention, "liposomal composition" means a composition containing a liposome and further containing eribulin etc. in the internal phase of the liposome. In the present invention, the liposomal composition includes solid and liquid compositions.

[0023] In the present invention, "liposomal dispersion" means a composition comprising liposomes in which eribulin and the like are not yet encapsulated in the internal phase of the liposome.

[0024] In the present invention, "liposomal preparation liquid" means a composition containing a liposome in which the outer phase of the liposome has not yet been adjusted to encapsulate eribulin and the like into the inner phase of the liposome.

[0025] [Lipid]

In one embodiment, the liposome preferably comprises a phospholipid and/or phospholipid derivative as a membrane component.

[0026] Examples of the phospholipid and/or phospholipid derivative include phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, cardiolipin, sphingomyelin, ceramide phosphorylethanolamine, ceramide phosphorylglycerol, ceramide phosphorylglycerol phosphate, 1,2-dimyristoyl-1,2-deoxyphosphatidylcholine, plasmalogen, and phosphatidate.

[0027] The phospholipid and/or phospholipid derivative may be one or a combination of two or more of them.

[0028] The fatty acid residues in the phospholipid and/or phospholipid derivative are not particularly limited; and examples thereof include saturated or unsaturated fatty acid residues having 12 to 20 carbon atoms, and specific examples thereof include acyl groups derived from fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid and linoleic acid. As the phospholipid and/or phospholipid derivative, a phospholipid derived from a natural product such as egg yolk lecithin and soybean lecithin, and partially hydrogenated egg yolk lecithin, (fully) hydrogenated egg yolk lecithin, partially hydrogenated soybean lecithin and (fully) hydrogenated soybean lecithin in which the unsaturated fatty acid residues are partially or completely hydrogenated, and the like can be used.

[0029] The mixing amount (molar fraction) of the phospholipid and/or phospholipid derivative used in the preparation of the liposome is not particularly limited and in one embodiment is 10-80%, and in a certain embodiment is 30-60%, based on the total amount of the components of the liposomal membrane.

[0030] In the present invention, the liposome may contain, as a membrane component, a kind of sterol such as cholesterol and cholestanol, and a kind of fatty acid having a saturated or unsaturated acyl group containing 8 to 22 carbon atoms as a membrane stabilizing agent, and an antioxidant such as α-tocopherol, in addition to a phospholipid and/or a phospholipid derivative.

[0031] The mixing amount (molar fraction) of the sterol used in the preparation of the liposome is not particularly limited and in one embodiment is 1-60%, 10-50%, or 30-50% based on the total amount of the components of the liposomal membrane.

[0032] The mixing amount (molar fraction) of the fatty acid is not particularly limited and in one embodiment is 0-30%, 0-20%, or 0-10% based on the total amount of the components of the liposomal membrane.

[0033] The mixing amount (molar fraction) of the antioxidant is not particularly limited, as long as an amount providing an antioxidant effect is added, and in one embodiment, the amount is 0-15%, 0-10%, or 0-5% based on the total amount of the components of the liposomal membrane.

[0034] In the present invention, the liposome may contain a functional lipid or a modified lipid as a membrane component.

[0035] Examples of the functional lipid include a lipid derivative that provides blood retention, a lipid derivative that is sensitive to a temperature change, and a lipid derivative that is sensitive to pH.

[0036] Examples of the modified lipid include a PEGylated lipid, a glycolipid, an antibody-modified lipid, and a peptide-modified lipid.

[0037] Examples of blood retention lipid derivatives include polyethylene glycol derivatives (such as condensation products of methoxypolyethylene glycol) such as condensation products of phosphoethanolamine and methoxypolyethylene glycol: N-{carbonyl methoxypolyethylene glycol-2000}-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, N-{carbonyl methoxypolyethylene glycol-5000}-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, N-{carbonyl methoxypolyethylene glycol-750}-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, N-{carbonyl methoxypolyethylene glycol-2000}-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (MPEG2000-distearoylphosphatidylethanolamine) and N-{carbonyl methoxypolyethylene glycol-5000}-1,2-distearoyl-sn-glycero-3-phosphoethanolamine.

[0038] The mixing amount (molar fraction) of the blood retention lipid derivative used in the preparation of the liposome is not particularly limited and in one embodiment is 0-50%, 0-30%, or 0-20% based on the total amount of the components of the liposomal membrane.

[0039] Examples of the temperature-sensitive lipid derivative include dipalmitoylphosphatidylcholine. By incorporating the temperature-sensitive lipid derivative into liposomes, it becomes possible to destroy the liposomes at a certain temperature, change the surface properties of the liposome, etc. Further, by combining this with heating a target site such as a tumor, it becomes possible to destroy the liposomes at the target site and release an active compound at the target site, etc.

[0040] Examples of the pH-sensitive lipid derivative include dioleoylphosphatidylethanolamine. By incorporating the pH-sensitive lipid derivative into a liposome, it becomes possible to promote the fusion of the membranes of the liposome and the endosome when the liposome is taken up by the cell through endocytosis, and to improve the delivery of the active compound into the cytoplasm, etc.

[0041] Examples of a glycolipid, an antibody-modified lipid, and a peptide-modified lipid include lipids linked to a sugar, an antibody, or a peptide having affinity for a target cell or target tissue. Using a modified lipid allows liposomes to be actively delivered to a target cell or target tissue.

[0042] The composition of the membrane components for liposomes having a practically acceptable level of membrane permeability can be selected by a person skilled in the art depending on the active compound, target tissue, etc. (see Hiroshi Kikuchi et al. "Liposome I -How to prepare and assay-" Cell technology (1983) 2 (9): pp. 1136-1149 and references cited therein, etc.). The liposomal composition can be used not only for targeting a target tissue such as solid cancer, but also for delivering an active compound to the site of localization of hematological malignancy, etc.

[0043] In one embodiment, the components of the liposomal membrane include a phospholipid, cholesterol, and a condensation product of methoxypolyethyleneglycol.

[0044] [Liposomal composition]

In the liposomal composition of the present invention, eribulin and the like are encapsulated in a liposome having a lipid membrane. In the liposomal composition, eribulin and the like can be distributed in a lipid bilayer.

[0045] The liposome composition according to the present invention can be obtained by the method described in Patent Literature 7.

[0046] If the liposomal composition is solid, it can be dissolved or suspended in a specific solvent described below to obtain a liquid liposomal composition. If the liposomal composition is in the form of a frozen solid, it can be thawed by leaving it at room temperature, etc., to obtain a liquid liposomal composition.

[0047] The liposome composition according to the present invention is not limited as long as it contains (1) eribulin and the like. The liposome composition according to the present invention may further contain (2) at least one ammonium salt and (3) at least one acid, salt, base and/or amino acid.

[0048] Examples of the at least one ammonium salt in (2) include ammonium chloride, ammonium borate, ammonium sulfate, ammonium formate, ammonium acetate, ammonium citrate, ammonium tartrate, ammonium succinate and ammonium phosphate, and one embodiment is ammonium sulfate, ammonium citrate and ammonium tartrate.

[0049] Regarding the acid, salt, base and/or amino acid in (3), examples of the acid include ascorbic acid, benzoic acid, succinic acid, citric acid, glutamic acid, phosphoric acid, acetic acid, propionic acid, tartaric acid, carbonic acid, lactic acid, boric acid, maleic acid, fumaric acid, malic acid, adipic acid, hydrochloric acid and sulfuric acid; examples of the salt include sodium salts of the above acids, potassium salts of the above acids and ammonium salts of the above acids; examples of the base include trihydroxymethylaminomethane, ammonia, sodium hydroxide and potassium hydroxide; and examples of the amino acid include arginine, histidine and glycine.

[0050] In one embodiment of the liposomal composition according to the present invention, the acid, salt, base and/or amino acid (3) in the internal phase of the liposome are hydrochloric acid, acetic acid, lactic acid, tartaric acid, succinic acid, citric acid and phosphoric acid, sodium salts of the above acids, and sodium hydroxide and ammonia, and in a particular embodiment, the acid, salt, base and/or amino acid in (3) are acetic acid, lactic acid, tartaric acid, citric acid and phosphoric acid, sodium salts of the above acids, and sodium hydroxide and ammonia.

[0051] An example of each component of the liposomal composition is provided in Table 1. In another specific example, 96 mg/mL sucrose can be used instead of 9 mg/mL sodium chloride as an osmotic agent (outer phase of the liposome).

[0052] [Table 1]

Component Concentration Purpose of inclusion Eribulina mesylate 0.2 mg/ml Medicine HSPC ^[1] 7.1 mg/ml Component of the lipid membrane Cholesterol 2.3 mg/ml Component of the lipid membrane MPEG2000-DSPE ^[2] 2.7 mg/ml Component of the lipid membrane Ammonium sulfate 100 mM Component of the internal phase of a liposome Citric acid monohydrate 30 mm Component of the internal phase of a liposome Sodium chloride 9 mg/ml Component of the outer phase of a liposome L-histidine 1.6 mg/ml Component of the outer phase of a liposome Sodium hydroxide/hydrochloric acid How much will it take? pH regulator

[1] Hydrogenated soy phosphatidylcholine.

[2] N-{carbonylmethoxypolyethyleneglycol-2000}-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (MPEG2000-distearoylphosphatidylethanolamine)

[Table 2]

Component Concentration Purpose of inclusion Eribulina mesylate 0.20 mg/ml Medicine HSPC ^[1] 7.10 mg/ml Component of the lipid membrane Cholesterol 2.32 mg/ml Component of the lipid membrane MPEG2000-DSPE ^[2] 2.69 mg/ml Component of the lipid membrane Ammonium sulfate 100 mM Component of the internal phase of a liposome Citric acid monohydrate 30 mm Component of the internal phase of a liposome Sucrose 96 mg/ml Component of the outer phase of a liposome L-histidine 1.55 mg/ml Component of the outer phase of a liposome Sodium hydroxide/hydrochloric acid How much will it take? pH regulator

[1] Hydrogenated soy phosphatidylcholine.

[2] N-{carbonylmethoxypolyethyleneglycol-2000}-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (MPEG2000-distearoylphosphatidylethanolamine)

[0053] The liposome composition of the present invention can be administered by injection (intravenous injection, intraarterial injection, local injection), orally, intranasally, transdermally, transpulmonarily, ophthalmically and the like, and examples of the administration route include injection such as intravenous injection, subcutaneous injection, intradermal injection, intraarterial injection, and local injection into a target cell and a target organ. Examples of the dosage form of the liposome composition for oral administration include tablets, powders, granules, syrups, capsules and oral solutions. Examples of the dosage form of the liposome composition for parenteral administration include injection, drip infusion, ophthalmic solution, ointment, suppository, suspension, poultice, lotion, aerosol and patch, and one embodiment thereof is injection or drip infusion. The liposomal composition according to the present invention can be formulated by a method such as described in the 17th edition of the Japanese Pharmacopoeia (JP), the United States Pharmacopoeia (USP), or the European Pharmacopoeia (EP).

[0054] If the liposomal composition is a liquid formulation, it can be used as is. When using the liposomal composition as a drug, for example, a physician or a patient can add a solvent to a vial in which the solid formulation is encapsulated to prepare at the time of use. If the solid formulation is obtained by freezing the liquid liposomal composition, it can be stored in a frozen state and thawed by leaving it at room temperature, or quickly thawed by heating to a liquid state at the time of use for use as a liquid formulation.

[0055] The dose for single administration of the liposomal composition varies significantly depending on the type of the target disease or the age, sex, body weight, severity of symptoms, etc. of the patient. The liposomal composition is administered, for example, at a dose of 0.1-10 mg/ ^m2 (body surface area) in terms of eribulin mesylate per day for an adult. In one embodiment, the liposomal composition is administered at a dose of 0.5-3 mg/ ^m2 (body surface area) in terms of eribulin mesylate once every 1 week, 2 weeks, or 3 weeks. In a specific embodiment, the liposomal composition is more preferably administered at a dose of 0.5-2 mg/ ^m2 (body surface area) in terms of eribulin mesylate once every 1 week, 2 weeks, or 3 weeks.

[0056] In another embodiment, the liposomal composition is preferably administered at a dose of about 1.5 mg/ ^m2 (body surface area) based on eribulin mesylate once every 1 week, 2 weeks, or 3 weeks.

[0057] More specifically, the liposomal composition is administered intravenously at a dose of 0.5-1.4 mg/ ^m2 or 0.5-3.0 mg/ ^m2 on day 1 of a 21-day cycle, or is administered intravenously at a dose of 0.5-1.5 mg/ ^m2 or 0.5-3.0 mg/ ^m2 on day 1 and day 15 of a 28-day cycle, based on eribulin mesylate.

[0058] Eribulin and the like contained in a liposomal composition can be administered once a day or in several divided daily doses.

[0059] The liposomal composition may be a liposomal composition containing, for example, 0.01-300 mg/ml of eribulin and the like in the internal phase of the liposome.

[0060] The liposomal composition is formulated, for example, as an injection solution containing 0.20 mg/ml eribulin mesylate (0.18 mg/ml eribulin) incorporated into liposomes having a lipid membrane consisting of HSPC, cholesterol and MPEG2000-DSPE. Such an injection solution may contain sucrose or sodium chloride as an isotonic agent, ammonium sulfate, citric acid and L-histidine, as well as sodium hydroxide and hydrochloric acid to adjust the pH. The injection solution is administered to the patient immediately or is diluted with physiological saline solution to a concentration of 0.0035 mg/ml or higher and below 0.2 mg/ml before administration to the patient.

[0061] The PD-1 antagonist of the present invention may include any compound or biological molecule that blocks the binding of PD-L1 expressed in cancer cells to PD-1 expressed in immune cells (T cells, B cells, or natural killer T (NKT) cells), or further blocks the binding of PD-L2 expressed in cancer cells to PD-1 expressed in immune cells. The PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and in one embodiment, blocks the binding of both human PD-L1 and PD-L2 to human PD-1. The amino acid sequence of human PD-1 can be found in NCBI Locus No.: NP_005009. The amino acid sequence of human PD-L1 and PD-L2 can be found in NCBI Locus under No: NP_054862 and NP_079515, respectively.

[0062] The PD-1 antagonist used in the present invention may include a monoclonal antibody (mAb) or an antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1, or specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may comprise a human constant region. The human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in one embodiment, the human constant region is an IgG1 or IgG4 constant region. The antigen-binding fragment may be selected from the group consisting of Fab, Fab'-SH, F(ab') ₂ , scFv, and an Fv fragment.

[0063] An example of useful PD-1 antagonists is an anti-PD-1 antibody, which in one embodiment is an anti-human PD-1 antibody, and in a specific embodiment is an anti-human PD-1 monoclonal antibody (anti-human PD-1 mAb). Examples of mAbs that bind human PD-1 are described in U.S. Patent No. 7,488,802, U.S. Patent No. 7,521,051, U.S. Patent No. 8,008,449, U.S. Patent No. 8,354,509, U.S. Patent No. 8,168,757, WO 2004/004771, WO 2004/072286, WO 2004/056875, and U.S. Patent Application Publication No. 2011/0271358. Monoclonal antibodies to human PD-1 that can be used as a PD-1 antagonist according to the present invention include nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab. The PD-1 antibodies that can be used as the PD-1 antagonist according to the present invention further include spartalizumab, tislelizumab, dostarlimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, zimberelimab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[0064] Another example of useful PD-1 antagonists is an anti-PD-L1 antibody, which in one embodiment is an anti-human PD-L1 antibody, and in a specific embodiment, an anti-human PD-L1 monoclonal antibody (anti-human PD-L1 mAb). Anti-PD-L1 antibodies that can be used as a PD-1 antagonist according to the present invention include atezolizumab, avelumab, durvalumab, manelimab, pacmilimab, envafolimab, cosibelimab, BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, and KL-A16.

[0065] The PD-1 antagonist of the present invention can be administered by injection (intravenous injection, intra-arterial injection, local injection), orally, nasally, transdermally, transpulmonarily, ophthalmically, etc., and examples of the administration route include injection such as intravenous injection, subcutaneous injection, intradermal injection, intra-arterial injection, and local injection into target cells and a target organ. Examples of the dosage form of the PD-1 antagonist for oral administration include tablet, powder, granule, syrup, capsule, and oral solution. Examples of the dosage form of the PD-1 antagonist for parenteral administration include injection, drip infusion, ophthalmic solution, ointment, suppository, suspension, poultice, lotion, aerosol, and patch, and one embodiment thereof is injection or drip infusion. The PD-1 antagonist of the present invention can be formulated by a method such as described in the 17th edition of the Japanese Pharmacopoeia (JP), the United States Pharmacopoeia (USP), or the European Pharmacopoeia (EP).

[0066] If the PD-1 antagonist of the present invention is an anti-PD-1 antibody, the anti-PD-1 antibody may be provided as a liquid preparation or prepared by rehydrating its lyophilized powder with sterile water for injection before use.

[0067] When an anti-human PD-1 mAb is administered to a patient alone as a PD-1 antagonist, the dose thereof varies significantly depending on the type of target disease or the age, gender, body weight, severity of symptoms, etc. of the patient. The anti-human PD-1 mAb is administered, for example, at a dose of 1, 2, 3, 5, or 10 mg/kg at intervals of about 14 days (± 2 days), about 21 days (± 2 days), or about 30 days (± 2 days).

[0068] If pembrolizumab is administered as a PD-1 antagonist, then it is administered intravenously, for example, at a dose selected from the group consisting of 1 mg/kg every 2 weeks, 2 mg/kg every 2 weeks, 3 mg/kg every 2 weeks, 5 mg/kg every 2 weeks, 10 mg every 2 weeks, 1 mg/kg every 3 weeks, 2 mg/kg every 3 weeks, 3 mg/kg every 3 weeks, 5 mg/kg every 3 weeks, and 10 mg/kg every 3 weeks. In another embodiment, pembrolizumab is administered intravenously at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks. Pembrolizumab is administered as a liquid formulation containing, for example, 25 mg/mL pembrolizumab, 7% (w/v) sucrose, and 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer, pH 5.5, with the drug at the selected dose administered intravenously by drip over approximately 30 minutes.

[0069] If nivolumab is administered as a PD-1 antagonist, then it is administered intravenously, for example, at a dose selected from the group consisting of 1 mg/kg every 2 weeks, 2 mg/kg every 2 weeks, 3 mg/kg every 2 weeks, 4 mg/kg every 2 weeks, 5 mg/kg every 2 weeks, 6 mg/kg every 2 weeks, 1 mg/kg every 3 weeks, 2 mg/kg every 3 weeks, 3 mg/kg every 3 weeks, 4 mg/kg every 3 weeks, 5 mg/kg every 3 weeks, 6 mg/kg every 3 weeks, 8 mg/kg every 3 weeks, and 10 mg/kg every 3 weeks. In another embodiment, nivolumab is administered intravenously at a dose of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks. For example, nivolumab is administered intravenously by drip over about 30 minutes or longer as a liquid formulation that further contains D-mannitol, sodium citrate hydrate, sodium chloride, diethylenetriaminepentaacetic acid, polysorbate 80, and a pH adjusting agent.

[0070] If cemiplimab is administered as a PD-1 antagonist, it is administered intravenously, for example at a dose of 350 mg every 3 weeks.

[0071] The doses of the liposomal composition and the PD-1 antagonist in the combined administration of the present invention can generally be set at a lower dose than the doses when they are administered separately, respectively. Specific doses, administration routes, administration frequency, administration cycles, etc. are appropriately determined in consideration of the kind of the target disease or the age, sex, body weight, severity of symptoms, etc. of the patient.

[0072] The methods of administering the liposomal composition and the PD-1 antagonist in the present invention are not particularly limited, as long as the liposomal composition and the PD-1 antagonist are administered in combination when administered. For example, the liposomal composition and the PD-1 antagonist are administered to a patient simultaneously, separately, continuously, or at certain time intervals. As used herein, "simultaneously" means that each component is administered at the same time, or strictly simultaneously, or via the same route of administration. It also means that each component is administered without a significant time interval between them to cause an additive effect, preferably a synergistic effect. "Separately" means that each component is administered at different dosing intervals or frequencies, or via different routes of administration. "Continuously" means that each component is administered via the same or different routes of administration in any order over a certain period of time. "At intervals of time" means that each component is administered by one or different routes of administration, and each component is administered at intervals of time. If the PD-1 antagonist is administered in period 1 of the liposomal composition administration cycle or in a period in which the cycle is repeated, both are considered to be administered in combination.

[0073] The method of combination is not particularly limited, so a person skilled in the art can combine the liposomal composition and the PD-1 antagonist by various methods.

[0074] In the case of a combination of a liposomal composition containing eribulin mesylate and nivolumab, for example, eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 360 mg on day 1 of a 21-day cycle, or eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle.

[0075] The tumor to be treated according to the present invention is, for example, breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, kidney cancer, thymus carcinoma, intrahepatic cholangiocarcinoma, and the like.

[0076] Patients to be treated according to the present invention are, for example, a patient whose disease has progressed before, during or after previous chemotherapy. Examples of chemotherapy include the use of a platinum-based drug, a fluorinated pyrimidine-based drug, a taxane-based drug and a combination thereof.

[0077] A patient to be treated according to the present invention is, for example, a patient with advanced, unresectable or recurrent solid tumors without standard therapy or other effective therapy (patients receiving nivolumab monotherapy as standard therapy are eligible for participation in the study). In another embodiment, the patient is a patient with inoperable gastric cancer, esophageal cancer or small cell lung cancer that has been definitively diagnosed and whose disease has progressed according to the physician's judgment during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for his or her advanced or recurrent cancer, wherein the patient is also a patient with gastric cancer who has received combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine drug as primary chemotherapy and chemotherapy comprising a taxane drug as secondary chemotherapy; is a patient with esophageal cancer who has received combination chemotherapy comprising a platinum-based drug and a fluorinated pyrimidine drug (but not comprising a taxane drug) as primary chemotherapy; or is a patient with small cell lung cancer who has received combination chemotherapy that includes a platinum-based drug as primary chemotherapy. More specifically, the patient is a patient with intrahepatic cholangiocarcinoma who has received combination therapy with gemcitabine and cisplatin as primary therapy and combination therapy with S-1 and resminostat as secondary therapy for upfront treatment; or a patient with thymic carcinoma who has received combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, and gemcitabine as tertiary therapy for upfront treatment.

EXAMPLES

[0078] Liposomal compositions containing eribulin mesylate were prepared with the components shown in Table 1 or Table 2 according to the following methods and use variants in the following examples.

[0079] A method for producing a liposomal composition as shown in Table 1

<Preparation of aqueous solution for the internal phase of liposome>

Ammonium sulfate and citric acid monohydrate were dissolved and diluted with pure water to obtain a 200 mM ammonium sulfate/60 mM citric acid aqueous solution. The 200 mM ammonium sulfate/60 mM citric acid aqueous solution was adjusted to pH 5.5 with aqueous ammonium solution and then diluted with pure water to obtain a 100 mM ammonium sulfate/30 mM citric acid aqueous solution.

[0080] <Obtaining liposomal preparatory fluid>

Hydrogenated soybean phosphatidylcholine, cholesterol and MPEG2000-distearoylphosphatidylethanolamine were weighed according to a weight ratio of 71:23:27, respectively. They were dissolved in chloroform, respectively, and these solutions were mixed. Then, chloroform was evaporated under reduced pressure in a rotary evaporator to obtain a lipid film. The obtained aqueous solution for the liposome internal phase heated to about 80°C was added to the obtained lipid film, and the resulting mixture was stirred to obtain a liposome preparatory liquid. Adjustment to a desired size was performed using an extruder (an apparatus manufactured by Lipex Biomembranes Inc.) heated to about 80°C to obtain a liposome preparatory liquid with liposomes of a desired size.

[0081] <Preparation of liposomal dispersion>

By eluting the obtained liposome preparative liquid through a Sephadex G-50 column with a 0.9% sodium chloride/10 mM histidine aqueous solution (pH=7.6), the outer phase of the liposome was replaced with a 0.9% sodium chloride/10 mM histidine aqueous solution. After replacing the outer phase of the liposome, the liquid was centrifuged at 400,000 x g for 30 minutes. After centrifugation, re-dispersion was performed and the volume of the liquid was adjusted with a 0.9% sodium chloride/10 mM histidine aqueous solution to obtain a liposome dispersion.

[0082] <Preparation of eribulin mesylate solution>

Eribulin mesylate was dissolved in 0.9% sodium chloride/10 mM histidine aqueous solution to obtain eribulin mesylate solution.

[0083] <Preparation of liposomal composition>

The liposomal dispersion and eribulin mesylate solution were mixed in a glass container and incubated in a water bath at 60°C for 3 minutes to obtain a liposomal composition with an internal phase of the liposome into which eribulin mesylate was introduced. An aqueous solution of 0.9% sodium chloride/10 mM histidine was added to the liposomal composition, and sterilization was performed using a polyvinylidene fluoride (PVDF) filter with a pore size of 0.22 μm to obtain a liposomal composition based on eribulin mesylate.

[0084] Method 1 for producing a liposomal composition as shown in Table 2

<Preparation of aqueous solution for the internal phase of liposome>

Ammonium sulfate and citric acid monohydrate were dissolved in pure water. The pH of the solution was adjusted to 7.5 with 1 mol/L sodium hydroxide aqueous solution and then diluted with pure water to obtain a 100 mM ammonium sulfate/30 mM citric acid aqueous solution.

[0085] <Obtaining liposomal preparatory fluid>

The obtained aqueous solution for the internal phase of the liposome heated to about 80°C was added to a lipid mixture containing hydrogenated soybean phosphatidylcholine, cholesterol and MPEG2000-distearoylphosphatidylethanolamine at a weight ratio of 710:232:269, and the resulting mixture was stirred to obtain a liposomal preparatory liquid. Adjustment to a desired size was performed using an extruder (an apparatus manufactured by Lipex Biomembranes Inc.) heated to about 80°C to obtain a liposomal preparatory liquid with liposomes of a desired size.

[0086] <Preparation of liposomal dispersion>

The outer phase of the liposome was replaced with an aqueous solution of 96 mg/mL sucrose/10 mM histidine by tangential flow filtration to obtain a liposomal dispersion.

[0087] <Preparation of eribulin mesylate solution>

Eribulin mesylate was dissolved in an aqueous solution of 96 mg/mL sucrose/10 mM histidine to obtain an eribulin mesylate solution.

[0088] <Preparation of liposomal composition>

The liposomal dispersion and the eribulin mesylate solution were mixed, and the resulting solution was adjusted to about pH 10 using hydrochloric acid or sodium hydroxide, and incubated in a water bath at 60°C to incorporate eribulin mesylate into the internal phase of the liposome. The solution was adjusted to pH 7.5 using hydrochloric acid or sodium hydroxide, and an aqueous solution of 9.6% sucrose/10 mM histidine was added thereto to obtain 0.2 mg/mL eribulin mesylate for preparing the eribulin mesylate-based liposomal composition.

[0089] Method 2 for producing the liposomal composition presented in Table 2

[0090] <Preparation of aqueous solution for the internal phase of liposome>

105.68 g of ammonium sulfate and 50.40 g of citric acid monohydrate were dissolved in water for injection, and the resulting solution was adjusted to pH 7.5 using hydrochloric acid or sodium hydroxide to obtain an aqueous solution for the internal phase of the liposome.

[0091] <Obtaining liposomal preparatory fluid>

106.5 g of hydrogenated soybean phosphatidylcholine, 34.8 g of cholesterol and 40.35 g of MPEG2000-distearoylphosphatidylethanolamine were dissolved in ethanol, and the solution was mixed with an aqueous solution of the liposome internal phase heated to about 70°C. Water for injection was added to the resulting mixture to make a total weight of 8.26 kg. To obtain particles of about 80 nm, size adjustment was performed using an extruder (manufactured by Lipex Biomembranes Inc.) heated to about 70°C to obtain a liposome preparatory liquid.

[0092] <Preparation of liposomal dispersion>

A Pellicon 2 ultrafiltration cassette with a Biomax module (300 kDa) was used to replace the outer phase of the liposomal preparative fluid with an aqueous solution of 9.6% sucrose/10 mM histidine (pH=7.5) to obtain a liposomal dispersion.

[0093] <Preparation of eribulin mesylate solution>

Eribulin mesylate was dissolved in 9.6% sucrose/10 mM histidine aqueous solution to obtain eribulin mesylate solution.

[0094] <Preparation of liposomal composition>

The liposomal dispersion and the eribulin mesylate solution were mixed, and the resulting solution was adjusted to about pH 10 using hydrochloric acid or sodium hydroxide, and incubated in a water bath at 60°C to incorporate eribulin mesylate into the internal phase of the liposome. The solution was adjusted to pH 7.5 using hydrochloric acid or sodium hydroxide, and an aqueous solution of 9.6% sucrose/10 mM histidine was added thereto to obtain 0.2 mg/mL eribulin mesylate for preparing the eribulin mesylate-based liposomal composition.

[0095] [Example 1] Antitumor effect of combined administration of low-dose eribulin mesylate (0.1 mg/kg) or low-dose eribulin mesylate-based liposomal formulation (0.1 mg/kg) and mouse anti-PD-1 antibody in P-glycoprotein knockout 4T1 mouse breast cancer transplantation model (Pgp-KO 4T1)

[0096] An AP-glycoprotein knockout cell line derived from 4T1 mouse breast cancer cells (purchased from ATCC) was cultured using RPMI1640 medium (SIGMA) containing 10% FBS (fetal bovine serum), 1 mM sodium pyruvate and antibiotics in an incubator at 37°C with 5% carbon dioxide. The cells were harvested using trypsin-EDTA when they reached approximately 80% confluence. The above-described medium (RPMI1640) was added to the collected cells, from which a suspension of 1.0 x ¹⁰⁷ cells/mL was prepared, and 0.1 mL of the suspension was subcutaneously transplanted into the right flank of 6 mice (BALB/cAJcl, CLEA Japan, Inc.) for each group of the control group, the eribulin mesylate-based liposomal formulation alone group, the eribulin mesylate-based liposomal formulation alone group, the anti-mouse PD-1 antibody (Bio X cells) antibody alone group, the eribulin mesylate and anti-mouse PD-1 antibody combined administration group, and the eribulin mesylate and anti-mouse PD-1 antibody combined administration group. Starting from day 5 after transplantation, eribulin mesylate (0.1 mg/kg, once a week, twice in total, tail vein injection), eribulin mesylate liposomal formulation (0.1 mg/kg, once a week, twice in total, tail vein injection), and anti-mouse PD-1 antibody (200 μg/mouse, once a week, twice in total, tail vein injection) were administered alone or in combination to the alone administration group or the anti-mouse PD-1 antibody combination administration group, respectively. The control group did not receive the drug. The maximum tolerated dose of eribulin mesylate liposomal formulation for mice is 2.5 mg/kg, and the dose in this experiment was set very low at 0.1 mg/kg, which is 1/25 of the maximum tolerated dose.

[0097] A P-glycoprotein knockout cell line (Pgp-KO 4T1 cells) was generated as follows. Single guide RNA (sgRNA) sequences were designed based on the information of two types of P-glycoprotein genes (mouse, Abcb1a and Abcb1b) to be knocked out, and plasmid DNAs for expression in animal cells (U6 promoter) into which sgRNAs for each gene were inserted were generated (pRGEN_Mouse-Abcb1a_U6_SG_1 and pRGEN_Mouse-Abcb1b_U6_SG_1). In addition, plasmid DNA expressing Cas9 (CMV promoter) was generated (pRGEN_CMV_Cas9). The resulting plasmid DNAs were purified with NucleoBond Xtra Midi EF and used for transfection. First, pRGEN_CMV_Cas9 and pRGEN_Mouse-Abcb1a_U6_SG_1 were used to edit the first gene (Abcb1a). 4T1 mouse breast cancer cells (purchased from ATCC) were cultured in RPMI1640 medium (SIGMA) containing 10% FBS (fetal bovine serum) and antibiotics in an incubator at 37°C with 5% carbon dioxide. After culture, the cells were dissociated and collected using trypsin-EDTA, and the above plasmid DNAs were transfected by conventional methods using electroporation (NeppaGene) under multiple mixing ratios. The transfection cells were seeded in a 6-well microplate, cultured for 3 days, and then a portion of the cells were collected to determine whether genome editing was possible. Using the genomic DNA extracted from the collected cells by a conventional method, the digestion of the genomic DNA was confirmed by a T7 endonuclease I (T7E1) assay. Cloning was performed from cells with a mixing ratio such that a larger amount of genomic DNA was digested in the T7E1 assay. The cloned cells were subsequently cultured for expansion and cryopreserved, while the gene sequence was determined by sequence analysis to confirm the mutation of the target gene. One cloned cell line was selected from the plurality of cloned cells in which the mutation was confirmed, and gene editing (using pRGEN_CMV_Cas9 and pRGEN_Mouse-Abcb1b_U6_SG_1) for the second gene (Abcb1b) was performed in the same manner as described above. Finally, a 4T1 cell line (Pgp-KO 4T1 cells) with knockout of two types of P-glycoprotein genes (mouse, Abcb1a and Abcb1b) was obtained.

[0098] On day 3, day 7, day 10, day 13, day 16, day 20, day 23, day 27, day 30, and day 34 after administration, where the administration start date is day 0, the largest diameter and short axis size of the tumor grown in each mouse were measured with a Digimatic caliper (manufactured by Mitutoyo Corporation).

[0099] The tumor volume was calculated according to the following formula.

Tumor volume ( ^mm3 ) = greatest diameter (mm) x short axis dimension ² ( ^mm2 )/2.

[0100] The results of tumor volume measurement in each group are shown as the mean and standard deviation (SD) in Fig. 1. As a statistical analysis, repeated measures analysis of variance followed by Dunnett's multiple comparison was performed compared with the control group for tumor volumes on all measurement days in all groups (*: p < 0.05, ***: p < 0.001). Statistical comparison between two groups, the eribulin mesylate and anti-mouse PD-1 antibody combined administration group and the eribulin mesylate and anti-mouse PD-1 antibody liposomal formulation combined administration group, was performed by repeated measures analysis of variance (#: p < 0.05).

[0101] As a result, the combined administration of the liposomal formulation based on eribulin mesylate at a low dose (0.1 mg/kg) and the mouse anti-PD-1 antibody demonstrated a pronounced antitumor effect compared with the control group in the Pgp-KO 4T1 tumor transplantation model. * and *** in Fig. 1 indicate that the combined administration of the liposomal formulation based on eribulin mesylate and the mouse anti-PD-1 antibody statistically significantly inhibited tumor growth compared with the control group. # indicates that the combined administration of the liposomal formulation based on eribulin mesylate and the mouse anti-PD-1 antibody statistically significantly inhibited tumor growth compared with the combined administration of eribulin mesylate and the mouse anti-PD-1 antibody. Conversely, no antitumor effect was observed with the administration of eribulin mesylate (0.1 mg/kg) alone and the administration of a liposomal formulation based on eribulin mesylate (0.1 mg/kg) alone, which were administered at low doses, and with the administration of an antibody to mouse PD-1 alone and even with the combined administration of eribulin mesylate (0.1 mg/kg) and an antibody to mouse PD-1.

[0102] The result of the comparison of the groups for the time until the tumor volume exceeded 5 times the volume relative to the start date of administration (Tx5) in the experiment is shown in Fig. 2, and the median Tx5 in each group and their corresponding percentages (%) relative to the control group are shown in Table 3. For statistical analysis, the log rank test was used compared with the control group to calculate the p-value with Bonferroni correction (*: p < 0.05).

[0103] As a result, the combined administration of eribulin mesylate-based liposomal formulation (0.1 mg/kg) and mouse anti-PD-1 antibody showed an effect of increasing (243%) the tumor growth suppression time (Tx5) in the Pgp-KO 4T1 tumor transplantation model. In contrast, no effect of increasing the time was observed when eribulin mesylate (0.1 mg/kg) was administered alone, when eribulin mesylate-based liposomal formulation (0.1 mg/kg) was administered alone, which were administered at low doses, when anti-mouse anti-PD-1 antibody was administered alone, and even when eribulin mesylate and anti-mouse anti-PD-1 antibody were administered in combination. * in Table 3 indicates that the combined administration of a liposomal composition based on eribulin mesylate (0.1 mg/kg) and an antibody to mouse PD-1 statistically significantly increased the time of tumor growth suppression compared to the control group.

[0104] [Table 3]

The effect of combined administration of liposomal composition based on eribulin mesylate (0.1 mg/kg) and mouse anti-PD-1 antibody on Tx5

Group Tx5 (days) Percentage share relative to control Control 10.5 100% Eribulin mesylate separately 12.0 114% Liposomal composition based on eribulin mesylate separately 11.5 110% Antibody to mouse PD-1 alone 14.5 138% Eribulina mesylate
+ mouse anti-PD-1 antibody, combined administration 14.5 138% Liposomal composition based on eribulin mesylate
+ mouse anti-PD-1 antibody, combined administration 25.5* 243%

[0105] [Example 2] Antitumor effect of combined administration of low-dose eribulin mesylate (0.3 mg/kg) or low-dose eribulin mesylate-based liposomal formulation (0.3 mg/kg) and mouse anti-PD-1 antibody in transplantation model with Pgp-KO 4T1 cell line

Pgp-KO 4T1 cells were cultured in RPMI1640 medium containing 10% FBS, 1 mM sodium pyruvate and antibiotics in an incubator at 37°C with 5% carbon dioxide. Cells were harvested using trypsin-EDTA when they reached approximately 80% confluency. The above medium was added to the harvested cells to obtain a suspension of 1.0 x 10 ⁷ cells/mL. 0.1 ml of the cell suspension was subcutaneously injected into the right flank of 6 mice (BALB/cAJcl, CLEA Japan, Inc.) per group each of the control group, the eribulin mesylate liposomal formulation alone administered group, the anti-mouse PD-1 antibody (Bio X cells) alone administered group, and the eribulin mesylate liposomal formulation and anti-mouse PD-1 antibody combined administered group. Starting from day 4 after transplantation, the eribulin mesylate liposomal formulation (0.3 mg/kg, once a week, twice in total, tail vein injection) and anti-mouse PD-1 antibody (200 μg/mouse, once a week, twice in total, tail vein injection) were administered alone or in combination to the alone administered groups or the combined administered groups, respectively. The control group did not receive the drug.

[0106] On day 3, day 7, day 9, day 13, day 17, day 20, day 24, day 27, day 31, day 34, day 38, day 41, day 44, day 48, and day 51 after administration, where the administration start date is day 0, the largest diameter and short axis size of the tumor grown in each mouse were measured with a Digimatic caliper (manufactured by Mitutoyo Corporation).

[0107] The tumor volume was calculated according to the following formula.

Tumor volume ( ^mm3 ) = greatest diameter (mm) x short axis dimension ² ( ^mm2 )/2.

[0108] The mean and standard deviation (SD) of the tumor volume measurement results in each group are shown in Fig. 3, and the tumor disappearance rates in mice are shown in Table 4. For statistical analysis, statistical comparison was performed between two groups: the eribulin mesylate-based liposomal formulation alone administered group or the anti-mouse PD-1 antibody alone administered group and the eribulin mesylate-based liposomal formulation and anti-mouse PD-1 antibody combined administered group, using repeated measures analysis of variance (?, #: p < 0.05).

[0109] As a result, in the Pgp-KO 4T1 tumor transplantation model, the combined administration of the eribulin mesylate-based liposomal formulation at a low dose (0.3 mg/kg) and the mouse anti-PD-1 antibody showed a superior antitumor effect compared with the eribulin mesylate-based liposomal formulation alone or the mouse anti-PD-1 antibody alone. In Fig. 3, (?) indicates that the combined administration of the eribulin mesylate-based liposomal formulation and the mouse anti-PD-1 antibody statistically significantly inhibited tumor growth compared with the administration of the eribulin mesylate-based liposomal formulation alone, and (#) indicates that the combined administration of the eribulin mesylate-based liposomal formulation and the mouse anti-PD-1 antibody statistically significantly inhibited tumor growth compared with the administration of the mouse anti-PD-1 antibody alone. Tumor disappearance was observed in the group receiving the combined administration of liposomal formulation based on eribulin mesylate (0.3 mg/kg) and antibody to mouse PD-1 at a higher frequency than in the other groups.

[0110] [Table 4]

Tumor clearance rates in mice in each group

Group Frequency (%) of tumor disappearance in mice Control 0/6 (0%) Liposomal composition based on eribulin mesylate separately 1/6 (17%) Antibody to mouse PD-1 alone 0/6 (0%) Liposomal composition based on eribulin mesylate
+ mouse anti-PD-1 antibody, combined administration 4/6 (67%)

[0111] The comparison result of the groups for the time until the tumor volume exceeded 5 times the volume at the start of administration (Tx5) in the experiment is shown in Fig. 4, and the median Tx5 in each group and their percentages (%) relative to the control group are shown in Table 5. For statistical analysis, the log rank test was used between the two groups: the combined administration group of the liposomal formulation based on eribulin mesylate and the anti-mouse PD-1 antibody and the separate administration group of the anti-mouse PD-1 antibody (#: p < 0.05).

[0112] As a result, in the Pgp-KO 4T1 tumor transplantation model, the combined administration of eribulin mesylate-based liposomal formulation (0.3 mg/kg) and mouse anti-PD-1 antibody demonstrated the effect of increasing the tumor growth suppression time (Tx5) compared with the control group, the group receiving the eribulin mesylate-based liposomal formulation alone, and the group receiving the mouse anti-PD-1 antibody alone. # in Table 5 indicates that the combined administration of eribulin mesylate-based liposomal formulation and mouse anti-PD-1 antibody statistically significantly increased the tumor growth suppression time compared with the individual administration of mouse anti-PD-1 antibody.

[0113] [Table 5]

The effect of combined administration of liposomal composition based on eribulin mesylate (0.3 mg/kg) and mouse anti-PD-1 antibody on Tx5

Group Tx5 (days) Relationship with control Control 11.5 100% Liposomal composition based on eribulin mesylate separately 33.0 287% Antibody to mouse PD-1 alone 18.0 157% Liposomal composition based on eribulin mesylate
+ mouse anti-PD-1 antibody, combined administration > 51.0 ? > 443%

[0114] [Example 3] Antitumor effect of combined administration of low-dose eribulin mesylate (0.3 mg/kg) or low-dose eribulin mesylate-based liposomal formulation (0.3 mg/kg) and mouse anti-PD-1 antibody in P-glycoprotein-knockout CT-26 mouse cell line (Pgp-KO CT-26) colorectal cancer transplantation model

[0115] A P-glycoprotein knockout cell line (Pgp-KO CT-26) was generated from CT-26 mouse colorectal cancer cells (purchased from ATCC) according to the same materials and procedures used to generate Pgp-KO 4T1 cells. Pgp-KO CT-26 cells were cultured using RPMI1640 medium (FUJIFILM Wako Pure Chemical Corporation) containing 10% FBS (fetal bovine serum) and antibiotics in an incubator at 37°C with 5% carbon dioxide. The cells were harvested using trypsin-EDTA when they reached approximately 80% confluency. HBSS medium was added to the harvested cells, which were suspended at 2.0 x 10⁷cells/ml, and 0.1 ml of the suspension was subcutaneously transplanted into the right flank of 7 mice (BALB/cAJcl, CLEA Japan, Inc.) for each group from the control group, the eribulin mesylate administration group alone, the eribulin mesylate-based liposomal formulation administration group alone, the mouse anti-PD-1 antibody administration group alone (Bio X cells), the eribulin mesylate and mouse anti-PD-1 antibody combined administration group, and the combination administration of eribulin mesylate-based liposomal formulation and anti-mouse PD-1 antibody. Starting from day 15 after transplantation, eribulin mesylate (0.3 mg/kg, once a week, three times in total, tail vein injection), eribulin mesylate-based liposomal formulation (0.3 mg/kg, once a week, three times in total, tail vein injection), and anti-mouse PD-1 antibody (200 μg/mouse, once a week, three times in total, tail vein injection) were administered alone or in combination to the individual administration groups or the combination administration groups with anti-mouse PD-1 antibody, respectively. The control group did not receive the drug.

[0116] Given that the administration start date was day 0, the largest diameter and short axis size of the tumor grown in each mouse were measured over time until day 18 using a Digimatic caliper (manufactured by Mitutoyo Corporation).

[0117] The tumor volume was calculated according to the following formula.

Tumor volume ( ^mm3 ) = greatest diameter (mm) x short axis dimension ² ( ^mm2 )/2.

[0118] The results of tumor volume measurements in each group are presented as mean and standard deviation (SD) in Table 6. As a statistical analysis, repeated measures analysis of variance followed by Dunnett's multiple comparison was performed compared with the control group for tumor volumes in all groups (*: p < 0.05,).

[0119] As a result, the combined administration of a low-dose (0.3 mg/kg) eribulin mesylate-based liposomal formulation and mouse anti-PD-1 antibody demonstrated a significant antitumor effect compared with the control group in the Pgp-KO CT-26 tumor transplantation model. * in Table 6 indicates that the combined administration of a low-dose (0.3 mg/kg) eribulin mesylate-based liposomal formulation and mouse anti-PD-1 antibody statistically significantly inhibited tumor growth compared with the control group. In contrast, the absence of an antitumor effect at low doses with separate administration of eribulin mesylate (0.3 mg/kg), separate administration of a liposomal composition based on eribulin mesylate (0.3 mg/kg), separate administration of an antibody to mouse PD-1, and even with the combined administration of eribulin mesylate (0.3 mg/kg) and an antibody to mouse PD-1 was observed with a significant difference compared to the control group.

[0120] [Table 6]

Effect of Combination Treatment with Liposomal Formulation of Eribulin Mesylate (0.3 mg/kg) and Anti-Mouse PD-1 Antibody on Tumor Growth in Pgp-KO CT-26 Tumor Transplant Model

Group Tumor volume Control 1851 ± 517 ( ^mm3 ) Eribulin mesylate separately 1139 ± 733 ( ^mm3 ) Liposomal composition based on eribulin mesylate separately 1012 ± 575 ( ^mm3 ) Antibody to mouse PD-1 alone 1378 ± 632 ( ^mm3 ) Eribulina mesylate
+ mouse anti-PD-1 antibody, combined administration 1170 ± 772 ( ^mm3 ) Liposomal composition based on eribulin mesylate
+ mouse anti-PD-1 antibody, combined administration 770 ± 593 (mm ³ )*

[0121] [Example 4] Antitumor effect of combined administration of a liposomal formulation based on eribulin mesylate at a low dose (0.3 mg/kg) and an antibody to mouse PD-1 in a transplant model of mouse kidney cancer with the RAG cell line

[0122] RAG cells (purchased from ATCC) used in the transplantation model were preconditioned in mice (BALB/cAnNCrlCrlj, Charles River Laboratories, Japan). RAG cells were suspended in HBSS (Wako Pure Chemical Industries, Ltd.) at a concentration of 2× ¹⁰⁸ cells/mL. To this suspension, an equal volume of Matrigel ^™ matrix (Nippon Becton Dickinson Co., Ltd.) was added and mixed well. The mixture was implanted into the subcutaneous region of the right flank of each mouse in an amount of 0.1 mL. On day 38 after transplantation, the resulting tumor was removed and cut into small pieces, reagents of the Tumor Dissociation Kit, Mouse (Miltenyi) were added to them, and mixed using Gentle MACS (Miltenyi). After passing through a 70 μm cell strainer, the cells were collected by centrifugation and cultured in EMEM medium (Wako Pure Chemical Industries, Ltd.) containing 10% bovine serum in an incubator at 37°C with 5% carbon dioxide and cryopreserved.

The cells obtained by the above procedure were cultured using EMEM medium containing 10% FBS and antibiotics. The cells were harvested using trypsin-EDTA when they reached approximately 80% confluency. HBSS was added to the harvested cells to obtain a suspension of 2.5 x ¹⁰⁷ cells/mL. 0.1 mL of the cell suspension was transplanted subcutaneously into the right flank of 10 mice (BALB/cAnNCrlCrlj, Charles River Laboratories, Japan) for each group of control group, eribulin mesylate-based liposomal formulation alone group, anti-mouse PD-1 antibody (Bio X cells) alone group, and combined eribulin mesylate-based liposomal formulation and anti-mouse PD-1 antibody administration group. Starting from day 6 after transplantation, liposomal formulation of eribulin mesylate (0.3 mg/kg, once a week, total three times, tail vein injection) and mouse anti-PD-1 antibody (200 μg/mouse, once every three days, total ten times, intraperitoneal administration) were administered alone or in combination to the single administration group or combination administration group, respectively. The control group did not receive the drug.

[0123] On day 3, day 7, day 10, day 14, day 17, day 21, day 24, day 28, day 31, day 35, day 38, and day 42 after administration, where the administration start date is day 0, the largest diameter and short axis size of the tumor grown in each mouse were measured with a Digimatic caliper (manufactured by Mitutoyo Corporation).

[0124] The tumor volume was calculated according to the following formula.

Tumor volume ( ^mm3 ) = greatest diameter (mm) x short axis dimension ² ( ^mm2 )/2.

[0125] Table 7 shows the rates of tumor reduction of 50% or more in mice at best in each group as the response rate, and Table 8 shows the rates of tumor disappearance in mice. For statistical analysis, a comparison was made between the eribulin mesylate-based liposomal formulation alone administered group, the anti-mouse PD-1 antibody alone administered group, or the eribulin mesylate-based liposomal formulation and anti-mouse PD-1 antibody combined administered group and the control group using a two-sided Fisher's exact test (#: p < 0.05).

[0126] As a result, in the RAG tumor transplantation model, the combined administration of the eribulin mesylate-based liposomal formulation at a low dose (0.3 mg/kg) and the mouse anti-PD-1 antibody showed high response rates compared with the eribulin mesylate-based liposomal formulation alone or the mouse anti-PD-1 antibody alone. In Table 7, (*) indicates that the combined administration of the eribulin mesylate-based liposomal formulation and the mouse anti-PD-1 antibody yielded a statistically significant response. On the other hand, no significant response was observed with the eribulin mesylate-based liposomal formulation (0.3 mg/kg) alone or with the mouse anti-PD-1 antibody alone. Tumor disappearance was observed in the group receiving the combined administration of liposomal formulation based on eribulin mesylate (0.3 mg/kg) and antibody to mouse PD-1 at a higher frequency than in the other groups.

[0127] [Table 7]

Response rate in each group

Group Number of mice showing response/number of mice in each group
(response rate, %) Control 0/10 (0%) Liposomal composition based on eribulin mesylate separately 4/10 (40%) Antibody to mouse PD-1 alone 2/10 (20%) Liposomal composition based on eribulin mesylate
+ mouse anti-PD-1 antibody, combined administration 5/10 (50%)

[0128] [Table 8]

Tumor clearance rates in mice in each group

Group Frequency (%) of tumor disappearance in mice Control 0/10 (0%) Liposomal composition based on eribulin mesylate separately 2/10 (20%) Antibody to mouse PD-1 alone 1/10 (10%) Liposomal composition based on eribulin mesylate
+ mouse anti-PD-1 antibody, combined administration 4/10 (40%)

[0129] Example 5

An open-label, phase 1b/2 study of a combination of eribulin mesylate-based liposomal formulation and nivolumab in patients with solid tumors

[0130] This is a multicenter, single-arm, open-label study. The Phase 1b portion of the study is designed to enroll patients with solid tumors without standard therapy or other effective therapy, and the Phase 2 portion is designed to enroll patients with esophageal cancer that has progressed during or after primary chemotherapy (combination chemotherapy containing a platinum-based agent and a fluorinated pyrimidine agent), patients with small cell lung cancer that has progressed during or after primary chemotherapy (combination chemotherapy containing a platinum-based agent), or patients with gastric cancer that has progressed during or after secondary chemotherapy (combination chemotherapy containing a platinum-based agent and a fluorinated pyrimidine agent as primary chemotherapy and chemotherapy containing a taxane as secondary chemotherapy).

[0131] The study consists of three periods: a pre-administration period, an administration period, and a follow-up period (Phase 2 portion only). The pre-administration period includes screening to verify eligibility and baseline to verify disease status and is 28 days in duration. During the administration period, subjects received the eribulin mesylate-based liposomal formulation and nivolumab. Tumor assessments were performed every 6 weeks from the start of administration. The follow-up period (Phase 2 portion only) begins after discontinuation of the eribulin mesylate-based liposomal formulation and nivolumab to examine the survival and post-treatment status of subjects.

[0132] In the Phase 1b portion, two routes of administration were studied: Regimen 1 and Regimen 2. In Regimen 1, the eribulin mesylate liposomal formulation and nivolumab were administered intravenously on Day 1 of a 21-day cycle at a dose of 360 mg nivolumab and a dose of 1.7 or 2.1 mg/ ^m2 of the eribulin mesylate liposomal formulation (as the mesylate). In Regimen 2, the eribulin mesylate liposomal formulation and nivolumab were administered intravenously on Day 1 and Day 15 of a 28-day cycle at a dose of 240 mg nivolumab and a dose of 1.1 or 1.4 mg/ ^m2 of the eribulin mesylate liposomal formulation (as the mesylate).

[0133] The Phase 2 portion used the recommended dosage determined in the Phase 1b portion.

[0134] The primary objective of the study was to evaluate the safety and tolerability of the combination of eribulin mesylate-based liposomal formulation and nivolumab to determine the recommended dose for phase 2 (Phase 1b portion) and to evaluate the objective response rate in each cancer at the recommended dose (Phase 2 portion). The secondary objective of the study was to evaluate the safety, pharmacokinetics, and progression-free survival of the combination of eribulin mesylate-based liposomal formulation and nivolumab.

[0135] Patients who met all of the following criteria were eligible to participate in the study.

Inclusion Criteria

(1) For the portion representing phase 1b only:

patients with advanced, unresectable, or recurrent solid tumors without standard therapy or other effective therapy (patients receiving nivolumab monotherapy as standard therapy are eligible for inclusion in the study).

(2) For the portion representing Phase 2 only:

a patient with inoperable gastric cancer, esophageal cancer, or small cell lung cancer who has been definitively diagnosed and whose disease is judged by the physician to be progressing during or after primary chemotherapy (or secondary chemotherapy for gastric cancer), and who has not received other systemic chemotherapy for advanced or recurrent cancer.

(3) For the portion representing phase 2 only:

patients who received the following chemotherapy as pre-chemotherapy.

Gastric cancer: combination chemotherapy containing a platinum-based drug and a fluorinated pyrimidine-based drug as primary chemotherapy and chemotherapy containing a taxane-based drug as secondary chemotherapy.

Esophageal cancer: Combination chemotherapy containing a platinum-based drug and a fluorinated pyrimidine-based drug (but not including a taxane-based drug) as primary chemotherapy.

Small cell lung cancer: combination chemotherapy that includes a platinum-based drug as primary chemotherapy.

(4) Patients with tumor lesions from which biopsies can be obtained and who consent to tumor biopsy before and after administration of the investigational medicinal product (if biopsy before administration is not possible for safety reasons, provision of stored tumor samples is permitted).

(5) Patients expected to survive 12 weeks or longer.

(6) Patients with ECOG-PS 0-1.

(7) Japanese patients aged 20 years or older at the time of consent.

(8) Patients whose adverse events (except grade 2 hair loss and peripheral neuropathy) caused by prior anticancer therapy recovered to grade 0-1 (kidney/bone marrow/liver/pancreas function must recover to meet inclusion criteria).

(9) Patients who completed the following period from completion of pre-treatment to C1D1 (day 1 of cycle 1):

a) Non-cytotoxic anticancer drug: 4 weeks (or 5 half-lives, whichever is shorter) or for a longer period.

b) Cytotoxic anticancer drug and radiotherapy: 3 weeks or for a longer period.

c) Treatment with an anticancer drug or antibody drug: 4 weeks or longer.

d) Investigational medicinal product or investigational medical device: 4 weeks or longer.

e) Blood transfusion, platelet transfusion or G-CSF preparations: 2 weeks or for a longer period.

f) Live or attenuated vaccine: 4 weeks or for a longer period.

(10) Patients with acceptable renal function: serum creatinine ≤ 1.5 x upper limit of normal (ULN) (in case of > 1.5 x ULN, patients with creatinine clearance according to the Cockcroft-Gault method ≥ 40 ml/min are eligible for participation in the study).

(11) Patients with acceptable bone marrow function:

a) neutrophil count ≥ 2000/ ^mm3 ,

b) platelet count ≥ 100,000/mm ³ ,

c) hemoglobin ≥ 8.5 g/dl.

(12) Patients with acceptable liver function:

a) international normalized ratio (INR) as anticoagulant capacity ≤ 1.5,

c) total bilirubin ≤ 1.5 x ULN (for patients with Gilbert's syndrome ≤ 3.0 x ULN),

c) alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (for patients with liver damage ≤ 5 x ULN).

(13) Patients with acceptable pancreatic function: amylase and lipase ≤ 1.5 x ULN (for patients with pancreatic disease ≤ 3 x ULN).

(14) For the phase 2 portion only: patients with measurable lesions in RECIST 1.1 (if lesions treated with radiotherapy or local therapy are considered measurable lesions, then lesions must be classified as worsening).

(15) Patients who can provide consent regarding documents and comply with the clinical trial protocol.

[0136] Patients meeting any of the following criteria will be excluded from the study.

Exclusion criteria

(1) Patients with any of the following heart diseases:

heart failure class II or higher according to the New York Heart Association (NYHA) classification;

unstable coronary artery disease (myocardial infarction within 6 months before C1D1, angina requiring nitrovasodilators at least twice a week);

QTcF > 480 ms, prolonged QT interval.

(2) Patients with a history of hypersensitivity reactions to liposomal preparations.

(3) Patients who have undergone major surgery within 21 days of C1D1.

(4) Patients with a history of eribulin or nivolumab use.

(5) Patients who experienced grade 3 or higher immune-related adverse events or discontinued treatment with anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-CD137 antibodies, anti-CTLA-4 antibodies, or other antibodies and drugs that target T cell costimulation or immune checkpoints, or cancer vaccines.

(6) Patients with intolerance to the investigational medicinal product or any of its excipients or antibody-based products.

(7) Patients with known positive status for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS).

(8) Patients with active hepatitis B or C (positive hepatitis B surface antigen [HBs] test, negative HBs antigen test and positive HBs antibody test, or positive HBc antibody test and positive HBV DNA test, or positive HCV RNA test)

(9) Patients with active infections who required systemic treatment for 14 days for C1D1.

(10) Patients with membranous carcinomatosis.

(11) Patients with metastasis or tumor invasion to the brain or subdural space. Patients who completed local treatment and discontinued corticosteroids within 4 weeks before C1D1 were excluded. Signs (e.g., radiographic examination) and symptoms must be stable within 4 weeks of C1D1.

(12) Patients with pulmonary lymphangitis and respiratory failure who require active treatment (including oxygen inhalation).

(13) Patients with active or known autoimmune diseases or suspected autoimmune diseases. Except:

patients with vitiligo vulgaris, type I diabetes, recovered from childhood asthma or atopy.

Patients with suspected autoimmune thyroid disorders who still have normal thyroid function or who can maintain normal thyroid function with hormone replacement therapy alone in case of residual hypothyroidism.

(14) Patients with clinically or visually diagnosed interstitial lung disease or pulmonary fibrosis or patients with a history of these diseases (patients with radiation pneumonitis with confirmed stable fibrosis and no risk of relapse are eligible for inclusion in the study).

(15) Patients with a history of organ transplantation who required administration of immunosuppressive drugs.

(16) Patients requiring systemic corticosteroids (equivalent to more than 10 mg/day prednisolone) or other immunosuppressive drugs for 14 days for C1D1. Patients taking inhaled or topical corticosteroids (if less absorbed into the body) may be included in the study provided they do not have active autoimmune disease.

(17) For the phase 2 portion only: Patients with active malignancies existing within 24 months of C1D1 (primary disease, completely cured non-invasive melanoma, basal cell carcinoma of the skin/squamous cell carcinoma, non-invasive cervical cancer/bladder cancer, and early stage gastric cancer/colorectal cancer are excluded).

(18) Patients with a clinically significant disease/condition (e.g., cardiac, respiratory, gastrointestinal, renal disease) that, in the judgment of the investigator or co-investigator, impacts the safety of the subject or the evaluation of the study.

(19) For female patients who are lactating or pregnant at screening or at baseline (patients with a positive human chorionic gonadotropin [hCG] or beta-subunit of human chorionic gonadotropin [β-hCG] test result). If the screening result is negative but within 72 hours of C1D1, the test should be repeated.

(20) In fertile men and women of childbearing potential, patients who do not agree to use clinically appropriate contraception ^(NOTE) during the study and for up to 5 months (7 months for men) after administration of the study drug.

Note: Dual contraception using two of the following methods: vasectomy, tubal ligation, use of a condom*, contraceptive sponge**, contraceptive foam**, contraceptive gel**, contraceptive diaphragm*, or contraceptive ring*, or use of an oral contraceptive* for 28 days or more before starting administration of this investigational medicinal product (regardless of whether the medicinal products have been approved or licensed in Japan or not) [*: yes, **: no]).

[0137] It was decided to continue administration of the eribulin mesylate and nivolumab-based liposomal formulation until disease progression, occurrence of intolerable side effects, subject's request for discontinuation, withdrawal of consent, or termination of the study by the sponsor.

[0138] Interim results of the part representing phase 1b

Case 1

A case of intrahepatic cholangiocarcinoma (scheme 2, the dose of liposomal formulation based on eribulin mesylate is 1.1 mg/ ^m2 )

A patient who received combination therapy with gemcitabine and cisplatin as primary therapy, combination therapy with S-1 and resminostat as secondary therapy, and study drug (details not given) as tertiary therapy for pretreatment was administered 1.1 mg/ ^m2 of liposomal formulation of eribulin mesylate and 240 mg of nivolumab once every two weeks according to schedule 2. After administration at week 6/12/18/24/30/36, the sum of target lesion diameters decreased by 10.3%, 14.7%, 23.5%, 40.8%, 46.2%, and 51.4%, respectively, compared with baseline, and this was considered a partial response.

[0139] Case 2

A case of thymic carcinoma (scheme 1, the dose of liposomal formulation based on eribulin mesylate is 1.7 mg/ ^m2 )

A patient who received combination therapy with carboplatin and paclitaxel as primary therapy, S-1 as secondary therapy, gemcitabine as tertiary therapy, and study drug (combination of unidentified drug and anti-PD-L1 antibody) as quaternary therapy for pretreatment was administered 1.7 mg/ ^{m2 of} eribulin mesylate-based liposomal formulation and 360 mg of nivolumab once every three weeks according to schedule 1. After administration at week 6/12/18, the sum of target lesion diameters decreased by 17.8%, 100%, and 100%, respectively, compared with baseline, and this was considered a partial response.

Claims (8)

1. A method for treating a tumor comprising administering nivolumab and a liposomal composition containing eribulin mesylate to a patient in need thereof, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma or intrahepatic cholangiocarcinoma and wherein eribulin mesylate is administered intravenously at a dose of 1.7-2.1 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 360 mg per day of 1 cycle lasting 21 days. 2. A method for treating a tumor comprising administering nivolumab and a liposomal composition containing eribulin mesylate to a patient in need thereof, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic carcinoma or intrahepatic cholangiocarcinoma and wherein eribulin mesylate is administered intravenously at a dose of 1.1-1.4 mg/ ^m2 (body surface area) and nivolumab is administered intravenously at a dose of 240 mg on days 1 and 15 of a 28-day cycle. 3. The method according to claim 1 or 2, wherein nivolumab and the liposomal composition containing eribulin mesylate are administered simultaneously, separately, continuously or with a time interval. 4. The method according to claim 1 or 2, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, or kidney cancer. 5. The method according to claim 1 or 2, wherein the tumor is breast cancer. 6. The method according to claim 1 or 2, wherein the tumor is gastric cancer. 7. The method according to claim 1 or 2, wherein the tumor is esophageal cancer. 8. The method according to claim 1 or 2, wherein the tumor is small cell lung cancer.