Pharmaceutical composition for treating tumors

Abstract

In the present invention, the combined administration of a liposome composition containing eribulin or a pharmaceutically acceptable salt thereof and a PD-1 antagonist exhibits an unexpected anti-tumor effect.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for treating tumors. [Background technology]

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

[0003] Patent Document 1 discloses eribulin or a pharmaceutically acceptable salt thereof and a method for producing the same. Patent Documents 2 and 3 disclose methods for producing eribulin and its mesylate (methanesulfonic acid) salt, eribulin mesylate. Patent Document 4 discloses a method for suppressing the growth of cancer in a patient by administering eribulin or a pharmaceutically acceptable salt thereof to the patient. Patent Document 5 discloses a method for treating cancer in a patient by administering eribulin or a pharmaceutically acceptable salt thereof in combination with a specific second anticancer drug to the patient. Patent Document 6 discloses a method for treating cancer in a patient by administering eribulin or a pharmaceutically acceptable salt thereof in combination with a second treatment means to the patient. Patent Documents 7 and 8 disclose liposome compositions containing eribulin mesylate. Patent Document 9 discloses a method for treating breast cancer by combining eribulin or a pharmaceutically acceptable salt thereof with a programmed cell death 1 protein (PD-1) antagonist.

[0004] PD-1 is recognized as an important factor in immune regulation and the maintenance of peripheral immune tolerance. PD-1 is moderately expressed in naive T cells, B cells, and NKT cells, and is upregulated by T / B cell receptor signaling in lymphocytes, monocytes, and myeloid cells (Non-Patent Document 1). On the other hand, PD-L1 is expressed in various cancer cells, T / B cells, macrophages, mDCs, lymphoid DCs (plasmacytoid DCs: pDCs), bone marrow mast cells, and the like.

[0005] Two known PD-1 ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers occurring in various tissues. In a large sample set of, for example, ovarian, renal, colorectal, pancreatic, hepatic and melanoma, PD-L1 expression was shown to correlate with poor prognosis and reduced overall survival, regardless of subsequent treatment (Non-Patent Documents 2-13). Similarly, PD-1 expression on tumor-infiltrating lymphocytes was found to be a hallmark of dysfunctional T cells in breast cancer and melanoma (Non-Patent Documents 14-15) and correlates with poor prognosis in renal cancer (Non-Patent Document 16). It has therefore been proposed that tumor cells expressing PD-L1 interact with T cells expressing PD-1, thus releasing the immune suppressive mechanisms exerted by the cancer cells, thereby resulting in an immune response against the tumor.

[0006] Several monoclonal antibodies that block the interaction between PD-1 and one or both of its ligands, PD-L1 and PD-L2, are in clinical development for the treatment of cancer. It has been proposed that the efficacy of such antibodies may be enhanced when administered in combination with other approved or experimental cancer therapies, such as radiation, surgery, chemotherapy agents, targeted therapies, agents that block other signaling pathways that are dysregulated in tumors, and other immune enhancing agents. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO 99 / 65894 [Patent Document 2] International Publication No. 2005 / 118565 [Patent Document 3] International Publication No. 2011 / 094339 [Patent Document 4] U.S. Patent No. 6,469,182 [Patent Document 5] US Publication No. 2006 / 104984 [Patent Document 6] U.S. Patent No. 6,653,341 [Patent Document 7] International Publication No. 2010 / 113984 [Patent Document 8] International Publication No. 2017 / 188350 [Patent Document 9] International Publication No. 2016 / 141209 [Non-patent literature]

[0008] [Non-Patent Document 1] Sharpe, AH, Wherry, EJ, Ahmed R., and Freeman GJ, The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunology (2007); 8: 239-245. [Non-Patent Document 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 Document 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 Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

[0009] An object of the present invention is to provide a novel pharmaceutical composition for treating tumors. [Means for solving the problem]

[0010] As a result of intensive research, the inventors have found that combined administration of a liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and a PD-1 antagonist shows an unexpected antitumor effect, and have completed the present invention.

[0011] In other words, the present disclosure is as follows. [1] A pharmaceutical composition for tumor treatment, comprising a liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof, characterized in that it is administered in combination with a PD-1 antagonist. [2] A pharmaceutical composition for tumor treatment containing a PD-1 antagonist, characterized in that it is administered in combination with a liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof. [3] The pharmaceutical composition described in [1] or [2] above, wherein the liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, sequentially, or with a time lag. [4-1] The pharmaceutical composition according to any one of the above-mentioned [1] to [3], wherein the eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate. [4-2] Eribulin mesylate is administered at a dose of 0.5 to 3 mg / m every week, every 2 weeks, or every 3 weeks. 2 (body surface area), the pharmaceutical composition described in [4-1] above. [4-3] Eribulin mesylate is administered at a dose of 0.5-2 mg / m every week, every 2 weeks, or every 3 weeks. 2 (body surface area), the pharmaceutical composition described in [4-1] above. [4-4] Eribulin mesylate is administered at approximately 1.5 mg / m once every week, every two weeks, or every three weeks. 2 (body surface area), the pharmaceutical composition described in [4-1] above. [4-5] Eribulin mesylate was administered at 0.5-1.4 mg / m on day 1 of a 21-day cycle. 2 (body surface area) or 0.5-3.0 mg / m 2 (body surface area) intravenously or on days 1 and 15 of a 28-day cycle, 0.5 to 1.5 mg / m 2 (body surface area) or 0.5-3.0 mg / m 2 The pharmaceutical composition described in [4-1] above, which is administered intravenously (by body surface area). [5] The pharmaceutical composition according to any one of the above [1] to [4-5], wherein the PD-1 antagonist is an anti-PD-1 antibody. [6-1] Anti-PD-1 antibodies include nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostallimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, and 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. The pharmaceutical composition according to [5] above, [6-2] The pharmaceutical composition described in [5] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, and toripalimab. [6-3] The pharmaceutical composition described in [5] above, wherein the anti-PD-1 antibody is nivolumab. [6-4] The pharmaceutical composition according to the above [6-3], 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 described in [5] above, wherein the anti-PD-1 antibody is pembrolizumab. [6-6] The pharmaceutical composition according to the above [6-5], wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. [6-7] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7-2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) intravenously, and nivolumab is administered intravenously at 360 mg. [6-8] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1-1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) intravenously and 240 mg of nivolumab is administered intravenously. [7-1] The pharmaceutical composition according to any one of the above [1] to [6-8], wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer, renal cancer, thymic cancer or intrahepatic bile duct cancer. [7-2] The pharmaceutical composition according to any one of the above [1] to [6-8], wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer or renal 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 one of [1] to [6-8] above, for use in patients with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment. [7-5] The pharmaceutical composition according to any of the above [1] to [6-8], which is for a patient with unresectable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a doctor, and who has not been administered other systemic chemotherapy for advanced or recurrent cancer, and who has been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug as first-line chemotherapy or chemotherapy including a taxane drug as second-line chemotherapy, a patient with esophageal cancer who has been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug (but not including a taxane drug) as first-line chemotherapy, or a patient with small cell lung cancer who has been administered combination chemotherapy including a platinum preparation as first-line chemotherapy. [7-6] The pharmaceutical composition according to any one of [1] to [6-8] above, which is for use in patients with intrahepatic bile duct cancer who have been administered, as prior treatment, a combination therapy of gemcitabine and cisplatin as a first-line treatment and a combination therapy of S-1 and leminostat as a second-line treatment, or for patients with thymic carcinoma who have been administered, as prior treatment, a combination therapy of carboplatin and paclitaxel as a first-line treatment, S-1 as a second-line treatment, and gemcitabine as a third-line treatment. [8] A tumor therapeutic agent comprising a liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof, characterized in that it is administered in combination with a PD-1 antagonist. [9] A tumor therapeutic agent containing a PD-1 antagonist, characterized in that it is administered in combination with a liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof.

[10] The therapeutic agent described in [8] or [9] above, wherein the liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, sequentially, or with a time lag. [11-1] The therapeutic agent according to any one of the above-mentioned [8] to

[10] , wherein eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate. [11-2] Eribulin mesylate is administered at a dose of 0.5 to 3 mg / m every week, 2 weeks, or 3 weeks. 2 (body surface area), [11-3] Eribulin mesylate is administered at a dose of 0.5 to 2 mg / m every week, every 2 weeks, or every 3 weeks. 2 (body surface area), [11-4] Eribulin mesylate is administered at approximately 1.5 mg / m once every week, every two weeks, or every three weeks. 2 (body surface area), [11-5] Eribulin mesylate was administered at 0.5-1.4 mg / m on day 1 of a 21-day cycle. 2 (body surface area) or 0.5-3.0 mg / m 2 (body surface area) intravenously or on days 1 and 15 of a 28-day cycle, 0.5 to 1.5 mg / m2 (body surface area) or 0.5-3.0 mg / m 2 The therapeutic agent according to the above-mentioned [11-1], which is administered intravenously (by body surface area).

[12] The therapeutic agent according to any one of the above [8] to [11-5], wherein the PD-1 antagonist is an anti-PD-1 antibody. [13-1] Anti-PD-1 antibodies include nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostallimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, and cetrelimab. The therapeutic agent described in

[12] above, which is selected from the group consisting of 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 described in

[12] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab. [13-3] The therapeutic agent described in

[12] above, wherein the anti-PD-1 antibody is nivolumab. [13-4] The therapeutic agent according to the above [13-3], 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 described in

[12] above, wherein the anti-PD-1 antibody is pembrolizumab. [13-6] The therapeutic agent according to the above [13-5], wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. [13-7] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7-2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) intravenously, and nivolumab is administered intravenously at 360 mg. [13-8] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1-1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) intravenously and 240 mg of nivolumab is administered intravenously. [14-1] The therapeutic agent according to any one of the above [8] to [13-8], wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer, renal cancer, thymic cancer or intrahepatic bile duct cancer. [14-2] The therapeutic agent according to any one of the above [8] to [13-8], wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer or renal cancer. [14-3] The therapeutic agent according to any one of the above [8] to [13-8], wherein the tumor is breast cancer. [14-4] A therapeutic agent described in any of [8] to [13-8] above for use in patients with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment. [14-5] The therapeutic agent according to any of the above [8] to [13-8], for use in patients with unresectable gastric cancer, esophageal cancer or small cell lung cancer who have been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a doctor, and who have not been administered other systemic chemotherapy for advanced or recurrent cancer, and who are gastric cancer patients who have been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug as first-line chemotherapy or chemotherapy including a taxane drug as second-line chemotherapy, esophageal cancer patients who have been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug (but not including a taxane drug) as first-line chemotherapy, or small cell lung cancer patients who have been administered combination chemotherapy including a platinum preparation as first-line chemotherapy. [14-6] The therapeutic agent described in any of [8] to [13-8] above, for use in patients with intrahepatic bile duct cancer who have been administered, as prior treatment, a combination therapy of gemcitabine and cisplatin as the first-line treatment and a combination therapy of S-1 and leminostat as the second-line treatment, or for patients with thymic carcinoma who have been administered, as prior treatment, a combination therapy of carboplatin and paclitaxel as the first-line treatment, S-1 as the second-line treatment, and gemcitabine as the third-line treatment.

[15] A method for treating a tumor, comprising administering a liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof and a PD-1 antagonist to a patient in need thereof.

[16] The method according to

[15] above, wherein the liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, sequentially, or with a time lag. [17-1] The method according to

[15] or

[16] above, wherein eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate. [17-2] Eribulin mesylate is administered at a dose of 0.5 to 3 mg / m once every week, every 2 weeks, or every 3 weeks. 2 The method according to [17-1] above, wherein the dose is administered by body surface area. [17-3] Eribulin mesylate is administered at a dose of 0.5 to 2 mg / m every week, every 2 weeks, or every 3 weeks. 2 The method according to [17-1] above, wherein the dose is administered by body surface area. [17-4] Eribulin mesylate is administered at approximately 1.5 mg / m once every week, every two weeks, or every three weeks. 2 The method according to [17-1] above, wherein the dose is administered by body surface area. [17-5] Eribulin mesylate was administered at 0.5-1.4 mg / m on day 1 of a 21-day cycle. 2 (body surface area) or 0.5-3.0 mg / m 2 (body surface area) intravenously or on days 1 and 15 of a 28-day cycle, 0.5 to 1.5 mg / m 2 (body surface area) or 0.5-3.0 mg / m 2 The method according to [17-1] above, wherein the compound is administered intravenously by (body surface area).

[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] Anti-PD-1 antibodies include nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostallimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, and cetelima. The method according to

[18] above, wherein the medicament is selected from the group consisting of b, 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 described in

[18] above, wherein the anti-PD-1 antibody is nivolumab. [19-4] The method described in [19-3] above, wherein 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. [19-5] The method described in

[18] above, wherein the anti-PD-1 antibody is pembrolizumab. [19-6] The method described in [19-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. [19-7] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7-2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) intravenously and nivolumab is administered at 360 mg intravenously. [19-8] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1-1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) intravenously and 240 mg of nivolumab is administered intravenously. [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, colon cancer, renal cancer, thymic cancer or intrahepatic bile duct cancer. [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, colon cancer or renal cancer. [20-3] The method according to any one of

[15] to [19-8] above, wherein the tumor is breast cancer. [20-4] A method according to any of

[15] to [19-8] above, administered to patients with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment. [20-5] The method according to any of the above

[15] to [19-8], administered to a patient with unresectable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a physician, and who has not been administered other systemic chemotherapy for advanced or recurrent cancer, and who has been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug as first-line chemotherapy or chemotherapy including a taxane drug as second-line chemotherapy, a patient with esophageal cancer who has been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug (but not including a taxane drug) as first-line chemotherapy, or a patient with small cell lung cancer who has been administered combination chemotherapy including a platinum preparation as first-line chemotherapy. [20-6] A method according to any of the above

[15] to [19-8], administered to patients with intrahepatic cholangiocarcinoma who have been administered, as prior treatment, a combination therapy of gemcitabine and cisplatin as the first-line treatment and a combination therapy of S-1 and leminostat as the second-line treatment, or to patients with thymic carcinoma who have been administered, as prior treatment, a combination therapy of carboplatin and paclitaxel as the first-line treatment, S-1 as the second-line treatment, and gemcitabine as the third-line treatment.

[21] Use of eribulin or a pharma- ceutical acceptable salt thereof for the manufacture of a pharmaceutical composition for tumor treatment, characterized in that it is administered in combination with a PD-1 antagonist.

[22] Use of a PD-1 antagonist for the manufacture of a pharmaceutical composition for tumor treatment, characterized in that it is administered in combination with a liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof.

[23] The use described in

[21] or

[22] above, wherein the liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, sequentially, or with a time lag. [24-1] The use according to any of the above

[21] to

[23] , wherein eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate. [24-2] Eribulin mesylate is administered at a dose of 0.5 to 3 mg / m every week, 2 weeks, or 3 weeks. 2 The use described in [24-1] above, administered by body surface area. [24-3] Eribulin mesylate is administered at a dose of 0.5 to 2 mg / m every week, every 2 weeks, or every 3 weeks. 2 The use described in [24-1] above, administered by body surface area. [24-4] Eribulin mesylate is administered at approximately 1.5 mg / m once every week, every 2 weeks, or every 3 weeks. 2 The use described in [24-1] above, administered by body surface area. [24-5] Eribulin mesylate was administered at 0.5-1.4 mg / m on day 1 of a 21-day cycle. 2 (body surface area) or 0.5-3.0 mg / m 2(body surface area) intravenously or on days 1 and 15 of a 28-day cycle, 0.5 to 1.5 mg / m 2 (body surface area) or 0.5-3.0 mg / m 2 The use described in [24-1] above, administered intravenously (by body surface area).

[25] The use described in any of

[21] to [24-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody. [26-1] Anti-PD-1 antibodies include nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostallimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, and cetelima. b) The use according to the above-mentioned

[25] , wherein the compound is selected from the group consisting of 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] The use described in

[25] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab. [26-3] The use described in

[25] above, wherein the anti-PD-1 antibody is nivolumab. [26-4] The use of [26-3] above, wherein 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. [26-5] The use described in

[25] above, wherein the anti-PD-1 antibody is pembrolizumab. [26-6] The use described in [26-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. [26-7] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7-2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) intravenously and nivolumab is administered at 360 mg intravenously. Use as described in

[25] above. [26-8] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1-1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) intravenously and nivolumab is administered at 240 mg intravenously. Use as described in

[25] above. [27-1] The use described in any of

[21] to [26-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic cancer or intrahepatic bile duct cancer. [27-2] The use described in any of

[21] to [26-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer or renal cancer. [27-3] The use described in any of

[21] to [26-8] above, wherein the tumor is breast cancer. [27-4] The use of any of the above

[21] to [26-8] for patients with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment. [27-5] The use described in any of

[21] to [26-8] above for patients with unresectable gastric cancer, esophageal cancer, or small cell lung cancer who have been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a physician, and who have not been administered other systemic chemotherapy for advanced or recurrent cancer, and who are gastric cancer patients who have been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug as first-line chemotherapy or chemotherapy including a taxane drug as second-line chemotherapy, esophageal cancer patients who have been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug (but not including a taxane drug) as first-line chemotherapy, or small cell lung cancer patients who have been administered combination chemotherapy including a platinum preparation as first-line chemotherapy. [27-6] The use of any of the above

[21] to [26-8] for patients with intrahepatic cholangiocarcinoma who have been administered, as prior treatment, a combination therapy of gemcitabine and cisplatin as the first-line treatment and a combination therapy of S-1 and leminostat as the second-line treatment, or for patients with thymic carcinoma who have been administered, as prior treatment, a combination therapy of carboplatin and paclitaxel as the first-line treatment, S-1 as the second-line treatment, and gemcitabine as the third-line treatment.

[28] A liposome composition comprising eribulin or a pharma- ceutically acceptable salt thereof for use in tumor treatment, wherein the liposome composition is administered in combination with a PD-1 antagonist.

[29] A PD-1 antagonist for use in tumor treatment, administered in combination with a liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof.

[30] The liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and the PD-1 antagonist described in

[28] or

[29] above, wherein the liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, sequentially, or with a time lag, respectively. [31-1] The liposome composition or PD-1 antagonist described in any one of

[28] to

[30] above, wherein eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate. [31-2] Eribulin mesylate is administered at a dose of 0.5 to 3 mg / m once every week, 2 weeks, or 3 weeks. 2 The liposome composition or PD-1 antagonist described in [31-1] above, which is administered by body surface area. [31-3] Eribulin mesylate is administered at a dose of 0.5 to 2 mg / m every week, every 2 weeks, or every 3 weeks. 2 The liposome composition or PD-1 antagonist described in [31-1] above, which is administered by body surface area. [31-4] Eribulin mesylate is administered at approximately 1.5 mg / m once every week, every 2 weeks, or every 3 weeks. 2 The liposome composition or PD-1 antagonist described in [31-1] above, which is administered by body surface area. [31-5] Eribulin mesylate was administered at 0.5-1.4 mg / m on day 1 of a 21-day cycle. 2 (body surface area) or 0.5-3.0 mg / m 2 (body surface area) intravenously or on days 1 and 15 of a 28-day cycle, 0.5 to 1.5 mg / m 2 (body surface area) or 0.5-3.0 mg / m 2 The liposome composition or PD-1 antagonist described in [31-1] above, which is administered intravenously (by body surface area).

[32] The liposome composition or PD-1 antagonist described in any one of

[28] to [31-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody. [33-1] Anti-PD-1 antibodies include nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostallimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, and zimbrel. The liposome composition or the PD-1 antagonist according to

[32] above, which is selected from the group consisting of imab, 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] The liposome composition or PD-1 antagonist described in

[32] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab. [33-3] The liposome composition or PD-1 antagonist described in

[32] above, wherein the anti-PD-1 antibody is nivolumab. [33-4] The liposome composition or PD-1 antagonist described in [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] The liposome composition or PD-1 antagonist described in

[32] above, wherein the anti-PD-1 antibody is pembrolizumab. [33-6] The liposome composition or PD-1 antagonist described in [33-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. [33-7] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7-2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) intravenously and nivolumab is administered intravenously at 360 mg, the liposome composition or PD-1 antagonist described in

[32] above. [33-8] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1-1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) intravenously and 240 mg of nivolumab is administered intravenously. The liposome composition or PD-1 antagonist described in

[32] above. [34-1] The liposome composition or PD-1 antagonist described in any one of

[28] to [33-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colorectal cancer, renal cancer, thymic cancer or intrahepatic bile duct cancer. [34-2] The liposome composition or PD-1 antagonist described in any one of

[28] to [33-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer or renal cancer. [34-3] The liposome composition or PD-1 antagonist described in any one of

[28] to [33-8] above, wherein the tumor is breast cancer. [34-4] A liposome composition or PD-1 antagonist described in any of

[28] to [33-8] above for use in patients with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment. [34-5] The liposome composition or PD-1 antagonist described in any of

[28] to [33-8] above, for use in patients with unresectable gastric cancer, esophageal cancer, or small cell lung cancer who have been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a doctor, and who have not been administered other systemic chemotherapy for advanced or recurrent cancer, and who have been administered combination chemotherapy containing a platinum preparation and a fluoropyrimidine drug as first-line chemotherapy or chemotherapy containing a taxane drug as second-line chemotherapy, in patients with esophageal cancer who have been administered combination chemotherapy containing a platinum preparation and a fluoropyrimidine drug (but not including a taxane drug) as first-line chemotherapy, or in patients with small cell lung cancer who have been administered combination chemotherapy containing a platinum preparation as first-line chemotherapy. [34-6] The liposome composition or PD-1 antagonist described in any one of

[28] to [33-8] above, for use in patients with intrahepatic bile duct carcinoma who have been administered, as prior treatment, a combination therapy of gemcitabine and cisplatin as a first-line treatment and a combination therapy of S-1 and leminostat as a second-line treatment, or for patients with thymic carcinoma who have been administered, as prior treatment, a combination therapy of carboplatin and paclitaxel as a first-line treatment, S-1 as a second-line treatment, and gemcitabine as a third-line treatment.

[35] A kit for tumor treatment comprising a formulation containing a liposome composition containing eribulin or a pharma-ceutical acceptable salt thereof, and a formulation containing a PD-1 antagonist.

[36] The kit described in

[35] above, wherein the liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, sequentially, or with a time lag. [37-1] The kit described in

[35] or

[36] above, wherein the eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate. [37-2] Eribulin mesylate is administered at a dose of 0.5 to 3 mg / m every week, every 2 weeks, or every 3 weeks.2 The kit described in [37-1] above, which is administered by (body surface area). [37-3] Eribulin mesylate is administered at a dose of 0.5 to 2 mg / m every week, every 2 weeks, or every 3 weeks. 2 The kit described in [37-1] above, which is administered by (body surface area). [37-4] Eribulin mesylate is administered at approximately 1.5 mg / m once every week, every 2 weeks, or every 3 weeks. 2 The kit described in [37-1] above, which is administered by (body surface area). [37-5] Eribulin mesylate was administered at 0.5-1.4 mg / m on day 1 of a 21-day cycle. 2 (body surface area) or 0.5-3.0 mg / m 2 (body surface area) intravenously or on days 1 and 15 of a 28-day cycle, 0.5 to 1.5 mg / m 2 (body surface area) or 0.5-3.0 mg / m 2 The kit described in [37-1] above, which is administered intravenously (by body surface area).

[38] The kit described in any one of

[35] to [37-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody. [39-1] Anti-PD-1 antibodies include nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostallimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, and 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 described in

[38] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab. [39-3] The kit described in

[38] above, wherein the anti-PD-1 antibody is nivolumab. [39-4] The kit described in [39-3] above, wherein 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 described in

[38] above, wherein the anti-PD-1 antibody is pembrolizumab. [39-6] The kit described in [39-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. [39-7] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7-2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) intravenously and 360 mg of nivolumab is administered intravenously. [39-8] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1-1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) intravenously and 240 mg of nivolumab is administered intravenously. [40-1] The kit according to any one of

[35] to [39-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer, renal cancer, thymic cancer or intrahepatic bile duct cancer. [40-2] The kit according to any one of

[35] to [39-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer or renal cancer. [40-3] The kit according to any one of

[35] to [39-8] above, wherein the tumor is breast cancer. [40-4] A kit described in any of

[35] to [39-8] above, for use in patients with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment. [40-5] A kit described in any of

[35] to [39-8] above, for use in a patient with unresectable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a doctor, and who has not been administered other systemic chemotherapy for advanced or recurrent cancer, and who has been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug as first-line chemotherapy or chemotherapy including a taxane drug as second-line chemotherapy, a patient with esophageal cancer who has been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug (but not including a taxane drug) as first-line chemotherapy, or a patient with small cell lung cancer who has been administered combination chemotherapy including a platinum preparation as first-line chemotherapy. [40-6] A kit described in any of

[35] to [39-8] above, for use in patients with intrahepatic cholangiocarcinoma who have been administered, as prior treatment, a combination therapy of gemcitabine and cisplatin as the first-line treatment and a combination therapy of S-1 and leminostat as the second-line treatment, or for patients with thymic carcinoma who have been administered, as prior treatment, a combination therapy of carboplatin and paclitaxel as the first-line treatment, S-1 as the second-line treatment, and gemcitabine as the third-line treatment.

[41] The pharmaceutical composition according to any one of the above [1] to [7-6] or the therapeutic agent according to any one of the above [8] to [14-6], further comprising a pharma-ceutically acceptable carrier.

[42] A tumor therapeutic agent, in which a formulation containing a liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof and a formulation containing a PD-1 antagonist are administered simultaneously, separately, sequentially, or with a time lag. [43-1] The tumor therapeutic agent described in

[42] above, wherein eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate. [43-2] Eribulin mesylate is administered at a dose of 0.5 to 3 mg / m every week, 2 weeks, or 3 weeks. 2 The tumor therapeutic agent according to the above-mentioned [43-1], which is administered by body surface area. [43-3] Eribulin mesylate is administered at 0.5-2 mg / m once every 1, 2, or 3 weeks. 2 The tumor therapeutic agent according to the above-mentioned [43-1], which is administered by body surface area. [43-4] Eribulin mesylate is administered at approximately 1.5 mg / m once every week, every 2 weeks, or every 3 weeks. 2 The tumor therapeutic agent according to the above-mentioned [43-1], which is administered by body surface area. [43-5] Eribulin mesylate was administered at 0.5-1.4 mg / m on day 1 of a 21-day cycle. 2 (body surface area) or 0.5-3.0 mg / m 2 (body surface area) intravenously or on days 1 and 15 of a 28-day cycle, 0.5 to 1.5 mg / m 2 (body surface area) or 0.5-3.0 mg / m 2 The tumor therapeutic agent according to the above-mentioned [43-1], which is administered intravenously by (body surface area).

[44] The tumor therapeutic agent described in

[42] or [43-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody. [45-1] Anti-PD-1 antibodies include nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostallimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, The tumor therapeutic agent according to

[44] above, which is selected from the group consisting of 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] The tumor therapeutic agent described in

[44] above, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab. [45-3] The tumor therapeutic agent described in

[44] above, wherein the anti-PD-1 antibody is nivolumab. [45-4] The tumor therapeutic agent according to the above [45-3], 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] The tumor therapeutic agent described in

[44] above, wherein the anti-PD-1 antibody is pembrolizumab. [45-6] The tumor therapeutic agent described in [45-5] above, wherein pembrolizumab is administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. [45-7] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7-2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) intravenously and nivolumab is administered at 360 mg intravenously. [45-8] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1-1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) intravenously and 240 mg of nivolumab is administered intravenously. [46-1] A tumor therapeutic agent according to any one of the above

[42] to [45-8], wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer, renal cancer, thymic cancer or intrahepatic bile duct cancer. [46-2] The tumor therapeutic agent according to any one of the above

[42] to [45-8], wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer or renal cancer. [46-3] A tumor therapeutic agent according to any one of

[42] to [45-8] above, wherein the tumor is breast cancer. [46-4] A tumor therapeutic agent described in any of

[42] to [45-8] above, for use in patients with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment. [46-5] A tumor therapeutic agent according to any of the above

[42] to [45-8], for use in patients with unresectable gastric cancer, esophageal cancer or small cell lung cancer who have been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a doctor, and who have not been administered other systemic chemotherapy for advanced or recurrent cancer, and who have been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug as first-line chemotherapy or chemotherapy including a taxane drug as second-line chemotherapy, in patients with esophageal cancer who have been administered combination chemotherapy including a platinum preparation and a fluoropyrimidine drug (but not including a taxane drug) as first-line chemotherapy, or in patients with small cell lung cancer who have been administered combination chemotherapy including a platinum preparation as first-line chemotherapy. [46-6] A tumor therapeutic agent described in any of

[42] to [45-8] above, for use in patients with intrahepatic bile duct cancer who have been administered, as prior treatment, a combination therapy of gemcitabine and cisplatin as the first-line treatment and a combination therapy of S-1 and leminostat as the second-line treatment, or for patients with thymic carcinoma who have been administered, as prior treatment, a combination therapy of carboplatin and paclitaxel as the first-line treatment, S-1 as the second-line treatment, and gemcitabine as the third-line treatment.

[47] A combination for tumor treatment comprising a liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and a PD-1 antagonist.

[48] ​​The combination described in

[49] above, wherein the liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and the PD-1 antagonist are administered simultaneously, separately, sequentially, or with a time lag. [49-1] The combination described in

[49] or

[50] above, wherein eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate. [49-2] Eribulin mesylate is administered at a dose of 0.5 to 3 mg / m once every week, 2 weeks, or 3 weeks. 2 (body surface area). [49-3] Eribulin mesylate is administered at a dose of 0.5 to 2 mg / m every week, every 2 weeks, or every 3 weeks. 2 (body surface area). [49-4] Eribulin mesylate is administered at approximately 1.5 mg / m once every week, every 2 weeks, or every 3 weeks. 2 (body surface area). [49-5] Eribulin mesylate was administered at 0.5-1.4 mg / m on day 1 of a 21-day cycle. 2 (body surface area) or 0.5-3.0 mg / m 2 (body surface area) intravenously or on days 1 and 15 of a 28-day cycle, 0.5 to 1.5 mg / m 2 (body surface area) or 0.5-3.0 mg / m 2 (body surface area) administered intravenously.

[50] The combination described in any one of

[47] to [49-5] above, wherein the PD-1 antagonist is an anti-PD-1 antibody. [51-1] Anti-PD-1 antibodies include nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dostallimab, camrelizumab, genolimzumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, prolgolimab, sasanlimab, cetrelimab, 50. The combination according to claim 50, wherein the combination is selected from the group consisting of 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 described in

[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 described in

[50] above, wherein the anti-PD-1 antibody is nivolumab. [51-4] The combination described in [51-3] above, in which 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. [51-5] The combination described in

[50] above, wherein the anti-PD-1 antibody is pembrolizumab. [51-6] The combination described in [51-5] above, in which pembrolizumab is administered at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. [51-7] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7-2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) administered intravenously and nivolumab administered intravenously at 360 mg. [51-8] Eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1-1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) administered intravenously and nivolumab administered intravenously at 240 mg. [52-1] The combination according to any one 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 cancer or intrahepatic bile duct cancer. [52-2] The combination according to any one of

[47] to [51-8] above, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer or renal cancer. [52-3] The combination described in any one of

[47] to [51-8] above, wherein the tumor is breast cancer. [52-4] A combination described in any of

[47] to [51-8] above for patients with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment. [52-5] A combination according to any of the above

[47] to [51-8] for use in patients with unresectable gastric cancer, esophageal cancer or small cell lung cancer who have been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a physician, and who have not received other systemic chemotherapy for advanced or recurrent cancer, and who have received combination chemotherapy including a platinum preparation and a fluoropyrimidine drug as their first-line chemotherapy or chemotherapy including a taxane drug as their second-line chemotherapy, or in patients with esophageal cancer who have received combination chemotherapy including a platinum preparation and a fluoropyrimidine drug (but not including a taxane drug) as their first-line chemotherapy, or in patients with small cell lung cancer who have received combination chemotherapy including a platinum preparation as their first-line chemotherapy. [52-6] A combination described in any of

[47] to [51-8] above, for use in patients with intrahepatic cholangiocarcinoma who have been administered, as prior treatment, a combination of gemcitabine and cisplatin as the first-line treatment and a combination of S-1 and leminostat as the second-line treatment, or for patients with thymic carcinoma who have been administered, as prior treatment, a combination of carboplatin and paclitaxel as the first-line treatment, S-1 as the second-line treatment, and gemcitabine as the third-line treatment. Effect of the Invention

[0012] The combined administration of a liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof and a PD-1 antagonist shows unexpected anti-tumor effects. [Brief description of the drawings]

[0013] [Figure 1] 1 is a graph showing the effect of combined treatment of 0.1 mg / kg eribulin mesylate liposome formulation and anti-PD-1 antibody on tumor growth. [Diagram 2] This is a graph showing the effect of combination treatment with 0.1 mg / kg eribulin mesylate liposomal formulation and anti-PD-1 antibody on T×5. [Diagram 3] 1 is a graph showing the effect of combined treatment of 0.3 mg / kg eribulin mesylate liposome formulation and anti-PD-1 antibody on tumor growth. [Figure 4]This is a graph showing the effect of combination treatment with 0.3 mg / kg eribulin mesylate liposome formulation and anti-PD-1 antibody on T×5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The following describes embodiments of the present disclosure. The following embodiments are examples for explaining the present disclosure, and are not intended to limit the present disclosure to these embodiments. The present disclosure can be implemented in various forms without departing from the gist of the disclosure.

[0015] The liposome composition of the present disclosure contains eribulin or a pharma- ceutically acceptable salt thereof (hereinafter referred to as "eribulin, etc.").

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

[0017] The pharma- ceutically acceptable salt of eribulin may be a salt of eribulin with aluminum, calcium, lithium, magnesium, sodium, zinc, or diethanolamine.

[0018] In the present disclosure, eribulin and the like includes eribulin mesylate.

[0019] Eribulin and the like are compounds or salts thereof described in Patent Document 1 or U.S. Patent No. 6,214,865, and have pharmacological activities including antitumor and antimitotic activities. Patent Document 1 discloses that eribulin and the like, as an antitumor agent, have antitumor activity against melanoma, fibrosarcoma, monocytic leukemia, colon cancer, ovarian cancer, breast cancer, osteosarcoma, prostate cancer, lung cancer, and ras-transformed fibroblasts. Eribulin and the like can be obtained by the production methods described in Patent Documents 1 to 3.

[0020] In the present disclosure, the term "liposome" refers to a minute closed vesicle having an internal phase surrounded by a lipid bilayer. Liposomes include small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), even larger unilamellar vesicles (GUVs), multilamellar vesicles (MLVs) having multiple concentric membranes, and multivesicular vesicles (MVVs) having multiple membranes that are not concentric but irregular.

[0021] In the present disclosure, the term "liposome internal phase" refers to the aqueous region surrounded by the lipid bilayer of the liposome, and is used synonymously with "internal aqueous phase" and "internal aqueous phase of the liposome." The term "liposome external phase" refers to the region not surrounded by the lipid bilayer of the liposome when the liposome is dispersed in a liquid (i.e., the region other than the internal phase and the lipid bilayer).

[0022] In the present disclosure, the term "liposome composition" refers to a composition that contains liposomes and further contains eribulin etc. in the liposome internal phase. In the present disclosure, the liposome composition includes those in solid and liquid forms.

[0023] In the present disclosure, the term "liposome dispersion" refers to a composition containing liposomes, before eribulin and the like are encapsulated in the liposome internal phase.

[0024] In the present disclosure, the term "liposome preparation solution" refers to a composition containing liposomes, which is the composition before the liposome external phase is adjusted in order to encapsulate eribulin or the like in the liposome internal phase.

[0025] [Fat] In one embodiment, the liposome preferably contains a phospholipid and / or a phospholipid derivative as a membrane component.

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

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

[0028] The fatty acid residue in the phospholipid and / or phospholipid derivative is 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, linoleic acid, etc. Furthermore, as the phospholipid and / or phospholipid derivative, phospholipids derived from natural products such as egg yolk lecithin and soybean lecithin, as well as partially hydrogenated egg yolk lecithin, (fully) hydrogenated egg yolk lecithin, partially hydrogenated soybean lecithin, (fully) hydrogenated soybean lecithin, etc., in which unsaturated fatty acid residues are partially or completely hydrogenated, can also be used.

[0029] The amount (molar fraction) of the phospholipid and / or phospholipid derivative used in preparing the liposome is not particularly limited, but in one embodiment it is 10 to 80% relative to the total liposome membrane components, and in a specific embodiment it is 30 to 60%.

[0030] In the present disclosure, the liposome may contain, as a membrane constituent component, in addition to a phospholipid and / or a phospholipid derivative, sterols such as cholesterol and cholestanol, fatty acids having a saturated or unsaturated acyl group having 8 to 22 carbon atoms, and an antioxidant such as α-tocopherol, as a membrane stabilizer.

[0031] The amount (molar fraction) of the sterols used in preparing the liposomes is not particularly limited, but in one embodiment, is 1 to 60%, 10 to 50%, or 30 to 50% based on the total liposome membrane components.

[0032] The amount (molar fraction) of the fatty acids is not particularly limited, but in one embodiment, it is 0 to 30%, 0 to 20%, or 0 to 10% based on the total liposome membrane components.

[0033] The amount (molar fraction) of the antioxidant is not particularly limited as long as an amount that provides an antioxidant effect is added, but in one embodiment, it is 0 to 15%, 0 to 10%, or 0 to 5% based on the total liposome membrane components.

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

[0035] Examples of functional lipids include blood-retentive lipid derivatives, temperature-sensitive lipid derivatives, and pH-sensitive lipid derivatives.

[0036] Examples of modified lipids include PEGylated lipids, glycolipids, antibody-modified lipids, and peptide-modified lipids.

[0037] Examples of lipid derivatives that remain in the blood include condensates of phosphoethanolamine and methoxypolyethylene glycol, such as N-{carbonyl-methoxypolyethylene glycol-2000}-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, N-{carbonyl-methoxypolyethylene glycol-5000}-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, and N-{carbonyl-methoxypolyethylene glycol-750}-1,2-distearoyl-sn-glycero-3-phosphoethanolamine. -glycero-3-phosphoethanolamine, N-{carbonyl-methoxypolyethylene glycol-2000}-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (MPEG2000-distearoylphosphatidylethanolamine), and polyethylene glycol derivatives (e.g., methoxypolyethylene glycol condensates) such as N-{carbonyl-methoxypolyethylene glycol-5000}-1,2-distearoyl-sn-glycero-3-phosphoethanolamine.

[0038] The amount (molar fraction) of the blood-retentive lipid derivative used in preparing liposomes is not particularly limited, but in one embodiment, it is 0 to 50%, 0 to 30%, or 0 to 20% of the total liposome membrane components.

[0039] Examples of temperature-sensitive lipid derivatives include dipalmitoylphosphatidylcholine. By containing a temperature-sensitive lipid derivative in a liposome, it is possible to collapse the liposome at a specific temperature, change the surface properties of the liposome, etc. Furthermore, by combining with heating of a target site such as a tumor, it is possible to collapse the liposome at the target site and release the active compound at the target site.

[0040] Examples of pH-sensitive lipid derivatives include dioleoylphosphatidylethanolamine, etc. When the liposome contains a pH-sensitive lipid derivative, it is possible to promote membrane fusion between the liposome and the endosome when the liposome is taken up into the cell by endocytosis, thereby improving the delivery of the active compound to the cytoplasm.

[0041] Glycolipids, antibody-modified lipids, and peptide-modified lipids include lipids bound to sugars, antibodies, or peptides that have affinity for target cells or tissues. By using modified lipids, liposomes can be actively delivered to target cells or tissues.

[0042] Those skilled in the art can appropriately determine the composition of membrane components for liposomes having a practical level of membrane permeability depending on the active compound, target tissue, etc. (see Kikuchi Kan et al., "Liposome I-Preparation and Assay Methods-", Saibo Kogaku, (1983) 2(9): pp. 1136-1149 and references cited therein). Furthermore, liposome compositions can be used not only for targeting to target tissues such as solid cancers, but also for delivery of active compounds to blood cancers and the like.

[0043] In one embodiment, the membrane components of the liposome contain phospholipid, cholesterol and a methoxypolyethylene glycol condensate.

[0044] [Liposome composition] In the liposome composition of the present disclosure, eribulin etc. is encapsulated in a liposome having a lipid membrane. In the liposome composition, eribulin etc. may be distributed in the lipid bilayer.

[0045] The liposome composition according to the present disclosure can be obtained by the method described in US Pat. No. 5,399,633.

[0046] When the liposome composition is in a solid state, it can be made into a liquid liposome composition by dissolving or suspending it in a predetermined solvent as described below. When the liposome composition is in a frozen solid state, it can be made into a liquid liposome composition by melting it by leaving it at room temperature or the like.

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

[0048] (2) At least one ammonium salt includes, for example, ammonium chloride, ammonium borate, ammonium sulfate, ammonium formate, ammonium acetate, ammonium citrate, ammonium tartrate, ammonium succinate, and ammonium phosphate. In one embodiment, the at least one ammonium salt is ammonium sulfate, ammonium citrate, or ammonium tartrate.

[0049] Examples of the acids, salts, bases and / or amino acids in (3) include, as acids, 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; as salts, for example, the sodium salts, potassium salts and ammonium salts of the above acids; as bases, for example, trishydroxymethylaminomethane, ammonia, sodium hydroxide and potassium hydroxide; and as amino acids, for example, arginine, histidine and glycine.

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

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

[0052] [Table 1] [Table 2]

[0053] The liposome composition according to the present disclosure can be administered by injection (intravenous injection, intraarterial injection, local injection), orally, nasally, transdermally, pulmonary, or ophthalmic administration, and examples of such injections include intravenous injection, subcutaneous injection, intradermal injection, intraarterial injection, and local injection into target cells or organs. Examples of the dosage form of the liposome composition when administered orally include tablets, powders, granules, syrups, capsules, and oral liquids. Examples of the dosage form of the liposome composition when administered parenterally include injections, drops, eye drops, ointments, suppositories, suspensions, poultices, lotions, aerosols, and plasters, and in one embodiment, the liposome composition is an injection or drops. The liposome composition according to the present disclosure can be formulated, for example, by a method described in the 17th revised Japanese Pharmacopoeia (JP), the United States Pharmacopoeia (USP), or the European Pharmacopoeia (EP).

[0054] When the liposome composition is a liquid, it can be used as it is. When the liposome composition is used as a medicine, the doctor or patient can prepare it at the time of use by, for example, injecting a solvent into a vial containing a solid preparation. In addition, when the liposome composition is a solid preparation obtained by freezing a liquid liposome composition, it can be stored in a frozen state and used as a liquid by leaving it to melt at room temperature or by rapidly melting it by heating to return it to a liquid state.

[0055] The dosage of the liposome composition when administered alone varies significantly depending on the type of target disease, the age, sex, weight, and severity of symptoms of the patient, etc. For example, the liposome composition is administered in an amount of 0.1 to 10 mg / m per day for an adult as eribulin mesylate. 2 (body surface area). In one embodiment, the liposome composition is administered at a dose of 0.5 to 3 mg / m2 as eribulin mesylate once every week, every two weeks, or every three weeks. 2 (body surface area). In a specific embodiment, the liposome composition is administered at a dose of 0.5 to 2 mg / m2 as eribulin mesylate once every week, every two weeks, or every three weeks. 2 It is more preferred that the dose be administered per unit of body surface area.

[0056] In another embodiment, the liposome composition is administered at about 1.5 mg / m2 of eribulin mesylate once every week, every two weeks, or every three weeks. 2 (body surface area) dose.

[0057] More specifically, the liposome composition is administered at a dose of 0.5 to 1.4 mg / m2 as eribulin mesylate on day 1 of a 21-day cycle. 2 Or 0.5 to 3.0 mg / m 2 or 0.5-1.5 mg / m on days 1 and 15 of a 28-day cycle. 2 Or 0.5 to 3.0 mg / m 2 is administered intravenously.

[0058] The eribulin and the like contained in the liposome composition can be administered once a day, or the daily dose can be divided into several doses.

[0059] The liposome composition may be, for example, a liposome composition containing 0.01 to 300 mg / mL of eribulin or the like in the liposome internal phase.

[0060] The liposome composition is formulated as an injection containing 0.20 mg / mL eribulin mesylate (0.18 mg / mL eribulin) incorporated into liposomes having a lipid membrane composed of HSPC, cholesterol, and MPEG2000-DSPE. The injection may also contain sucrose or sodium chloride, ammonium sulfate, citric acid, and L-histidine as isotonicity agents, and sodium hydroxide and hydrochloric acid for adjusting pH. The injection is administered directly to a patient or diluted with physiological saline to a concentration range of 0.0035 mg / mL or more and less than 0.2 mg / mL before administration to a patient.

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

[0062] The PD-1 antagonists useful in the present disclosure may comprise 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 Fv fragments.

[0063] One example of a useful PD-1 antagonist is an anti-PD-1 antibody, which in one embodiment is an anti-human PD-1 antibody, and in a particular embodiment is an anti-human PD-1 monoclonal antibody (anti-human PD-1 mAb). Examples of mAbs that bind to 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. Anti-human PD-1 monoclonal antibodies useful as PD-1 antagonists in the present disclosure include Nivolumab, Pembrolizumab, Cemiplimab, Sintilimab, and Toripalimab. Anti-PD-1 antibodies useful as PD-1 antagonists in the present disclosure further include Spartalizumab, Tislelizumab, Dostarlimab, Camrelizumab, Genolimzumab, Lodapolimab, Retifanlimab, Balstilimab, Serplulimab, Budigalimab, and others. ab, 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 a useful PD-1 antagonist is an anti-PD-L1 antibody, which in one embodiment is an anti-human PD-L1 antibody, and in a particular embodiment, an anti-human PD-L1 monoclonal antibody (anti-human PD-L1 mAb). Anti-PD-L1 antibodies useful as PD-1 antagonists in the present disclosure include Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, and KL-A16.

[0065] The PD-1 antagonist according to the present disclosure can be administered by injection (intravenous injection, intraarterial injection, local injection), orally, nasally, transdermally, pulmonary, or ophthalmic administration, and examples of such administration include intravenous injection, subcutaneous injection, intradermal injection, intraarterial injection, and local injection into target cells or organs. Examples of the dosage form of the PD-1 antagonist when administered orally include tablets, powders, granules, syrups, capsules, and oral liquids. Examples of the dosage form of the PD-1 antagonist when administered parenterally include injections, drips, eye drops, ointments, suppositories, suspensions, poultices, lotions, aerosols, and plasters, and in one embodiment, the PD-1 antagonist is an injection or drip. The PD-1 antagonist according to the present disclosure can be formulated, for example, by a method described in the 17th Edition of the Japanese Pharmacopoeia (JP), the United States Pharmacopoeia (USP), or the European Pharmacopoeia (EP).

[0066] When the PD-1 antagonist of the present disclosure is an anti-PD-1 antibody, the anti-PD-1 antibody may be provided as a liquid formulation or may be prepared by reconstituting a lyophilized powder with sterile water for injection prior to use.

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

[0068] When pembrolizumab is administered as the PD-1 antagonist, it is administered intravenously at a dose selected from the group consisting of, for example, 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / kg Q2W, 5 mg / kg Q2W, 10 mg Q2W, 1 mg / kg Q3W, 2 mg / kg Q3W, 3 mg / kg Q3W, 5 mg / kg Q3W, and 10 mg / kg Q3W. In another embodiment, pembrolizumab is administered intravenously at 200 mg Q3W or 400 mg Q6W. Pembrolizumab is administered, for example, as a liquid medication containing 25 mg / ml pembrolizumab, 7% (w / v) sucrose, 0.02% (w / v) polysorbate 80 in 10 mM histidine buffer pH 5.5, with the selected dose of medication administered by intravenous infusion over a time period of about 30 minutes.

[0069] When nivolumab is administered as a PD-1 antagonist, it is intravenously administered at a dose selected from the group consisting of, for example, 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / kg Q2W, 4 mg / kg Q2W, 5 mg / kg Q2W, and 6 mg / kg Q2W, 1 mg / kg Q3W, 2 mg / kg Q3W, 3 mg / kg Q3W, 4 mg / kg Q3W, 5 mg / kg Q3W, 6 mg / kg Q3W, 8 mg / kg Q3W, and 10 mg / kg Q3W. In another embodiment, nivolumab is intravenously administered at 240 mg Q2W, 360 mg Q3W, or 480 mg Q4W. Nivolumab is administered by intravenous infusion over about 30 minutes or longer, for example, as a liquid medication further comprising D-mannitol, sodium citrate hydrate, sodium chloride, diethylenetriaminepentaacetic acid, polysorbate 80, and a pH adjuster.

[0070] When cemiplimab is administered as a PD-1 antagonist, for example, 350 mg is administered intravenously Q3W.

[0071] The dosages of the liposome composition and the PD-1 antagonist in the combined administration of the present disclosure can be set to lower dosages than those usually administered alone. The specific dosage, administration route, administration frequency, administration cycle, etc. are appropriately determined taking into consideration the type of the target disease, the age, sex, weight, severity of symptoms, etc. of the patient.

[0072] The administration form of the liposome composition and the PD-1 antagonist in the present disclosure is not particularly limited, and it is sufficient that the liposome composition and the PD-1 antagonist are administered in combination at the time of administration. For example, the liposome composition and the PD-1 antagonist are administered to a patient simultaneously, separately, consecutively, or with a time lag. Here, "simultaneously" means that each component is administered within the same period or exactly at the same time, or by the same administration route. Also, it means that each component is administered without a significant interval between them so that they can exert an additive effect, preferably a synergistic effect. "Separately" means that each component is administered at different administration intervals or frequencies, or by different administration routes. "Sequentially" means that each component is administered in any order within a certain period of time by the same or different administration routes. "With a time lag" means that each component is administered by the same or different administration routes with an interval between each administration of each component. When a PD-1 antagonist is administered during one cycle of administration of a liposome composition or during a period during which the cycle is repeated, the two are considered to be administered in combination.

[0073] The form of the combination is not particularly limited, and those skilled in the art can combine the liposome composition and the PD-1 antagonist in various ways.

[0074] When a liposome composition containing eribulin mesylate is combined with nivolumab, for example, eribulin mesylate is administered at 1.7 to 2.1 mg / m on day 1 of a 21-day cycle. 2 (body surface area) intravenously, nivolumab 360 mg intravenously, or eribulin mesylate 1.1 to 1.4 mg / m on days 1 and 15 of a 28-day cycle. 2 (body surface area) intravenously and nivolumab 240 mg intravenously.

[0075] Tumors to be treated in the present disclosure include, for example, breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer, renal cancer, thymic cancer, and intrahepatic bile duct cancer.

[0076] Patients to be treated in the present disclosure are, for example, patients whose disease has progressed during or after completion of prior chemotherapy, such as platinum agents, fluoropyrimidine agents, taxane agents, and combinations thereof.

[0077] In the present disclosure, the patient to be treated is, for example, a patient with advanced, unresectable or recurrent solid cancer for which there is no standard treatment or no other effective treatment (patients who are eligible for administration of nivolumab alone as standard treatment are acceptable). In another embodiment, the patient is, for example, a patient with unresectable gastric cancer, esophageal cancer or small cell lung cancer who has been definitively diagnosed, whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a physician, and who has not been administered other systemic chemotherapy for advanced or recurrent cancer, and who is a gastric cancer patient who has been administered combination chemotherapy including a platinum agent and a fluoropyrimidine drug as first-line chemotherapy, or chemotherapy including a taxane drug as second-line chemotherapy, an esophageal cancer patient who has been administered combination chemotherapy including a platinum agent and a fluoropyrimidine drug (but not including a taxane drug) as first-line chemotherapy, or a small cell lung cancer patient who has been administered combination chemotherapy including a platinum agent as first-line chemotherapy. More specifically, the patient may be, for example, an intrahepatic cholangiocarcinoma patient who has received, as prior treatment, a combination therapy of gemcitabine and cisplatin as first-line treatment and a combination therapy of S-1 and leminostat as second-line treatment, and a thymic carcinoma patient who has received, as prior treatment, a combination therapy of carboplatin and paclitaxel as first-line treatment, S-1 as second-line treatment, and gemcitabine as third-line treatment. EXAMPLES

[0078] A liposome composition containing eribulin mesylate was prepared using the components shown in Table 1 or Table 2 according to the following method and used in the following examples.

[0079] Methods for preparing the liposome compositions of Table 1 <Preparation of aqueous solution for the liposome internal phase> Ammonium sulfate and citric acid monohydrate were dissolved in pure water and diluted to prepare a 200 mM ammonium sulfate / 60 mM citric acid aqueous solution. The pH of the 200 mM ammonium sulfate / 60 mM citric acid aqueous solution was adjusted to pH 5.5 with ammonia water, and then diluted with pure water to obtain a 100 mM ammonium sulfate / 30 mM citric acid aqueous solution.

[0080] <Preparation of liposome preparation solution> Hydrogenated soybean phosphatidylcholine, cholesterol, and MPEG2000-distearoylphosphatidylethanolamine were weighed out in a weight ratio of 71:23:27. Each was dissolved in chloroform, and the solutions were mixed, after which the chloroform was removed under reduced pressure using a rotary evaporator to prepare a lipid film. The aqueous solution for the liposome internal phase prepared above was heated to about 80°C and added to the obtained lipid film, followed by stirring to prepare a liposome preparatory solution. The mixture was sized using an extruder (manufactured by Lipex Biomembranes) heated to about 80°C to obtain a sized liposome preparatory solution.

[0081] <Preparation of liposome dispersion> Using a Sephadex G-50 column, the obtained liposome preparation solution was eluted with 0.9% sodium chloride / 10 mM histidine aqueous solution (pH = 7.6) to replace the liposome external phase with 0.9% sodium chloride / 10 mM histidine aqueous solution. After replacing the liposome external phase, the mixture was centrifuged at 400,000 x g for 30 minutes. After centrifugation, the mixture was redispersed and the liquid volume was adjusted using 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 a 0.9% sodium chloride / 10 mM histidine aqueous solution to obtain an eribulin mesylate solution.

[0083] <Preparation of liposome composition> The liposome dispersion and the eribulin mesylate solution were mixed in a glass container and incubated in a water bath at 60°C for 3 minutes to obtain a liposome composition in which eribulin mesylate was introduced into the liposome internal phase. A 0.9% sodium chloride / 10 mM histidine aqueous solution was added to the liposome composition, and the mixture was sterilized by filtration using a 0.22 µm polyvinylidene fluoride (PVDF) filter to obtain a liposome composition of eribulin mesylate.

[0084] Preparation method 1 of the liposome composition in Table 2 <Preparation of aqueous solution for the liposome internal phase> Ammonium sulfate and citric acid monohydrate were dissolved in pure water. The pH was adjusted to pH 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] <Preparation of liposome preparation solution> The prepared aqueous solution for the liposome internal phase was heated to about 80°C and added to a lipid mixture containing hydrogenated soybean phosphatidylcholine, cholesterol, and MPEG2000-distearoylphosphatidylethanolamine in a weight ratio of 710:232:269, and stirred to prepare a liposome preparatory solution. The mixture was sized using an extruder (manufactured by Lipex Biomembranes) heated to about 80°C, to obtain a sized liposome preparatory solution.

[0086] <Preparation of liposome dispersion> The liposome external phase was replaced with a 96 mg / mL sucrose / 10 mM histidine aqueous solution by tangential flow filtration to obtain a liposome dispersion.

[0087] <Preparation of eribulin mesylate solution> Eribulin mesylate was dissolved in a 96 mg / mL sucrose / 10 mM histidine aqueous solution to obtain an eribulin mesylate solution.

[0088] <Preparation of liposome composition> The liposome dispersion and eribulin mesylate solution were mixed, the pH was adjusted to about 10 using hydrochloric acid or sodium hydroxide, and the mixture was incubated at 60° C. to introduce eribulin mesylate into the liposome internal phase. The pH of this solution was adjusted to 7.5 using hydrochloric acid or sodium hydroxide, and a 9.6% sucrose / 10 mM histidine aqueous solution was added to make the eribulin mesylate concentration 0.2 mg / mL, thereby obtaining a liposome composition of eribulin mesylate.

[0089] Preparation method 2 of the liposome composition in Table 2

[0090] <Preparation of aqueous solution for the liposome internal phase> 105.68 g of ammonium sulfate and 50.40 g of citric acid monohydrate were dissolved in water for injection, and the pH was adjusted to 7.5 using hydrochloric acid or sodium hydroxide to obtain an aqueous solution for the liposome internal phase.

[0091] <Preparation of liposome preparation solution> 106.5 g of hydrogenated soybean phosphatidylcholine, 34.8 g of cholesterol, and 40.35 g of MPEG2000-distearoylphosphatidylethanolamine were dissolved in ethanol and mixed with an aqueous solution for the liposome internal phase that had been heated to about 70° C. Water for injection was added to this mixture to bring the total weight to 8.26 kg, and the mixture was granulated to a particle size of about 80 nm using an extruder (Northern Lipids) that had been heated to about 70° C. to obtain a liposome preparatory solution.

[0092] <Preparation of liposome dispersion> Using a Pellicon 2-cassette ultrafiltration module Biomax (300 kDa), the external phase of the liposome preparation solution was replaced with a 9.6% sucrose / 10 mM histidine aqueous solution (pH = 7.5) to obtain a liposome dispersion.

[0093] <Preparation of eribulin mesylate solution> Eribulin mesylate was dissolved in a 9.6% sucrose / 10 mM histidine aqueous solution to obtain an eribulin mesylate solution.

[0094] <Preparation of liposome composition> The liposome dispersion and eribulin mesylate solution were mixed, the pH was adjusted to about 10 using hydrochloric acid or sodium hydroxide, and the mixture was incubated at 60° C. to introduce eribulin mesylate into the liposome internal phase. The pH of this solution was adjusted to 7.5 using hydrochloric acid or sodium hydroxide, and a 9.6% sucrose / 10 mM histidine aqueous solution was added to make the eribulin mesylate concentration 0.2 mg / mL, thereby obtaining a liposome composition of eribulin mesylate.

[0095] [Example 1] Antitumor effect of low-dose eribulin mesylate (0.1 mg / kg) or a low-dose eribulin mesylate liposomal formulation (0.1 mg / kg) in combination with an anti-mouse PD-1 antibody in a transplant model of P-glycoprotein knockout mouse breast cancer 4T1 cell line (Pgp-KO 4T1)

[0096] P-glycoprotein knockout cell line prepared from mouse breast cancer 4T1 cells (purchased from ATCC) was cultured in RPMI1640 medium (SIGMA) containing 10% FBS (fetal bovine serum), 1 mM sodium pyruvate and antibiotics in a 5% carbon dioxide incubator at 37°C. When the cells reached approximately 80% confluence, they were harvested using trypsin-EDTA. The above medium was added to the harvested cells, and 1.0 × 10 7A suspension was prepared to give a concentration of 1000 cells / mL, and 0.1 mL of the suspension was subcutaneously transplanted into the right side of six mice (BALB / cAJcl, Nippon Clea) in each of the following groups: control group, eribulin mesylate alone group, eribulin mesylate liposome formulation alone group, anti-mouse PD-1 antibody (Bio X cell) alone group, eribulin mesylate and anti-mouse PD-1 antibody combined group, and eribulin mesylate liposome formulation and anti-mouse PD-1 antibody combined group. From the fifth day after transplantation, eribulin mesylate (0.1 mg / kg, once a week, twice in total, administered via tail vein), eribulin mesylate liposome formulation (0.1 mg / kg, once a week, twice in total, administered via tail vein), and anti-mouse PD-1 antibody (200 μg / mouse, once a week, twice in total, administered via tail vein) were administered alone or in combination to the groups administered alone or in combination with anti-mouse PD-1 antibody, respectively. The control group was not administered any drug.The maximum tolerated dose of eribulin mesylate liposomal formulation in mice is 2.5 mg / kg, and the dose of 0.1 mg / kg in this experiment was set as 1 / 25 of the maximum tolerated dose, which is an extremely low dose.

[0097] The P-glycoprotein knockout cell line (Pgp-KO 4T1 cells) was created as follows. A single guide RNA (sgRNA) sequence was designed based on the information of the two types of P-glycoprotein genes (mouse, Abcb1a, and Abcb1b) to be knocked out, and plasmid DNA (U6 promoter) for animal cell expression was created with sgRNAs targeted to each gene inserted (pRGEN_Mouse-Abcb1a_U6_SG_1, and pRGEN_Mouse-Abcb1b_U6_SG_1). In addition, Cas9 expression plasmid DNA (CMV promoter) was created (pRGEN_CMV_Cas9). The created plasmid DNA was purified with NucleoBond Xtra Midi EF and used for cell introduction. First, gene editing was performed on the first gene (Abcb1a) using pRGEN_CMV_Cas9 and pRGEN_Mouse-Abcb1a_U6_SG_1. Mouse breast cancer 4T1 cells (purchased from ATCC) were cultured in RPMI1640 medium (SIGMA) containing 10% FBS (fetal bovine serum) and antibiotics in a 5% carbon dioxide incubator at 37°C, then detached and collected using Trypsin-EDTA, and the above plasmid DNA was introduced into cells at several mixing ratios using a standard method using an electroporator (Nepa Gene). The introduced cells were seeded on a 6-well microplate, and after 3 days of culture, some cells were separated to determine whether genome editing was possible. Genomic DNA was extracted from the separated cells using a standard method and cleavage of genomic DNA was confirmed using T7 Endonuclease I (T7E1) Assay. Cloning was performed from the cells with the mixing ratio condition in which more genomic DNA cleavage was observed as a result of the T7E1 Assay. The cloned cells were expanded and frozen as appropriate, and the gene base sequence was measured by sequence analysis to confirm the mutation of the target gene.From the multiple clonal cells in which mutations were confirmed, one clonal cell line was selected and gene editing of the second gene (Abcb1b) was performed using the same method as above (using pRGEN_CMV_Cas9 and pRGEN_Mouse-Abcb1b_U6_SG_1), and finally a 4T1 cell line in which two types of P-glycoprotein genes (mouse, Abcb1a and Abcb1b) were knocked out (Pgp-KO 4T1 cells).

[0098] The start date of administration was set as day 0, and the long and short diameters of the tumors grown in each mouse were measured using a Digimatic Caliper (Mitutoyo Corporation) on the following days: 3, 7, 10, 13, 16, 20, 23, 27, 30, and 34.

[0099] Tumor volume was calculated according to the following formula: Tumor volume (mm 3 ) = tumor long axis (mm) × tumor short axis 2 (mm 2 ) / 2

[0100] The tumor volume measurements for each group are shown in Figure 1 as the mean and standard deviation (SD). For statistical analysis, the tumor volumes of all groups and on all measurement days were compared with the control group using time-course analysis of variance followed by Dunnett's multiple comparison (*: p<0.05, ***: p<0.001). In addition, a statistical comparison was made between the two groups, the group administered the combination of eribulin mesylate and anti-mouse PD-1 antibody, and the group administered the combination of eribulin mesylate liposomal formulation and anti-mouse PD-1 antibody, using time-course analysis of variance (♯: p<0.05).

[0101] As a result, in the Pgp-KO 4T1 tumor xenograft model, the combination of low-dose eribulin mesylate liposome formulation (0.1 mg / kg) and anti-mouse PD-1 antibody showed a remarkable antitumor effect compared to the control group. In Figure 1, * and *** indicate that the combination of eribulin mesylate liposome formulation and anti-mouse PD-1 antibody inhibited tumor growth statistically significantly compared to the control group. Also, ♯ indicates that the combination of eribulin mesylate liposome formulation and anti-mouse PD-1 antibody inhibited tumor growth statistically significantly compared to the combination of eribulin mesylate and anti-mouse PD-1 antibody. On the other hand, no antitumor effect was observed with low-dose eribulin mesylate (0.1 mg / kg) alone, eribulin mesylate liposome formulation (0.1 mg / kg) alone, anti-mouse PD-1 antibody alone, or the combination of eribulin mesylate (0.1 mg / kg) and anti-mouse PD-1 antibody.

[0102] In the same experiment, the results of comparing the time period until the tumor volume exceeded 5 times the amount on the day of administration (T×5) between groups are shown in Figure 2, and the median value of T×5 in each group and the ratio (%) to the control group are shown in Table 3. For statistical analysis, a Log-rank test was performed to compare with the control group, and the Bonferroni adjusted p value was calculated (*: p<0.05).

[0103] As a result, in the Pgp-KO 4T1 tumor xenograft model, the combined administration of eribulin mesylate liposome formulation (0.1 mg / kg) and anti-mouse PD-1 antibody extended the tumor growth inhibition period (TX5) by 243%. On the other hand, the combined administration of low doses of eribulin mesylate (0.1 mg / kg), eribulin mesylate liposome formulation (0.1 mg / kg), anti-mouse PD-1 antibody, and the combined administration of eribulin mesylate and anti-mouse PD-1 antibody did not extend the tumor growth inhibition period. * in Table 3 indicates that the combined administration of eribulin mesylate liposome formulation (0.1 mg / kg) and anti-mouse PD-1 antibody extended the tumor growth inhibition period statistically significantly compared to the control group.

[0104] [Table 3]

[0105] [Example 2] Antitumor effect of low-dose eribulin mesylate (0.3 mg / kg) or a combination of low-dose eribulin mesylate liposomal formulation (0.3 mg / kg) and anti-mouse PD-1 antibody in a Pgp-KO 4T1 cell line transplant model Pgp-KO 4T1 cells were cultured in RPMI1640 medium containing 10% FBS, 1 mM sodium pyruvate, and antibiotics in a 5% carbon dioxide incubator at 37°C. When the cells reached approximately 80% confluence, they were harvested using trypsin-EDTA. The above medium was added to the harvested cells, and 1.0 × 10 7 The suspension was prepared to give a cell concentration of 1000 cells / mL. 0.1 mL of the cell suspension was subcutaneously transplanted into the right side of six mice (BALB / cAJcl, Japan CLEA) in each of the following groups: control group, eribulin mesylate liposome preparation alone administration group, anti-mouse PD-1 antibody (Bio X cell) alone administration group, and eribulin mesylate liposome preparation and anti-mouse PD-1 antibody combined administration group. From the fourth day after transplantation, eribulin mesylate liposome preparation (0.3 mg / kg, once a week, twice in total, administered via tail vein) and anti-mouse PD-1 antibody (200 μg / mouse, once a week, twice in total, administered via tail vein) were administered alone or in combination to the single administration group or combined administration group, respectively. The control group was not administered any drug.

[0106] The first day of administration was set as day 0, and the long and short diameters of the tumors grown in each mouse were measured using a Digimatic Caliper (Mitutoyo Corporation) on the following days: 3, 7, 9, 13, 17, 20, 24, 27, 31, 34, 38, 41, 44, 48, and 51.

[0107] Tumor volume was calculated according to the following formula: Tumor volume (mm 3 ) = tumor long axis (mm) × tumor short axis 2 (mm 2 ) / 2

[0108] The mean and standard deviation (SD) of the tumor volume measurement results for each group are shown in Figure 3, and the frequency of mice in which tumors disappeared is shown in Table 4. Statistical analysis was performed by time-course analysis of variance between the group administered eribulin mesylate liposome formulation alone or the group administered anti-mouse PD-1 antibody alone and the group administered eribulin mesylate liposome formulation in combination with anti-mouse PD-1 antibody (†, #: p<0.05).

[0109] As a result, in the Pgp-KO 4T1 tumor xenograft model, the combination of low-dose eribulin mesylate liposome formulation (0.3 mg / kg) and anti-mouse PD-1 antibody showed superior antitumor effects compared to the groups administered eribulin mesylate liposome formulation alone or anti-mouse PD-1 antibody alone. In Figure 3, (†) indicates that the combination of eribulin mesylate liposome formulation and anti-mouse PD-1 antibody inhibited tumor growth statistically significantly more than the group administered eribulin mesylate liposome formulation alone, and (#) indicates that the combination of eribulin mesylate liposome formulation and anti-mouse PD-1 antibody inhibited tumor growth statistically significantly more than the group administered anti-mouse PD-1 antibody alone. In addition, the group administered eribulin mesylate liposome formulation (0.3 mg / kg) and anti-mouse PD-1 antibody in combination showed a higher frequency of tumor disappearance than the other groups.

[0110] [Table 4]

[0111] In addition, in the same experiment, the results of the comparison of the time until the tumor volume exceeded 5 times the amount on the day of administration (T×5) between the groups are shown in Figure 4, and the median T×5 value in each group and the ratio (%) to the control group are shown in Table 5. For statistical analysis, a Log-rank test was performed between the group administered anti-mouse PD-1 antibody alone and the group administered eribulin mesylate liposome preparation in combination with anti-mouse PD-1 antibody (#: p<0.05).

[0112] As a result, in the Pgp-KO 4T1 tumor xenograft model, the combined administration of eribulin mesylate liposome formulation (0.3 mg / kg) and anti-mouse PD-1 antibody showed an effect of extending the period of tumor growth inhibition (T x 5) compared to the control group, the group administered eribulin mesylate liposome formulation alone, and the group administered anti-mouse PD-1 antibody alone. # in Table 5 indicates that the combined administration of eribulin mesylate liposome formulation and anti-mouse PD-1 antibody statistically significantly extended the period of tumor growth inhibition compared to the administration of anti-mouse PD-1 antibody alone.

[0113] [Table 5]

[0114] [Example 3] Antitumor effect of low-dose eribulin mesylate (0.3 mg / kg) or a low-dose eribulin mesylate liposomal formulation (0.3 mg / kg) in combination with an anti-mouse PD-1 antibody in a transplant model of P-glycoprotein knockout mouse colon cancer CT-26 cell line (Pgp-KO CT-26)

[0115] A P-glycoprotein knockout cell line (Pgp-KO CT-26) was generated from mouse colon cancer CT-26 cells (purchased from ATCC) using the same materials and procedures as those for generating Pgp-KO 4T1 cells. Pgp-KO CT-26 cells were cultured in RPMI1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% FBS (fetal bovine serum) and antibiotics in a 5% carbon dioxide incubator at 37°C. When the cells reached approximately 80% confluence, they were harvested using trypsin-EDTA. HBSS was added to the harvested cells, and 2.0 × 10 7A suspension was prepared to give a concentration of 1000 cells / mL, and 0.1 mL of the suspension was subcutaneously transplanted into the right side of seven mice (BALB / cAJcl, Nippon Clea) in each of the following groups: control group, eribulin mesylate alone group, eribulin mesylate liposome formulation alone group, anti-mouse PD-1 antibody (Bio X cell) alone group, eribulin mesylate and anti-mouse PD-1 antibody combined group, and eribulin mesylate liposome formulation and anti-mouse PD-1 antibody combined group. From the 15th day after transplantation, eribulin mesylate (0.3 mg / kg, once a week, three times in total, administered via tail vein), eribulin mesylate liposome formulation (0.3 mg / kg, once a week, three times in total, administered via tail vein), and anti-mouse PD-1 antibody (200 μg / mouse, once a week, three times in total, administered via tail vein) were administered alone or in combination to the groups administered alone or in combination with anti-mouse PD-1 antibody, respectively. The control group received no drug.

[0116] The day administration began was designated day 0, and over the course of the 18th day, the major and minor diameters of the tumors that had grown in each mouse were measured using a Digimatic Caliper (manufactured by Mitutoyo Corporation).

[0117] Tumor volume was calculated according to the following formula: Tumor volume (mm 3 ) = tumor long axis (mm) × tumor short axis 2 (mm 2 ) / 2

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

[0119] As a result, in the Pgp-KO CT-26 tumor xenograft model, the combination of low-dose eribulin mesylate liposome formulation (0.3 mg / kg) and anti-mouse PD-1 antibody showed a significant antitumor effect compared to the control group. The * in Table 6 indicates that the combination of eribulin mesylate liposome formulation and anti-mouse PD-1 antibody inhibited tumor growth statistically significantly compared to the control group. On the other hand, the combination of low-dose eribulin mesylate (0.3 mg / kg) alone, eribulin mesylate liposome formulation (0.3 mg / kg) alone, anti-mouse PD-1 antibody alone, and the combination of eribulin mesylate (0.3 mg / kg) and anti-mouse PD-1 antibody did not show a significant antitumor effect compared to the control group.

[0120] [Table 6]

[0121] [Example 4] Antitumor effect of combined administration of low-dose eribulin mesylate liposomal formulation (0.3 mg / kg) and anti-mouse PD-1 antibody in a mouse renal cancer RAG cell line transplant model

[0122] The RAG cells used in the transplantation model (purchased from ATCC) were previously conditioned in mice (BALB / cAnNCrlCrlj, Charles River Japan). RAG cells were diluted in HBSS (Wako Pure Chemical Industries, Ltd.) at 2 × 10 8 The cells were suspended at a concentration of 1000 / mL. The same volume of MatrigelTM matrix (Becton Dickinson Japan Co., Ltd.) was added to the suspension and mixed thoroughly. 0.1 mL of the mixture was transplanted into the subcutaneous tissue of the right flank of each mouse. 38 days after transplantation, the formed tumor was excised and cut into small pieces, and Tumor Dissociation Kit, Mouse (Military) was added and stirred using Gentle MACS (Military). After passing through a 70 μm cell strainer, the cells were centrifuged to collect them, and they were cultured in EMEM medium (Wako Pure Chemical Industries, Ltd.) containing 10% bovine serum at 37°C in a 5% carbon dioxide incubator, and then frozen and stored. The cells obtained by the above treatment were cultured in EMEM medium containing 10% FBS and antibiotics, and when the cells reached about 80% confluence, they were harvested using trypsin-EDTA. HBSS was added to the harvested cells, and 2.5 × 10 7 A suspension was prepared to give a cell density of 1000 cells / mL. 0.1 mL of the cell suspension was transplanted subcutaneously into the right side of 10 mice (BALB / cAnNCrlCrlj, Charles River Japan) in each of the following groups: control group, eribulin mesylate liposome preparation alone administration group, anti-mouse PD-1 antibody (Bio X cell) alone administration group, and eribulin mesylate liposome preparation and anti-mouse PD-1 antibody combination administration group. From day 6 after transplantation, eribulin mesylate liposome preparation (0.3 mg / kg, once a week, a total of three times, administered via tail vein) and anti-mouse PD-1 antibody (200 μg / mouse, once a day, a total of 10 times, administered intraperitoneally) were administered alone or in combination to the single administration group or combination administration group, respectively. The control group was not administered any drug.

[0123] The first day of administration was set as day 0, and the long and short diameters of the tumors grown in each mouse were measured using a Digimatic Caliper (Mitutoyo Corporation) on the following days: 3, 7, 10, 14, 17, 21, 24, 28, 31, 35, 38, and 42.

[0124] Tumor volume was calculated according to the following formula: Tumor volume (mm 3 ) = tumor long axis (mm) × tumor short axis 2 (mm 2 ) / 2

[0125] The frequency of mice in each group that showed a tumor shrinkage of at least 50% is shown as the response rate in Table 7, and the frequency of mice in which the tumor disappeared is shown in Table 7. Statistical analysis was performed by comparing the eribulin mesylate liposomal formulation group alone, the anti-mouse PD-1 antibody group alone, and the eribulin mesylate liposomal formulation and anti-mouse PD-1 antibody combination administration group with the control group using 2-sided Fisher's exact test (*: p<0.05).

[0126] As a result, in the RAG tumor transplant model, the combination of low-dose eribulin mesylate liposome preparation (0.3 mg / kg) and anti-mouse PD-1 antibody showed higher efficacy than the group administered eribulin mesylate liposome preparation alone or the group administered anti-mouse PD-1 antibody alone. (*) in Table 7 indicates that the combination of eribulin mesylate liposome preparation and anti-mouse PD-1 antibody was statistically significantly effective. On the other hand, no significant efficacy was observed in the group administered eribulin mesylate liposome preparation (0.3 mg / kg) alone or the anti-mouse PD-1 antibody alone. In addition, the group administered the combination of eribulin mesylate liposome preparation (0.3 mg / kg) and anti-mouse PD-1 antibody showed a higher frequency of tumor disappearance than the other groups.

[0127] [Table 7]

[0128] [Table 8]

[0129] [Example 5] An open-label phase 1b / 2 study of eribulin mesylate liposomal formulation in combination with nivolumab in patients with solid tumors

[0130] The Phase 1b part of this clinical trial will involve patients with solid tumors for which there is no standard or other effective treatment, while the Phase 2 part will involve patients with esophageal cancer whose disease has progressed during or after first-line chemotherapy (combination chemotherapy including a platinum agent and a fluoropyrimidine drug), patients with small cell lung cancer whose disease has progressed during or after first-line chemotherapy (combination chemotherapy including a platinum agent), or patients with gastric cancer whose disease has progressed during or after second-line chemotherapy (combination chemotherapy including a platinum agent and a fluoropyrimidine drug as first-line chemotherapy, and chemotherapy including a taxane drug as second-line chemotherapy).This is a multicenter, single-arm, open-label study.

[0131] This clinical trial consists of three periods: pre-treatment, treatment, and follow-up (Phase 2 only). The pre-treatment period included screening to confirm eligibility and baseline to confirm disease status, and was within 28 days. During the treatment period, subjects received eribulin mesylate liposomal formulation and nivolumab. Tumor evaluations were performed every 6 weeks from the start of treatment. The follow-up period (Phase 2 only) began after cessation of eribulin mesylate liposomal formulation and nivolumab, and investigated subjects' survival and follow-up treatment.

[0132] In the Phase 1b part, two dosing methods were investigated: Schedule 1 and Schedule 2. In Schedule 1, eribulin mesylate liposomal formulation and nivolumab were administered intravenously on Day 1 of a 21-day cycle, with the dose of nivolumab at 360 mg and the dose of eribulin mesylate liposomal formulation (as mesylate) at 1.7 or 2.1 mg / m 2 In Schedule 2, eribulin mesylate liposomal formulation and nivolumab were administered intravenously on Days 1 and 15 of a 28-day cycle, with the dose of nivolumab at 240 mg and the dose of eribulin mesylate liposomal formulation (as mesylate) at 1.1 or 1.4 mg / m 2 It was decided.

[0133] Phase 2 will use the recommended dosing regimen determined in Phase 1b.

[0134] The primary objectives of this study are to evaluate the safety and tolerability of the combination of eribulin mesylate liposomal formulation and nivolumab, to determine the recommended dosage for Phase 2 (Phase 1b part), and to evaluate the objective response rate for each cancer type at the recommended dosage (Phase 2 part). The secondary objectives of this study are to evaluate the safety, pharmacokinetics, and progression-free survival of the combination of eribulin mesylate liposomal formulation and nivolumab.

[0135] Patients who meet all of the following criteria will be eligible for this clinical trial. Selection Criteria (1) Phase 1b part only: Patients with advanced, unresectable or recurrent solid cancers for which there is no standard or other effective treatment (patients who are eligible for single agent nivolumab as standard treatment are accepted) (2) 2-phase part only: Patients with unresectable gastric cancer, esophageal cancer, or small cell lung cancer who have been definitively diagnosed and whose disease has progressed during or after the completion of first-line chemotherapy (second-line chemotherapy in the case of gastric cancer) as determined by a physician, and who have not received other systemic chemotherapy for advanced or recurrent cancer. (3) Phase 2 part only: Patients who received the following chemotherapy as pre-chemotherapy Gastric cancer: First-line chemotherapy with combination chemotherapy including platinum agents and fluoropyrimidine drugs, second-line chemotherapy with chemotherapy including taxane drugs Esophageal cancer: First-line chemotherapy with combination chemotherapy including platinum agents and fluoropyrimidine drugs (but not including taxane drugs) Small cell lung cancer: Platinum-containing combination chemotherapy as first-line chemotherapy (4) Patients who have tumor lesions that can be biopsied and who agree to undergo tumor biopsy before and after administration of the investigational drug (if a biopsy cannot be performed before administration due to safety concerns, submission of preserved tumor samples will be permitted). (5) Patients expected to survive for 12 weeks or longer (6) Patients with ECOG-PS 0-1 (7) Japanese aged 20 years or older at the time of obtaining informed consent (8) Patients whose adverse events due to previous cancer treatment (excluding alopecia and Grade 2 peripheral neuropathy) have recovered to Grade 0-1 (kidney / bone marrow / liver / pancreas functions meet the inclusion criteria) (9) Patients who have completed the following period from the end of previous treatment to C1D1 (cycle 1 day 1): a) Non-cytotoxic anticancer drugs: 4 weeks or more (or 5 half-lives, whichever is shorter) b) Cytotoxic chemotherapy and radiotherapy: 3 weeks or more c) Anti-cancer drug therapy with antibody preparations: 4 weeks or more d) Investigational new drug or medical device: 4 weeks or more e) Blood transfusion, platelet transfusion, or G-CSF preparation: 2 weeks or more f) Live or attenuated vaccines: 4 weeks or more (10) Patients with adequate renal function: Serum creatinine ≦1.5 × upper limit of normal (ULN) (if >1.5 × ULN, creatinine clearance by Cockcroft-Gault method ≧40 mL / min is required) (11) Patients with adequate bone marrow function: a) Neutrophil count ≥ 2,000 / mm 3 b) Platelet count ≧100,000 / mm 3 c) Hemoglobin ≥ 8.5g / dL (12) Patients with adequate liver function: a) Anticoagulant capacity: International normalized ratio (INR) ≦ 1.5 b) Total bilirubin ≦1.5×ULN (≦3.0×ULN in Gilbert syndrome) c) Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN if liver disease is present) (13) Patients with adequate pancreatic function: amylase and lipase ≦1.5×ULN (≦3×ULN if pancreatic lesions exist) (14) Phase 2 part only: Patients with measurable lesions according to RECIST 1.1 (if a lesion treated with radiation therapy or local therapy is considered a measurable lesion, the lesion must have progressed) (15) Patients who can provide written consent and comply with the clinical trial protocol

[0136] Patients who fall under any of the following categories will be excluded from this clinical trial. Exclusion criteria (1) Patients with any of the following heart diseases: New York Heart Association (NYHA) Class II or higher heart failure - Unstable ischemic heart disease (myocardial infarction within 6 months prior to C1D1, angina requiring nitrates more than twice a week) Prolonged QT interval (QTcF>480ms) (2) Patients with a history of hypersensitivity reactions to liposome preparations (3) Patients who underwent major surgery within 21 days of C1D1 (4) Patients with a history of eribulin or nivolumab (5) Patients who have experienced Grade 3 or higher immune-related adverse events or discontinued treatment due to anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody, or other antibodies and drugs targeting T cell costimulation or checkpoints, or cancer vaccines (6) Patients who have been shown to have intolerance to investigational drugs or additives, or antibody preparations (7) Patients who are known to be human immunodeficiency virus (HIV) positive or have acquired immune deficiency syndrome (AIDS) (8) Patients with active type B or type C viral hepatitis (hepatitis B surface antigen [HBs] positive, HBs antigen negative but HBs antibody positive or HBc antibody positive and HBV-DNA positive, or HCV-RNA positive). (9) Patients with active infections requiring systemic treatment within 14 days of C1D1 (10) Patients with membranous carcinomatosis (11) Patients with brain or subdural metastasis / invasion, except for patients who have completed local treatment and discontinued corticosteroids 4 weeks prior to C1D1. Signs (e.g., radiological) and symptoms must be stable for 4 weeks prior to C1D1. (12) Patients with pulmonary lymphangitis who are in a state of respiratory failure requiring active treatment (including oxygen inhalation) (13) Patients with an active or known autoimmune disease, or suspected of having such a disease, except for the following: Vitiligo, type I diabetes, and recovered childhood asthma or atopic dermatitis patients Patients suspected of having an autoimmune thyroid disorder who currently have normal thyroid function or who have residual hypothyroidism and can maintain normal thyroid function with hormone replacement therapy alone (14) Patients with interstitial lung disease or pulmonary fibrosis diagnosed clinically or by imaging, or with a history of such disease (patients with radiation pneumonitis whose fibrosis has been confirmed to be stable and who have no concerns about recurrence are eligible). (15) Patients with a history of organ transplantation who require the administration of immunosuppressants (16) Patients who have a condition requiring systemic administration of corticosteroids (equivalent to more than 10 mg / day of prednisolone) or other immunosuppressants within 14 days of C1D1. Patients who are using inhaled or topical corticosteroids (if they are poorly absorbed) may be enrolled if they have no active autoimmune disease. (17) Phase 2 part only: Patients with active malignant tumors within 24 months of C1D1 (excluding primary disease, completely treated non-invasive melanoma, basal cell carcinoma / squamous cell carcinoma of the skin, non-invasive cervical cancer / bladder cancer, and early gastric cancer / colorectal cancer) (18) Patients with clinically significant diseases / conditions (e.g., cardiac, respiratory, gastrointestinal, or renal diseases) that the investigator or co-investigator determines may affect the safety of the subject or the evaluation of the study. (19) In the case of females, patients who are breastfeeding or pregnant at screening or baseline (patients with a positive human chorionic gonadotropin [hCG] or human chorionic gonadotropin beta subunit [β-hCG] test). If the test is negative at screening but not performed within 72 hours of C1D1, the test should be repeated. (20) For men of reproductive potential and women of childbearing potential, they and their partners must use medically appropriate contraception during the study period and for 5 months (7 months for male subjects) after the end of study drug administration. 注) Patients who do not consent to using Note) Dual contraception using two of the following: vasectomy, tubal ligation, use of condoms*, contraceptive sponges**, contraceptive foams**, contraceptive jelly**, contraceptive pessaries*, contraceptive rings*, or use of oral contraceptives* for at least 28 days prior to the start of administration of this study drug (whether or not the drug or medical device has been approved or certified in Japan [*: Yes, **: No])

[0137] Administration of eribulin mesylate liposomal formulation and nivolumab was to be continued until disease progression, the occurrence of intolerable side effects, the subject's desire to discontinue treatment, consent withdrawal, or termination of the trial by the sponsor.

[0138] Interim results from Phase 1b Case 1 One case of intrahepatic cholangiocarcinoma (Schedule 2, eribulin mesylate liposomal formulation dose 1.1 mg / m 2 ) Patients who had received gemcitabine and cisplatin combination therapy as first-line treatment, S-1 and reminostat combination therapy as second-line treatment, and an investigational drug (details unknown) as third-line treatment were randomized to receive eribulin mesylate liposomal formulation at a dose of 1.1 mg / m2 in Schedule 2. 2 and nivolumab 240 mg administered once every 2 weeks. After administration, the sum of the diameters of the target lesions from baseline had decreased by 10.3%, 14.7%, 23.5%, 40.8%, 46.2%, and 51.4%, respectively, at Week 6 / 12 / 18 / 24 / 30 / 36, and were judged to be partial responses.

[0139] Case 2 One case of thymic carcinoma (Schedule 1, dose of eribulin mesylate liposomal formulation was 1.7 mg / m 2 ) Patients who had received carboplatin and paclitaxel combination therapy as first-line treatment, S-1 as second-line treatment, gemcitabine as third-line treatment, an investigational drug (unspecified and combination with anti-PD-L1 antibody) as fourth-line treatment, and an investigational drug (unspecified) as fifth-line treatment were randomized to receive eribulin mesylate liposomal formulation at a dose of 1.7 mg / m2 in Schedule 1. 2 and nivolumab 360 mg administered once every 3 weeks. After administration, as of Week 6 / 12 / 18, the sum of the diameters of the target lesions from baseline had decreased by 17.8%, 100%, and 100%, respectively, and were judged to be partial responses.

Claims

1. A pharmaceutical composition for tumor treatment comprising a liposome composition containing eribulin or a pharma- ceutically acceptable salt thereof, characterized in that it is administered in combination with an anti-programmed cell death 1 protein (PD-1) antibody.

2. A pharmaceutical composition for tumor treatment comprising an anti-programmed cell death 1 protein (PD-1) antibody, characterized in that it is administered in combination with a liposome composition containing eribulin or a pharma- ceutical acceptable salt thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein the liposome composition comprising eribulin or a pharma- ceutical acceptable salt thereof and the anti-PD-1 antibody are administered simultaneously, separately, sequentially, or with a time lag.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the eribulin or a pharma- ceutically acceptable salt thereof is eribulin mesylate.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab and toripalimab.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the anti-PD-1 antibody is nivolumab, and nivolumab is administered at a dose of 3 mg / kg (body weight) every 2 weeks, at a dose of 240 mg every 2 weeks, at a dose of 360 mg every 3 weeks, or at a dose of 480 mg every 4 weeks.

7. The eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.7 to 2.1 mg / m on day 1 of a 21-day cycle. ２ The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is administered intravenously at a dose of 360 mg / kg (body surface area) and nivolumab is administered intravenously at a dose of 360 mg / kg.

8. The eribulin or a pharma- ceutical acceptable salt thereof is eribulin mesylate, the anti-PD-1 antibody is nivolumab, and eribulin mesylate is administered at 1.1 to 1.4 mg / m on days 1 and 15 of a 28-day cycle. ２ The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is administered intravenously at a dose of 240 mg / kg (body surface area) and nivolumab is administered intravenously at a dose of 240 mg / kg.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer, renal cancer, thymic cancer, or intrahepatic bile duct cancer.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the tumor is breast cancer, gastric cancer, esophageal cancer, small cell lung cancer, colon cancer or renal cancer.

11. The pharmaceutical composition according to any one of claims 1 to 8, wherein the tumor is breast cancer.

12. The pharmaceutical composition according to any one of claims 1 to 8, wherein the tumor is gastric cancer.

13. The pharmaceutical composition according to any one of claims 1 to 8, wherein the tumor is esophageal cancer.

14. The pharmaceutical composition according to any one of claims 1 to 8, wherein the tumor is small cell lung cancer.

15. The pharmaceutical composition according to any one of claims 1 to 8, wherein the tumor is intrahepatic bile duct cancer.

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