Cancer therapy by combination with CD47 inhibitory substance, immune checkpoint inhibitory substance and standard therapy

Abstract

To provide a therapeutic agent of cancer.SOLUTION: Provided are a progression inhibitory agent, a recurrence inhibitory agent and / or a therapeutic agent of solid cancer which contains a CD47 inhibitory substance as an active ingredient, and is administered in combination with standard therapy and immune checkpoint inhibitory substance, where the standard therapy is FOLFIRINOX therapy or low dose regimen thereof, the immune checkpoint inhibitory substance is Nivolumab, the CD47 inhibitory substance is Magrolimab, solid cancer is pancreatic cancer having distant metastasis.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to a cancer treatment method using a CD47 inhibitor, an immune checkpoint inhibitor, and a standard therapy in combination (sometimes abbreviated as the treatment method of the present invention), and the like. [Background technology]

[0002] CD47 is a five-transmembrane glycoprotein, and CD47 expressed on cancer cells binds to signal regulatory protein alpha (SIRPα) expressed on macrophages and dendritic cells, thereby transmitting a "don't eat me" signal to macrophages and is involved in suppressing the phagocytosis of cancer cells by macrophages. CD47 inhibitors bind to CD47 on the cancer cell membrane, inhibiting the transmission of the "don't eat me" signal to macrophages and promoting the phagocytosis of cancer cells by macrophages, and are therefore considered to be useful in cancer treatment (see Non-Patent Documents 1 to 4).

[0003] Patent Document 1 discloses that a CD47 inhibitor promotes the phagocytosis of cancer cells by macrophages and is useful as a cancer therapeutic agent (see Patent Document 1).

[0004] On the other hand, various immune checkpoint molecules that inhibit immune responses against cancer exist in cancer cells and the cancer microenvironment. Immune checkpoint inhibitors are a new treatment that releases immune suppression mechanisms and activates immune responses against cancer. Immune checkpoint inhibitors, such as the anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) antibody ipilimumab and the anti-PD-1 (programmed cell death-1) antibodies nivolumab and pembrolizumab, have already been approved in Japan and overseas and are being used in cancer treatment.

[0005] Chemotherapy is applied to unresectable advanced or recurrent colorectal cancer, and the standard treatment is a combination therapy of FOLFOX therapy, which combines fluorouracil (5-FU), levofolinate, and oxaliplatin, with bevacizumab, a molecular targeted drug for vascular endothelial growth factor (VEGF), or cetuximab or panitumumab, a molecular targeted drug for epidermal growth factor receptor (EGFR).

[0006] The main treatment for unresectable pancreatic cancer with distant metastasis is chemotherapy, and the standard treatment is FOLFIRINOX therapy (hereinafter sometimes abbreviated as "FFX therapy"), which combines a regimen containing fluorouracil (5-FU) with oxaliplatin and irinotecan, and modified FOLFIRINOX therapy (hereinafter sometimes abbreviated as "mFFX therapy"), which omits the rapid administration of fluorouracil and reduces the dose of irinotecan in the hope of reducing toxicity from FFX therapy.

[0007] Although these treatments have shown some efficacy, there remains an unmet need for further treatments that can extend survival. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO2009 / 091601 [Non-patent literature]

[0009] [Non-Patent Document 1] Trends in Cell Biology, Vol. 11(3), pp. 130-135, 2001. [Non-Patent Document 2] Journal of Experimental Medicine, Vol. 194(4), pp. 541-549, 2001 [Non-Patent Document 3] Journal of Immunology, Vol. 174(4), pp. 2004-2011, 2005 [Non-Patent Document 4] Cell, Vol. 138(2), pp. 286-299, 2009 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a new method for treating cancer (e.g., colon cancer, pancreatic cancer). [Means for solving the problem]

[0011] Means for Solving the Problems The present inventors conducted intensive research to solve the above problems and discovered that combining standard therapy with a CD47 inhibitor and an immune checkpoint inhibitor could be an effective cancer treatment method.

[0012] Thus, in one embodiment, [1] An agent for inhibiting progression, inhibiting recurrence and / or treating solid cancer, comprising a CD47 inhibitor as an active ingredient, which is administered in combination with standard therapy and an immune checkpoint inhibitor; [2] Provided is an agent for inhibiting the progression and recurrence of and / or treating solid cancer, which contains an immune checkpoint inhibitor as an active ingredient and is administered in combination with standard therapy and a CD47 inhibitor. Effect of the Invention

[0013] The therapeutic methods of the present invention are useful in the treatment of cancer. [Brief description of the drawings]

[0014] [Figure 1]Figure 1 shows an overview of a multicenter, open-label, uncontrolled study evaluating the tolerability, safety, and efficacy of Magrolimab, Nivolumab, and FOLFOX therapy plus bevacizumab or cetuximab in combination in patients with unresectable advanced or recurrent colorectal cancer, as described below. [Diagram 2] Figure 2 shows an overview of a multicenter, open-label, uncontrolled study evaluating the tolerability, safety, and efficacy of Magrolimab, Nivolumab, and the mFFX therapy described below in combination in patients with pancreatic cancer with distant metastasis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] (1) CD47 inhibitors In the present invention, the CD47 inhibitor is not particularly limited as long as it is a compound having a CD47 inhibitory effect. In one embodiment, the CD47 inhibitor is an agent (preferably an antibody, more preferably a monoclonal antibody) that inhibits the binding of CD47 to SIRPα, and examples of such agents include an anti-CD47 antibody, an anti-SIRPα antibody, and an antigen-binding fragment of the antibody (e.g., Fv, Fab, Fab', (Fab') 2, scFv, scFv-Fc). Examples of anti-CD47 antibodies include Magrolimab (Hu5F9-G4), CC-90002, STI-6643, ZL-1201, TAY-018, SGN-CD47M, GenSci-059, lemzoparlimab, letaplimab, IMC-002, SHR-1603, AO-176, AVI-105, MIL-95, AK-117, HLX-24, SG-404, SY-102, IMM-01, KD-015, BAT-6004, ALX-148, SRF-231, TJ-011133, letaplimab, TQB-2928, AL-008, JMT-601, and DSP-107. Examples of anti-SIRPα antibodies include ES-004, CTX-5861, ADU-1805, BI-765063, BYON-4228, FSI-189, and CC-95251. CD47 inhibitors may be used alone or in combination of two or more. A preferred CD47 inhibitor is an anti-CD47 antibody, and a preferred anti-CD47 antibody is Magrolimab (CAS number: 2169232-81-7). In addition, an antibody or an antigen-binding fragment thereof comprising the heavy and light chain complementarity determining regions (CDRs) or variable regions (VR) of the above-mentioned known antibodies is also an embodiment of the CD47 inhibitor. For example, a further embodiment of the anti-CD47 antibody includes an antibody or an antigen-binding fragment thereof comprising the heavy and light chain complementarity determining regions (CDRs) or variable regions (VR) of Magrolimab. Furthermore, one embodiment of the anti-CD47 antibody includes an antibody that competes with Magrolimab for binding to CD47, or an antibody that binds to the same CD47 epitope as Magrolimab, or an antigen-binding fragment thereof.

[0016] In the present invention, the CD47 inhibitor can be produced according to known methods. For example, Magrolimab can be produced in accordance with the method described in WO2011 / 143624.

[0017] The dosage of the CD47 inhibitor used in the treatment of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., and is adjusted so as to achieve the optimal desired effect.

[0018] For example, the therapeutically effective dose (therapeutic dose) of an anti-CD47 antibody (e.g., Magrolimab) in one embodiment is about 15 mg / kg to about 60 mg / kg (preferably about 15 mg / kg to about 45 mg / kg, more preferably about 15 mg / kg to about 30 mg / kg, and in preferred embodiments, about 15 mg / kg, about 20 mg / kg, about 30 mg / kg, about 45 mg / kg). The administration interval may be, for example, half a week (3 or 4 days), one week, or two weeks, and the administration time may be, for example, about 60 minutes or more, about 90 minutes or more, about 120 minutes or more, or about 2 hours (± 30 minutes). Of course, as described above, the dosage varies depending on various conditions, so that a dosage less than the above dosage may be sufficient, or it may be necessary to administer the drug beyond the range. In one embodiment, the therapeutic dose may be gradually increased in order to optimize safety and efficacy.

[0019] In one embodiment, a priming agent is administered before a therapeutically effective dose of an anti-CD47 antibody (e.g., Magrolimab) is administered. Suitable priming agents include an erythropoiesis stimulating agent (ESA) and / or an initial dose of an anti-CD47 antibody (e.g., Magrolimab). After administration of the priming agent, a period effective for increasing reticulocyte production is allowed (e.g., at least about 3 days (e.g., at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, or at least about 10 days) after administration of the priming agent), and then a therapeutic dose of an anti-CD47 antibody (e.g., Magrolimab) is administered. A specific suitable initial dose of an anti-CD47 antibody (e.g., Magrolimab) is, in one embodiment, about 0.5 mg / kg to about 5 mg / kg (preferably about 1 mg / kg) and is administered intravenously over about 2.5 hours to about 6 hours (e.g., about 3 hours to about 4 hours, or about 3 hours (±30 minutes)). In one embodiment, the anti-CD47 antibody (e.g., Magrolimab) is administered intravenously at about 1 mg / kg for the initial administration, and from the second administration onwards, about 15 mg / kg to about 30 mg / kg (preferably about 20 mg / kg or about 30 mg / kg) is administered intravenously at weekly or biweekly intervals.

[0020] (2) Immune checkpoint inhibitors In the present invention, an immune checkpoint molecule means a molecule that exerts an immunosuppressive function by transmitting an inhibitory co-signal. Immune checkpoint molecules include CTLA-4, PD-1, PD-L1 (programmed cell death-ligand 1), PD-L2 (programmed cell death-ligand 2), LAG-3 (lymphocyte activation gene 3), TIM3 (T cell immunoglobulin and mucin-3), BTLA (B and T lymphocyte attenuator), B7H3, B7H4, CD160, CD39, CD73, A2aR (adenosine A2a receptor), KIR (killer inhibitory receptor), VISTA (V-domain Ig-containing suppressor of T cell activation), IDO1 (indoleamine 2,3-dioxygenase), Arginase I, TIGIT (T cell immunoglobulin and ITIM domain), and CD115 (Nature Reviews Cancer, 12, pp. 252-264, 2012). Cell, 27, pp. 450-461, 2015), is not particularly limited as long as it is a molecule having a function that meets the definition.

[0021] In the present invention, an immune checkpoint inhibitor is a substance that inhibits the function of an immune checkpoint molecule. There are no particular limitations on the immune checkpoint inhibitor, so long as it is a substance that can suppress the function (signal) of an immune checkpoint molecule. One type of immune checkpoint inhibitor may be used alone, or two or more types may be used in combination. A preferred immune checkpoint inhibitor is an antibody (preferably a monoclonal antibody) or an antigen-binding fragment thereof (e.g., Fv, Fab, Fab', (Fab') 2 , scFv, and scFv-Fc).

[0022] Examples of immune checkpoint inhibitors include anti-PD-1 antibodies (e.g., Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB-A317), AMP-514 (MEDI0680), Dostarlimab (ANB011 / TSR-042), Toripalimab (JS001), Camrelizumab (SHR-1210), Genolimzumab (CBT-501), Sintilimab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, Retifanlimab (MGA012), Balstilimab (AGEN2034), CS1003, Serplulimab (HLX10), BAT-1306, AK105, AK103, BI754091, LZM009, CMAB819, Sym021, Geptanolimab (GB226), SSI-361, JY034, HX008, ISU106, Budigalim ab (ABBV181), Prolgolimab (BCD-100), Sasanlimab (PF-06801591), CX-188, Cetrelimab (JNJ-6372328) 3) and Zimberelimab (AB122), etc.), anti-PD-L1 antibodies (e.g., Atezolizumab (RG7446 / MPDL3280A), Avelumab (PF-06834635 / MSB0010718C), Durvalumab (MEDI4736), BMS-936559, STI-1014, Envafolimab (KN035), Lodapol imab (LY3300054), HLX20, SHR-1316, CS1001 (WBP3155), MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502 (TQB2450), JS003, and CX-072, etc.) or anti-CTLA-4 antibodies (e.g., Ipilimumab (MDX- 010), Zalifrelimab (AGEN1884) and Tremelimumab, etc.), anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein (e.g., AMP-224), anti-Tim-3 antibody (e.g., MBG453), anti-LAG-3 antibody (e.g., BMS-986016, LAG525), anti-KIR antibody (e.g., Lirilumab), etc. In addition, an antibody or an antigen-binding fragment thereof comprising the heavy and light chain complementarity determining regions (CDRs) or variable regions (VR) of the above-mentioned known antibodies is also an embodiment of the immune checkpoint inhibitor. For example, a further embodiment of the anti-PD-1 antibody includes an antibody or an antigen-binding fragment thereof comprising the heavy and light chain complementarity determining regions (CDRs) or variable regions (VR) of Nivolumab, for example. Furthermore, one embodiment of the anti-PD-1 antibody includes an antibody that competes with Nivolumab for binding to PD-1, or an antibody that binds to the same PD-1 as Nivolumab, or an antigen-binding fragment thereof.

[0023] In the present invention, the immune checkpoint inhibitor is preferably an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody, more preferably an anti-PD-1 antibody or an anti-PD-L1 antibody. The anti-PD-1 antibody is preferably at least one selected from the group consisting of Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Toripalimab, Sintilimab, and Camrelizumab, the anti-PD-L1 antibody is preferably at least one selected from the group consisting of Atezolizumab, Avelumab, Durvalumab, and BMS-936559, and the anti-CTLA-4 antibody is preferably at least one selected from the group consisting of Ipilimumab and Tremelimumab. Furthermore, the anti-PD-1 antibody is more preferably at least one selected from the group consisting of Nivolumab, Cemiplimab, and Pembrolizumab, more preferably Nivolumab. In the present invention, the immune checkpoint inhibitor is preferably an anti-PD-1 antibody, and more preferably Nivolumab.

[0024] In the present invention, immune checkpoint inhibitors can be produced by known methods. For example, Nivolumab can be produced according to the method described in WO2006 / 121168, Pembrolizumab can be produced according to the method described in WO2008 / 156712, BMS-936559 can be produced according to the method described in WO2007 / 005874, and Ipilimumab can be produced according to the method described in WO2001 / 014424.

[0025] In the present invention, any one or more of these immune checkpoint inhibitors can be used in combination with the compound used in the present invention.

[0026] The dosage of the immune checkpoint inhibitor used in the treatment of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is adjusted to achieve the optimal desired effect.

[0027] For example, the active ingredient of the immune checkpoint inhibitor can be administered intravenously (e.g., by intravenous drip) at a dose of about 1 mg / kg (body weight) to about 10 mg / kg (body weight) or about 200 mg to about 1,200 mg at a dose every 2 to 4 weeks over a period of about 30 to about 60 minutes or over about 60 minutes or more. Here, examples of the dosage per administration in terms of body weight include 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg, while examples of the dosage per administration include 200 mg, 240 mg, 250 mg, 280 mg, 300 mg, 320 mg, 350 mg, 360 mg, 400 mg, 420 mg, 450 mg, 480 mg, 500 mg, 540 mg, 560 mg, 600 mg, 640 mg, 700 mg, 720 mg, 750 mg, 800 mg, 840 mg, 900 mg, 1000 mg, 1080 mg, 1100 mg, 1120 mg, or 1200 mg. The administration interval can be, for example, 2 weeks, 3 weeks, or 4 weeks, and the administration time for one administration can be, for example, about 30 minutes to about 60 minutes, or about 60 minutes or more.

[0028] Nivolumab, whose active ingredient is an anti-PD-1 antibody, is administered according to the following dosage regimen: For patients with malignant melanoma, Nivolumab is administered intravenously at 3 mg / kg (body weight) every 2 weeks or 2 mg / kg (body weight) every 3 weeks, or 240 mg every 2 weeks or 480 mg every 4 weeks. For patients with non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, head and neck cancer, gastric cancer, and malignant pleural mesothelioma, Nivolumab is administered intravenously at 3 mg / kg (body weight) every 2 weeks. As an alternative dosage regimen, for example, nivolumab is administered intravenously at 240 mg every two weeks or 480 mg every four weeks to patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, MSI-H or dMMR positive colorectal cancer (including pediatric patients aged 12 years or older), gastric cancer, esophageal cancer, hepatocellular carcinoma, small cell lung cancer, and malignant pleural mesothelioma. In addition, as another dosage regimen, for example, for patients with malignant melanoma, in combination with ipilimumab, Nivolumab may be intravenously infused at 1 mg / kg (body weight) at 3-week intervals for 4 doses, followed by intravenous infusion of 3 mg / kg (body weight) at 2-week intervals, or Nivolumab may be intravenously infused at 80 mg at 3-week intervals for 4 doses, followed by intravenous infusion of 240 mg at 2-week intervals or 480 mg at 4-week intervals. Also, for example, for patients with renal cell carcinoma or colorectal cancer, Nivolumab may be intravenously infused at 240 mg at 3-week intervals for 4 doses, followed by intravenous infusion of 240 mg at 2-week intervals or 480 mg at 4-week intervals.

[0029] In addition, Cemiplimab, another anti-PD-1 antibody, is administered at a dose of 350 mg every three weeks.

[0030] In addition, the same anti-PD-1 antibody, pembrolizumab, is administered in the following dosage regimen: For patients with malignant melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, MSI-H or dMMR positive solid tumors, or colorectal cancer, urothelial cancer, cervical cancer, primary mediastinal B-cell lymphoma, hepatocellular carcinoma, gastric cancer, and Merkel cell carcinoma, pembrolizumab is administered intravenously at 200 mg once every 3 weeks or 400 mg once every 6 weeks. In addition, as another dosage regimen, for example, for patients with classical Hodgkin lymphoma, MSI-H or dMMR positive solid tumors, or colorectal cancer and primary mediastinal B-cell lymphoma in children aged 2 years or older, pembrolizumab is administered intravenously at 2 mg / kg (body weight) once (up to 200 mg once) once every 3 weeks.

[0031] In the case of Avelumab, whose active ingredient is an anti-PD-L1 antibody, 10 mg / kg (body weight) of Avelumab is administered intravenously every two weeks to patients with Merkel cell carcinoma and urothelial carcinoma. Atezolizumab, another PD-L1 antibody, is administered intravenously at 1,200 mg of Atezolizumab every three weeks to patients with non-small cell lung cancer, urothelial carcinoma, and hepatocellular carcinoma, and at 840 mg of Atezolizumab in combination with paclitaxel is administered intravenously every two weeks to patients with triple-negative breast cancer. In addition, durvalumab, the same PD-L1 antibody, will be administered intravenously at 10 mg / kg (body weight) every two weeks to patients with non-small cell lung cancer and urothelial cancer, and at 1,500 mg every four weeks to patients with extensive-stage small cell lung cancer.

[0032] In the case of ipilimumab, an anti-CTLA-4 antibody, patients with malignant melanoma are given 3 mg / kg (body weight) of ipilimumab administered intravenously once a day at three-week intervals for four doses, either alone or in combination with Nivolumab; patients with renal cell carcinoma and MSI-H or dMMR-positive colorectal cancer are given 1 mg / kg (body weight) of ipilimumab administered intravenously once a day at three-week intervals for four doses, in combination with Nivolumab; and patients with non-small cell lung cancer are given 1 mg / kg (body weight) of ipilimumab administered intravenously once a day at six-week intervals.

[0033] In the present invention, the above-mentioned dosage and administration method can also be used in the therapeutic method of the present invention.

[0034] The preferred form of administration for intravenous administration of the immune checkpoint inhibitor of the present invention is intravenous drip infusion.

[0035] (3) Combination therapy with FOLFOX therapy and molecular targeted drugs (e.g., bevacizumab, cetuximab) (an example of standard therapy) The "standard therapy" in the present invention refers to a treatment whose therapeutic effect and safety have been confirmed by the results of many clinical trials, and which is the most recommended treatment based on scientific evidence. The "FOLFOX therapy" in the present invention refers to a cancer treatment method using a triple combination of oxaliplatin, levofolinate calcium (hereinafter abbreviated as "levofolinate"), and fluorouracil, and in one embodiment, (1a) oxaliplatin 85 mg / m 2 ~130mg / m 2 intravenously, (1b) levofolinate 100 mg / m 2 ~200mg / m 2 intravenous administration of 400 mg / m fluorouracil; 2 bolus intravenous administration of 600 mg / m fluorouracil, and (1d) 2 ~2400mg / m 2The treatment comprises intravenous administration of (1a), (1b), (1c) and (1d) at two-week intervals. The dosages in the treatment are all calculated based on the body surface area per administration. There are several known formulations of FOLFOX therapy, depending on the dosages and administration methods of the three drugs. For example, rapid intravenous administration of fluorouracil in (1c) is not required, and the dosage of oxaliplatin in (1a) is 85 mg / m 2 , 100 mg / m 2 , 130 mg / m 2 , or 85 mg / m 2 ~130mg / m 2 and the dose of levofolinate in (1b) may be any dose between 100 mg / m 2 , 200 mg / m 2 , or 100 mg / m 2 ~200mg / m 2 and the dose of fluorouracil administered continuously intravenously in (1d) may be any dose between 600 mg / m 2 , 1500mg / m 2 , 2400mg / m 2 or 600 mg / m 2 ~2400mg / m 2 The dosage may be any dosage between 100 mg and 200 mg.

[0036] In one embodiment, rapid intravenous administration provides administration of the agent within 15 minutes.

[0037] In one embodiment, for example, the FOLFOX regimen, also known as FOLFOX4 regimen, comprises: (1a) oxaliplatin 85 mg / m 2 and (1b) levofolinate 100 mg / m 2 (1c) administer fluorouracil 400 mg / m intravenously over a period of 2 hours after administration of oxaliplatin in (1a) and levofolinate in (1b) is completed. 2 (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 600 mg / m should be administered intravenously. 2intravenously over 22 hours, followed by (1e) levofolinate 100 mg / m 2 (1f) After the administration of levofolinate in (1e) is completed, fluorouracil 400 mg / m 2 (1g) After the administration of fluorouracil in (1f) is completed, fluorouracil at 600 mg / m should be administered intravenously. 2 over 22 hours by intravenous administration of a series of doses of (1a), (1b), (1c), (1d), (1e), (1f) and (1g) administered at 2-week intervals. All doses in this treatment are based on body surface area per administration.

[0038] In another embodiment, the FOLFOX regimen, referred to as mFOLFOX6 regimen, comprises: (1a) oxaliplatin 85 mg / m 2 and (1b) levofolinate 200 mg / m 2 (1c) administer fluorouracil 400 mg / m intravenously over a period of 2 hours after administration of oxaliplatin in (1a) and levofolinate in (1b) is completed. 2 (1d) administer 2400 mg / m fluorouracil intravenously after the administration of fluorouracil in (1c) is completed. 2 over 46 hours by intravenous administration of a series of doses of (1a), (1b), (1c) and (1d) administered at 2-week intervals. All doses in this treatment are based on body surface area per administration.

[0039] In the present specification, FOLFOX therapy includes all methods that are used depending on the administration method of each drug, such as FOLFOX4 therapy and mFOLFOX6 therapy.

[0040] In addition, the interval between administrations of the combination therapy of the FOLFOX therapy and a molecular targeted drug may be set to 2 weeks, or may be set to 3 weeks or more (e.g., 3 or 4 weeks) temporarily or continuously depending on the severity of side effects in the patient. The interruption, reduction, or resumption of the combination therapy of the FOLFOX therapy and bevacizumab or cetuximab is performed at the discretion of the principal investigator or co-investigator, referring to the latest package insert.

[0041] Examples of molecular targeted drugs include anti-EGFR antibodies (e.g., cetuximab, panitumumab) and anti-VEGF antibodies (e.g., bevacizumab). One type of molecular targeted drug may be used alone, or two or more types may be used in combination. In one embodiment, the molecular targeted drug is selected for appropriate patients, taking into consideration the presence or absence of RAS gene (KRAS / NRAS gene) mutation. In one embodiment, anti-EGFR antibodies (e.g., cetuximab, panitumumab) are used for RAS gene wild-type colon cancer. In one embodiment, anti-VEGF antibodies (e.g., bevacizumab) are used for RAS gene mutant colon cancer.

[0042] In one embodiment, the initial dose of bevacizumab for patients with RAS gene mutation is 5 mg / kg (body weight) and is administered by intravenous drip infusion over 90 minutes. If the first dose is well tolerated, the second dose can be administered over 60 minutes. If the second dose is also well tolerated, subsequent doses can be administered over 30 minutes. The administration interval can be 2 weeks or more (e.g., 2 weeks, 3 weeks, 4 weeks).

[0043] In one embodiment, the starting dose of cetuximab for patients with a wild-type RAS gene is 400 mg / m 2 (body surface area) and infused intravenously over 2 hours. After the second dose, the dose is 250 mg / m2 once a week or at 2-week intervals. 2 Infusion of cetuximab at 500 mg / m2 will be administered intravenously over 1 hour. 2 It can also be administered by intravenous infusion over two hours at two-week intervals, with the dosage reduced as appropriate depending on the patient's condition.

[0044] In one embodiment, panitumumab is administered intravenously to patients with wild-type RAS gene at a dose of 6 mg / kg (body weight) over 60 minutes or more once every two weeks. The dose is appropriately reduced depending on the patient's condition.

[0045] (4) Combination therapy with FOLFOX therapy and molecular targeted drugs (e.g., bevacizumab, cetuximab) In one embodiment, the CD47 inhibitor in combination with the combination therapy of FOLFOX therapy and a molecular targeted drug (e.g., bevacizumab, cetuximab) is administered in the dosage and administration described in (1) CD47 inhibitor. In one embodiment, Magrolimab, an example of a CD47 inhibitor, is administered intravenously at 1 mg / kg over 3 hours (± 30 minutes) as the initial dose, and then intravenously at 20 mg / kg or 30 mg / kg once every week or every two weeks. In one embodiment, Magrolimab is administered intravenously at 1 mg / kg over 3 hours (± 30 minutes) as the initial dose on the first day of the first cycle, and then intravenously at 20 mg / kg or 30 mg / kg once every 2 hours (± 30 minutes) once every week in the first cycle and every two weeks from the second cycle onwards. Depending on the degree of side effects experienced by the patient, the dosage of Magrolimab may be reduced step by step, or administration itself may be discontinued. In addition, if the criteria for resumption are met, administration of Magrolimab can be resumed, and in the case of resumption, Magrolimab can be resumed at a reduced dose at the discretion of the investigator or subinvestigator. In one embodiment, when Magrolimab as a CD47 inhibitor is administered at a starting dose of 30 mg / kg, the dose after one step reduction is 20 mg / kg, and after two step reduction is 15 mg / kg. When Magrolimab as a CD47 inhibitor is administered at a starting dose of 20 mg / kg, the dose after reduction is 15 mg / kg.

[0046] In one embodiment, the immune checkpoint inhibitor in combination with the combination therapy of FOLFOX therapy and a molecular targeted drug (e.g., bevacizumab, cetuximab) is administered according to the dosage and administration described in (2) Immune Checkpoint Inhibitor. In one embodiment, Nivolumab as the immune checkpoint inhibitor is administered by intravenous drip infusion at 240 mg once every two weeks, at 360 mg once every three weeks, and at 480 mg once every four weeks. Preferably, Nivolumab is administered by intravenous drip infusion at 480 mg once every four weeks. More preferably, Nivolumab is administered by intravenous drip infusion at 480 mg once every four weeks over about 30 minutes. Depending on the degree of side effects experienced by the patient, administration of Nivolumab itself may be discontinued. In addition, administration of Nivolumab can be resumed if the criteria for resumption are met.

[0047] In the treatment method of the present invention, when a combination therapy of a CD47 inhibitor (preferably Magrolimab) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) and a molecular targeted drug (preferably bevacizumab or cetuximab) added to FOLFOX therapy is administered in combination (e.g., on the same day or starting on the same day), in one embodiment, the CD47 inhibitor and the immune checkpoint inhibitor are administered first. In one embodiment, the combination therapy of FOLFOX therapy and bevacizumab or cetuximab is performed after the CD47 inhibitor and the immune checkpoint inhibitor are administered.

[0048] (5) FFX therapy or its reduced dose regimen (another example of standard therapy) The "FFX therapy" in the present invention is a cancer treatment method using four drugs in combination: oxaliplatin, irinotecan hydrochloride hydrate (hereinafter abbreviated as "irinotecan"), levofolinate calcium (hereinafter abbreviated as "levofolinate"), and fluorouracil. The recommended dosage is, for example, (2a) oxaliplatin 85 mg / m 2 to be administered intravenously over 2 hours, followed by (2b) levofolinate 200 mg / m 2(2c) 30 minutes after the start of administration of levofolinate in (2b), irinotecan 180 mg / m 2 (2d) After the administration of levofolinate in (2b) is completed, fluorouracil 400 mg / m 2 (2e) After the administration of fluorouracil in (2d) is completed, fluorouracil at 2400 mg / m should be administered intravenously. 2 over 46 hours by intravenous administration of a series of doses of (2a), (2b), (2c), (2d) and (2e) administered at 2-week intervals. All doses in this treatment are based on body surface area per administration.

[0049] The "reduction regimen" of the FFX therapy is a prescription in which the dosage of any of the four drugs administered in the FFX therapy is reduced from the first administration or the administration itself is discontinued, or the dosage is reduced in any of the subsequent administrations from the second cycle onwards, or the administration of any of the four drugs is discontinued, depending on the degree of side effects observed in any administration from the first cycle onwards. In one embodiment, for example, rapid intravenous administration of fluorouracil in (2d) is not required from the first administration, and the dosage of oxaliplatin in (2a) is 50 mg / m 2 , 65 mg / m 2 , or 50-85 mg / m 2 and the dose of irinotecan in (2c) may be any dose between 90 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 or 90-180 mg / m 2 and the dose of the fluorouracil administered continuously intravenously in (2e) may be any dose between 1200 mg / m 2 , 1800mg / m 2 or 1200-2400 mg / m 2 The dosage may be any dosage between 100 mg and 200 mg.

[0050] In another embodiment of the dose reduction regimen, in any administration from the second cycle onward in the FFX therapy, the rapid intravenous administration of fluorouracil in (2d) may be discontinued depending on the severity of side effects experienced by the patient, and the dose of oxaliplatin in (2a) may be reduced to 50 mg / m or less depending on the severity of side effects experienced by the patient. 2 , 65 mg / m 2 or 50-85 mg / m 2 or discontinue administration of oxaliplatin, and the dose of irinotecan in (2c) may be reduced to any dose between 90 mg / m and 90 mg / m depending on the severity of side effects observed in the patient. 2 , 120 mg / m 2 , 150 mg / m 2 or 90-180 mg / m 2 or discontinue administration of irinotecan, and the dose of fluorouracil administered continuously intravenously in (2e) may be reduced to 1200 mg / m or 1,200 mg / m depending on the severity of side effects in the patient. 2 , 1800mg / m 2 or 1200-2400 mg / m 2 The dosage may be reduced to any dose between 100 mg and 150 mg, or administration of fluorouracil may be discontinued.

[0051] Another aspect of the reduced dose regimen, known as modified FOLFIRINOX therapy (mFFX therapy), is, for example, (2a) oxaliplatin 85 mg / m 2 to be administered intravenously over 2 hours, followed by (2b) levofolinate 200 mg / m 2 (2c) 30 minutes after the start of administration of levofolinate in (2b), irinotecan 150 mg / m 2 (2e) After the administration of levofolinate in (2b) is completed, fluorouracil at 2400 mg / m 2over 46 hours by intravenous administration of a series of doses of (2a), (2b), (2c) and (2e) administered at 2-week intervals. All doses in this treatment are based on body surface area per administration.

[0052] As a further dose reduction regimen of the mFFX therapy, for example, the dose of oxaliplatin in (2a) is reduced to 50 mg / m from the first administration. 2 , 65 mg / m 2 or 50-85 mg / m 2 and the dose of irinotecan in (2c) may be any dose between 120 mg / m 2 , 140 mg / m 2 or 120-140 mg / m 2 and the dose of the fluorouracil administered continuously intravenously in (2e) may be any dose between 1200 mg / m 2 , 1800mg / m 2 , 2400mg / m 2 or 1200-2400 mg / m 2 The dosage may be any dosage between 100 mg and 200 mg.

[0053] In addition, in any administration from the second cycle onward in the mFFX therapy, the dose of oxaliplatin in (2a) may be increased to 50 mg / m or less depending on the degree of side effects observed in the patient. 2 , 65 mg / m 2 or 50-85 mg / m 2 or discontinue administration of the oxaliplatin, and the dose of the irinotecan in (2c) may be reduced to any dose between 90 mg / m and 90 mg / m depending on the severity of side effects in the patient. 2 , 120 mg / m 2 or 90-150 mg / m 2 or the administration of the irinotecan may be discontinued, and the dose of the fluorouracil administered continuously intravenously in (2e) may be reduced to any dose between 1200 mg / m and 1,200 mg / m depending on the degree of side effects observed in the patient. 2 , 1800mg / m 2 or 1200-2400 mg / m 2The dosage may be reduced to any dose between 100 mg and 150 mg, or administration of fluorouracil may be discontinued.

[0054] In addition, the interval between successive administrations of the FFX therapy or its reduced-dose regimen (e.g., mFFX therapy) may be set to 3-week or 4-week intervals, temporarily or continuously, depending on the severity of side effects experienced by the patient. The suspension, reduction, and resumption of FFX therapy or its reduced-dose regimen (e.g., mFFX therapy) will be carried out at the discretion of the investigator or subinvestigator, with reference to the latest package insert.

[0055] (6) Combination with FFX therapy or its reduced dose regimen In one embodiment, the CD47 inhibitor in combination with FFX therapy or its reduced dose regimen (e.g., mFFX therapy) is administered at the dosage described in (1) CD47 inhibitor. In one embodiment, Magrolimab, an example of a CD47 inhibitor, is administered intravenously at 1 mg / kg over 3 hours (± 30 minutes) as the initial dose, and then intravenously at 20 mg / kg or 30 mg / kg once every week or every two weeks. In one embodiment, Magrolimab is administered intravenously at 1 mg / kg over 3 hours (± 30 minutes) as the initial dose on the first day of the first cycle, and then intravenously at 20 mg / kg or 30 mg / kg once every 2 hours (± 30 minutes) once every week in the first cycle and every two weeks from the second cycle onwards. Depending on the degree of side effects experienced by the patient, the dose of Magrolimab may be reduced step by step, or administration itself may be discontinued. In addition, if the criteria for resumption are met, administration of Magrolimab can be resumed, and in the case of resumption, Magrolimab can be resumed at a reduced dose at the discretion of the investigator or subinvestigator. In one embodiment, when Magrolimab as a CD47 inhibitor is administered at a starting dose of 30 mg / kg, the dose after one step reduction is 20 mg / kg, and after two step reduction is 15 mg / kg. When Magrolimab as a CD47 inhibitor is administered at a starting dose of 20 mg / kg, the dose after reduction is 15 mg / kg.

[0056] In one embodiment, the immune checkpoint inhibitor in combination with FFX therapy or its reduced dose regimen is administered at the dosage described in (2) immune checkpoint inhibitor. In one embodiment, Nivolumab as the immune checkpoint inhibitor is administered by intravenous infusion at 240 mg as Nivolumab every 2 weeks, 360 mg as Nivolumab every 3 weeks, and 480 mg as Nivolumab every 4 weeks. Preferably, Nivolumab is administered by intravenous infusion at 480 mg every 4 weeks. More preferably, Nivolumab is administered by intravenous infusion at 480 mg over about 30 minutes every 4 weeks. Depending on the degree of side effects of the patient, administration of Nivolumab itself may be discontinued. In addition, if the criteria for resumption are met, administration of Nivolumab can be resumed.

[0057] In the treatment method of the present invention, when a CD47 inhibitor (preferably Magrolimab) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered in combination with FFX therapy or a dose reduction regimen thereof (e.g., mFFX therapy) (e.g., administered on the same day or started on the same day), in one embodiment, the CD47 inhibitor and the immune checkpoint inhibitor are administered first. In one embodiment, the CD47 inhibitor and the immune checkpoint inhibitor are administered, and then the FFX therapy or a dose reduction regimen thereof (e.g., mFFX therapy) is performed.

[0058] [Applicable diseases and patients] The therapeutic method of the present invention is applicable to cancer.

[0059] More specifically, examples of cancer include leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia), malignant lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., adult T-cell leukemia, follicular lymphoma, diffuse large B-cell lymphoma)), multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, duodenal cancer, colon cancer (e.g., colorectal cancer), liver cancer (e.g., hepatocellular carcinoma), gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer (e.g., pancreatic ductal carcinoma, insulinoma, intraductal papillary mucinous neoplasm, pancreatic cancer with distant metastasis, pancreatic ductal carcinoma), thyroid cancer, lung cancer (e.g., non-small cell lung cancer (e.g., squamous non-small cell lung cancer, non-squamous non-small cell lung cancer), small cell lung cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer), cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer (e.g., renal cell carcinoma), renal pelvis and ureter cancer, urothelial carcinoma (e.g., bladder cancer, upper urinary tract cancer), penile cancer, prostate cancer, testicular tumors (e.g., germ cell tumors), bone and soft tissue sarcomas, malignant bone tumors, skin cancer (e.g., uveal malignant melanoma, malignant melanoma, Merkel cell carcinoma), thymoma, mesothelioma, malignant pleural mesothelioma, glioblastoma, blood cancer, and cancer of unknown primary origin.

[0060] One embodiment of the disease to be treated by the therapeutic method of the present invention is a solid cancer. Examples of solid cancer include head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, duodenal cancer, colon cancer (e.g., colon and rectal cancer), liver cancer (e.g., hepatocellular carcinoma), gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer (e.g., pancreatic ductal cancer, insulinoma, intraductal papillary mucinous neoplasm, pancreatic cancer with distant metastasis, pancreatic ductal cancer with distant metastasis), thyroid cancer, lung cancer (e.g., non-small cell lung cancer (e.g., squamous non-small cell lung cancer, non-squamous non-small cell lung cancer), small cell lung cancer, and the like. cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer), cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer (e.g., renal cell carcinoma), renal pelvis and ureter cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer), penile cancer, prostate cancer, testicular tumors (e.g., germ cell tumors), bone and soft tissue sarcoma, malignant bone tumors, skin cancer (e.g., uveal melanoma, malignant melanoma, Merkel cell carcinoma), thymoma, mesothelioma, malignant pleural mesothelioma, glioblastoma, and cancer of unknown primary origin.

[0061] The disease to which the therapeutic method of the present invention is applied is preferably colon cancer or pancreatic cancer, more preferably inoperable advanced or recurrent colon cancer or pancreatic cancer with distant metastasis, and even more preferably inoperable advanced or recurrent colorectal cancer or pancreatic ductal cancer with distant metastasis.

[0062] As used herein, "treatment" of cancer includes, for example, treatments performed to (i) reduce tumor cell proliferation, (ii) reduce symptoms caused by cancer, (iii) improve the quality of life of cancer patients, (iv) reduce the dose of other anticancer drugs or cancer treatment adjuvant drugs already administered, and / or (v) extend the survival of cancer patients, and "suppression of progression" of cancer means delaying the progression of cancer, stabilizing symptoms associated with cancer, and reversing the progression of symptoms. In addition, "suppression of recurrence" of cancer means preventively suppressing the recurrence of cancer in patients whose cancer lesions have been completely or substantially eradicated or removed by cancer treatment or resection surgery.

[0063] The therapeutic method of the present invention may be prescribed to the following cancer patients, namely: (a) patients for whom the therapeutic effect of anticancer drugs is insufficient or insufficient or whose disease worsens after treatment with anticancer drugs; (b) patients with curable or inresectable, metastatic, recurrent, refractory and / or distant metastatic cancer; (c) patients with cancer whose TPS (Tumor Proportion Score) is 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more; (d) patients with cancer whose CPS (Combined Positive Score) is 20% or more, 10% or more, 5% or more, or 1% or more; (e) patients with cancer that has dMMR (deficient mismatch repair) and / or MSI-H (Microsatellite instability-High); or (f) patients with cancer that has a high frequency of TMB (Tumor Mutational Burden). On the other hand, the therapeutic method of the present invention may be more likely to be prescribed to the following cancer patients: (g) patients with no history of anticancer drug treatment, (h) patients with cancers with TPS less than 50%, less than 25%, less than 10%, less than 5%, or less than 1%, (i) patients with cancers with CPS less than 20%, less than 10%, less than 5%, or less than 1%, (j) patients with cancers that do not have dMMR and / or MSI-H or have MSI-L (Microsatellite instability-Low), or (k) patients with cancers with low TMB frequency. In particular, cancer patients for whom the therapeutic method of the present invention is prescribed include patients with no history of anticancer drug treatment and / or patients with unresectable advanced or recurrent cancer, particularly patients with colorectal cancer or pancreatic cancer. In one embodiment, patients with no history of treatment for colorectal cancer or patients with no history of treatment for pancreatic cancer may be included. Preferred examples include patients with no history of treatment with a systemic anti-cancer agent for colorectal cancer or patients with no history of treatment with a systemic anti-cancer agent for pancreatic cancer. More preferred examples include patients with no history of treatment with a systemic anti-cancer agent for inoperable, advanced or recurrent colorectal cancer or patients with no history of treatment with a systemic anti-cancer agent for pancreatic cancer with distant metastasis.

[0064] In one embodiment, the therapeutic method of the present invention is used as a first-line treatment for patients with unresectable, advanced or recurrent colorectal cancer who have no history of treatment with a systemic anti-cancer agent.

[0065] In one embodiment, the therapeutic method of the present invention is used as a first-line treatment for patients with pancreatic cancer having distant metastasis who have no history of treatment with a systemic anti-cancer agent.

[0066] In one embodiment, the therapeutic method of the present invention is applicable to the treatment of metastatic cancer and the inhibition of cancer metastasis.

[0067] In one embodiment, the treatment method of the present invention suppresses recurrence.

[0068] In the present invention, treatment, in one embodiment, means causing at least one of the following: reduction in tumor size, inhibition (slowing or halting) of tumor growth, inhibition (slowing or halting) of tumor metastasis, inhibition (preventing or slowing) of recurrence, and alleviation of one or more symptoms associated with cancer.

[0069] In one embodiment, the therapeutic method of the present invention may be used in combination with other drugs (e.g., known anticancer drugs, antiemetic drugs) to (1) complement and / or enhance the therapeutic effect, (2) improve kinetics and absorption, reduce the dosage, and / or (3) reduce side effects.

[0070] As used herein, "about" means that the numerical value recited may vary below or above the stated value within a range of 10%.

[0071] The present invention provides, for example, the following embodiments. [1] An agent for inhibiting the progression and recurrence of and / or treating solid cancers, which contains a CD47 inhibitor as an active ingredient and is administered in combination with standard therapy and an immune checkpoint inhibitor. [2] An agent for inhibiting the progression and recurrence of and / or treating solid cancers, which contains an immune checkpoint inhibitor as an active ingredient, characterized by being administered in combination with standard therapy and a CD47 inhibitor. [3] The agent according to [1] or [2] above, wherein the standard therapy is a combination therapy of FOLFOX therapy with a molecular targeted drug (preferably, a VEGF inhibitor (preferably, bevacizumab) or an EGFR inhibitor (preferably, cetuximab or panitumumab)). [4] The agent according to any one of the above [1] to [3], wherein the standard therapy is a combination therapy of FOLFOX therapy with bevacizumab or cetuximab. [5] The agent according to any one of the above [1] to [4], wherein the solid cancer is colorectal cancer. [6] The agent according to [5] above, wherein the colon cancer is colorectal cancer. [7] The agent described in [6] above, wherein the colorectal cancer is unresectable, advanced or recurrent colorectal cancer. [8] The agent according to any one of [1] to [7] above, which is administered as a first-line treatment to patients with unresectable advanced or recurrent colorectal cancer who have no history of treatment with a systemic anticancer agent. [9] The agent according to any one of the above [1] to [8], wherein the CD47 inhibitor is an anti-CD47 antibody.

[10] The agent described in [9] above, wherein the anti-CD47 antibody is Magrolimab.

[11] The agent according to the above item

[10] , wherein the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at weekly or biweekly intervals.

[12] The agent according to

[10] or

[11] above, wherein the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 20 mg / kg (body weight) is administered intravenously once a week or every two weeks (preferably, the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 20 mg / kg (body weight) is administered intravenously once a week in the first cycle and once every two weeks in the second cycle onwards).

[13] The agent according to

[10] or

[11] above, wherein the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 30 mg / kg (body weight) is administered intravenously once a week or every two weeks (preferably, the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 30 mg / kg (body weight) is administered intravenously once a week in the first cycle and once every two weeks in the second cycle onwards).

[14] The agent according to any one of [1] to

[13] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.

[15] The agent described in

[14] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[16] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, AMP-514, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, Retifanlimab, Balstilimab, CS1003, Serplulimab, BAT-1306, AK105, AK103, BI The agent according to

[14] or

[15] , which is 754091, LZM009, CMAB819, Sym021, Geptanolimab, SSI-361, JY034, HX008, ISU106, Budigalimab, Prolgolimab, Sasanlimab, CX-188, Cetrelimab or Zimberelimab.

[17] The agent according to

[14] above, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, BMS-936559, STI-1014, envafolimab, lodapolimab, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 or CX-072.

[18] The agent described in

[14] above, wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipilimumab, AGEN1884 or tremelimumab.

[19] The agent according to

[15] above, wherein the anti-PD-1 antibody is Nivolumab.

[20] The agent according to

[15] above, wherein the anti-PD-1 antibody is pembrolizumab.

[21] The agent according to

[15] above, wherein the anti-PD-1 antibody is Cemiplimab.

[22] The agent according to

[17] above, wherein the anti-PD-L1 antibody is Avelumab.

[23] The agent according to

[17] above, wherein the anti-PD-L1 antibody is atezolizumab.

[24] The agent according to

[17] above, wherein the anti-PD-L1 antibody is durvalumab.

[25] The agent according to

[18] above, wherein the anti-CTLA-4 antibody is ipilimumab.

[26] The agent according to the above item

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

[27] The agent described in

[19] above, wherein 480 mg of nivolumab is administered intravenously every 4 weeks.

[28] The agent according to

[19] above, wherein 480 mg of nivolumab is administered intravenously over approximately 30 minutes every 4 weeks.

[29] The agent according to

[20] above, wherein pembrolizumab is administered at a dose of 2 mg / kg (body weight) or 200 mg every 3 weeks, or 400 mg every 6 weeks.

[30] The agent described in

[21] above, wherein 350 mg of cemiplimab is administered once every 3 weeks.

[31] The agent according to

[22] above, wherein avelumab is administered at a dose of 10 mg / kg (body weight) once every two weeks.

[32] The agent described in

[23] above, wherein 1,200 mg of atezolizumab is administered once every 3 weeks.

[33] The agent according to

[24] above, wherein durvalumab is administered intravenously at a dose of 10 mg / kg (body weight) every 2 weeks, or at a dose of 1,500 mg every 4 weeks for four doses.

[34] The agent according to

[25] above, wherein ipilimumab is administered intravenously at a dose of 3 mg / kg (body weight) or 1 mg / kg (body weight) at three-week intervals for four doses, or at a dose of 1 mg / kg (body weight) at six-week intervals.

[35] The agent according to any one of the above [4] to

[34] , wherein the combination therapy of FOLFOX therapy with bevacizumab or cetuximab is a therapy in which (1A-1) bevacizumab or (1A-2) cetuximab, (1B) oxaliplatin, (1C) levofolinate calcium, and (1D) fluorouracil are administered in combination.

[36] The agent according to any one of the above [4] to

[35] , wherein the combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy is a therapy in which (1A-1) bevacizumab, (1B) oxaliplatin, (1C) levofolinate calcium, and (1D) fluorouracil are administered in combination.

[37] The agent according to any one of the above [4] to

[35] , wherein the combination therapy of FOLFOX therapy with bevacizumab or cetuximab is a therapy in which (1A-2) cetuximab, (1B) oxaliplatin, (1C) levofolinate calcium, and (1D) fluorouracil are administered in combination.

[38] Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) Bevacizumab 5 mg / kg (body weight) intravenously or cetuximab 400 mg / m 2 (body surface area), 250 mg / m2 from the second dose onwards 2 (body surface area) administered intravenously; (1a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously; (1b) Calcium levofolinate 200 mg / m 2 (body surface area) administered intravenously; (1c) Fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration, The agent according to any one of the above [4] to

[35] , which is a therapy comprising:

[39] Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) Bevacizumab 5mg / kg (body weight) administered intravenously; (1a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously; (1b) Calcium levofolinate 200 mg / m 2 (body surface area) administered intravenously; (1c) Fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration, The agent according to any one of the above [4] to

[36] and

[38] , which is a therapy comprising:

[40] Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) Cetuximab 1st dose 400mg / m 2 (body surface area), 250 mg / m2 from the second dose onwards 2 (body surface area) administered intravenously; (1a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously; (1b) Calcium levofolinate 200 mg / m 2 (body surface area) administered intravenously; (1c) Fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration, The agent according to any one of the above [4] to

[35] ,

[37] , and

[38] , which is a therapy comprising the steps of:

[41] Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) Bevacizumab 5 mg / kg body weight administered intravenously over 90 minutes or cetuximab 400 mg / m 2 (body surface area) over 2 hours, 250 mg / m 2 (body surface area) administered intravenously over 1 hour, (1a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously over 2 hours, (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2 (body surface area) administered intravenously over 2 hours, (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) administered intravenously over 46 hours, wherein a series of administrations of (1x), (1a), (1b), (1c) and (1d) is carried out at 2-week intervals.

[42] Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) Bevacizumab 5 mg / kg (body weight) administered intravenously over 90 minutes; (1a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously over 2 hours, (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2 (body surface area) administered intravenously over 2 hours, (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) administered intravenously over 46 hours, wherein a series of administrations of (1x), (1a), (1b), (1c) and (1d) is carried out at 2-week intervals.

[43] Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) Cetuximab 1st dose 400mg / m 2 (body surface area) over 2 hours, 250 mg / m 2 (body surface area) administered intravenously over 1 hour, (1a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously over 2 hours, (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2 (body surface area) administered intravenously over 2 hours, (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) administered intravenously over 46 hours, The agent according to any one of the above [4] to

[35] ,

[37] ,

[38] ,

[40] , and

[41] , which is a therapy comprising a series of administrations of (1x), (1a), (1b), (1c) and (1d) at two-week intervals.

[44] The agent according to any one of [4] to

[43] above, which is a combination therapy of FOLFOX therapy with bevacizumab or cetuximab, or a therapy in which administration of an immune checkpoint inhibitor and a CD47 inhibitor is started on the same day.

[45] A cancer progression suppression, recurrence suppression and / or treatment agent containing a CD47 inhibitor as an active ingredient, which is administered in combination with a combination therapy of FOLFOX therapy with bevacizumab or cetuximab and an immune checkpoint inhibitor, (i) the CD47 inhibitor is Magrolimab, and the initial dose of Magrolimab is 1 mg / kg (body weight) administered intravenously, and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously once every week or every two weeks; (ii) the immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks (preferably 480 mg once every 4 weeks); (iii) The combination therapy of the FOLFOX therapy with bevacizumab or cetuximab (1x) Bevacizumab 5 mg / kg (body weight) administered intravenously (preferably over 90 minutes) or cetuximab 400 mg / m 2 (body surface area) (preferably over 2 hours), and 250 mg / m 2 (body surface area) intravenously (preferably over 1 hour); (1a) Oxaliplatin 85 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the series of administrations of (1x), (1a), (1b), (1c) and (1d) are administered at two week intervals.

[46] A cancer progression suppression, recurrence suppression and / or treatment agent containing a CD47 inhibitor as an active ingredient, which is administered in combination with a combination therapy of FOLFOX therapy with bevacizumab or cetuximab and an immune checkpoint inhibitor, (i) the CD47 inhibitor is Magrolimab, and the initial dose of Magrolimab is 1 mg / kg (body weight) administered intravenously, and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously once every week or every two weeks; (ii) the immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks (preferably 480 mg once every 4 weeks); (iii) The combination therapy of the FOLFOX therapy with bevacizumab or cetuximab (1x) bevacizumab 5 mg / kg body weight administered intravenously (preferably over 90 minutes); (1a) Oxaliplatin 85 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the series of administrations of (1x), (1a), (1b), (1c) and (1d) are administered at two week intervals.

[47] A cancer progression suppression, recurrence suppression and / or treatment agent containing a CD47 inhibitor as an active ingredient, which is administered in combination with a combination therapy of FOLFOX therapy with bevacizumab or cetuximab and an immune checkpoint inhibitor, (i) the CD47 inhibitor is Magrolimab, and the initial dose of Magrolimab is 1 mg / kg (body weight) administered intravenously, and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously once every week or every two weeks; (ii) the immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks (preferably 480 mg once every 4 weeks); (iii) The combination therapy of the FOLFOX therapy with bevacizumab or cetuximab (1x) Cetuximab 1st dose 400mg / m 2 (body surface area) (preferably over 2 hours), and 250 mg / m 2 (body surface area) intravenously (preferably over 1 hour); (1a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously over 2 hours, (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2(body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the series of administrations of (1x), (1a), (1b), (1c) and (1d) are administered at two week intervals.

[48] ​​A cancer progression suppression, recurrence suppression and / or treatment agent containing an immune checkpoint inhibitor as an active ingredient, which is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and a CD47 inhibitor, (i) the CD47 inhibitor is Magrolimab, and the initial dose of Magrolimab is 1 mg / kg (body weight) administered intravenously, and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously once every week or every two weeks; (ii) the immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks (preferably 480 mg once every 4 weeks); (iii) The combination therapy of the FOLFOX therapy with bevacizumab or cetuximab (1x) Bevacizumab 5 mg / kg (body weight) administered intravenously (preferably over 90 minutes) or cetuximab 400 mg / m 2 (body surface area) (preferably over 2 hours), and 250 mg / m 2 (body surface area) intravenously (preferably over 1 hour); (1a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously over 2 hours, (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the series of administrations of (1x), (1a), (1b), (1c) and (1d) are administered at two week intervals.

[49] A cancer progression suppression, recurrence suppression and / or treatment agent containing an immune checkpoint inhibitor as an active ingredient, which is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and a CD47 inhibitor, (i) the CD47 inhibitor is Magrolimab, and the initial dose of Magrolimab is 1 mg / kg (body weight) administered intravenously, and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously once every week or every two weeks; (ii) the immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks (preferably 480 mg once every 4 weeks); (iii) The combination therapy of the FOLFOX therapy with bevacizumab or cetuximab (1x) bevacizumab 5 mg / kg body weight administered intravenously (preferably over 90 minutes); (1a) Oxaliplatin 85 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the series of administrations of (1x), (1a), (1b), (1c) and (1d) are administered at two week intervals.

[50] A cancer progression suppression, recurrence suppression and / or treatment agent containing an immune checkpoint inhibitor as an active ingredient, which is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and a CD47 inhibitor, (i) the CD47 inhibitor is Magrolimab, and the initial dose of Magrolimab is 1 mg / kg (body weight) administered intravenously, and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously once every week or every two weeks; (ii) the immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks (preferably 480 mg once every 4 weeks); (iii) The combination therapy of the FOLFOX therapy with bevacizumab or cetuximab (1x) Cetuximab 1st dose 400mg / m 2 (body surface area) (preferably over 2 hours), and 250 mg / m 2 (body surface area) intravenously (preferably over 1 hour); (1a) Oxaliplatin 85 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (1b) Simultaneously with administration of oxaliplatin in (1a), levofolinate calcium 200 mg / m 2(body surface area) intravenously (preferably over 2 hours); (1c) After the administration of calcium levofolinate in (1b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (1d) After the administration of fluorouracil in (1c) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the series of administrations of (1x), (1a), (1b), (1c) and (1d) are administered at two week intervals.

[51] The agent described in any one of

[36] ,

[39] ,

[42] ,

[46] , and

[49] above, wherein the cancer is a RAS gene mutant cancer.

[52] The agent according to any one of

[37] ,

[40] ,

[43] ,

[47] and

[50] , wherein the cancer is a wild-type RAS gene cancer.

[53] The agent according to any one of the above

[45] to

[52] , wherein the cancer is unresectable, advanced or recurrent colorectal cancer.

[54] The agent according to

[53] above, which is administered as a first-line treatment to patients with unresectable advanced or recurrent colorectal cancer who have no history of treatment with a systemic anticancer agent.

[55] The agent according to any one of the above

[45] to

[54] , which is a combination therapy in which FOLFOX therapy is added with bevacizumab or cetuximab, Magrolimab, and Nivolumab are administered starting on the same day.

[56] The agent described in [1] or [2] above, wherein the standard therapy is FOLFIRINOX therapy or a reduced dose regimen thereof.

[57] The agent according to any one of [1], [2] and

[56] above, wherein the solid cancer is pancreatic cancer.

[58] The agent described in

[57] above, wherein the pancreatic cancer is pancreatic cancer with distant metastasis.

[59] The agent described in any one of [1], [2],

[56] ,

[57] , and

[58] above, which is administered as a first-line treatment to patients with pancreatic cancer with distant metastasis who have no history of treatment with a systemic anticancer agent.

[60] The agent according to any one of [1], [2], and

[56] to

[59] above, wherein the CD47 inhibitor is an anti-CD47 antibody.

[61] The agent according to

[60] above, wherein the anti-CD47 antibody is Magrolimab.

[62] The agent according to the above item

[61] , wherein the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at weekly or biweekly intervals.

[63] The agent according to

[61] or

[62] above, wherein the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 20 mg / kg (body weight) is administered intravenously once a week or every two weeks (preferably, the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 20 mg / kg (body weight) is administered intravenously once a week in the first cycle and once every two weeks in the second cycle onwards).

[64] The agent according to

[61] or

[62] above, wherein the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 30 mg / kg (body weight) is administered intravenously once a week or every two weeks (preferably, the initial dose of magnolimab is administered intravenously at 1 mg / kg (body weight), and from the second dose onwards, 30 mg / kg (body weight) is administered intravenously once a week in the first cycle and once every two weeks in the second cycle onwards).

[65] The agent according to any one of [1], [2], and

[56] to

[64] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[66] The agent described in

[65] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[67] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, AMP-514, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, Retifanlimab, Balstilimab, CS1003, Serplulimab, BAT-1306, AK105, AK103, BI The agent according to

[65] or

[66] , which is 754091, LZM009, CMAB819, Sym021, Geptanolimab, SSI-361, JY034, HX008, ISU106, Budigalimab, Prolgolimab, Sasanlimab, CX-188, Cetrelimab or Zimberelimab.

[68] The agent according to

[67] above, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, BMS-936559, STI-1014, envafolimab, lodapolimab, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 or CX-072.

[69] The agent described in

[65] above, wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipilimumab, AGEN1884 or tremelimumab.

[70] The agent according to

[66] above, wherein the anti-PD-1 antibody is Nivolumab.

[71] The agent according to

[66] above, wherein the anti-PD-1 antibody is pembrolizumab.

[72] The agent according to

[66] above, wherein the anti-PD-1 antibody is Cemiplimab.

[73] The agent according to

[68] above, wherein the anti-PD-L1 antibody is Avelumab.

[74] The agent according to

[68] above, wherein the anti-PD-L1 antibody is atezolizumab.

[75] The agent according to

[68] above, wherein the anti-PD-L1 antibody is durvalumab.

[76] The agent according to

[69] above, wherein the anti-CTLA-4 antibody is ipilimumab.

[77] The agent according to the above

[70] , wherein nivolumab is administered at a dose of 3 mg / kg (body weight) or 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably, 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks).

[78] The agent according to

[70] above, wherein 480 mg of nivolumab is administered intravenously every 4 weeks.

[79] The agent according to

[70] above, wherein 480 mg of nivolumab is administered intravenously over approximately 30 minutes every 4 weeks.

[80] The agent according to

[71] above, wherein pembrolizumab is administered at a dose of 2 mg / kg (body weight) or 200 mg every 3 weeks, or 400 mg every 6 weeks.

[81] The agent according to

[72] above, wherein 350 mg of cemiplimab is administered once every 3 weeks.

[82] The agent according to

[73] above, wherein avelumab is administered at a dose of 10 mg / kg (body weight) once every 2 weeks.

[83] The agent described in

[74] above, wherein 1,200 mg of atezolizumab is administered once every 3 weeks.

[84] The agent according to

[75] above, wherein durvalumab is administered intravenously at a dose of 10 mg / kg (body weight) every 2 weeks, or at a dose of 1,500 mg every 4 weeks for four doses.

[85] The agent according to

[76] above, wherein ipilimumab is administered intravenously at a dose of 3 mg / kg (body weight) or 1 mg / kg (body weight) at three-week intervals for four doses, or at a dose of 1 mg / kg (body weight) at six-week intervals.

[86] The agent according to any one of the above

[56] to

[85] , wherein the FOLFIRINOX therapy or a reduced dose regimen thereof is a therapy in which (2A) oxaliplatin, (2B) levofolinate calcium, (2C) irinotecan hydrochloride hydrate, and (2D) fluorouracil are administered in combination.

[87] FOLFIRINOX therapy (2a) Oxaliplatin 50-85 mg / m 2 (Body surface area) (preferably 50 mg / m 2 (body surface area), 65mg / m 2 (body surface area), 85mg / m 2 (body surface area), more preferably 85 mg / m 2 (body surface area)) intravenously; (2b) Calcium levofolinate 200 mg / m 2 (body surface area) administered intravenously; (2c) Irinotecan hydrochloride hydrate 90~180mg / m 2 (Body surface area) (preferably 90 mg / m 2 (body surface area), 120mg / m 2 (body surface area), 150mg / m 2 (body surface area), 180mg / m 2 (body surface area), more preferably 180 mg / m 2 (body surface area)) intravenously; (2d) Fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (2e) After the administration of fluorouracil in (2d), fluorouracil at 1200 to 2400 mg / m 2 (Body surface area) (preferably 1200 mg / m 2 (body surface area), 1800mg / m 2 (body surface area), 2400mg / m 2(body surface area), more preferably 2400 mg / m 2 (body surface area)) administered intravenously continuously; The agent according to any one of the above

[56] to

[86] , which is a therapy comprising the steps of:

[88] The reduced dose regimen of FOLFIRINOX therapy (2a) Oxaliplatin 50-85 mg / m 2 (Body surface area) (preferably 50 mg / m 2 (body surface area), 65mg / m 2 (body surface area), 85mg / m 2 (body surface area), more preferably 85 mg / m 2 (body surface area)) intravenously; (2b) Calcium levofolinate 200 mg / m 2 (body surface area) administered intravenously; (2c) Irinotecan hydrochloride hydrate 120-150 mg / m 2 (Body surface area) (preferably 150 mg / m 2 (body surface area)) intravenously; and (2e) Fluorouracil 1200-2400mg / m 2 (Body surface area) (preferably 1200 mg / m 2 (body surface area), 1800mg / m 2 (body surface area), 2400mg / m 2 (body surface area), more preferably 2400 mg / m 2 (body surface area)) administered intravenously continuously; The agent according to any one of the above

[56] to

[86] , which is a therapy comprising the steps of:

[89] The agent according to any one of the above

[56] to

[88] , wherein the FOLFIRINOX therapy or a reduced dose regimen thereof is a therapy in which a series of administrations is performed at intervals of 2 to 4 weeks (preferably at intervals of 2 weeks, 3 weeks, or 4 weeks, more preferably at intervals of 2 weeks).

[90] FOLFIRINOX therapy (2a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously; (2b) Calcium levofolinate 200 mg / m 2 (body surface area) administered intravenously; (2c) Irinotecan hydrochloride hydrate 180 mg / m 2 (body surface area) administered intravenously; (2d) Fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (2e) After the administration of fluorouracil in (2d) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration, wherein a series of administrations of (2a), (2b), (2c), (2d) and (2e) is carried out at 2-week intervals.

[91] The reduced dose regimen of FOLFIRINOX therapy (2a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously; (2b) Calcium levofolinate 200 mg / m 2 (body surface area) administered intravenously; (2c) Irinotecan hydrochloride hydrate 150 mg / m 2 (body surface area) intravenously, and (2e) Fluorouracil 2400mg / m 2 (body surface area) by continuous intravenous administration, The agent according to any one of the above

[56] to

[86] ,

[88] , and

[89] , which is a therapy comprising a series of administrations of (2a), (2b), (2c), and (2e) at two-week intervals.

[92] FOLFIRINOX therapy (2a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously over 2 hours, (2b) (preferably after the administration of oxaliplatin in (2a) is completed) levofolinate calcium 200 mg / m 2 (body surface area) administered intravenously over 2 hours, (2c) 30 minutes after the start of administration of calcium levofolinate in (2b), irinotecan hydrochloride hydrate 180 mg / m 2 (body surface area) administered intravenously over 1.5 hours, (2d) After the administration of calcium levofolinate in (2b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (2e) After the administration of fluorouracil in (2d) is completed, fluorouracil at 2400 mg / m 2 (body surface area) administered intravenously over 46 hours, The agent according to any one of the above

[56] to

[87] ,

[89] , and

[90] , which is a therapy comprising a series of administrations of (2a), (2b), (2c), (2d), and (2e) at two-week intervals.

[93] The reduced dose regimen of FOLFIRINOX therapy (2a) Oxaliplatin 85 mg / m 2 (body surface area) administered intravenously over 2 hours, (2b) (preferably after the administration of oxaliplatin in (2a) is completed) levofolinate calcium 200 mg / m 2 (body surface area) administered intravenously over 2 hours, (2c) 30 minutes after the start of administration of levofolinate calcium in (2b), irinotecan hydrochloride hydrate 150 mg / m 2 (body surface area) administered intravenously over 1.5 hours, and (2e) After the administration of calcium levofolinate in (2b) is completed, fluorouracil 2400 mg / m 2 (body surface area) administered intravenously over 46 hours, The agent according to any one of the above

[56] to

[86] ,

[88] ,

[89] , and

[91] , which is a therapy comprising a series of administrations of (2a), (2b), (2c), and (2e) at two-week intervals.

[94] The agent according to any one of

[56] to

[93] above, which is a therapy in which administration of FOLFIRINOX therapy or a reduced regimen thereof, an immune checkpoint inhibitor, and a CD47 inhibitor is started on the same day.

[95] A cancer progression suppression, recurrence suppression and / or treatment agent comprising a CD47 inhibitor as an active ingredient, which is administered in combination with FOLFIRINOX therapy or a reduced dose regimen thereof, and an immune checkpoint inhibitor, (i) the CD47 inhibitor is Magrolimab, and the initial dose of Magrolimab is 1 mg / kg (body weight) administered intravenously, and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously once every week or every two weeks; (ii) the immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks (preferably 480 mg once every 4 weeks); (iii) The FOLFIRINOX therapy is (2a) Oxaliplatin 85 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (2b) (preferably after the administration of oxaliplatin in (2a) is completed) levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (2c) (preferably 30 minutes after the start of administration of levofolinate calcium in (2b)) irinotecan hydrochloride hydrate 180 mg / m 2 (body surface area) intravenously (preferably over 1.5 hours); (2d) After the administration of calcium levofolinate in (2b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (2e) After the administration of fluorouracil in (2d) is completed, fluorouracil at 2400 mg / m 2(body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the sequential administration of (2a), (2b), (2c), (2d) and (2e) is administered at two-week intervals; or The FOLFIRINOX therapy reduction regimen is (2a) Oxaliplatin 85 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (2b) (preferably after the administration of oxaliplatin in (2a) is completed) levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (2c) (preferably 30 minutes after the start of administration of levofolinate calcium in (2b)) irinotecan hydrochloride hydrate 150 mg / m 2 (body surface area) intravenously (preferably over 1.5 hours); and (2e) After the administration of calcium levofolinate in (2b) is completed, fluorouracil 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the series of administrations of (2a), (2b), (2c) and (2e) are administered at two-week intervals.

[96] A cancer progression suppression, recurrence suppression and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, which is administered in combination with FOLFIRINOX therapy or a reduced dose regimen thereof, and a CD47 inhibitor, (i) the CD47 inhibitor is Magrolimab, and the initial dose of Magrolimab is 1 mg / kg (body weight) administered intravenously, and from the second dose onwards, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously once every week or every two weeks; (ii) the immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks (preferably 480 mg once every 4 weeks); (iii) The FOLFIRINOX therapy is (2a) Oxaliplatin 85 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (2b) (preferably after the administration of oxaliplatin in (2a) is completed) levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (2c) (preferably 30 minutes after the start of administration of levofolinate calcium in (2b)) irinotecan hydrochloride hydrate 180 mg / m 2 (body surface area) intravenously (preferably over 1.5 hours); (2d) After the administration of calcium levofolinate in (2b) is completed, fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous administration, and (2e) After the administration of fluorouracil in (2d) is completed, fluorouracil at 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the sequential administration of (2a), (2b), (2c), (2d) and (2e) is administered at two-week intervals; or The FOLFIRINOX therapy reduction regimen is (2a) Oxaliplatin 85 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (2b) (preferably after the administration of oxaliplatin in (2a) is completed) levofolinate calcium 200 mg / m 2 (body surface area) intravenously (preferably over 2 hours); (2c) (preferably 30 minutes after the start of administration of levofolinate calcium in (2b)) irinotecan hydrochloride hydrate 150 mg / m 2 (body surface area) intravenously (preferably over 1.5 hours); and (2e) After the administration of calcium levofolinate in (2b) is completed, fluorouracil 2400 mg / m 2 (body surface area) by continuous intravenous administration (preferably over 46 hours); wherein the series of administrations of (2a), (2b), (2c) and (2e) are administered at two-week intervals.

[97] The agent according to

[95] or

[96] above, wherein the cancer is pancreatic cancer with distant metastasis.

[98] The agent according to

[97] above, which is administered as a first-line treatment to a patient with pancreatic cancer having distant metastasis who has no history of treatment with a systemic anticancer agent.

[99] The agent according to any one of

[95] to

[98] above, wherein administration of FOLFIRINOX therapy or a reduced regimen thereof, Magrolimab, and Nivolumab is started on the same day.

[0072] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0073] Furthermore, the contents of all patent and non-patent literature or references explicitly cited in this specification are hereby incorporated by reference in their entirety. EXAMPLES

[0074] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these.

[0075] Example 1: An open-label, uncontrolled study of first-line treatment with Magrolimab, Nivolumab, and standard FOLFOX therapy plus bevacizumab or cetuximab in patients with unresectable advanced or recurrent colorectal cancer. The purpose of this study is to investigate the tolerability, safety and efficacy of the combination of Magrolimab, Nivolumab and FOLFOX with bevacizumab or cetuximab as first-line treatment in patients with unresectable advanced or recurrent colorectal cancer. This clinical trial will allow us to evaluate the efficacy of the combination of Magrolimab, Nivolumab and FOLFOX with bevacizumab or cetuximab.

[0076] (1) Target patients Patients with unresectable advanced or recurrent colorectal cancer

[0077] (2) Patient selection criteria Patients who met all of the following criteria at the time of enrollment were selected. If it became clear that the following criteria were not met before the first administration of the study drug, administration of the study drug was not started and the study was discontinued. 1. Gender: No restrictions. 2. Age (at the time of obtaining consent): 20 years of age or older. 3. Patients who can be hospitalized from the day before the start of study drug administration until the end of examination on at least the 15th day after the start of study drug administration (only for tolerability evaluation part). 4. Patients who have been histologically diagnosed with primary adenocarcinoma of the colon or rectum (excluding appendix cancer and anal canal cancer) and are not eligible for curative resection. 5. Patients with measurable lesions as defined by RECIST 1.1 on imaging diagnostics within 28 days prior to administration of the study drug. Patients who received radiation therapy for measurable disease had confirmed progression on imaging after radiation therapy. 6. Patients with unresectable advanced or recurrent colorectal cancer who have not received systemic anti-cancer drug treatment. - In cases where curative surgery (confirmed R0 resection) was performed in conjunction with neoadjuvant and adjuvant therapy, there must be no recurrence within 6 months after completion of adjuvant therapy. 7. Patients who can provide tumor tissue samples for biomarker testing. Tumor tissue samples will be obtained during the screening phase. If a new tumor biopsy is difficult, archived samples may be used. However, archived samples must be collected within 180 days prior to administration of the investigational drug and after the last dose of the most recent systemic anti-cancer therapy. 8. Patients with RAS mutations who will receive a combination of FOLFOX (fluorouracil, levofolinate, oxaliplatin) and bevacizumab (Cohort 1), or patients with RAS wild-type disease whose primary tumor occupies the left side (descending colon, sigmoid colon, rectum) who will receive a combination of FOLFOX (fluorouracil, levofolinate, oxaliplatin) and cetuximab (Cohort 2). 9.ECOG performance status is 0-1. 10.Patients expected to survive for 3 months or longer at the time of enrollment. 11. Women of childbearing potential (including patients who have not had menstruation due to medical reasons such as chemical menopause) who agree to use double contraception for the contraceptive period specified for each drug from the time of obtaining consent until 5 months after the last dose of the investigational drug and after the last dose of the standard treatment drug. In addition, patients who agree not to breastfeed during the period during which breastfeeding is restricted by each drug from the time of obtaining consent until 5 months after the last dose of the investigational drug and after the last dose of the standard treatment drug. Here, women of childbearing potential include all women who have experienced menarche, have not undergone sterilization (hysterectomy, bilateral tubal ligation, bilateral oophorectomy, etc.), and have not yet reached menopause. Menopause is defined as amenorrhea for 12 or more consecutive months without any notable reason. Women who use oral contraceptives or intrauterine devices or diaphragms are considered to be of childbearing potential. 12. For men, patients who agree to use double contraception from the start of treatment with the investigational drug for 4 months after the last dose of the investigational drug and for the contraceptive period specified for each drug after the last dose of the standard treatment drug. In this case, double contraception must be provided by any two of the following means: vasectomy or condoms for male patients or male partners, and tubal ligation, pessary, intrauterine device, or oral contraceptives for female patients or female partners. 13. Patients whose most recent clinical test results performed within 14 days prior to the start of administration of the investigational drug meet the following criteria: Patients must not have received hematopoietic factor preparations such as granulocyte colony-stimulating factor (G-CSF) or blood transfusions within 14 days prior to the test. Neutrophil count 1,500 / mm 3 The end. Platelet count 100,000 / mm 3 The end. Hemoglobin level is 11.0 g / dL or higher. -AST (GOT) and ALT (GPT) are 3.0 times or less the upper limit of the facility's normal range (however, if there is liver metastasis, they must be 5.0 times or less the upper limit of the facility's normal range). Total bilirubin is 1.5 times or less the upper limit of the facility's standard value (however, for patients with Gilbert syndrome, total bilirubin is 3.0 times or less the upper limit of the facility's standard value). Serum creatinine is 1.5 times or less of the upper limit of the facility's standard value, or creatinine clearance (actual measurement or Cockcroft / Gault estimated value) is 40mL / min or more. -Albumin level ≥ 3.0g / dL. [Cohort 1 only] Urinary protein ≤ 1+. However, patients with urinary protein ≥ 2+ in urine or urine dipstick tests may be enrolled if urinary protein is ≤ 1g / 24h in a 24h urine collection or if urinary protein / creatinine ratio (UPCR) is < 1g / gCr. 14. Patients who have been fully informed of the contents of this clinical trial by the principal investigator or co-investigator using a consent form and an information sheet, and who voluntarily consent in writing to participate in this clinical trial.

[0078] (3) Patient exclusion criteria Patients who met any of the following criteria at the time of enrollment were excluded. If any of the following criteria was met before the first administration of the study drug, administration of the study drug was not started and the study was discontinued. 1. Patients with RAS / BRAF wild-type primary tumors on the right side (cecum, ascending colon, transverse colon). 2. Patients with BRAF mutations and those with microsatellite instability-high (MSI-High) or mismatch repair deficiency (dMMR). 3. Patients receiving or having a disease requiring anticoagulant therapy. 4.Patients with persistent gastrointestinal bleeding of Grade 2 or higher. 5. Patients with gastrointestinal perforation, severe fistula, or tracheoesophageal fistula. 6. Patients with pericardial effusion, pleural effusion, or ascites that cannot be controlled by medical therapy. 7. Patients with a history of severe hypersensitivity reactions to antibody preparations. 8.Patients with contraindications to any of the standard therapies used in each cohort. [Cohort 1] Fluorouracil, levofolinate, oxaliplatin and bevacizumab. [Cohort 2] Fluorouracil, levofolinate, oxaliplatin and cetuximab. 9.Patients with peripheral neuropathy of Grade 2 or higher. 10. Patients with concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease, except for those with concurrent skin disease not requiring systemic therapy (e.g., vitiligo, psoriasis, alopecia) or disease not expected to recur in the absence of external triggers. 11.Patients who are judged by the investigator or co-investigator to have an adverse effect on the safety and efficacy evaluation of the investigational drug due to the effects of surgical treatment. 12.Patients with multiple cancers. However, patients with completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, or superficial bladder cancer, or other cancers that have not recurred for 3 years or more, may be enrolled. 13. Patients with brain or meningeal metastases. However, asymptomatic patients who do not require treatment may be enrolled. 14.Patients with interstitial lung disease diagnosed by imaging or clinical findings, or with or a history of pulmonary fibrosis. 15. Patients with tumor-related pain that is not stably controlled. 16. Patients with a history of hemolytic anemia within 90 days prior to enrollment. 17. Patients with a history of transient ischemic attack, cerebrovascular accident, thrombosis or thromboembolism (pulmonary embolism or deep vein thrombosis) within 180 days prior to enrollment, and poorly controlled thrombosis or thromboembolism. However, venous thrombosis related to central venous catheters is permitted. 18.Patients with any of the following uncontrolled or significant cardiovascular diseases: - Acute myocardial infarction within 6 months prior to enrollment. - Unstable angina or angina requiring medical treatment. -New York Heart Association (NYHA) class III to IV congestive heart failure. -Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure above 150mmHg or diastolic blood pressure above 100mmHg for more than 24 hours). ·Uncontrolled or serious cardiac arrhythmias. 19. Patients with uncontrolled diabetes mellitus. 20. Patients with systemic infections requiring treatment. 21. Patients who require transplant therapy or have a history of transplant therapy (excluding autologous transplants). 22. Patients who are positive for HIV-1 and HIV-2 antibody tests, HTLV-1 antibody tests, HBs antigen tests, or HCV antibody tests. Also, patients who are negative for HBs antigen tests, but positive for either HBs antibody tests or HBc antibody tests, and whose HBV-DNA quantification is above the detection sensitivity. Even if the HCV antibody test is positive, patients who are negative for HCV-RNA will be allowed to register. 23.Patients who have received the following treatments before obtaining consent and before administration of the investigational drug. -Patients who have previously been treated with Magrolimab or drugs targeting the CD47-SIRPα pathway. -Patients who have previously received treatment including anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CTLA-4 antibody, or other antibody therapy aimed at regulating T cells, or cancer vaccine. -Patients who received more than 2 units of red blood cell transfusion within 28 days prior to obtaining informed consent. -Patients who underwent surgical treatment involving local anesthesia within 14 days prior to administration of the study drug. -Patients who underwent pleural or pericardial adhesion surgery within 14 days prior to administration of the study drug. Patients who have received systemic corticosteroids (except for temporary use for the purposes of examinations, local administration, treatment and prevention of contrast allergic reactions, or reduction of edema associated with radiation therapy) or immunosuppressants at a dose equivalent to more than 10 mg / day of prednisone within 14 days prior to administration of the study drug. Patients who received palliative localized radiation therapy within 28 days prior to administration of the study drug. -Patients who underwent surgical treatment involving general anesthesia within 28 days prior to administration of the study drug. -Patients who have received a live or attenuated vaccine within 28 days prior to administration of the study drug. Patients who have received radiopharmaceuticals (excluding the use of radiopharmaceuticals for diagnostic and diagnostic purposes) within 56 days prior to administration of the investigational drug. Patients who have received other unapproved drugs (including those administered in clinical studies, unapproved combination drugs, and new dosage forms) within 28 days prior to administration of the investigational drug. 24. Patients who are pregnant, breastfeeding, or possibly pregnant. 25. Patients who are judged to lack the capacity to consent due to dementia or other reasons. 26. Any patient who is otherwise deemed inappropriate for this clinical trial by the principal investigator or co-investigator.

[0079] (4) Dosage and administration period [Magrolimab] Magrolimab was administered intravenously at a dose of 1 mg / kg over 3 hours (± 30 minutes) on day 1 of cycle 1, followed by 20 mg / kg or 30 mg / kg administered intravenously over 2 hours (± 30 minutes) every week in cycle 1, and 20 mg / kg or 30 mg / kg administered intravenously over 2 hours (± 30 minutes) every 2 weeks in cycles 2 and onward until the prescribed discontinuation criteria for Magrolimab were met. When Magrolimab, Nivolumab, and FOLFOX plus bevacizumab or cetuximab were administered on the same day, administration was started in the following order: Magrolimab, Nivolumab, and FOLFOX plus bevacizumab or cetuximab.

[0080] [Nivolumab] Nivolumab was administered intravenously at a dose of 480 mg over 30 minutes every 4 weeks until the prescribed nivolumab discontinuation criteria were met, with administration of nivolumab occurring on or after the 25th day after the previous administration, at least 24 days after the previous administration.

[0081] [FOLFOX plus bevacizumab or cetuximab] Regarding the choice of bevacizumab or cetuximab, bevacizumab was used for patients with RAS mutant type and cetuximab was used for patients with RAS wild type. The initial dose of bevacizumab was 5 mg / kg body weight, administered intravenously over 90 minutes. If the first dose was well tolerated, the second dose could be administered over 60 minutes. If the second dose was also well tolerated, subsequent doses could be administered over 30 minutes. The interval between doses was at least 2 weeks. The starting dose of cetuximab was 400 mg / m 2 (body surface area) and administered intravenously over 2 hours. From the second dose onwards, the dose was 250 mg / m2 once a week or at 2-week intervals. 2 Cetuximab was administered intravenously at 500 mg / m2 for 1 hour once every 2 weeks as needed. 2It was also possible to administer the drug by intravenous drip infusion over two hours at two-week intervals. The dosage was reduced as appropriate depending on the patient's condition. (1x) Bevacizumab or cetuximab was administered, followed by (1a) oxaliplatin at 85 mg / m 2 (body surface area) was administered intravenously over 2 hours. (1b) Simultaneously with the administration of oxaliplatin, levofolinate calcium was administered at 200 mg / m 2 (body surface area) was administered intravenously over a period of 2 hours. (1c) Fluorouracil was administered at 400 mg / m after the end of intravenous administration of calcium levofolinate. 2 (body surface area) was administered intravenously for 1 d, followed by 2400 mg / m 2 (body surface area) was administered intravenously over 46 hours. The series of administrations (1x), (1a), (1b), (1c) and (1d) were administered at 2-week intervals. Bevacizumab, cetuximab, oxaliplatin, levofolinate calcium and fluorouracil were commercially available.

[0082] [Clinical trial schedule] This study consists of a screening period, a treatment period, and a follow-up period. The clinical trial schedule is outlined in Figure 1. The screening period was within 28 days prior to administration of the investigational drug, and patients who were deemed by the principal investigator or co-investigator to be eligible for this clinical trial, who met the inclusion criteria above and did not violate the exclusion criteria above, were enrolled. The treatment period was 28 days per cycle, and the first administration of the study drug was designated as day 1 of cycle 1. Day 1 of each cycle from the second cycle onward was designated as [28 × (number of cycles - 1) + 1]. Magrolimab, Nivolumab, and FOLFOX therapy plus bevacizumab or cetuximab were administered according to the above-mentioned dosage and administration methods, and were continued according to the administration guidelines, dose reduction guidelines, and dose reduction doses for Magrolimab, Nivolumab, and FOLFOX therapy plus bevacizumab or cetuximab. The end of the treatment period was the end of the evaluation at the end of administration (discontinuation) of the combination therapy of Magrolimab, Nivolumab, and FOLFOX therapy plus bevacizumab or cetuximab. Among all subjects who received the study drug, those who discontinued or completed the combination therapy of Magrolimab, Nivolumab, and FOLFOX with bevacizumab or cetuximab were evaluated at the time of the end of treatment (discontinuation) and entered the follow-up period.

[0083] [Dosage guidelines for Magrolimab and Nivolumab] At the start of each treatment, subjects were required to meet all of the prescribed treatment criteria, which were determined based on the treatment criteria in previous clinical trials of Magrolimab and Nivolumab. If any of the criteria were not met, the scheduled treatment of Magrolimab and Nivolumab was interrupted. Subjects who were interrupted were examined weekly or more frequently if clinically necessary to determine whether treatment could be resumed.

[0084] [Criteria for discontinuing Magrolimab] During the treatment period, subjects who met any of the predefined discontinuation criteria, which were determined taking into account the discontinuation criteria in previous clinical trials of Magrolimab, discontinued administration of Magrolimab.

[0085] [Criteria for discontinuing Nivolumab] During the treatment period, subjects who met any of the prescribed discontinuation criteria, which were determined taking into consideration the discontinuation criteria in previous clinical trials of Nivolumab, discontinued administration of Nivolumab.

[0086] [Administration criteria for combination therapy with FOLFOX plus bevacizumab or cetuximab] At the start of each treatment, subjects must meet all of the prescribed treatment criteria determined in consideration of the latest package insert for the combination therapy of FOLFOX with bevacizumab or cetuximab. Treatment was postponed until the clinical test values ​​on the scheduled day of treatment recovered to meet the conditions of the criteria, and treatment was administered only after confirming that there were no contraindications for each drug.

[0087] [Dose reduction and dose reduction criteria for FOLFOX plus bevacizumab or cetuximab] The dosage was reduced in accordance with the latest package insert.

[0088] [Discontinuation criteria for FOLFOX plus bevacizumab or cetuximab] During the treatment period, subjects who met any of the prescribed discontinuation criteria for FOLFOX plus bevacizumab or cetuximab, determined in consideration of the latest package insert, discontinued FOLFOX plus bevacizumab or cetuximab.

[0089] [Efficacy evaluation criteria] (Imaging diagnosis) CT / magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis were performed. The principal investigator or co-investigator measured the tumor diameter of the target lesions in accordance with RECIST guidelines version 1.1 and assessed the antitumor effect. (Evaluation items) (1) Overall response rate (ORR), (2) Disease control rate (DCR), (3) Overall survival (OS), (4) Progression-free survival (PFS), (5) Duration of response (DOR), (6) Time to response (TTR), (7) Best overall response (BOR), (8) Percentage change in the sum of tumor diameters of target lesions, (9) Maximum percentage change in the sum of tumor diameters of target lesions, (10) Changes in tumor markers (CEA and CA19-9) (Evaluation of target lesions) Complete response (CR) This refers to the disappearance of all non-lymph node target lesions and the reduction in the short axis of all lymph node lesions selected as target lesions to less than 10 mm. Partial response (PR) This means a reduction of 30% or more in the sum of the diameters of target lesions compared to the baseline sum of diameters. Progressive disease (PD) This means that the sum of diameters of the target lesions has increased by 20% or more compared to the smallest sum of diameters during the course of disease, and the absolute value of the sum of diameters has increased by 5 mm or more. Stable disease (SD) This means that, compared to the smallest sum of diameters during the course of disease, there is no shrinkage corresponding to PR and no increase corresponding to PD. Not Evaluable (NE) This refers to cases where testing cannot be performed for some reason or where the patient cannot be determined to be CR, PR, PD, or SD.

[0090] (1) Response rate The response rate indicates the proportion of subjects whose best overall response was determined to be CR or PR.

[0091] (2) Disease control rate The disease control rate indicates the proportion of subjects whose best overall response was determined to be CR, PR, or SD.

[0092] (3) Overall survival period Overall survival time is calculated using the following formula: Overall survival (days) = "date of death from any cause" - "date of start of study drug administration" + 1 For subjects who were lost to follow-up or had not died by the data cut-off date, the date of last confirmed survival will be used as the censoring date.

[0093] (4) Progression-free survival Progression-free survival is calculated using the following formula: Progression-free survival (days) = "the date on which the overall response was determined to be PD or the date of death from any cause, whichever comes first" - "the date on which the investigational drug was first administered" + 1 For subjects who have not been determined to have a PD overall response and have not died, the censoring date will be the date of the last evaluable diagnostic imaging.For subjects who have not been determined to have a PD overall response and have not died, the censoring date will be the date of the start of investigational drug administration.For subjects who received follow-up cancer treatment before the overall response was determined to be PD or before they died, the censoring date will be the date of the last evaluable diagnostic imaging before the start of follow-up cancer treatment.

[0094] (5) Duration of response The duration of response is calculated using the following formula: Duration of response (days) = "the date of the first confirmed overall response as PD or the date of death from any cause, whichever occurs first" - "the date of the first confirmed CR or PR" + 1 The subjects to be evaluated were those who demonstrated confirmed CR or PR through the clinical trial.

[0095] (6) Time to response The time to response will be calculated using the following formula: Time to response (days) = "date of first confirmed CR or PR" - "date of first administration of investigational drug" + 1

[0096] (7) Best overall effect The best overall response will be determined from the overall responses determined by the end of this study. However, CR and PR must be confirmed by consecutive evaluations at intervals of at least 4 weeks (28 days) and will be determined according to the criteria in Table 1.

[0097] [Table 1]

[0098] (8) Change in the sum of tumor diameters of target lesions For subjects with target lesions, the rate of change in the sum of tumor diameters of target lesions will be calculated using the following formula. However, the rate of change in the sum of tumor diameters of target lesions after subsequent treatment will not be calculated.

[0099]

number

[0100] (9) Maximum change in tumor diameter of target lesions The maximum rate of change in the sum of tumor diameters of target lesions is the rate of change at the time when the sum of tumor diameters of target lesions was smallest. However, the sum of tumor diameters of target lesions after the overall response was judged to be PD or after post-treatment was administered will not be used in calculating the maximum rate of change.

[0101]

number

[0102] (10) Changes in tumor markers (CEA and CA19-9) The rate of change in tumor markers will be calculated using the following formula, except that the rate of change in tumor markers after post-treatment will not be calculated.

[0103]

number

[0104] [Safety evaluation items] The principal investigator and others conducted measurements, examinations, and investigations of the following items at specified times. (1) Dose-limiting toxicity (DLT), (2) Adverse events, (3) Laboratory tests (hematology, blood biochemistry, immunology, hormone surveys, blood coagulation tests, and urinary qualitative tests), peripheral blood smear, (4) Vital signs (systolic blood pressure / diastolic blood pressure, pulse rate, body temperature, respiratory rate), transcutaneous oxygen saturation (SpO 2 ), weight, (5) 12-lead electrocardiogram, (6) ECOG performance status, and (7) chest x-ray.

[0105] [Efficacy evaluation results] For the combination of Magrolimab, Nivolumab, and FOLFOX plus bevacizumab, two cases were judged to have a PR 8 months after the first subject was enrolled. For the combination of cetuximab plus Magrolimab, Nivolumab, and FOLFOX, three cases were judged to have a PR 8 months after the first subject was enrolled.

[0106] Example 2 : An open-label, uncontrolled study of first-line treatment with Magrolimab, Nivolumab and standard mFFX therapy in patients with metastatic pancreatic cancer The purpose of this study is to investigate the tolerability, safety, and efficacy of the combination of Magrolimab, Nivolumab, and mFFX therapy as first-line treatment in patients with metastatic pancreatic cancer. This clinical trial will enable the evaluation of the efficacy of the combination with Magrolimab, Nivolumab, and mFFX therapy.

[0107] (1) Target patients Pancreatic cancer patients with distant metastases

[0108] (2) Patient selection criteria Patients who met all of the following criteria at the time of enrollment were selected. If it became clear that the following criteria were not met between enrollment and the first administration of the study drug, the administration of the study drug was not started and the study was discontinued. 1. Gender: No restrictions. 2. Age (at the time of obtaining consent): 20 years of age or older. 3. Patients who can be hospitalized from the day before the start of study drug administration until the end of examination on at least the 15th day after the start of study drug administration (only for tolerability evaluation part). 4.Patients with invasive pancreatic ductal carcinoma diagnosed as adenocarcinoma by histology or cytology. 5. Patients with no history of systemic anti-cancer drug treatment for pancreatic cancer with distant metastasis. However, patients who have previously received chemoradiotherapy, postoperative adjuvant chemotherapy, or neoadjuvant chemotherapy and experience recurrence more than 180 days after the completion of anti-cancer drug treatment will be allowed to register. 6. Patients with measurable lesions as defined by RECIST version 1.1 in diagnostic imaging within 14 days prior to administration of the investigational drug. However, in cases where patients have only measurable lesions with a history of radiation therapy, this is limited to lesions that have progressed in diagnostic imaging after radiation therapy. 7.Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 8. Patients expected to survive for 90 days or more. 9. Patients who can provide tumor tissue samples for biomarker testing. Tumor tissue samples will be obtained during the screening phase. If a new tumor biopsy is difficult, archived samples may be used, provided that the archived samples were collected within 180 days prior to administration of the investigational drug. 10. Women of childbearing potential (including patients who have not had menstruation due to medical reasons such as chemical menopause) who agree to use double contraception from the time of obtaining consent until 5 months after the last dose of the investigational drug and for the period prescribed for contraception after the last dose of the standard treatment drug. In addition, patients who agree not to breastfeed from the time of obtaining consent until 5 months after the last dose of the investigational drug and for the period prescribed for contraception after the last dose of the standard treatment drug. Here, women of childbearing potential include all women who have experienced menarche, have not undergone sterilization (hysterectomy, bilateral tubal ligation, bilateral oophorectomy, etc.), and have not yet undergone menopause. Menopause is defined as amenorrhea for 12 or more consecutive months without any notable reason. Women who use oral contraceptives, intrauterine devices, or contraceptive diaphragms are considered to be of childbearing potential. 11. For men, patients who agree to use dual contraception from the start of treatment with the investigational drug until 4 months after the last treatment with the investigational drug and for the period specified for each drug after the last treatment with the standard treatment. Dual contraception must be provided by any two of the following means: vasectomy or condoms for male patients or male partners, or tubal ligation, contraceptive diaphragm, intrauterine device, or oral contraceptives for female patients or partners. 12. Patients whose most recent clinical test results performed within 14 days prior to the start of administration of the investigational drug meet the following criteria: Patients must not have received hematopoietic factor preparations such as granulocyte colony-stimulating factor (G-CSF) or blood transfusions within 14 days prior to the test date. Neutrophil count: 2,000 / mm 3 The end. ·Platelet count: 100,000 / mm 3 The end. Hemoglobin: ≥ 11.0 g / dL. -AST (GOT) and ALT (GPT): 3.0 times or less the upper limit of the facility's normal range (however, if there is liver metastasis, 5.0 times or less the upper limit of the facility's normal range). Total bilirubin: 1.5 times or less of the upper limit of the facility's standard value. -Albumin: ≥ 3.0g / dL. Creatinine: 1.5 times or less of the upper limit of the facility's standard value or creatinine clearance (actual measurement or Cockcroft / Gault estimate) 40mL / min or more. 13. Patients who have been fully explained the contents of this clinical trial by the principal investigator or clinical investigator using a consent form and an information sheet, and who voluntarily consent in writing to participate in this clinical trial.

[0109] (3) Patient exclusion criteria Patients who met any of the following criteria at the time of registration were excluded. If any of the following criteria were met between registration and the first administration of the study drug, the study drug was not administered and the patient was discontinued. 1.Patients for whom administration of oxaliplatin, irinotecan, fluorouracil or levofolinate calcium is contraindicated. 2. Patients with clinically significant diarrhea (including watery stools). 3.Patients with peripheral motor neuropathy or peripheral sensory neuropathy. 4. UDP-glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism; patients with homozygotes (UGT1A1*6 / *6, UGT1A1*28 / *28) or heterozygotes (compound heterozygote: UGT1A1*6 / *28). 5. Patients with a history or current severe hypersensitivity reaction to antibody preparations. 6. Patients who are judged by the investigator or co-investigator to have an adverse effect on the efficacy and safety evaluation of the investigational drug due to the effects of surgical treatment. 7. Patients with autoimmune diseases or a history of chronic or recurrent autoimmune diseases. However, patients with type 1 diabetes, hypothyroidism that can be managed with hormone replacement therapy, or skin diseases that do not require systemic therapy (vitiligo, psoriasis, alopecia, etc.) may be enrolled. 8.Patients with multiple cancers (patients with completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, or superficial bladder cancer, or other cancers that have not recurred for more than 3 years, may be enrolled). 9. Patients with metastatic lesions in the brain or meninges. However, asymptomatic patients who do not require treatment may be enrolled. 10. Patients with a history of interstitial lung disease or pulmonary fibrosis diagnosed by imaging or clinical findings. 11. Patients with diverticulitis or symptomatic gastrointestinal ulcer disease. 12. Patients with pericardial effusion, pleural effusion, or ascites that cannot be controlled by medical therapy. 13.Patients with uncontrollable cancer pain. 14. Patients with severe peritoneal dissemination, such as continuous accumulation of ascites beyond the pelvic cavity. 15. Patients who require transplant therapy or have a history of transplant therapy (excluding autologous transplants). 16. Patients with a history of hemolytic anemia within 90 days prior to enrollment. 17. Patients with a history of transient ischemic attack, cerebrovascular accident, thrombosis or thromboembolism (pulmonary embolism or deep vein thrombosis) within 180 days prior to enrollment. 18.Patients with any of the following uncontrolled or significant cardiovascular diseases: - Myocardial infarction within 180 days prior to enrollment. -Uncontrolled angina within 180 days prior to enrollment. -New York Heart Association (NYHA) class III or IV congestive heart failure. Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure above 150mmHg or diastolic blood pressure above 90mmHg for more than 24 hours). -Irregular heartbeat requiring treatment. 19.Patients with uncontrolled diabetes mellitus. 20. Patients with systemic infections requiring treatment. 21. Patients who test positive for HIV-1 and HIV-2 antibodies, HTLV-1 antibodies, HBs antigen, or HCV antibodies (excluding HCV-RNA negative) at screening. Even if the HCV antibody test is positive, if the HCV RNA is negative, registration will be permitted. 22. Patients whose HBs antigen test is negative, but either the HBs antibody test or the HBc antibody test is positive and whose HBV-DNA quantification is above the detection sensitivity at the time of screening. 23.Patients who have received the following treatments before obtaining consent and before administration of the investigational drug. -Patients who have previously been treated with Magrolimab or drugs targeting the CD47-SIRPα pathway, Nivolumab, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-CD137 antibodies, anti-CTLA-4 antibodies, or other antibody therapies aimed at regulating T cells, or chemotherapy including cancer vaccines. -Patients who received more than 2 units of red blood cells transfusion within 28 days prior to obtaining informed consent. -Patients who underwent surgical treatment involving local anesthesia within 14 days prior to administration of the study drug. -Patients who underwent pleural or pericardial adhesion surgery within 14 days prior to administration of the study drug. Patients who have received systemic corticosteroids (except for temporary use for the purposes of examinations, local administration, treatment and prevention of contrast allergic reactions, or reduction of edema associated with radiation therapy) or immunosuppressants at a dose equivalent to more than 10 mg / day of prednisolone within 14 days prior to administration of the study drug. Patients who received palliative radiation therapy within 28 days prior to receiving the study drug. -Patients who underwent surgical treatment involving general anesthesia within 28 days prior to administration of the study drug. -Patients who have received a live or attenuated vaccine within 28 days prior to administration of the study drug. Patients who have received other unapproved drugs (including those administered in clinical research studies, unapproved combination drugs, and new dosage forms) within 28 days (90 days for antibody preparations) prior to administration of the investigational drug. Patients who have received radiopharmaceuticals (excluding the use of radiopharmaceuticals for diagnostic and diagnostic purposes) within 56 days prior to administration of the investigational drug. 24. Patients who are known to have a germline BRCA gene mutation (pathogenic or suspected pathogenic mutation). 25. Patients who are pregnant, breastfeeding, or possibly pregnant (patients who are breastfeeding will not be able to register even if they have stopped breastfeeding). 26. Patients who are judged to lack the capacity to consent due to dementia or other reasons. 27. Patients who are otherwise deemed inappropriate for the clinical trial by the principal investigator or clinical investigator.

[0110] (4) Dosage and administration period [Magrolimab] Magrolimab was administered intravenously at 1 mg / kg over 3 hours (± 30 minutes) on day 1 of cycle 1 as the initial dose, followed by intravenous administration at 20 mg / kg or 30 mg / kg over 2 hours (± 30 minutes) every week in cycle 1, and then intravenous administration at 20 mg / kg or 30 mg / kg over 2 hours (± 30 minutes) every 2 weeks in cycles 2 and onwards, until the prescribed discontinuation criteria for Magrolimab were met. When Magrolimab, Nivolumab and mFFX therapy were administered on the same day, administration was started in the following order: Magrolimab, Nivolumab, and mFFX therapy.

[0111] [Nivolumab] Nivolumab was administered intravenously at a dose of 480 mg over 30 minutes every 4 weeks until the prescribed nivolumab discontinuation criteria were met, with administration of nivolumab occurring on or after the 25th day after the previous administration, at least 24 days after the previous administration.

[0112] [mFFX Therapy] (2a) Oxaliplatin is 85 mg / m 2 (body surface area) was administered intravenously over 2 hours. (2b) Calcium levofolinate was administered at 200 mg / m 2 (body surface area) was administered intravenously over a period of 2 hours. (2c) Irinotecan hydrochloride hydrate was administered at 150 mg / m2 from 30 minutes after the start of administration of levofolinate calcium. 2 (body surface area) was administered intravenously over 1.5 hours. (2e) Fluorouracil was administered at 2400 mg / m 2(body surface area) was administered intravenously over 46 hours. The series of administrations of (2a), (2b), (2c) and (2e) were performed at 2-week intervals. Commercially available products were used for oxaliplatin, irinotecan hydrochloride hydrate, levofolinate calcium and fluorouracil.

[0113] [Clinical trial schedule] This study consists of a screening period, a treatment period, and a follow-up period. The clinical trial schedule is shown in Figure 2. The screening period was within 28 days prior to administration of the investigational drug, and patients who were deemed by the principal investigator or co-investigator to be eligible for this clinical trial, who met the inclusion criteria above and did not violate the exclusion criteria above, were enrolled. The treatment period was 28 days per cycle, and the first day of administration of the study drug was designated as day 1 of cycle 1. Day 1 of each cycle from the second cycle onward was designated as [28 × (number of cycles - 1) + 1]. Magrolimab, Nivolumab, and mFFX therapy were started according to the above-mentioned dosage and administration methods, and administration was continued according to the administration guidelines, dose reduction guidelines, and dose reduction guidelines for Magrolimab, Nivolumab, and mFFX therapy. The end of the treatment period was the end of the evaluation at the end (discontinuation) of administration of Magrolimab, Nivolumab, and mFFX therapy. Of all subjects who received the study drug, subjects who discontinued or completed administration of Magrolimab, Nivolumab, and mFFX therapy were evaluated at the end (discontinuation) of administration and moved to the follow-up period. After the end of the follow-up period, a follow-up survey was conducted.

[0114] [Dosage guidelines for Magrolimab and Nivolumab] At the start of each treatment, subjects were required to meet all of the prescribed treatment criteria, which were determined based on the treatment criteria in previous clinical trials of Magrolimab and Nivolumab. If any of the criteria were not met, the scheduled treatment of Magrolimab and Nivolumab was interrupted. Subjects who were interrupted were examined weekly or more frequently if clinically necessary to determine whether treatment could be resumed.

[0115] [Criteria for discontinuing Magrolimab] During the treatment period, subjects who met any of the predefined discontinuation criteria, which were determined taking into account the discontinuation criteria in previous clinical trials of Magrolimab, discontinued administration of Magrolimab.

[0116] [Criteria for discontinuing Nivolumab] During the treatment period, subjects who met any of the prescribed discontinuation criteria, which were determined taking into consideration the discontinuation criteria in previous clinical trials of Nivolumab, discontinued administration of Nivolumab.

[0117] [mFFX therapy administration criteria] At the start of each treatment, subjects must meet all of the prescribed treatment criteria for mFFX therapy, which were determined taking into consideration the latest package insert. Treatment was postponed until the clinical test values ​​on the scheduled day of treatment had recovered to meet the conditions of the criteria, and treatment was administered only after confirming that there were no contraindications for each drug.

[0118] [Reduction in dose of mFFX therapy and reduction criteria] The dosage was reduced in accordance with the latest package insert.

[0119] [Criteria for discontinuing mFFX therapy] During the treatment period, subjects who met any of the prescribed discontinuation criteria for mFFX therapy, determined in consideration of the latest package insert, discontinued mFFX therapy.

[0120] [Efficacy evaluation criteria] (Imaging diagnosis) CT / magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis were performed. The principal investigator or co-investigator measured the tumor diameter of the target lesions in accordance with RECIST guidelines version 1.1 and assessed the antitumor effect. (Evaluation items) (1) Overall response rate (ORR), (2) Disease control rate (DCR), (3) Overall survival (OS), (4) Progression-free survival (PFS), (5) Duration of response (DOR), (6) Time to response (TTR), (7) Best overall response (BOR), (8) Percentage change in the sum of tumor diameters of target lesions, (9) Maximum percentage change in the sum of tumor diameters of target lesions, (10) Changes in tumor markers (CEA and CA19-9) (Evaluation of target lesions) Complete response (CR) This refers to the disappearance of all non-lymph node target lesions and the reduction in the short axis of all lymph node lesions selected as target lesions to less than 10 mm. Partial response (PR) This means a reduction of 30% or more in the sum of the diameters of target lesions compared to the baseline sum of diameters. Progressive disease (PD) This means that the sum of diameters of the target lesions has increased by 20% or more compared to the smallest sum of diameters during the course of disease, and the absolute value of the sum of diameters has increased by 5 mm or more. Stable disease (SD) This means that, compared to the smallest sum of diameters during the course of disease, there is no shrinkage corresponding to PR and no increase corresponding to PD. Not Evaluable (NE) This refers to cases where testing cannot be performed for some reason or where the patient cannot be determined to be CR, PR, PD, or SD.

[0121] (1) Response rate The response rate indicates the proportion of subjects whose best overall response was determined to be CR or PR.

[0122] (2) Disease control rate The disease control rate indicates the proportion of subjects whose best overall response was determined to be CR, PR, or SD.

[0123] (3) Overall survival period Overall survival time is calculated using the following formula: Overall survival (days) = "date of death from any cause" - "date of start of study drug administration" + 1 For subjects who were lost to follow-up or had not died by the data cut-off date, the date of last confirmed survival will be used as the censoring date.

[0124] (4) Progression-free survival Progression-free survival is calculated using the following formula: Progression-free survival (days) = "the date on which the overall response was determined to be PD or the date of death from any cause, whichever comes first" - "the date on which the investigational drug was first administered" + 1 For subjects who have not been determined to have a PD overall response and have not died, the censoring date will be the date of the last evaluable diagnostic imaging.For subjects who have not been determined to have a PD overall response and have not died, the censoring date will be the date of the start of investigational drug administration.For subjects who received follow-up cancer treatment before the overall response was determined to be PD or before they died, the censoring date will be the date of the last evaluable diagnostic imaging before the start of follow-up cancer treatment.

[0125] (5) Duration of response The duration of response is calculated using the following formula: Duration of response (days) = "the date of the first confirmed overall response as PD or the date of death from any cause, whichever occurs first" - "the date of the first confirmed CR or PR" + 1 The subjects to be evaluated were those who demonstrated confirmed CR or PR through the clinical trial.

[0126] (6) Time to response The time to response will be calculated using the following formula: Time to response (days) = "date of first confirmed CR or PR" - "date of first administration of investigational drug" + 1

[0127] (7) Best overall effect The best overall response will be determined from the overall responses determined by the end of this study. However, CR and PR must be confirmed by consecutive evaluations at intervals of at least 4 weeks (28 days) and will be determined according to the criteria in Table 2.

[0128] [Table 2]

[0129] (8) Change in the sum of tumor diameters of target lesions For subjects with target lesions, the rate of change in the sum of tumor diameters of target lesions will be calculated using the following formula. However, the rate of change in the sum of tumor diameters of target lesions after subsequent treatment will not be calculated.

[0130]

number

[0131] (9) Maximum change in tumor diameter of target lesions The maximum rate of change in the sum of tumor diameters of target lesions is the rate of change at the time when the sum of tumor diameters of target lesions was smallest. However, the sum of tumor diameters of target lesions after the overall response was judged to be PD or after post-treatment was administered will not be used in calculating the maximum rate of change.

[0132]

number

[0133] (10) Changes in tumor markers (CEA and CA19-9) The rate of change in tumor markers will be calculated using the following formula, except that the rate of change in tumor markers after post-treatment will not be calculated.

[0134]

number

[0135] [Safety evaluation items] The principal investigator and others conducted measurements, examinations, and investigations of the following items at specified times. (1) Dose-limiting toxicity (DLT), (2) Adverse events, (3) Laboratory tests (hematology, blood biochemistry, immunology, hormone surveys, blood coagulation tests, and urinary qualitative tests), peripheral blood smear, (4) Vital signs (systolic blood pressure / diastolic blood pressure, pulse rate, body temperature, respiratory rate), transcutaneous oxygen saturation (SpO 2 ), weight, (5) 12-lead electrocardiogram, (6) ECOG performance status, and (7) chest x-ray.

[0136] [Efficacy evaluation results] Regarding the combination therapy of Magrolimab, Nivolumab and mFFX therapy, 10 months after the first subject was enrolled, one case was judged to have been PR. [Industrial Applicability]

[0137] The present invention is useful in that it provides a new cancer treatment method.

Claims

1. An agent for inhibiting the progression and recurrence of and / or treating solid cancer, comprising a CD47 inhibitor as an active ingredient, which is administered in combination with standard therapy and an immune checkpoint inhibitor.

2. An agent for inhibiting the progression and recurrence of and / or treating solid cancer, comprising an immune checkpoint inhibitor as an active ingredient, which is administered in combination with standard therapy and a CD47 inhibitor.

3. The agent according to claim 1 or 2, wherein the standard therapy is a combination therapy of FOLFOX therapy with bevacizumab or cetuximab.

4. Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) bevacizumab 5 mg / kg (body weight) administered intravenously or cetuximab 400 mg / m ２ (body surface area), 250 mg / m for the second and subsequent doses ２ (body surface area) administered intravenously; (1a) oxaliplatin 85 mg / m ２ (body surface area) administered intravenously; (1b) Calcium levofolinate 200 mg / m ２ (body surface area) administered intravenously; (1c) Fluorouracil 400 mg / m ２ (body surface area) administered intravenously; and (1d) After the administration of fluorouracil in (1c), 2400 mg / m fluorouracil is administered. ２ (body surface area) by continuous intravenous administration; The method of claim 3, wherein the sequential administration of (1x), (1a), (1b), (1c) and (1d) is performed at two-week intervals.

5. Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) bevacizumab 5 mg / kg (body weight) administered intravenously; (1a) oxaliplatin 85 mg / m ２ (body surface area) administered intravenously; (1b) Calcium levofolinate 200 mg / m ２ (body surface area) administered intravenously; (1c) Fluorouracil 400 mg / m ２ (body surface area) administered intravenously; and (1d) After the administration of fluorouracil in (1c), 2400 mg / m fluorouracil is administered. ２ (body surface area) by continuous intravenous administration; The method of claim 4, wherein the sequential administration of (1x), (1a), (1b), (1c) and (1d) is performed at two-week intervals.

6. Combination therapy with FOLFOX plus bevacizumab or cetuximab (1x) Cetuximab 1st dose 400mg / m ２ (body surface area), 250 mg / m for the second and subsequent doses ２ (body surface area) administered intravenously; (1a) oxaliplatin 85 mg / m ２ (body surface area) administered intravenously; (1b) Calcium levofolinate 200 mg / m ２ (body surface area) administered intravenously; (1c) Fluorouracil 400 mg / m ２ (body surface area) administered intravenously; and (1d) After the administration of fluorouracil in (1c), 2400 mg / m fluorouracil is administered. ２ (body surface area) by continuous intravenous administration; The method of claim 4, wherein the sequential administration of (1x), (1a), (1b), (1c) and (1d) is performed at two-week intervals.

7. The agent according to any one of claims 1 to 6, wherein the solid cancer is colorectal cancer.

8. The agent according to claim 7, wherein the colorectal cancer is unresectable, advanced or recurrent colorectal cancer.

9. The agent according to any one of claims 1 to 8, which is administered as a first-line treatment to patients with unresectable advanced or recurrent colorectal cancer who have no history of treatment with a systemic anti-cancer agent.

10. The agent according to claim 1 or claim 2, wherein the standard therapy is FOLFIRINOX therapy or a reduced dose regimen thereof.

11. FOLFIRINOX therapy, (2a) oxaliplatin 85 mg / m ２ (body surface area) administered intravenously; (2b) Calcium levofolinate 200 mg / m ２ (body surface area) administered intravenously; (2c) Irinotecan hydrochloride hydrate 180 mg / m ２ (body surface area) administered intravenously; (2d) Fluorouracil 400 mg / m ２ (body surface area) administered intravenously; and (2e) After the administration of fluorouracil in (2d), 2400 mg / m fluorouracil is administered. ２ (body surface area) by continuous intravenous administration; The method of claim 10, wherein the sequential administration of (2a), (2b), (2c), (2d) and (2e) is performed at two-week intervals.

12. The weight loss regimen for FOLFIRINOX therapy is (2a) oxaliplatin 85 mg / m ２ (body surface area) administered intravenously; (2b) Calcium levofolinate 200 mg / m ２ (body surface area) administered intravenously; (2c) Irinotecan hydrochloride hydrate 150 mg / m ２ (body surface area) intravenously, and (2e) Fluorouracil 2400 mg / m ２ (body surface area) by continuous intravenous administration; The method of claim 10, wherein the sequential administration of (2a), (2b), (2c) and (2e) is performed at two-week intervals.

13. The agent according to any one of claims 1, 2, 10, 11 and 12, wherein the solid cancer is pancreatic cancer with distant metastasis.

14. The agent according to any one of claims 1, 2, 10, 11, 12 and 13, which is administered as a first-line treatment to a patient with pancreatic cancer having distant metastasis who has no history of treatment with a systemic anti-cancer agent.

15. The agent according to any one of claims 1 to 14, wherein the CD47 inhibitor is an anti-CD47 antibody.

16. The agent according to claim 15, wherein the anti-CD47 antibody is Magrolimab.

17. The agent according to claim 16, wherein the initial administration of Magrolimab is intravenously administered at 1 mg / kg (body weight), and from the second administration onwards, the agent is intravenously administered at 15 mg / kg (body weight) to 30 mg / kg (body weight) at weekly or biweekly intervals.

18. The agent according to claim 16 or 17, wherein the initial administration of Magrolimab is intravenously administered at 1 mg / kg (body weight), and from the second administration onwards, the agent is intravenously administered at 30 mg / kg (body weight) once every week or every two weeks.

19. The agent according to any one of claims 1 to 18, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

20. The agent according to any one of claims 1 to 19, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

21. Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, AMP-51 4. Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, Retifanlimab, Balstilimab, CS1003, Serplulimab, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, Geptanolimab, SSI-361, JY034, HX008, ISU106, Budigalimab, Prolgolimab, Sasanlimab, CX-188, Cetrelimab or Zimberelimab.

22. The agent according to claim 21, wherein the anti-PD-1 antibody is Nivolumab.

23. The agent according to claim 22, which is administered intravenously at a dose of 480 mg of nivolumab every four weeks.

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