Cancer treatment using a combination of CD47 inhibitors, immune checkpoint inhibitors, and standard therapies.

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] This disclosure relates to a cancer treatment method (sometimes abbreviated as the treatment method of the present invention) using a combination of CD47 inhibitors, immune checkpoint inhibitors, and standard therapies. [Background technology]

[0002] CD47 is a five-transmembrane glycoprotein. When expressed on cancer cells, CD47 binds to signal regulatory protein alpha (SIRPα), which is expressed on macrophages and dendritic cells. This binds to the SIRPα, transmitting a "don't eat me" signal to macrophages and inhibiting 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 phagocytosis of cancer cells by macrophages. Therefore, they are considered useful in cancer treatment (see Non-Patent Documents 1-4).

[0003] Patent Document 1 discloses that CD47 inhibitors promote phagocytosis of cancer cells by macrophages and are useful as cancer treatments (see Patent Document 1).

[0004] On the other hand, cancer cells and the tumor microenvironment contain various immune checkpoint molecules that interfere with the immune response to cancer. Immune checkpoint inhibitors are a new therapeutic approach that releases the immunosuppressive mechanism and activates the immune response to cancer. Already, 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 been approved both domestically and internationally and are being used in cancer treatment.

[0005] For advanced or recurrent colorectal cancer that is not resectable, drug therapy is applied. Standard therapy includes FOLFOX therapy, which combines fluorouracil (5-FU), levofolinate, and oxaliplatin, with combination therapy that adds 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 primary treatment for unresectable pancreatic cancer with distant metastases is drug therapy. Standard therapy includes 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 order to reduce toxicity from FFX therapy.

[0007] While these treatments show some effectiveness, there is an unmet need for treatments that further extend survival time. [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. [Overview of the project] [Problems that the invention aims to solve]

[0010] The object of this invention is to provide a new treatment method for cancer (for example, colorectal cancer, pancreatic cancer). [Means for solving the problem]

[0011] As a result of diligent research to solve the aforementioned problems, the inventors have found that combining CD47 inhibitors and immune checkpoint inhibitors with standard therapy can be an effective cancer treatment method.

[0012] Therefore, in a certain manner, [1] A solid tumor progression inhibitor, recurrence inhibitor and / or treatment agent containing a CD47 inhibitor as an active ingredient, characterized by being administered in combination with standard therapy and an immune checkpoint inhibitor. [2] Provided are agents for inhibiting the progression, recurrence, and / or treating solid tumors, comprising an immune checkpoint inhibitor as an active ingredient, characterized by being administered in combination with standard therapy and a CD47 inhibitor. [Effects of the Invention]

[0013] The treatment method of the present invention is useful for cancer treatment. [Brief explanation of the drawing]

[0014] [Figure 1]Figure 1 shows an overview of a multicenter, open-label, uncontrolled trial evaluating the tolerability, safety, and efficacy of combination therapy with magrolimab, nivolumab, and FOLFOX therapy plus bevacizumab or cetuximab in patients with unresectable advanced or recurrent colorectal cancer. [Figure 2] Figure 2 shows an overview of a multicenter, open-label, uncontrolled trial evaluating the tolerability, safety, and efficacy of the combination therapy of Magrolimab, Nivolumab, and mFFX in patients with pancreatic cancer with distant metastases, as described below. [Modes for carrying out the invention]

[0015] (1) CD47 inhibitors In the present invention, the CD47 inhibitor is not particularly limited as long as it is a compound having CD47 inhibitory activity. In one embodiment, it is a drug (preferably an antibody, more preferably a monoclonal antibody) that inhibits the binding of CD47 to SIRPα, and examples include anti-CD47 antibodies and anti-SIRPα antibodies. It may also be an antigen-binding fragment of the antibody (for example, 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 individually or in combination of two or more. Preferably, the CD47 inhibitor is an anti-CD47 antibody, and preferably Magrolimab (CAS number: 2169232-81-7). Furthermore, an antibody or its antigen-binding fragment containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VR) of the above-mentioned known antibodies is also a form of CD47 inhibitor. For example, a further form of an anti-CD47 antibody is an antibody or its antigen-binding fragment containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VR) of Magrolimab, for example. Furthermore, one embodiment of the anti-CD47 antibody is an antibody that competes with Magrolimab for binding to CD47, or an antibody that binds to the same CD47 epitope as Magrolimab, or antigen-binding fragments thereof.

[0016] In the present invention, CD47 inhibitors can be produced according to known methods; for example, Magrolimab can be produced according to the method described in WO2011 / 143624.

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

[0018] For example, the therapeutically effective dose (therapeutic dose) of an anti-CD47 antibody (e.g., Magrolimab) is, in one embodiment, 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, and about 45 mg / kg). The administration interval can be, for example, half a week (3 or 4 days), one week, or two weeks, and the duration of a single administration can 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 mentioned above, the dose will vary depending on various conditions, so in some cases a smaller dose than the above may be sufficient, and in other cases it may be necessary to administer a dose beyond the range. In one embodiment, the therapeutic dose may be gradually increased 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. A suitable priming agent includes an erythropoiesis-stimulating agent (ESA) and / or an initial dose of the anti-CD47 antibody (e.g., Magrolimab). After administration of the priming agent, and after providing an effective period for increasing reticulocyte production (e.g., at least about 3 days after administration of the priming agent (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)), a therapeutic dose of the anti-CD47 antibody (e.g., Magrolimab) is administered. In one embodiment, a specific appropriate initial dose of anti-CD47 antibody (e.g., Magrolimab) is approximately 0.5 mg / kg to approximately 5 mg / kg (preferably approximately 1 mg / kg), administered intravenously over approximately 2.5 hours to approximately 6 hours (e.g., approximately 3 hours to approximately 4 hours, or approximately 3 hours (±30 minutes)). In one embodiment, approximately 1 mg / kg of anti-CD47 antibody (e.g., Magrolimab) is administered intravenously for the initial dose, and from the second dose onward, approximately 15 mg / kg to approximately 30 mg / kg (preferably approximately 20 mg / kg or approximately 30 mg / kg) is administered intravenously at one-week or two-week intervals.

[0020] (2) Immune checkpoint inhibitors In this invention, an immune checkpoint molecule refers to a molecule that exerts an immunosuppressive function by transmitting an inhibitory co-signal. Known 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, Cancer). (See Cell, 27, pp. 450-461, 2015), it is not particularly limited as long as it is a molecule that has a function consistent with the definition.

[0021] In the present invention, an immune checkpoint inhibitor is a substance that inhibits the function of an immune checkpoint molecule. The immune checkpoint inhibitor is not particularly limited as long as it is a substance that can suppress the function (signaling) of an immune checkpoint molecule. An immune checkpoint inhibitor may be used alone or in combination of two or more. Preferably, the immune checkpoint inhibitor is an antibody (preferably a monoclonal antibody) or its antigen-binding fragment (e.g., Fv, Fab, Fab', (Fab')2, scFv, 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- Examples include 010), Zalifrelimab (AGEN1884) and Tremelimumab, anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-Tim-3 antibodies (e.g., MBG453), anti-LAG-3 antibodies (e.g., BMS-986016, LAG525), and anti-KIR antibodies (e.g., Lirilumab). Furthermore, antibodies or antigen-binding fragments containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of the above known antibodies are also a form of immune checkpoint inhibitor. For example, a further form of an anti-PD-1 antibody is an antibody or antigen-binding fragment containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of Nivolumab, for example. Furthermore, one embodiment of an anti-PD-1 antibody is an antibody that competes with Nivolumab for binding to PD-1, or an antibody that binds to the same PD-1 as Nivolumab, or antigen-binding fragments 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, and 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, and 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 manufactured by known methods. For example, Nivolumab can be manufactured according to the method described in WO2006 / 121168, Pembrolizumab can be manufactured according to the method described in WO2008 / 156712, BMS-936559 can be manufactured according to the method described in WO2007 / 005874, and Ipilimumab can be manufactured according to the method described in WO2001 / 014424.

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

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

[0027] For example, the active ingredient of an immune checkpoint inhibitor can be administered intravenously (e.g., by intravenous infusion) at intervals of 2 to 4 weeks, at doses of approximately 1 mg / kg (body weight) to 10 mg / kg (body weight) or approximately 200 mg to 1200 mg, over a period of approximately 30 to 60 minutes or more. Here, examples of dosages per administration based on 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. On the other hand, examples of dosages 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. Furthermore, the administration interval may be, for example, two weeks, three weeks, or four weeks, and the duration of a single administration may be, for example, approximately 30 minutes to approximately 60 minutes or approximately 60 minutes or more.

[0028] When the active ingredient is the anti-PD-1 antibody Nivolumab, it is administered according to the following dosage and administration instructions: For patients with malignant melanoma, Nivolumab is administered by intravenous infusion at a dose of 3 mg / kg (body weight) every two weeks or at a dose of 2 mg / kg (body weight) every three weeks, or at a dose of 240 mg every two weeks or at a dose of 480 mg every four 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 by intravenous infusion at a dose of 3 mg / kg (body weight) every two weeks. Additionally, for 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 patients aged 12 years and older), gastric cancer, esophageal cancer, hepatocellular carcinoma, small cell lung cancer, and malignant pleural mesothelioma, nivolumab is administered intravenously at a dose of 240 mg every two weeks or at a dose of 480 mg every four weeks. Furthermore, alternative dosages and administrations include, for example, in patients with malignant melanoma, Nivolumab may be administered in combination with Ipilimumab, with 1 mg / kg (body weight) intravenously infusion four times at 3-week intervals, followed by 3 mg / kg (body weight) intravenously infusion every two weeks, or 80 mg of Nivolumab may be administered in combination with Ipilimumab, followed by 240 mg of Nivolumab every two weeks or 480 mg of Nivolumab every four weeks. Also, for example, in patients with renal cell carcinoma or colorectal cancer, Nivolumab may be administered in combination with Ipilimumab, with 240 mg of Nivolumab administered in combination with Ipilimumab, followed by 240 mg of Nivolumab every two weeks or 480 mg of Nivolumab every four weeks.

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

[0030] Furthermore, in the case of Pembrolizumab, which is also an anti-PD-1 antibody, it is administered according to the following dosage and administration: 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 carcinoma, cervical cancer, primary mediastinal B-cell lymphoma, hepatocellular carcinoma, gastric cancer, and Merkel cell carcinoma, Pembrolizumab is administered by intravenous infusion at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks. Alternatively, for example, for children aged 2 years or older with classical Hodgkin lymphoma, MSI-H or dMMR-positive solid tumors or colorectal cancer, and primary mediastinal B-cell lymphoma, Pembrolizumab is administered by intravenous infusion at a dose of 2 mg / kg (body weight) (up to 200 mg) every 3 weeks.

[0031] Furthermore, in the case of Avelumab, which is an anti-PD-L1 antibody, patients with Merkel cell carcinoma and urothelial carcinoma are administered 10 mg / kg (body weight) of Avelumab intravenously every two weeks. For patients with non-small cell lung cancer, urothelial carcinoma, and hepatocellular carcinoma, Atezolizumab is administered 1200 mg every three weeks by intravenous infusion, and in patients with triple-negative breast cancer, when used in combination with paclitaxel, Atezolizumab is administered 840 mg every two weeks by intravenous infusion. Furthermore, Durvalumab, which is also a PD-L1 antibody, is administered intravenously at a dose of 10 mg / kg (body weight) every two weeks to patients with non-small cell lung cancer and urothelial carcinoma, respectively, while Durvalumab is administered intravenously at a dose of 1500 mg every four weeks to patients with advanced small cell lung cancer.

[0032] In addition, for patients with malignant melanoma, ipilimumab is administered by intravenous infusion at 3 mg / kg (body weight) once daily at 3-week intervals for 4 doses, either alone or in combination with nivolumab. For patients with renal cell carcinoma and MSI-H or dMMR-positive colorectal cancer, ipilimumab is administered by intravenous infusion at 1 mg / kg (body weight) once daily at 3-week intervals for 4 doses, in combination with nivolumab. For patients with non-small cell lung cancer, ipilimumab is administered by intravenous infusion at 1 mg / kg (body weight) once every 6 weeks.

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

[0034] For intravenous administration of the immune checkpoint inhibitor of the present invention, intravenous drip infusion is preferred.

[0035] (3) Combination therapy with molecularly targeted drugs (e.g., bevacizumab, cetuximab) added to FOLFOX therapy (an example of standard therapy) In this invention, "standard therapy" refers to the treatment that has been confirmed to be effective and safe through the results of many clinical trials and is the most recommended treatment based on scientific evidence. In this invention, "FOLFOX therapy" refers to a cancer treatment method using a combination of three drugs: oxaliplatin, leucovorin calcium (hereinafter abbreviated as "leucovorin"), and fluorouracil, and in one embodiment, (1a) oxaliplatin 85 mg / m² 2 ~130 mg / m² 2 Intravenous administration of (1b) levofolinate 100 mg / m² 2 ~200mg / m 2 Intravenous administration of (1c) fluorouracil 400 mg / m² 2 Rapid intravenous administration of (1d) fluorouracil 600 mg / m² 2 ~2400mg / m 2including intravenous administration, and performing the series of administrations of (1a), (1b), (1c) and (1d) at two-week intervals. The dosage in this treatment method is the dosage in terms of body surface area conversion per administration. There are multiple prescriptions for the FOLFOX treatment method depending on the dosages and administration methods of the three drugs to be administered. As an embodiment, for example, rapid intravenous administration of the fluorouracil in (1c) may not be necessary, and the dosage of the oxaliplatin in (1a) is 85 mg / m 2 2, 100 mg / m 2 2, 130 mg / m 2 2, or any dosage between 85 mg / m 2 2 and 130 mg / m 2 2 may be used, and the dosage of the levoleucovorin in (1b) is 100 mg / m 2 2, 200 mg / m 2 2, or any dosage between 100 mg / m 2 2 and 200 mg / m 2 2 may be used, and the dosage of the fluorouracil administered by intravenous continuous infusion in (1d) is 600 mg / m 2 2, 1500 mg / m 2 2, 2400 mg / m 2 2 or any dosage between 600 mg / m 2 2 and 2400 mg / m 2 2 may be used.

[0036] In one embodiment, rapid intravenous administration means that the drug is administered within 15 minutes.

[0037] In one embodiment, for example, the FOLFOX treatment method called FOLFOX4 treatment method involves intravenous administration of (1a) oxaliplatin 85 mg / m 2 2 and (1b) levoleucovorin 100 mg / m 2 2 over 2 hours, and after the administration of the oxaliplatin in (1a) and the levoleucovorin in (1b) is completed, rapid intravenous administration of fluorouracil 400 mg / m 2 2, and after the administration of the fluorouracil in (1c) is completed, further administration of fluorouracil 600 mg / m 2Administer intravenously over 22 hours, followed by (1e) levofolinate 100 mg / m². 2 (1f) After the completion of the administration of levofolinate in (1e), administer fluorouracil 400 mg / m². 2 Administer rapidly intravenously, and after the administration of (1g) fluorouracil (1f), further administer fluorouracil 600 mg / m². 2 This treatment involves administering (1a), (1b), (1c), (1d), (1e), (1f), and (1g) intravenously over 22 hours, with the series of administrations performed at 2-week intervals. All dosages in this treatment are calculated based on the body surface area per administration.

[0038] Another embodiment of FOLFOX therapy, called mFOLFOX6 therapy, involves (1a) oxaliplatin 85 mg / m² 2 and (1b) levofolinate 200 mg / m² 2 (1c) After the administration of oxaliplatin (1a) and levofolinate (1b), administer fluorouracil 400 mg / m². 2 (1d) After the completion of administration of fluorouracil in (1c), administer fluorouracil 2400 mg / m² rapidly intravenously, and (1d) further administer fluorouracil 2400 mg / m². 2 This treatment involves administering the drug intravenously over a 46-hour period, with the series of administrations (1a), (1b), (1c), and (1d) performed at 2-week intervals. All dosages in this treatment are calculated based on the body surface area per administration.

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

[0040] Furthermore, the interval between doses of the combination therapy of FOLFOX therapy with a molecularly targeted drug may be set at a 2-week interval, or it may be set to an interval of 3 weeks or longer (for example, 3-week or 4-week intervals) temporarily or continuously, depending on the severity of the patient's adverse reactions. The discontinuation, dose reduction, and resumption of the combination therapy of FOLFOX therapy with bevacizumab or cetuximab shall be carried out at the discretion of the principal investigator or co-investigator, referring to the latest package insert.

[0041] Examples of molecularly targeted drugs include anti-EGFR antibodies (e.g., cetuximab, panitumumab) and anti-VEGF antibodies (e.g., bevacizumab). Molecularly targeted drugs may be used individually or in combination of two or more. In one embodiment, the selection of patients for which the molecularly targeted drug is indicated takes into consideration the presence or absence of RAS gene (KRAS / NRAS gene) mutations. In one embodiment, anti-EGFR antibodies (e.g., cetuximab, panitumumab) are used for colorectal cancer with wild-type RAS genes. In one embodiment, anti-VEGF antibodies (e.g., bevacizumab) are used for colorectal cancer with RAS gene mutations.

[0042] In one embodiment, the initial dose of bevacizumab for patients with RAS gene mutations is 5 mg / kg (body weight), administered by intravenous 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 interval between doses can be two weeks or longer (for example, two weeks, three weeks, or four weeks).

[0043] In one embodiment, the initial dose of cetuximab for patients with the RAS gene wild type was 400 mg / m². 2 (Body surface area) is used, and the drug is administered by intravenous infusion over 2 hours. From the second dose onward, 250 mg / m² is administered once a week or every two weeks. 2 Administer by intravenous infusion over one hour. Additionally, if necessary, administer 500 mg / m² of cetuximab once every two weeks. 2 It is also possible to administer the drug intravenously over two hours at two-week intervals, and the dosage may be reduced as appropriate depending on the patient's condition.

[0044] In one embodiment, patients with the RAS gene wild type are administered 6 mg / kg (body weight) of panitumumab by intravenous infusion over 60 minutes or more, once every two weeks. The dose may be reduced as appropriate depending on the patient's condition.

[0045] (4) Combination therapy with FOLFOX therapy plus molecularly targeted drugs (e.g., bevacizumab, cetuximab) In combination therapy with FOLFOX therapy plus a molecularly targeted drug (e.g., bevacizumab, cetuximab), CD47 inhibitors are administered in one embodiment according to the dosage and administration described above for (1) CD47 inhibitors. Magrolimab, an example of a CD47 inhibitor, is administered in one embodiment as an initial dose of 1 mg / kg intravenously over 3 hours (±30 minutes), followed by 20 mg / kg or 30 mg / kg intravenously at weekly or bi-weekly intervals. In one embodiment, Magrolimab is administered as an initial dose of 1 mg / kg intravenously over 3 hours (±30 minutes) on day 1 of the first cycle, followed by 20 mg / kg or 30 mg / kg intravenously over 2 hours (±30 minutes) at weekly intervals for the first cycle and at bi-weekly intervals for subsequent cycles. Depending on the severity of the patient's adverse reactions, the dose of Magrolimab may be reduced one step at a time, or administration may be discontinued altogether. Furthermore, if the criteria for resumption are met, administration of Magrolimab can be resumed, and if resumption is made, the dose of Magrolimab may be reduced at the discretion of the principal investigator or co-investigator. In one embodiment, when Magrolimab as a CD47 inhibitor is administered at an initial dose of 30 mg / kg, the dose after the first reduction is 20 mg / kg, and after the second reduction is 15 mg / kg. When Magrolimab as a CD47 inhibitor is administered at an initial dose of 20 mg / kg, the dose after the reduction is 15 mg / kg.

[0046] In combination therapy with FOLFOX therapy plus a molecularly targeted drug (e.g., bevacizumab, cetuximab), the immune checkpoint inhibitor is administered in one embodiment according to the dosage and administration described in (2) Immune Checkpoint Inhibitors. In one embodiment, Nivolumab as the immune checkpoint inhibitor is administered by intravenous infusion at doses of 240 mg every two weeks, 360 mg every three weeks, and 480 mg every four weeks. Preferably, Nivolumab is administered by intravenous infusion at doses of 480 mg every four weeks. More preferably, Nivolumab is administered by intravenous infusion over approximately 30 minutes at doses of 480 mg every four weeks. Depending on the severity of the patient's adverse reactions, Nivolumab administration may be discontinued. Nivolumab administration can also be resumed if the criteria for resumption are met.

[0047] In the treatment method of the present invention, when a combination therapy is administered in combination with a CD47 inhibitor (preferably Magrolimab) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) and FOLFOX therapy with a molecularly targeted drug (preferably bevacizumab or cetuximab), (for example, administered on the same day or initiated on the same day), in one embodiment, the CD47 inhibitor and the immune checkpoint inhibitor are administered first. In one embodiment, after the CD47 inhibitor and the immune checkpoint inhibitor have been administered, the combination therapy of FOLFOX therapy with bevacizumab or cetuximab is performed.

[0048] (5) FFX therapy or its weight-reducing regimen (another example of standard therapy) In this invention, "FFX therapy" refers to a cancer treatment method using a combination of four drugs: oxaliplatin, irinotecan hydrochloride hydrate (hereinafter abbreviated as "irinotecan"), leucovorin calcium (hereinafter abbreviated as "leucovorin"), and fluorouracil. The recommended dosage is, for example, (2a) oxaliplatin 85 mg / m². 2 Administer intravenously over 2 hours, followed by (2b) levofolinate 200 mg / m². 2(2c) Administer intravenously over 2 hours, and 30 minutes after the start of administration of levofolinate in (2b), administer irinotecan 180 mg / m². 2 (2d) After the completion of the administration of levofolinate in (2b), administer fluorouracil 400 mg / m². 2 (2e) After the completion of the administration of fluorouracil in (2d), administer fluorouracil 2400 mg / m² in addition. 2 This treatment involves administering the drug intravenously over 46 hours, and performing the series of administrations (2a), (2b), (2c), (2d), and (2e) at 2-week intervals. All dosages in this treatment are calculated based on the body surface area per administration.

[0049] A “dose reduction regimen” for FFX therapy refers to a prescription in which the dosage of any of the four drugs administered in FFX therapy is reduced from the initial dose or discontinued altogether, or the dosage is reduced in subsequent cycles depending on the severity of side effects observed in any of the drugs from the first cycle onward, or the administration of any of the four drugs is discontinued. For example, this could involve not having to perform rapid intravenous administration of fluorouracil (2d) from the initial dose, and the dosage of oxaliplatin (2a) being 50 mg / m². 2 , 65 mg / m² 2 , or 50-85 mg / m² 2 Any dose between these two values ​​may be used, and the dose of irinotecan in (2c) may be 90 mg / m². 2 , 120 mg / m² 2 , 150 mg / m² 2 Or 90-180 mg / m² 2 The dosage may be any dose between the above, and the amount of fluorouracil administered intravenously in (2e) is 1200 mg / m². 2 , 1800 mg / m² 2 Or 1200-2400 mg / m² 2 Any dose between these two ranges may be used.

[0050] Furthermore, as another aspect of the dose reduction regimen, in any administration from the second cycle onward in the FFX therapy, the rapid intravenous administration of fluorouracil (2d) may be discontinued depending on the severity of the patient's adverse reactions, and the dose of oxaliplatin (2a) may be reduced to 50 mg / m² depending on the severity of the patient's adverse reactions. 2 , 65 mg / m² 2 Or 50-85 mg / m² 2 The dose may be reduced to any dose between these dates or oxaliplatin may be discontinued, and depending on the severity of the patient's adverse reactions, the dose of irinotecan in (2c) may be reduced to 90 mg / m². 2 , 120 mg / m² 2 , 150 mg / m² 2 Or 90-180 mg / m² 2 The dose may be reduced to any dose during this period or irinotecan may be discontinued, and the dose of fluorouracil administered intravenously in (2e) may be 1200 mg / m² depending on the severity of the patient's adverse reactions. 2 , 1800 mg / m² 2 Or 1200-2400 mg / m² 2 The dose may be reduced to any dose during that period, or the administration of fluorouracil may be discontinued.

[0051] Furthermore, another aspect of the dose reduction regimen, recognized as modified FOLFIRINOX therapy (mFFX therapy), has a recommended dosage and administration, for example, (2a) oxaliplatin 85 mg / m². 2 Administer intravenously over 2 hours, followed by (2b) levofolinate 200 mg / m². 2 (2c) Administer intravenously over 2 hours, and 30 minutes after the start of administration of levofolinate in (2b), administer irinotecan 150 mg / m². 2 (2e) After the completion of the administration of levofolinate in (2b), administer fluorouracil 2400 mg / m². 2This treatment involves administering the drug intravenously over a 46-hour period, with the series of administrations described in (2a), (2b), (2c), and (2e) performed at 2-week intervals. All dosages in this treatment are calculated based on the body surface area per administration.

[0052] As a further dose reduction regimen for the mFFX therapy, for example, the dose of oxaliplatin (2a) from the first dose is reduced to 50 mg / m². 2 , 65 mg / m² 2 Or 50-85 mg / m² 2 Any dose between these two values ​​may be used, and the dose of irinotecan in (2c) is 120 mg / m². 2 , 140 mg / m² 2 Or 120-140 mg / m² 2 The dosage may be any dose between the above, and the amount of fluorouracil administered intravenously in (2e) is 1200 mg / m². 2 , 1800 mg / m² 2 , 2400 mg / m² 2 Or 1200-2400 mg / m² 2 Any dose between these two ranges may be used.

[0053] Furthermore, in any administration from the second cycle onward in the mFFX therapy, the dose of oxaliplatin (2a) may be adjusted to 50 mg / m² depending on the severity of the patient's adverse reactions. 2 , 65 mg / m² 2 Or 50-85 mg / m² 2 The dose of oxaliplatin may be reduced to any dose between these two levels or discontinued, and depending on the severity of the patient's adverse reactions, the dose of irinotecan in (2c) may be reduced to 90 mg / m². 2 , 120 mg / m² 2 Or 90-150 mg / m² 2 The dose may be reduced to any dose between these dates or the administration of irinotecan may be discontinued, and the dose of fluorouracil administered intravenously in (2e) may be 1200 mg / m² depending on the severity of the patient's adverse reactions. 2 , 1800 mg / m² 2 Or 1200-2400 mg / m² 2The dose may be reduced to any dose during that period, or the administration of fluorouracil may be discontinued.

[0054] Furthermore, the interval between administrations of the FFX therapy or its dose reduction regimen (e.g., mFFX therapy) may be temporarily or permanently set to a 3-week or 4-week interval, depending on the severity of the patient's adverse reactions. Discontinuation, dose reduction, and resumption of FFX therapy or its dose reduction regimen (e.g., mFFX therapy) shall be carried out at the discretion of the principal investigator or co-investigator, with reference to the latest package insert.

[0055] (6) In combination with FFX therapy or a dose reduction regimen thereof In one embodiment, CD47 inhibitors used in combination with FFX therapy or a dose reduction regimen (e.g., mFFX therapy) are administered according to the dosage and administration described above for the CD47 inhibitor in (1) CD47 inhibitor. Magrolimab, an example of a CD47 inhibitor, is administered in one embodiment as an initial dose of 1 mg / kg intravenously over 3 hours (±30 minutes), followed by 20 mg / kg or 30 mg / kg intravenously at weekly or bi-weekly intervals. In one embodiment, 1 mg / kg of Magrolimab is administered intravenously over 3 hours (±30 minutes) as an initial dose on day 1 of the first cycle, followed by 20 mg / kg or 30 mg / kg intravenously over 2 hours (±30 minutes) at weekly intervals for the first cycle and at bi-weekly intervals for subsequent cycles. Depending on the severity of the patient's adverse reactions, the dose of Magrolimab may be reduced in increments or discontinued altogether. Furthermore, if the criteria for resumption are met, administration of Magrolimab can be resumed, and if resumption is made, the dose of Magrolimab may be reduced at the discretion of the principal investigator or co-investigator. In one embodiment, when Magrolimab as a CD47 inhibitor is administered at an initial dose of 30 mg / kg, the dose after the first reduction is 20 mg / kg, and after the second reduction is 15 mg / kg. When Magrolimab as a CD47 inhibitor is administered at an initial dose of 20 mg / kg, the dose after the reduction is 15 mg / kg.

[0056] In combination with FFX therapy or its dose reduction regimen, immune checkpoint inhibitors are administered in one embodiment according to the dosage and administration described in (2) Immune Checkpoint Inhibitors above. In one embodiment, Nivolumab as an immune checkpoint inhibitor is administered by intravenous infusion at doses of 240 mg every two weeks, 360 mg every three weeks, and 480 mg every four weeks. Preferably, Nivolumab is administered by intravenous infusion at doses of 480 mg every four weeks. More preferably, Nivolumab is administered by intravenous infusion over approximately 30 minutes at doses of 480 mg every four weeks. Depending on the severity of the patient's adverse reactions, Nivolumab administration may be discontinued. Nivolumab administration can also be resumed if the criteria for resumption are met.

[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 (e.g., mFFX therapy) (e.g., administered on the same day or initiated on the same day), in one embodiment, the CD47 inhibitor and the immune checkpoint inhibitor are administered first. In one embodiment, FFX therapy or a dose reduction regimen (e.g., mFFX therapy) is performed after the CD47 inhibitor and the immune checkpoint inhibitor have been administered.

[0058] [Applicable diseases and patients] The disease to which the present invention's treatment method can be applied is cancer.

[0059] More specifically, cancers include, for example, leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), malignant lymphoma (Hodgkin lymphoma, non-Hodgkin 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, gastroesophageal junction cancer, duodenal cancer, colorectal 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 carcinoma, insulinoma, intraductal papillary mucinous neoplasm, pancreatic cancer with distant metastasis, and pancreatic cancer with distant metastasis). Examples include pancreatic ductal cancer, thyroid cancer, lung cancer (e.g., non-small cell lung cancer (e.g., squamous cell non-small cell lung cancer, non-squamous cell 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 ureteral 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 sarcomas, malignant bone tumors, skin cancers (e.g., uveal melanoma, malignant melanoma, Merkel cell carcinoma), thymoma, mesothelioma, malignant pleural mesothelioma, glioblastoma, hematological cancers, and cancers of unknown primary origin.

[0060] One embodiment of a disease treated by the treatment method of the present invention is solid cancer. Examples of solid cancers include head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction cancer, duodenal cancer, colorectal cancer (e.g., colon-rectal cancer), liver cancer (e.g., hepatocellular carcinoma), gallbladder-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 with distant metastasis), thyroid cancer, lung cancer (e.g., non-small cell lung cancer (e.g., squamous cell non-small cell lung cancer, non-squamous cell non-small cell lung cancer), small cell lung cancer) These include cancers of unknown primary origin, 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 ureteral 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 sarcomas, malignant bone tumors, skin cancers (e.g., uveal melanoma, malignant melanoma, Merkel cell carcinoma), thymoma, mesothelioma, malignant pleural mesothelioma, glioblastoma, and cancers of unknown primary origin.

[0061] The treatment method of the present invention is preferably applicable to colorectal cancer or pancreatic cancer, more preferably to advanced or recurrent colorectal cancer that is unresectable, or to pancreatic cancer with distant metastasis. Even more preferably to advanced or recurrent colorectal cancer that is unresectable, or to pancreatic ductal carcinoma with distant metastasis.

[0062] In this specification, “treatment” of cancer includes, for example, treatments performed to (i) reduce the growth of tumor cells, (ii) reduce symptoms caused by cancer, (iii) improve the quality of life of cancer patients, (iv) reduce the dose of other anticancer drugs or adjuvant cancer treatments already being administered, and / or (v) extend the survival of cancer patients; “suppression of cancer progression” means delaying the progression of cancer, stabilizing cancer-related symptoms, and reversing the progression of symptoms; and “suppression of cancer recurrence” means prophylactically preventing the recurrence of cancer in patients whose cancerous lesions have been completely or substantially eliminated or removed by cancer treatment or surgical resection.

[0063] The treatment method of the present invention may be prescribed to the following cancer patients, namely (a) patients whose treatment response to anticancer drugs is insufficient or inadequate, or patients whose condition has worsened after treatment with anticancer drugs; (b) patients with curable or unresectable, metastatic, recurrent, refractory, and / or distant metastatic cancer; (c) patients with cancer whose TPS (Tumor Proportion Score) is 50% or higher, 25% or higher, 10% or higher, 5% or higher, or 1% or higher; (d) patients with cancer whose CPS (Combined Positive Score) is 20% or higher, 10% or higher, 5% or higher, or 1% or higher; (e) patients with cancer who have dMMR (deficient mismatch repair) and / or MSI-H (Microsatellite instability-High); or (f) patients with cancer who have a high frequency of TMB (Tumor Mutational Burden). On the other hand, the treatment method of the present invention may be more in demand for the following cancer patients, namely (g) patients with no prior treatment history with anticancer drugs, (h) patients with cancer whose TPS is less than 50%, less than 25%, less than 10%, less than 5%, or less than 1%, (i) patients with cancer whose CPS is less than 20%, less than 10%, less than 5%, or less than 1%, (j) patients with cancer who do not have dMMR and / or MSI-H, or who have MSI-L (Microsatellite instability-Low), or (k) patients with cancer who have a low frequency of TMB. In particular, cancer patients for whom the treatment method of the present invention is in demand include patients with advanced or recurrent cancer that is unresectable and / or has no prior treatment history with anticancer drugs, especially patients with colorectal cancer or pancreatic cancer. In one embodiment, this includes patients with no prior treatment history for colorectal cancer or patients with no prior treatment history for pancreatic cancer. Preferably, this includes patients with no prior treatment history with systemic anti-cancer agents for colorectal cancer, or patients with no prior treatment history with systemic anti-cancer agents for pancreatic cancer. More preferably, this includes patients with no prior treatment history with systemic anti-cancer agents for advanced or recurrent colorectal cancer that is unresectable, or patients with no prior treatment history with systemic anti-cancer agents for pancreatic cancer with distant metastases.

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

[0065] In one embodiment, the treatment method of the present invention is used as a first-line treatment for patients with pancreatic cancer having distant metastases who have not received prior treatment with systemic anti-cancer agents.

[0066] In one embodiment, the treatment method of the present invention can also be applied to the treatment of metastatic cancer and the suppression of cancer metastasis.

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

[0068] In the present invention, treatment means, in one embodiment, producing at least one of the following: a reduction in tumor size, inhibition (delay or cessation) of tumor growth, inhibition (delay or cessation) of tumor metastasis, inhibition (prevention or delay) of recurrence, and relief 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, antiemetics) for (1) complementing and / or enhancing the therapeutic effect, (2) improving kinetics and absorption, reducing the dosage, and / or (3) reducing side effects.

[0070] In this specification, "approximately" means that the displayed value may vary by a range of up to 10% below or above that value.

[0071] The present invention provides, for example, the following embodiments. [1] A solid tumor progression inhibitor, recurrence inhibitor and / or treatment agent comprising a CD47 inhibitor as an active ingredient, characterized by being administered in combination with standard therapy and an immune checkpoint inhibitor. [2] An agent for inhibiting the progression, preventing recurrence, and / or treating solid tumors, comprising 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 molecularly targeted drug (preferably a VEGF inhibitor (preferably bevacizumab) or an EGFR inhibitor (preferably cetuximab or panitumumab)). [4] The agent described in any one of the above [1] to [3], wherein the standard therapy is combination therapy consisting of FOLFOX therapy plus bevacizumab or cetuximab. [5] The agent according to any one of the above [1] to [4], wherein the solid tumor is colorectal cancer. [6] The agent according to [5] above, wherein the colorectal cancer is colon or rectal cancer. [7] The agent according to [6] above, wherein the colorectal cancer is advanced or recurrent colorectal cancer that is not resectable. [8] The agent according to any one of the above [1] to [7], characterized in that it is administered as first-line treatment to patients with advanced or recurrent colorectal cancer that is not curatively resectable and who have no prior treatment with systemic anti-cancer agents. [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 according to [9] above, wherein the anti-CD47 antibody is Magrolimab.

[11] The agent according to

[10] , characterized in that 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals thereafter.

[12] The agent according to

[10] or

[11] , characterized in that 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 20 mg / kg (body weight) is administered intravenously at one-week or two-week intervals thereafter (preferably, 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 20 mg / kg (body weight) is administered at one-week intervals for the first cycle and at two-week intervals thereafter).

[13] The agent according to

[10] or

[11] , characterized in that 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals thereafter (preferably, 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 30 mg / kg (body weight) is administered at one-week intervals for the first cycle and at two-week intervals thereafter).

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

[13] , 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 according to

[14] , 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 described in

[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] , 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 according to

[14] , 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] , wherein the anti-PD-1 antibody is nivolumab.

[20] The agent according to

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

[21] The agent according to

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

[22] The agent according to

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

[23] The agent according to

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

[24] The agent according to

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

[25] The agent according to

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

[26] The agent according to

[19] , characterized in that it is administered as nivolumab at a dose of 3 mg / kg (body weight) once, or 240 mg once every two weeks, 360 mg once every three weeks, or 480 mg once every four weeks (preferably 240 mg once every two weeks, 360 mg once every three weeks, or 480 mg once every four weeks).

[27] The agent according to

[19] , characterized by being administered intravenously at a dose of 480 mg of nivolumab every four weeks.

[28] The agent according to

[19] , characterized in that 480 mg of nivolumab is administered intravenously over approximately 30 minutes at intervals of four weeks.

[29] The agent according to

[20] , characterized in that 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 according to

[21] , characterized in that 350 mg of cemiplimab is administered at 3-week intervals.

[31] The agent according to

[22] , characterized in that 10 mg / kg (body weight) of avelumab is administered at intervals of two weeks.

[32] The agent according to

[23] , characterized in that 1200 mg of atezolizumab is administered at 3-week intervals.

[33] The agent according to

[24] , characterized in that 10 mg / kg (body weight) of Durvalumab is administered intravenously at intervals of two weeks or 1500 mg is administered intravenously four times at intervals of four weeks.

[34] The agent according to

[25] , characterized in that ipilimumab is administered intravenously at doses of 3 mg / kg (body weight) or 1 mg / kg (body weight) at 3-week intervals for 4 times, or at 1 mg / kg (body weight) at 6-week intervals.

[35] 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) leucovorin calcium, and (1D) fluorouracil is administered in combination, as described in any one of the preceding paragraphs [4] to

[34] .

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

[35] , which is a combination therapy of FOLFOX therapy with bevacizumab or cetuximab, comprising administering (1A-1) bevacizumab, (1B) oxaliplatin, (1C) leucovorin calcium, and (1D) fluorouracil.

[37] The combination therapy of FOLFOX therapy with bevacizumab or cetuximab, which is a therapy in which (1A-2) cetuximab, (1B) oxaliplatin, (1C) leucovorin calcium, and (1D) fluorouracil is administered in combination, as described in any one of the above [4] to

[35] .

[38] Combination therapy of FOLFOX therapy with bevacizumab or cetuximab, (1x) Administer bevacizumab 5 mg / kg (body weight) intravenously, or cetuximab 400 mg / m² for the first dose. 2 (Body surface area), 250 mg / m² from the second dose onwards. 2 (body surface area) to be administered intravenously. (1a) Oxaliplatin 85 mg / m² 2 (body surface area) to be administered intravenously. (1b) Leucovorin calcium 200 mg / m² 2 (body surface area) to be administered intravenously. (1c) Fluorouracil 400 mg / m² 2 (body surface area) to be administered rapidly intravenously, and (1d) After completion of administration of the fluorouracil in (1c), further administer 2400 mg / m 2 (body surface area) by continuous intravenous infusion, The agent according to any one of the above [4] to

[35] , which is a therapy comprising

[39] A combined therapy in which bevacizumab or cetuximab is added to FOLFOX therapy is (1x) Administer bevacizumab 5 mg / kg (body weight) by intravenous injection, (1a) Administer oxaliplatin 85 mg / m 2 (body surface area) by intravenous injection, (1b) Administer calcium levofolinate 200 mg / m 2 (body surface area) by intravenous injection, (1c) Administer fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous injection, and (1d) After completion of administration of the fluorouracil in (1c), further administer 2400 mg / m 2 (body surface area) by continuous intravenous infusion, The agent according to any one of the above [4] to

[36] , and

[38] , which is a therapy comprising

[40] A combined therapy in which bevacizumab or cetuximab is added to FOLFOX therapy is (1x) For the first administration of cetuximab, administer 400 mg / m 2 (body surface area), and for subsequent administrations, administer 250 mg / m 2 (body surface area) by intravenous injection, (1a) Administer oxaliplatin 85 mg / m 2 (body surface area) by intravenous injection, (1b) Administer calcium levofolinate 200 mg / m 2 (body surface area) by intravenous injection, (1c) Administer fluorouracil 400 mg / m 2 (body surface area) by rapid intravenous injection, and (1d) After completion of administration of the fluorouracil in (1c), further administer 2400 mg / m 2 (body surface area) by continuous intravenous infusion, The agent according to any one of the above paragraphs [4] to

[35] ,

[37] , and

[38] , which is a therapy comprising [the agent].

[41] Combination therapy of FOLFOX therapy with bevacizumab or cetuximab is (1x) Administer bevacizumab 5 mg / kg (body weight) intravenously over 90 minutes, or cetuximab 400 mg / m² for the first dose. 2 (Body surface area) over 2 hours, from the second dose onwards 250 mg / m² 2 (body surface area) to be administered intravenously over one hour. (1a) Oxaliplatin 85 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (body surface area) to be administered intravenously over 46 hours. The agent according to any one of the preceding paragraphs [4] to

[35] and

[38] , comprising a series of administrations of (1x), (1a), (1b), (1c), and (1d) performed at two-week intervals.

[42] Combination therapy of FOLFOX therapy with bevacizumab or cetuximab is (1x) Administer bevacizumab 5 mg / kg (body weight) intravenously over 90 minutes. (1a) Oxaliplatin 85 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (body surface area) to be administered intravenously over 46 hours. The agent according to any one of the preceding paragraphs [4] to

[36] ,

[38] ,

[39] , and

[41] , comprising, wherein a series of administrations of (1x), (1a), (1b), (1c), and (1d) are performed at two-week intervals.

[43] Combination therapy of FOLFOX therapy with bevacizumab or cetuximab is (1x) Cetuximab, first dose: 400 mg / m² 2 (Body surface area) over 2 hours, from the second dose onwards 250 mg / m² 2 (body surface area) to be administered intravenously over one hour. (1a) Oxaliplatin 85 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (body surface area) to be administered intravenously over 46 hours. The agent according to any one of the preceding paragraphs [4] to

[35] ,

[37] ,

[38] ,

[40] , and

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

[44] 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 initiated on the same day, as described in any one of the above [4] to

[43] .

[45] A combination therapy comprising a CD47 inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and in combination with an immune checkpoint inhibitor, (i) The CD47 inhibitor is Magrolimab. For the first dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) Combination therapy with bevacizumab or cetuximab added to the FOLFOX therapy, (1x) Administer bevacizumab 5 mg / kg (body weight) intravenously (preferably over 90 minutes), or administer cetuximab 400 mg / m² as the first dose. 2 (Body surface area) (preferably over 2 hours), 250 mg / m² from the second dose onwards. 2 (Body surface area) to be administered intravenously (preferably over 1 hour), (1a) Oxaliplatin 85 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A drug comprising a series of administrations of (1x), (1a), (1b), (1c), and (1d) performed at two-week intervals.

[46] A combination therapy comprising a CD47 inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and in combination with an immune checkpoint inhibitor, for the suppression of cancer progression, recurrence, and / or treatment, (i) The CD47 inhibitor is Magrolimab. For the first dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) Combination therapy with bevacizumab or cetuximab added to the FOLFOX therapy, (1x) Administer bevacizumab 5 mg / kg (body weight) intravenously (preferably over 90 minutes). (1a) Oxaliplatin 85 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A drug comprising a series of administrations of (1x), (1a), (1b), (1c), and (1d) performed at two-week intervals.

[47] A combination therapy comprising a CD47 inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and in combination with an immune checkpoint inhibitor, for the suppression of progression, recurrence, and / or treatment of cancer, (i) The CD47 inhibitor is Magrolimab. For the first dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) Combination therapy with bevacizumab or cetuximab added to the FOLFOX therapy, (1x) Cetuximab, first dose: 400 mg / m² 2 (Body surface area) (preferably over 2 hours), 250 mg / m² from the second dose onwards. 2 (Body surface area) to be administered intravenously (preferably over 1 hour), (1a) Oxaliplatin 85 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2(body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A drug comprising a series of administrations of (1x), (1a), (1b), (1c), and (1d) performed at two-week intervals.

[48] ​​A combination therapy comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and in combination with a CD47 inhibitor, for the suppression of progression, suppression of recurrence and / or treatment of cancer, (i) The CD47 inhibitor is Magrolimab. For the first dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) Combination therapy with bevacizumab or cetuximab added to the FOLFOX therapy, (1x) Administer bevacizumab 5 mg / kg (body weight) intravenously (preferably over 90 minutes), or administer cetuximab 400 mg / m² as the first dose. 2 (Body surface area) (preferably over 2 hours), 250 mg / m² from the second dose onwards. 2 (Body surface area) to be administered intravenously (preferably over 1 hour), (1a) Oxaliplatin 85 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A drug comprising a series of administrations of (1x), (1a), (1b), (1c), and (1d) performed at two-week intervals.

[49] A combination therapy comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and in combination with a CD47 inhibitor, for the suppression of cancer progression, recurrence, and / or treatment, (i) The CD47 inhibitor is Magrolimab. For the first dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) Combination therapy with bevacizumab or cetuximab added to the FOLFOX therapy, (1x) Administer bevacizumab 5 mg / kg (body weight) intravenously (preferably over 90 minutes). (1a) Oxaliplatin 85 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A drug comprising a series of administrations of (1x), (1a), (1b), (1c), and (1d) performed at two-week intervals.

[50] A combination therapy comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFOX therapy plus bevacizumab or cetuximab, and in combination with a CD47 inhibitor, for the suppression of progression, suppression of recurrence and / or treatment of cancer, (i) The CD47 inhibitor is Magrolimab. For the first dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) Combination therapy with bevacizumab or cetuximab added to the FOLFOX therapy, (1x) Cetuximab, first dose: 400 mg / m² 2 (Body surface area) (preferably over 2 hours), 250 mg / m² from the second dose onwards. 2 (Body surface area) to be administered intravenously (preferably over 1 hour), (1a) Oxaliplatin 85 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (1b) Simultaneously with the administration of oxaliplatin as in (1a), levofolinate calcium 200 mg / m² 2(Body surface area) to be administered intravenously (preferably over 2 hours), (1c) After the completion of administration of levofolinate calcium as described in (1b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (1d) After the completion of administration of fluorouracil as in (1c), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A drug comprising a series of administrations of (1x), (1a), (1b), (1c), and (1d) performed at two-week intervals.

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

[36] ,

[39] ,

[42] ,

[46] , and

[49] , wherein the cancer is a cancer of the RAS gene mutation type.

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

[37] ,

[40] ,

[43] ,

[47] , and

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

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

[45] to

[52] , wherein the cancer is advanced or recurrent colorectal cancer that is not resectable.

[54] The agent according to

[53] , characterized in that it is administered as first-line treatment to patients with unresectable advanced or recurrent colorectal cancer who have no prior treatment with systemic anti-cancer agents.

[55] A combination therapy of FOLFOX therapy with bevacizumab or cetuximab, or a therapy in which administration of Magrolimab and Nivolumab is initiated on the same day, as described in any one of the above

[45] to

[54] .

[56] The agent according to [1] or [2] above, wherein the standard therapy is FOLFIRINOX therapy or a dose reduction regimen thereof.

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

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

[58] The agent according to

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

[59] The agent according to any one of the above [1], [2],

[56] ,

[57] , and

[58] , characterized in that it is administered as first-line treatment to patients with pancreatic cancer having distant metastases who have no prior treatment with systemic anti-cancer agents.

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

[56] to

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

[61] The agent according to

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

[62] The agent according to

[61] , characterized in that 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals thereafter.

[63] The agent according to

[61] or

[62] , characterized in that 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 20 mg / kg (body weight) is administered intravenously at one-week or two-week intervals thereafter (preferably, 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 20 mg / kg (body weight) is administered at one-week intervals for the first cycle and at two-week intervals thereafter).

[64] The agent according to

[61] or

[62] , characterized in that 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals thereafter (preferably, 1 mg / kg (body weight) of Magrolimab is administered intravenously as the first dose, and 30 mg / kg (body weight) is administered at one-week intervals for the first cycle and at two-week intervals thereafter).

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

[65] , 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 described in

[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] , 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 according to

[65] , 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] , wherein the anti-PD-1 antibody is nivolumab.

[71] The agent according to

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

[72] The agent according to

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

[73] The agent according to

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

[74] The agent according to

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

[75] The agent according to

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

[76] The agent according to

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

[77] The agent according to

[70] , characterized in that it is administered as nivolumab at a dose of 3 mg / kg (body weight) once, or 240 mg once every two weeks, 360 mg once every three weeks, or 480 mg once every four weeks (preferably 240 mg once every two weeks, 360 mg once every three weeks, or 480 mg once every four weeks).

[78] The agent according to

[70] , characterized in that 480 mg of nivolumab is administered intravenously at 4-week intervals.

[79] The agent according to

[70] , characterized in that 480 mg of nivolumab is administered intravenously over approximately 30 minutes at intervals of four weeks.

[80] The agent according to

[71] , characterized in that 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] , characterized in that 350 mg of cemiplimab is administered at 3-week intervals.

[82] The agent according to

[73] , characterized in that 10 mg / kg (body weight) of avelumab is administered at intervals of two weeks.

[83] The agent according to

[74] , characterized by being administered at a dose of 1200 mg of atezolizumab at 3-week intervals.

[84] The agent according to

[75] , characterized in that Durvalumab is administered at a dose of 10 mg / kg (body weight) every two weeks or 1500 mg every four weeks intravenously four times.

[85] The agent according to

[76] , characterized in that ipilimumab is administered intravenously at doses of 3 mg / kg (body weight) or 1 mg / kg (body weight) at 3-week intervals for 4 doses, or at 1 mg / kg (body weight) at 6-week intervals.

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

[56] to

[85] , wherein the FOLFIRINOX therapy or a dose reduction regimen is administered in combination with (2A) oxaliplatin, (2B) leucovorin calcium, (2C) irinotecan hydrochloride hydrate, and (2D) fluorouracil.

[87] FOLFIRINOX therapy, (2a) Oxaliplatin 50-85 mg / m² 2 (Body surface area) (preferably 50 mg / m²) 2 (body surface area), 65mg / m 2 (body surface area), 85mg / m 2 (Body surface area), more preferably 85 mg / m² 2 (body surface area)) to be administered intravenously. (2b) Leucovorin calcium 200 mg / m² 2 (body surface area) to be administered intravenously. (2c) Irinotecan hydrochloride hydrate 90-180 mg / m² 2 (Body surface area) (preferably 90 mg / m²) 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 / m² 2 (body surface area)) to be administered intravenously. (2d) Fluorouracil 400 mg / m² 2 (body surface area) to be administered rapidly intravenously, and (2e) After the completion of administration of fluorouracil as described in (2d), administer an additional 1200-2400 mg / m² of fluorouracil. 2 (Body surface area) (preferably 1200 mg / m²) 2 (body surface area), 1800mg / m 2 (body surface area), 2400mg / m 2(Body surface area), more preferably 2400 mg / m² 2 (body surface area)) should be administered intravenously in a continuous manner. The agent described in any one of the above

[56] to

[86] , which is a therapy comprising [the agent].

[88] The FOLFIRINOX therapy reduction regimen is (2a) Oxaliplatin 50-85 mg / m² 2 (Body surface area) (preferably 50 mg / m²) 2 (body surface area), 65mg / m 2 (body surface area), 85mg / m 2 (Body surface area), more preferably 85 mg / m² 2 (body surface area)) to be administered intravenously. (2b) Leucovorin calcium 200 mg / m² 2 (body surface area) to be administered intravenously. (2c) Irinotecan hydrochloride hydrate 120-150 mg / m² 2 (Body surface area) (preferably 150 mg / m²) 2 (body surface area)) administered intravenously, and (2e) Fluorouracil 1200-2400 mg / m² 2 (Body surface area) (preferably 1200 mg / m²) 2 (body surface area), 1800mg / m 2 (body surface area), 2400mg / m 2 (Body surface area), more preferably 2400 mg / m² 2 (body surface area)) should be administered intravenously in a continuous manner. The agent described in any one of the above

[56] to

[86] , which is a therapy comprising [the agent].

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

[56] to

[88] , wherein FOLFIRINOX therapy or a dose reduction regimen is administered in a series of doses 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 / m² 2 (body surface area) to be administered intravenously. (2b) Leucovorin calcium 200 mg / m² 2 (body surface area) to be administered intravenously. (2c) Irinotecan hydrochloride hydrate 180 mg / m² 2 (body surface area) to be administered intravenously. (2d) Fluorouracil 400 mg / m² 2 (body surface area) to be administered rapidly intravenously, and (2e) After the completion of administration of fluorouracil as in (2d), administer fluorouracil 2400 mg / m². 2 (body surface area) to be administered intravenously continuously. The agent according to any one of the preceding paragraphs

[56] to

[87] and

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

[91] The FOLFIRINOX therapy reduction regimen is (2a) Oxaliplatin 85 mg / m² 2 (body surface area) to be administered intravenously. (2b) Leucovorin calcium 200 mg / m² 2 (body surface area) to be administered intravenously. (2c) Irinotecan hydrochloride hydrate 150 mg / m² 2 (body surface area) to be administered intravenously, and (2e) Fluorouracil 2400 mg / m² 2 (body surface area) to be administered intravenously continuously. The agent according to any one of the preceding paragraphs

[56] to

[86] ,

[88] , and

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

[92] FOLFIRINOX therapy, (2a) Oxaliplatin 85 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (2b) (preferably after the completion of administration of oxaliplatin as in (2a),) levofolinate calcium 200 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (2c) Starting 30 minutes after the start of administration of levofolinate calcium as in (2b), administer irinotecan hydrochloride hydrate 180 mg / m². 2 (Body surface area) to be administered intravenously over 1.5 hours. (2d) After the completion of administration of levofolinate calcium as described in (2b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (2e) After the completion of administration of fluorouracil as in (2d), administer fluorouracil 2400 mg / m². 2 (body surface area) to be administered intravenously over 46 hours. The agent according to any one of the preceding paragraphs

[56] to

[87] ,

[89] , and

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

[93] The FOLFIRINOX therapy reduction regimen is (2a) Oxaliplatin 85 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (2b) (preferably after the completion of administration of oxaliplatin as in (2a),) levofolinate calcium 200 mg / m² 2 (body surface area) should be administered intravenously over 2 hours. (2c) Irinotecan hydrochloride hydrate 150 mg / m² starting 30 minutes after the start of administration of levofolinate calcium in (2b). 2 (Body surface area) to be administered intravenously over 1.5 hours, and (2e) Furthermore, after the completion of administration of levofolinate calcium as described in (2b), administer fluorouracil 2400 mg / m². 2 (body surface area) to be administered intravenously over 46 hours. The agent according to any one of the preceding paragraphs

[56] to

[86] ,

[88] ,

[89] , and

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

[94] The agent described in any one of the above

[56] to

[93] , which is a therapy in which FOLFIRINOX therapy or a dose reduction regime thereof, an immune checkpoint inhibitor, and a CD47 inhibitor are initiated on the same day.

[95] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising a CD47 inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFIRINOX therapy or a dose reduction regimen thereof, and an immune checkpoint inhibitor, (i) The CD47 inhibitor is Magrolimab. For the first dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) The FOLFIRINOX therapy is (2a) Oxaliplatin 85 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (2b) (preferably after the completion of administration of oxaliplatin as in (2a),) levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (2c) (preferably starting 30 minutes after the administration of levofolinate calcium in (2b)) Irinotecan hydrochloride hydrate 180 mg / m² 2 (Body surface area) is administered intravenously (preferably over 1.5 hours). (2d) After the completion of administration of levofolinate calcium as described in (2b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (2e) After the completion of administration of fluorouracil as in (2d), administer fluorouracil 2400 mg / m². 2(Body surface area) is administered intravenously over a continuous period of 46 hours. A therapy comprising (2a), (2b), (2c), (2d), and (2e), wherein a series of administrations of (2a), (2b), (2c), (2d), and (2e) are performed at two-week intervals, or The FOLFIRINOX therapy reduction regimen in question is (2a) Oxaliplatin 85 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (2b) (preferably after the completion of administration of oxaliplatin as in (2a),) levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (2c) (preferably starting 30 minutes after the start of administration of levofolinate calcium as in (2b)) Irinotecan hydrochloride hydrate 150 mg / m² 2 (Body surface area) is administered intravenously (preferably over 1.5 hours), and (2e) After the completion of administration of levofolinate calcium as described in (2b), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A drug that includes (2a), (2b), (2c), and (2e), and is administered in a series of doses at two-week intervals.

[96] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFIRINOX therapy or a dose reduction regimen thereof, and a CD47 inhibitor, (i) The CD47 inhibitor is Magrolimab. For the first dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) The FOLFIRINOX therapy is (2a) Oxaliplatin 85 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (2b) (preferably after the completion of administration of oxaliplatin as in (2a),) levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (2c) (preferably starting 30 minutes after the administration of levofolinate calcium in (2b)) Irinotecan hydrochloride hydrate 180 mg / m² 2 (Body surface area) is administered intravenously (preferably over 1.5 hours). (2d) After the completion of administration of levofolinate calcium as described in (2b), administer fluorouracil 400 mg / m². 2 (body surface area) to be administered rapidly intravenously, and (2e) After the completion of administration of fluorouracil as in (2d), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A therapy comprising (2a), (2b), (2c), (2d), and (2e), wherein a series of administrations of (2a), (2b), (2c), (2d), and (2e) are performed at two-week intervals, or The FOLFIRINOX therapy reduction regimen in question is (2a) Oxaliplatin 85 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (2b) (preferably after the completion of administration of oxaliplatin as in (2a),) levofolinate calcium 200 mg / m² 2 (Body surface area) to be administered intravenously (preferably over 2 hours), (2c) (preferably starting 30 minutes after the start of administration of levofolinate calcium as in (2b)) Irinotecan hydrochloride hydrate 150 mg / m² 2 (Body surface area) is administered intravenously (preferably over 1.5 hours), and (2e) After the completion of administration of levofolinate calcium as described in (2b), administer fluorouracil 2400 mg / m². 2 (Body surface area) is administered intravenously over a continuous period of 46 hours. A drug that includes (2a), (2b), (2c), and (2e), and is administered in a series of doses at two-week intervals.

[97] The agent according to

[95] or

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

[98] The agent according to

[97] , characterized in that it is administered as first-line treatment to patients with pancreatic cancer having distant metastases who have no prior treatment with systemic anti-cancer agents.

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

[95] to

[98] , which is a therapy comprising initiating administration of FOLFIRINOX therapy or a dose reduction regimen thereof, Magrolimab, and Nivolumab on the same day.

[0072] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meanings as those commonly understood by those skilled in the art of the present invention.

[0073] Furthermore, all patent and non-patent documents or references explicitly cited herein may be incorporated herein by reference as part of this specification. [Examples]

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

[0075] Example 1This is an open-label, uncontrolled trial in patients with unresectable advanced or recurrent colorectal cancer, comparing combination therapy of magrolimab, nivolumab, and the standard FOLFOX regimen with bevacizumab or cetuximab as first-line treatment. This study aims to investigate the tolerability, safety, and efficacy of combination therapy with bevacizumab or cetuximab added to magrolimab, nivolumab, and FOLFOX as first-line treatment in patients with unresectable advanced or recurrent colorectal cancer. This trial will evaluate the combined efficacy of magrolimab, nivolumab, and FOLFOX with bevacizumab or cetuximab.

[0076] (1) Target patients Patients with advanced or recurrent colorectal cancer that is not resectable

[0077] (2) Patient selection criteria Patients who met all of the following criteria were selected at the time of registration. If it became clear that a patient did not meet the following criteria before the first dose of the investigational drug, the administration of the investigational drug was not started and the trial was terminated. 1. Gender: Any. 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 investigational drug administration until at least the end of the examination on the 15th day after the start of investigational drug administration (tolerability evaluation part only). 4. Patients whose histological diagnosis is an adenocarcinoma originating from the colon or rectum (excluding appendiceal cancer and anal canal cancer), and who are not candidates for curative resection. 5. Patients with measurable lesions as defined in RECIST Guideline 1.1, as observed on imaging within 28 days prior to administration of the investigational drug. • Patients who received radiotherapy for measurable lesions must have been confirmed to have progression in imaging studies following radiotherapy. 6. Patients with unresectable advanced or recurrent colorectal cancer who have not received prior treatment with systemic anti-cancer agents. • If a curative surgery (confirmed to be R0 excision) is performed in conjunction with preoperative and postoperative adjuvant therapy, no recurrence must be observed within 6 months after completion of adjuvant therapy. 7. Patients who can provide tumor tissue samples for biomarker testing. Tumor tissue samples are obtained during the screening phase. If a new tumor biopsy is difficult, a stored sample may be used. However, the stored sample 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 are scheduled to receive combination therapy with FOLFOX (fluorouracil, leucovorin, oxaliplatin) and bevacizumab (Cohort 1), or patients with RAS wild-type and primary tumor located on the left side (descending colon, sigmoid colon, rectum) who are scheduled to receive combination therapy with FOLFOX (fluorouracil, leucovorin, oxaliplatin) and cetuximab (Cohort 2). 9. Patients with an ECOG Performance Status of 0-1. 10. Patients who are expected to survive for three months or more at the time of registration. 11. In the case of women of childbearing potential (including patients who do not menstruate due to medical reasons such as chemical menopause), patients who agree to use double contraception for the 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 when 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 (such as hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), and have not gone through menopause. Menopause is defined as amenorrhea for 12 consecutive months or more without any notable reason. Women using oral contraceptives or intrauterine devices or diaphragms are considered to be of childbearing potential. 12. In the case of males, patients who have agreed to use double contraception for the period specified for each drug, from the start of administration of the investigational drug until 4 months after the last dose of the investigational drug and after the last dose of the standard treatment drug. Here, double contraception is required, consisting of two of the following: vasectomy or condoms for male patients or their male partners, and tubal ligation, diaphragms, intrauterine devices, or oral contraceptives for female patients or their female partners. 13. Patients whose most recent clinical laboratory test results, performed within 14 days prior to the start of investigational drug administration, meet the following criteria. Furthermore, the patient must not have received administration of 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 / mm³ 3 That's all. • Platelet count is 100,000 / mm³ 3 That's all. • Hemoglobin level is 11.0 g / dL or higher. • AST (GOT) and ALT (GPT) levels must be 3.0 times or less the upper limit of the facility's normal range (however, if liver metastases are present, the level must be 5.0 times or less the upper limit of the facility's normal range). • Total bilirubin levels should be 1.5 times or less the upper limit of the facility's reference range (however, in the case of patients with Gilbert's syndrome, total bilirubin levels should be 3.0 times or less the upper limit of the facility's reference range). • Serum creatinine level is 1.5 times or less the upper limit of the institutional reference range, or creatinine clearance (measured value or estimated value by the Cockcroft / Gault formula) is 40 mL / min or higher. • Albumin level is 3.0 g / dL or higher. • [Cohort 1 only] Urine protein is 1+ or less. However, patients with urinary protein of 2+ or higher as determined by urinalysis or urine test strips may be enrolled if their urinary protein is 1g / 24 hours or less in a 24-hour urine collection, or if their urinary protein / creatinine ratio (UPCR) is less than 1g / gCr. 14. Patients who have received a full explanation of the contents of this clinical trial from the principal investigator or co-investigator using the informed consent form and explanatory document, and who give written consent to participate in this clinical trial of their own free will.

[0078] (3) Patient exclusion criteria Patients who met any of the following criteria were excluded at the time of registration. Furthermore, if any of the following criteria were violated before the first dose of the investigational drug, the administration of the investigational drug was not initiated and the trial was terminated. 1. Patients with RAS / BRAF wild type whose primary tumor is located on the right side (cecum, ascending colon, transverse colon). 2. Patients with BRAF mutations and patients with high microsatellite instability (MSI-High) or mismatch repair deficiency (dMMR). 3. Patients who are receiving or require anticoagulant therapy. 4. Patients experiencing 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 with drug therapy. 7. Patients with a history of severe hypersensitivity reactions to antibody preparations. 8. Patients for whom administration of any of the standard therapy drugs used in each cohort is contraindicated. [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 concomitant autoimmune diseases or a history of chronic or relapsing autoimmune diseases. However, patients with concomitant skin diseases that do not require systemic therapy (such as vitiligo, psoriasis, or alopecia) or diseases that are not expected to recur in the absence of external triggers may be enrolled. 11. Patients whose surgical treatment has affected the safety and efficacy evaluation of the investigational drug, as determined by the principal investigator or co-investigator. 12. Patients with multiple cancers. However, patients with completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, carcinoma in mucosa, or superficial bladder cancer, or other cancers that have not recurred for three years or more, are eligible for registration. 13. Patients with metastatic lesions in the brain or meninges. However, asymptomatic patients who do not require treatment may be registered. 14. Patients with interstitial lung disease diagnosed by imaging or clinical findings, or with a history of or with pulmonary fibrosis. 15. Patients whose tumor-related pain is not stably controlled. 16. Patients with a history of hemolytic anemia within 90 days prior to registration. 17. Patients who have a history of transient ischemic attack, cerebrovascular accident, thrombosis, or thromboembolism (pulmonary embolism or deep vein thrombosis) within 180 days prior to registration, and whose thrombosis or thromboembolism is poorly controlled. However, venous thrombosis related to central venous catheters is acceptable. 18. Patients with the following uncontrolled or severe cardiovascular conditions: • Acute myocardial infarction within the 6 months prior to registration. Unstable angina or angina requiring treatment. • Congestive heart failure with functional classification III to IV according to the New York Heart Association (NYHA). • Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure of 150 mmHg or higher, or diastolic blood pressure of 100 mmHg or higher, lasting for 24 hours or more). • Uncontrollable or severe arrhythmia. 19. Patients with uncontrolled diabetes mellitus. 20. Patients with systemic infections requiring treatment. 21. Patients requiring transplant therapy or with a history of transplant therapy (excluding autologous transplantation). 22. Patients who test positive for any of the following: HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or HCV antibody. Also, patients who test negative for HBs antigen but test positive for either HBs antibody or HBc antibody and whose HBV-DNA quantification is above the detection limit. Note that even if the HCV antibody test is positive, registration is permitted if the HCV-RNA test is negative. 23. Patients who received the following treatments before obtaining informed consent and before administration of the investigational drug. Patients with a history of treatment with Magrolimab or drugs targeting the CD47-SIRPα pathway. Patients with a history of treatment including anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-CTLA-4 antibodies, or other antibody therapies or cancer vaccines aimed at controlling T cells. Patients who received more than 2 units of red blood cell transfusion within 28 days prior to obtaining consent. • Patients who underwent surgery with local anesthesia within 14 days prior to administration of the investigational drug. • Patients who underwent pleural or pericardial adhesion surgery within 14 days prior to administration of the investigational drug. Patients who have received more than 10 mg / day of prednisone-equivalent systemic corticosteroids (excluding temporary use for purposes such as examinations, local administration, treatment and prevention of contrast agent allergic reactions, or reduction of edema associated with radiotherapy) or immunosuppressants within 14 days prior to administration of the investigational drug. Patients who received palliative local radiotherapy within 28 days prior to administration of the investigational drug. • Patients who underwent surgery under general anesthesia within 28 days prior to administration of the investigational drug. Patients who received a live vaccine or attenuated vaccine within 28 days prior to administration of the investigational drug. Patients who received a radiopharmaceutical (excluding the use of radiopharmaceuticals for examination and diagnosis purposes) within 56 days prior to administration of the investigational drug. Patients who have received other unapproved drugs (including those administered in clinical research, unapproved combination drugs, or new dosage forms) within 28 days prior to administration of the investigational drug. 24. Pregnant, breastfeeding, or potentially pregnant patients. 25. Patients who are judged to lack the capacity to give consent due to complications such as dementia. 26. Any other patient whom the principal investigator or co-investigator deems unsuitable for this clinical trial.

[0079] (4) Dosage and administration and duration of administration [Magrolimab] Magrolimab was administered intravenously at a dose of 1 mg / kg over 3 hours (±30 minutes) as the initial dose on day 1 of the first cycle. Subsequently, 20 mg / kg or 30 mg / kg was administered intravenously over 2 hours (±30 minutes) at weekly intervals throughout the first cycle. From the second cycle onward, 20 mg / kg or 30 mg / kg was administered intravenously over 2 hours (±30 minutes) at two-week intervals, and administration continued until the prescribed discontinuation criteria for Magrolimab were met. When combination therapy with Magrolimab, Nivolumab, and FOLFOX therapy with bevacizumab or cetuximab was administered on the same day, the combination therapy was initiated in the following order: Magrolimab, Nivolumab, and FOLFOX therapy with bevacizumab or cetuximab.

[0080] [Nivolumab] Nivolumab 480 mg was administered intravenously over 30 minutes at 4-week intervals, and continued until the prescribed discontinuation criteria for Nivolumab were met. Note that Nivolumab administration was performed at least 24 days after the previous dose, starting on the 25th day or later.

[0081] [Combination therapy with FOLFOX therapy plus bevacizumab or cetuximab] Regarding the choice between bevacizumab and cetuximab, bevacizumab was used for patients with RAS mutations, and cetuximab was used for patients with RAS wild type. The initial dose of bevacizumab was 5 mg / kg (body weight), administered by intravenous infusion over 90 minutes. If the initial 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 should be at least two weeks. The starting dose of cetuximab is 400 mg / m². 2 (Body surface area) was used, and the drug was administered by intravenous infusion over 2 hours. Subsequent doses were 250 mg / m² once a week or every two weeks. 2 The drug was administered by intravenous infusion over one hour. Additionally, cetuximab 500 mg / m² was administered once every two weeks as needed. 2It was also possible to administer the drug intravenously over two hours at two-week intervals. The dosage was reduced as appropriate depending on the patient's condition. (1x) After administration of bevacizumab or cetuximab, (1a) oxaliplatin is administered at 85 mg / m². 2 (Body surface area) was administered intravenously over 2 hours. (1b) Simultaneously with the administration of oxaliplatin, levofolinate calcium was administered at a dose of 200 mg / m². 2 (Body surface area) was administered intravenously over 2 hours. (1c) Fluorouracil was administered at 400 mg / m² after the completion of intravenous administration of levofolinate calcium. 2 (Body surface area) is administered rapidly intravenously, (1d) followed by 2400 mg / m². 2 (Body surface area) was administered intravenously over 46 hours. The series of administrations (1x), (1a), (1b), (1c), and (1d) were performed at 2-week intervals. Bevacizumab, cetuximab, oxaliplatin, leucovorin calcium, and fluorouracil were commercially available products.

[0082] [Clinical Trial Schedule] This trial consists of a screening phase, a treatment phase, and a follow-up observation phase. Figure 1 shows an overview of the trial schedule. The screening period was within 28 days prior to administration of the investigational drug. The principal investigator or co-investigator enrolled patients who met the above selection criteria, did not violate the above exclusion criteria, and were deemed eligible to participate in this clinical trial. Each treatment cycle was 28 days long, with the first administration of the investigational drug being defined as day 1 of cycle 1. Day 1 of each subsequent cycle was defined as [28 × (number of cycles - 1) + 1] days. For combination therapies of Magrolimab, Nivolumab, and FOLFOX therapy with bevacizumab or cetuximab, administration was initiated according to the above-mentioned dosage and administration instructions, and continued according to the administration criteria, dose reduction criteria, and dose reduction dosage for each combination therapy. The treatment period ended when the evaluation of the discontinuation of the combination therapy of Magrolimab, Nivolumab, and FOLFOX therapy with bevacizumab or cetuximab was completed. Of all subjects who received the investigational drug, those who discontinued or terminated the combination therapy of Magrolimab, Nivolumab, and FOLFOX therapy with bevacizumab or cetuximab underwent an evaluation at the end of treatment (discontinuation) and proceeded to the post-observation period. After the end of the post-observation period, follow-up studies were conducted.

[0083] [Dosage criteria for Magrolimab and Nivolumab] At the start of each administration cycle, subjects must meet all of the prescribed administration criteria, which were determined based on the administration criteria from previous clinical trials for Magrolimab and Nivolumab. If any of these criteria were not met, the scheduled administration of Magrolimab and Nivolumab was discontinued. Subjects who had discontinued treatment were examined weekly, or more frequently if clinically necessary, to determine whether they were eligible to resume treatment.

[0084] [Criteria for discontinuing Magrolimab administration] During the treatment period, subjects who met any of the predetermined discontinuation criteria, determined based on the discontinuation criteria from previous clinical trials of Magrolimab, discontinued Magrolimab administration.

[0085] [Criteria for discontinuing Nivolumab administration] During the treatment period, subjects who met any of the predetermined discontinuation criteria, which were determined considering the discontinuation criteria from previous clinical trials of Nivolumab, discontinued Nivolumab administration.

[0086] [Administrative guidelines for combination therapy with bevacizumab or cetuximab added to FOLFOX therapy] At the start of each administration, subjects must meet all prescribed administration criteria determined in consideration of the latest prescribing information for FOLFOX therapy plus bevacizumab or cetuximab. Administration was postponed until clinical laboratory values ​​on the scheduled administration date recovered to meet the criteria, and administration was performed only after confirming that there were no contraindications for each drug.

[0087] [Dose reduction and criteria for combination therapy with bevacizumab or cetuximab added to FOLFOX therapy] The dosage reduction was carried out in accordance with the latest package insert.

[0088] [Discontinuation criteria for combination therapy with bevacizumab or cetuximab in addition to FOLFOX therapy] During the treatment period, subjects who met any of the prescribed discontinuation criteria, determined based on the latest prescribing information regarding combination therapy with bevacizumab or cetuximab in addition to FOLFOX therapy, discontinued the combination therapy with bevacizumab or cetuximab.

[0089] [Efficacy Evaluation Criteria] (Image diagnosis) CT / magnetic resonance imaging (MRI) scans were performed on the chest, abdomen, and pelvis. The principal investigator or co-investigator measured the tumor diameter of the target lesion and determined the antitumor effect in accordance with RECIST guideline version 1.1. (Evaluation criteria) (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) Change rate of the sum of tumor diameters of target lesions, (9) Maximum change rate of the sum of tumor diameters of target lesions, (10) Trends of tumor markers (CEA and CA19-9) (Evaluation of Target Lesions) Complete Response (CR) It means that all non-lymph node target lesions have disappeared and the short axis diameters of all lymph node lesions selected as target lesions have shrunk to less than 10 mm. Partial Response (PR) It means that the sum of diameters of target lesions has decreased by 30% or more compared to the baseline sum of diameters. Progressive Disease (PD) It means that the sum of diameters of target lesions has increased by 20% or more compared to the minimum sum of diameters during the course, and the sum of diameters has increased by 5 mm or more in absolute value. Stable Disease (SD) It means that there is no shrinkage corresponding to PR and no increase corresponding to PD compared to the minimum sum of diameters during the course. Not Evaluable (NE) It means that the examination cannot be performed for some reason or it cannot be determined as any of CR, PR, PD or SD.

[0090] (1) Overall Response Rate The overall response rate indicates the proportion of subjects whose best overall response is determined as CR or PR.

[0091] (2) Disease Control Rate The disease control rate indicates the proportion of subjects whose best overall response is determined as CR, PR or SD.

[0092] (3) Overall Survival The overall survival is calculated from the following formula. Overall survival (days) = "Date of death from any cause" - "Date of commencement of investigational drug administration" + 1 For subjects who become untrackable or who have not died by the data cutoff date, the last date of survival confirmation will be considered the termination date.

[0093] (4) Progression-free survival Progression-free survival is calculated using the following formula. Progression-free survival (days) = "The earlier of the day on which overall efficacy was determined to be PD, or the day of death due to any cause" - "Start date of investigational drug administration" + 1 For subjects whose overall response has not been determined to be PD and who have not died, the censorship date will be the date of the last evaluable imaging diagnosis performed. For subjects whose evaluable imaging diagnosis has not been performed and who have not died, the censorship date will be the date the investigational drug administration started. For subjects who received subsequent treatment for cancer before their overall response was determined to be PD or before they died, the censorship date will be the date of the last evaluable imaging diagnosis performed before the start of subsequent treatment for cancer.

[0094] (5) Duration of response The duration of effectiveness is calculated using the following formula. Duration of response (days) = "The earlier of the date on which the overall response was first determined to be PD after the confirmation of response, or the date of death from any cause" - "The date on which the first confirmed CR or PR was determined" + 1 The subjects to be evaluated are those who demonstrated a confirmed complete response (CR) or partial response (PR) during the clinical trial.

[0095] (6) Time to achieve a response The time required to achieve a response is calculated using the following formula. Time to response (days) = "First date of confirmed CR or PR" - "Start date of investigational drug administration" + 1

[0096] (7) Best Overall Effect The best overall response will be determined from the overall response assessed by the end of this clinical trial. However, complete response (CR) and partial response (PR) must be confirmed by continuous evaluations with an interval of at least 4 weeks (28 days) between evaluations, and will be determined according to the criteria in Table 1.

[0097]

Table 1

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

[0099]

Equation

[0100] (9) Maximum change rate of the sum of the tumor diameters of the target lesions The maximum change rate of the sum of the tumor diameters of the target lesions is the change rate at the time when the sum of the tumor diameters of the target lesions is the smallest. However, the sum of the tumor diameters of the target lesions after the overall effect is determined as PD or after subsequent treatment is not used for calculating the maximum change rate.

[0101]

Equation

[0102] (10) Transition of the change rate of tumor markers (CEA and CA19-9) The change rate of tumor markers is calculated using the following calculation formula. However, the change rate of tumor markers after subsequent treatment is not calculated.

[0103]

Equation

[0104] [Safety evaluation items] Regarding the following items, the principal investigator of the clinical trial, etc. performed measurements, examinations, and investigations at the prescribed times. (1) Dose-limiting toxicity (DLT), (2) Adverse events, (3) Clinical laboratory tests (hematological tests, blood biochemical tests, immunological tests, hormone tests, blood coagulation tests, urinalysis), peripheral blood smear, (4) Vital signs (systolic / diastolic blood pressure, pulse rate, body temperature, respiratory rate), transcutaneous oxygen saturation (SpO2), body weight, (5) 12-lead electrocardiogram, (6) ECOG Performance Status, and (7) Chest X-ray.

[0105] [Efficacy Evaluation Results] In combination therapy with bevacizumab added to Magrolimab, Nivolumab, and FOLFOX, two cases were determined to have achieved a partial response (PR) eight months after the enrollment of the first subject. In combination therapy with cetuximab added to Magrolimab, Nivolumab, and FOLFOX, three cases were determined to have achieved a partial response (PR) eight months after the enrollment of the first subject.

[0106] Example 2 This is an open-label, uncontrolled trial in patients with pancreatic cancer with distant metastases, comparing magrolimab, nivolumab, and the standard mFFX therapy as first-line treatment. This study aims to investigate the tolerability, safety, and efficacy of combining Magrolimab, Nivolumab, and mFFX therapy as first-line treatment in patients with pancreatic cancer with distant metastases. This trial will allow for the evaluation of the combined effects of 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 were selected at the time of registration. If it became clear that a patient did not meet the following criteria between registration and the first dose of the investigational drug, the administration of the investigational drug was not started and the trial was terminated. 1. Gender: Any. 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 investigational drug administration until at least the end of the examination on the 15th day after the start of investigational drug administration (tolerability evaluation part only). 4. Patients with invasive pancreatic ductal carcinoma diagnosed as adenocarcinoma by histological or cytological examination. 5. Patients with pancreatic cancer with distant metastases who have no prior treatment history with systemic anti-cancer agents. However, patients who have previously received chemoradiotherapy, adjuvant chemotherapy, or neoadjuvant chemotherapy and who have experienced recurrence more than 180 days after the completion of anti-cancer agent administration are permitted to register. 6. Patients with measurable lesions as defined in RECIST Guideline 1.1, as observed on imaging within 14 days prior to administration of the investigational drug. However, in cases where only measurable lesions with a history of radiation therapy are present, only lesions that have been confirmed to have worsened on imaging after radiation therapy are included. 7. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Patients expected to survive for 8.90 days or more. 9. Patients who can provide tumor tissue samples for biomarker testing. Tumor tissue samples are obtained during the screening phase. If a new tumor biopsy is difficult, a stored sample may be used. However, stored samples must be collected within 180 days prior to administration of the investigational drug. 10. In the case of women of childbearing potential (including patients who do not menstruate due to medical reasons such as chemical menopause), patients who agree to use double contraception from the time of consent acquisition until 5 months after the last dose of the investigational drug and for the period after the last dose of the standard treatment drug for which contraception is prescribed. In addition, patients who agree not to breastfeed from the time of consent acquisition until 5 months after the last dose of the investigational drug and for the period after the last dose of the standard treatment drug for which breastfeeding is restricted. Here, women of childbearing potential include all women who have experienced menarche, have not undergone sterilization surgery (such as hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), and have not gone through menopause. Menopause is defined as amenorrhea for 12 consecutive months or more without any notable reason. Women using oral contraceptives, intrauterine devices, or contraceptive diaphragms are considered to be of childbearing potential. 11. In the case of males, patients who have agreed to use double contraception from the start of administration of the investigational drug until 4 months after the last dose of the investigational drug, and for the period specified for contraception by each standard treatment drug after the last dose. Here, double contraception is required using two of the following: vasectomy or condoms for the male patient or male partner, or tubal ligation, contraceptive diaphragm, intrauterine device or oral contraceptives for the female patient or her partner. 12. Patients whose most recent clinical laboratory test results, performed within 14 days prior to the start of investigational drug administration, meet the following criteria. Furthermore, patients must not have received administration of 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 / mm³ 3 That's all. ·Platelet count: 100,000 / mm 3 That's all. • Hemoglobin: 11.0 g / dL or higher. • AST (GOT) and ALT (GPT): 3.0 times or less the upper limit of the facility's reference range (however, if liver metastases are present, 5.0 times or less the upper limit of the facility's reference range). • Total bilirubin: 1.5 times or less of the upper limit of the facility standard. Albumin: 3.0 g / dL or higher. • Creatinine: 1.5 times or less of the upper limit of the facility's reference value, or creatinine clearance (measured value or estimated value using the Cockcroft / Gault formula) of 40 mL / min or more. 13. Patients who have received a full explanation of the contents of this clinical trial from the principal investigator or co-investigator using the informed consent form and explanatory document, and who give written consent to participate in this clinical trial of their own free will.

[0109] (3) Patient exclusion criteria Patients who were thought to meet any of the following criteria were excluded at the time of registration. Furthermore, if any of the following criteria were violated between registration and the first dose of the investigational drug, the administration of the investigational drug was not initiated and the trial was terminated. 1. Patients for whom administration of oxaliplatin, irinotecan, fluorouracil, or leucovorin calcium is contraindicated. 2. Patients experiencing 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 homozygous (UGT1A1*6 / *6, UGT1A1*28 / *28) or heterozygous (compound heterozygous: UGT1A1*6 / *28) gene polymorphisms. 5. Patients with a history of or current severe hypersensitivity reactions to antibody preparations. 6. Patients whose surgical treatment has affected the efficacy and safety evaluation of the investigational drug, as determined by the principal investigator or co-investigator. 7. Patients with a history of or complications of autoimmune disease, or chronic or relapsing autoimmune disease. However, patients with type 1 diabetes, hypothyroidism manageable with hormone replacement therapy, or skin conditions that do not require systemic therapy (such as vitiligo, psoriasis, or alopecia) may be enrolled. 8. Patients with multiple cancers (patients with completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, carcinoma in mucosa, or superficial bladder cancer, or other cancers that have not recurred for more than 3 years, are eligible for registration). 9. Patients with metastatic lesions in the brain or meninges. However, asymptomatic patients who do not require treatment may be registered. 10. Patients with interstitial lung disease or pulmonary fibrosis, diagnosed by imaging or clinical findings, either currently or in the past. 11. Patients with diverticulitis or symptomatic gastrointestinal ulcer disease. 12. Patients with pericardial effusion, pleural effusion, or ascites that cannot be controlled with drug therapy. 13. Patients with unmanageable cancer pain. 14. Patients with severe peritoneal dissemination, such as continuous accumulation of ascites beyond the pelvic cavity. 15. Patients requiring transplantation therapy or those with a history of transplantation therapy (excluding autologous transplantation). 16. Patients with a history of hemolytic anemia within 90 days prior to registration. 17. Patients who have a history of transient ischemic attack, cerebrovascular accident, thrombosis, or thromboembolism (pulmonary embolism or deep vein thrombosis) within 180 days prior to registration. 18. Patients with the following unmanageable or severe cardiovascular diseases. • Myocardial infarction within 180 days prior to registration. • Uncontrolled angina within 180 days prior to registration. • Congestive heart failure, New York Heart Association (NYHA) functional class III or IV. • Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure of 150 mmHg or higher or diastolic blood pressure of 90 mmHg or higher for 24 hours or more). • Arrhythmia requiring treatment. 19. Patients with uncontrolled diabetes mellitus. 20. Patients with systemic infections requiring treatment. 21. Patients who test positive for any of the following during screening: HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or HCV antibody (excluding those negative for HCV-RNA). Note that even if the HCV antibody test is positive, registration is permitted if the HCV-RNA test is negative. 22. Patients who, during screening, have a negative HBs antigen test, but a positive HBs antibody test or HBc antibody test, and whose HBV-DNA quantification is above the detection limit. 23. Patients who received the following treatments before obtaining informed consent and before administration of the investigational drug. Patients with a history of treatment including 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 or cancer vaccines aimed at controlling T cells. Patients who received more than 2 units of red blood cell transfusions within 28 days prior to obtaining consent. • Patients who underwent surgery with local anesthesia within 14 days prior to administration of the investigational drug. • Patients who underwent pleural or pericardial adhesion surgery within 14 days prior to administration of the investigational drug. Patients who have received more than 10 mg / day of prednisolone-equivalent systemic corticosteroids (excluding temporary use for purposes such as examinations, local administration, treatment and prevention of contrast agent allergic reactions, or reduction of edema associated with radiotherapy) or immunosuppressants within 14 days prior to administration of the investigational drug. Patients who received palliative radiation therapy within 28 days prior to administration of the investigational drug. • Patients who underwent surgery under general anesthesia within 28 days prior to administration of the investigational drug. Patients who received a live vaccine or attenuated vaccine within 28 days prior to administration of the investigational drug. Patients who have received other unapproved drugs (including those administered in clinical research, unapproved combination drugs, or new dosage forms) within 28 days prior to administration of the investigational drug (or within 90 days in the case of antibody preparations). Patients who received a radiopharmaceutical (excluding the use of radiopharmaceuticals for examination and diagnosis purposes) within 56 days prior to administration of the investigational drug. 24. Patients who have been found to have germline BRCA gene mutations (pathogenic mutations or suspected pathogenic mutations). 25. Pregnant, breastfeeding, or potentially pregnant patients (breastfeeding patients are ineligible to register even if they have discontinued breastfeeding). 26. Patients who are judged to lack the capacity to give consent due to complications such as dementia. 27. Other patients whom the principal investigator or co-investigator deems unsuitable for the clinical trial.

[0110] (4) Dosage and administration and duration of administration [Magrolimab] Magrolimab was administered intravenously at a dose of 1 mg / kg over 3 hours (±30 minutes) as the initial dose on day 1 of the first cycle. Subsequently, 20 mg / kg or 30 mg / kg was administered intravenously over 2 hours (±30 minutes) at weekly intervals throughout the first cycle. From the second cycle onward, 20 mg / kg or 30 mg / kg was administered intravenously over 2 hours (±30 minutes) at two-week intervals, and administration continued 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 order of Magrolimab, Nivolumab, and then mFFX therapy.

[0111] [Nivolumab] Nivolumab 480 mg was administered intravenously over 30 minutes at 4-week intervals, and continued until the prescribed discontinuation criteria for Nivolumab were met. Note that Nivolumab administration was performed at least 24 days after the previous dose, starting on the 25th day or later.

[0112] [mFFX therapy] (2a) Oxaliplatin is 85 mg / m² 2 (Body surface area) was administered intravenously over 2 hours. (2b) Leucovorin calcium was administered at 200 mg / m². 2 (Body surface area) was administered intravenously over 2 hours. (2c) Irinotecan hydrochloride hydrate was administered at a dose of 150 mg / m² starting 30 minutes after the start of levofolinate calcium administration. 2 (Body surface area) was administered intravenously over 1.5 hours. (2e) Fluorouracil was administered at a dose of 2400 mg / m². 2(Body surface area) was administered intravenously over 46 hours. The series of administrations (2a), (2b), (2c), and (2e) were performed at 2-week intervals. Oxaliplatin, irinotecan hydrochloride hydrate, levofolinate calcium, and fluorouracil were commercially available products.

[0113] [Clinical Trial Schedule] This trial consists of a screening phase, a treatment phase, and a follow-up observation phase. An overview of the trial schedule is shown in Figure 2. The screening period was within 28 days prior to administration of the investigational drug. The principal investigator or co-investigator enrolled patients who met the above selection criteria, did not violate the above exclusion criteria, and were deemed eligible to participate in this clinical trial. Each treatment cycle was 28 days long, with the first administration of the investigational drug designated as day 1 of cycle 1. Day 1 of each subsequent cycle was designated as [28 × (number of cycles - 1) + 1] days. Administration of Magrolimab, Nivolumab, and mFFX therapy was initiated according to the above-mentioned dosage and administration guidelines, and continued according to the administration criteria, dose reduction criteria, and dose reduction levels for Magrolimab, Nivolumab, and mFFX therapy. The treatment period ended when the evaluation at the end of administration (discontinuation) of Magrolimab, Nivolumab, and mFFX therapy was completed. Of all subjects who received the investigational drug, those who discontinued or terminated administration of Magrolimab, Nivolumab, and mFFX therapy underwent an evaluation at the end of administration (discontinuation) and proceeded to the post-observation period. Follow-up surveys were conducted after the end of the post-observation period.

[0114] [Dosage criteria for Magrolimab and Nivolumab] At the start of each administration cycle, subjects must meet all of the prescribed administration criteria, which were determined based on the administration criteria from previous clinical trials for Magrolimab and Nivolumab. If any of these criteria were not met, the scheduled administration of Magrolimab and Nivolumab was discontinued. Subjects who had discontinued treatment were examined weekly, or more frequently if clinically necessary, to determine whether they were eligible to resume treatment.

[0115] [Criteria for discontinuing Magrolimab administration] During the treatment period, subjects who met any of the predetermined discontinuation criteria, determined based on the discontinuation criteria from previous clinical trials of Magrolimab, discontinued Magrolimab administration.

[0116] [Criteria for discontinuing Nivolumab administration] During the treatment period, subjects who met any of the predetermined discontinuation criteria, which were determined considering the discontinuation criteria from previous clinical trials of Nivolumab, discontinued Nivolumab administration.

[0117] [Dosage Criteria for mFFX Therapy] At the start of each administration, subjects must meet all prescribed administration criteria determined in consideration of the latest package insert for mFFX therapy. Administration was postponed until clinical laboratory values ​​on the scheduled administration date recovered to meet the criteria, and administration was performed only after confirming that there were no contraindications for each drug.

[0118] [Dose reduction and criteria for mFFX therapy] The dosage reduction was carried out 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, determined in consideration of the latest package insert for mFFX therapy, discontinued mFFX therapy.

[0120] [Efficacy Evaluation Criteria] (Image diagnosis) CT / magnetic resonance imaging (MRI) scans were performed on the chest, abdomen, and pelvis. The principal investigator or co-investigator measured the tumor diameter of the target lesion and determined the antitumor effect in accordance with RECIST guideline version 1.1. (Evaluation criteria) (1) Objective 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 means that all non-lymph node target lesions have disappeared, and the short diameter of all lymph node lesions selected as target lesions has shrunk to less than 10 mm. Partial response (PR) This means that the sum of the diameters of the target lesions has decreased by 30% or more compared to the sum of the diameters at baseline. Progressive disease (PD) This means that the sum of diameters of the target lesions has increased by 20% or more compared to the minimum sum of diameters during the course of the disease, and the sum of diameters has increased by 5 mm or more in absolute terms. Stable disease (SD) This means that, compared to the minimum sum of diametrical diameters over time, there is no reduction equivalent to PR and no increase equivalent to PD. Not Evaluable (NE) This refers to cases where testing cannot be performed for any reason, or where it cannot be determined whether the result is CR, PR, PD, or SD.

[0121] (1) Performance The response rate indicates the percentage of subjects whose best overall response was determined to be a complete response (CR) or partial response (PR).

[0122] (2) Disease control rate The disease control rate represents the percentage 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 commencement of investigational drug administration" + 1 For subjects who become untrackable or who have not died by the data cutoff date, the last date of survival confirmation will be considered the termination date.

[0124] (4) Progression-free survival Progression-free survival is calculated using the following formula. Progression-free survival (days) = "The earlier of the day on which overall efficacy was determined to be PD, or the day of death due to any cause" - "Start date of investigational drug administration" + 1 For subjects whose overall response has not been determined to be PD and who have not died, the censorship date will be the date of the last evaluable imaging diagnosis performed. For subjects whose evaluable imaging diagnosis has not been performed and who have not died, the censorship date will be the date the investigational drug administration started. For subjects who received subsequent treatment for cancer before their overall response was determined to be PD or before they died, the censorship date will be the date of the last evaluable imaging diagnosis performed before the start of subsequent treatment for cancer.

[0125] (5) Duration of response The duration of effectiveness is calculated using the following formula. Duration of response (days) = "The earlier of the date on which the overall response was first determined to be PD after the confirmation of response, or the date of death from any cause" - "The date on which the first confirmed CR or PR was determined" + 1 The subjects to be evaluated are those who demonstrated a confirmed complete response (CR) or partial response (PR) during the clinical trial.

[0126] (6) Time to achieve a response The time required to achieve a response is calculated using the following formula. Time to response (days) = "First date of confirmed CR or PR" - "Start date of investigational drug administration" + 1

[0127] (7) Best Overall Effect The best overall response will be determined from the overall response assessed by the end of this clinical trial. However, complete response (CR) and partial response (PR) must be confirmed by continuous evaluations with an interval of at least 4 weeks (28 days) between evaluations, and will be determined according to the criteria in Table 2.

[0128] [Table 2]

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

[0130]

number

[0131] (9) Maximum change in the sum of tumor diameters of the target lesion The maximum percentage change in the sum of tumor diameter of the target lesion is defined as the percentage change at the point when the sum of tumor diameter of the target lesion is smallest. However, the sum of tumor diameter of the target lesion after the overall effect is determined to be PD or after subsequent treatment is performed is not used in calculating the maximum percentage change.

[0132]

number

[0133] (10) Changes in tumor marker rates (CEA and CA19-9) The percentage change in tumor markers is calculated using the following formula. However, the percentage change in tumor markers after subsequent treatment is not calculated.

[0134]

number

[0135] [Safety evaluation criteria] The following items were measured, examined, and investigated by the principal investigator and other relevant personnel at predetermined times. (1) Dose-limiting toxicity (DLT), (2) Adverse events, (3) Clinical laboratory tests (hematological tests, blood biochemical tests, immunological tests, hormone tests, blood coagulation tests, urinalysis), peripheral blood smear, (4) Vital signs (systolic / diastolic blood pressure, pulse rate, body temperature, respiratory rate), transcutaneous oxygen saturation (SpO2), body 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, there was one case that was judged to have achieved a partial response (PR) 10 months after the enrollment of the first subject. [Industrial applicability]

[0137] This invention provides a novel cancer treatment method and is useful.

Claims

1. A solid tumor progression inhibitor, recurrence inhibitor, and / or treatment agent containing a CD47 inhibitor as an active ingredient, characterized by being administered in combination with standard therapy and an immune checkpoint inhibitor, wherein the standard therapy is a reduced-dose regimen of FOLFIRINOX therapy, the immune checkpoint inhibitor is Nivolumab, the CD47 inhibitor is Magrolimab, and the reduced-dose regimen of FOLFIRINOX therapy is (2a) Administer oxaliplatin 85 mg / m² (body surface area) intravenously. (2b) Administer 200 mg / m² (body surface area) of levofolinate calcium intravenously. (2c) Administer irinotecan hydrochloride hydrate 150 mg / m² (body surface area) intravenously, and (2e) Administer fluorouracil 2400 mg / m² (body surface area) intravenously on a continuous basis. This includes, and the series of administrations of (2a), (2b), (2c), and (2e) are carried out at two-week intervals. For the initial dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. This drug is characterized by intravenous administration of 480 mg of nivolumab every four weeks, and is used as a treatment agent for solid tumors, including pancreatic cancer with distant metastases, to suppress progression, prevent recurrence, and / or treat the disease.

2. A solid tumor progression inhibitor, recurrence inhibitor, and / or treatment agent containing an immune checkpoint inhibitor as an active ingredient, characterized by being administered in combination with standard therapy and a CD47 inhibitor, wherein the standard therapy is a reduced-dose regimen of FOLFIRINOX therapy, the immune checkpoint inhibitor is Nivolumab, the CD47 inhibitor is Magrolimab, and the reduced-dose regimen of FOLFIRINOX therapy is (2a) Administer oxaliplatin 85 mg / m² (body surface area) intravenously. (2b) Administer 200 mg / m² (body surface area) of levofolinate calcium intravenously. (2c) Administer irinotecan hydrochloride hydrate 150 mg / m² (body surface area) intravenously, and (2e) Administer fluorouracil 2400 mg / m² (body surface area) intravenously on a continuous basis. This includes, and the series of administrations of (2a), (2b), (2c), and (2e) are carried out at two-week intervals. For the initial dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. This drug is characterized by intravenous administration of 480 mg of nivolumab every four weeks, and is used as a treatment agent for solid tumors, including pancreatic cancer with distant metastases, to suppress progression, prevent recurrence, and / or treat the disease.

3. The agent according to claim 1 or 2, characterized in that it is administered as first-line treatment to patients with pancreatic cancer having distant metastases who have no prior treatment with systemic anti-cancer agents.

4. A solid tumor progression inhibitor, recurrence inhibitor and / or treatment agent comprising a CD47 inhibitor as an active ingredient, characterized in that it is administered in combination with a standard therapy and an immune checkpoint inhibitor, wherein the standard therapy is a reduced-dose regimen of FOLFIRINOX therapy, the immune checkpoint inhibitor is Nivolumab, the CD47 inhibitor is Magrolimab, and the reduced-dose regimen of FOLFIRINOX therapy is (2a) Administer oxaliplatin 85 mg / m² (body surface area) intravenously. (2b) Administer 200 mg / m² (body surface area) of levofolinate calcium intravenously. (2c) Administer irinotecan hydrochloride hydrate 150 mg / m² (body surface area) intravenously, and (2e) Administer fluorouracil 2400 mg / m² (body surface area) intravenously on a continuous basis. This includes, and the series of administrations of (2a), (2b), (2c), and (2e) are carried out at two-week intervals. For the initial dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. Nivolumab is administered intravenously at a dose of 240 mg every two weeks or 360 mg every three weeks, and is used as a treatment agent for solid tumors, specifically pancreatic cancer with distant metastases, to suppress progression, prevent recurrence, and / or treat the disease.

5. A solid tumor progression inhibitor, recurrence inhibitor and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with a standard therapy and a CD47 inhibitor, wherein the standard therapy is a reduced-dose regimen of FOLFIRINOX therapy, the immune checkpoint inhibitor is Nivolumab, the CD47 inhibitor is Magrolimab, and the reduced-dose regimen of FOLFIRINOX therapy is (2a) Administer oxaliplatin 85 mg / m² (body surface area) intravenously. (2b) Administer 200 mg / m² (body surface area) of levofolinate calcium intravenously. (2c) Administer irinotecan hydrochloride hydrate 150 mg / m² (body surface area) intravenously, and (2e) Administer fluorouracil 2400 mg / m² (body surface area) intravenously on a continuous basis. This includes, and the series of administrations of (2a), (2b), (2c), and (2e) are carried out at two-week intervals. For the initial dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. Nivolumab is administered intravenously at a dose of 240 mg every two weeks or 360 mg every three weeks, and is used as a treatment agent for solid tumors, specifically pancreatic cancer with distant metastases, to suppress progression, prevent recurrence, and / or treat the disease.

6. The agent according to claim 4 or 5, characterized in that it is administered as first-line treatment to a patient with pancreatic cancer having distant metastases who has no prior treatment history with systemic anti-cancer agents.

7. A solid tumor progression inhibitor, recurrence inhibitor and / or treatment agent comprising a CD47 inhibitor as an active ingredient, characterized in that it is administered in combination with a standard therapy and an immune checkpoint inhibitor, wherein the standard therapy is FOLFIRINOX therapy, the immune checkpoint inhibitor is Nivolumab, the CD47 inhibitor is Magrolimab, and the FOLFIRINOX therapy is (2a) Administer oxaliplatin 85 mg / m² (body surface area) intravenously. (2b) Administer 200 mg / m² (body surface area) of levofolinate calcium intravenously. (2c) Administer irinotecan hydrochloride hydrate 180 mg / m² (body surface area) intravenously. (2d) Rapid intravenous administration of fluorouracil 400 mg / m² (body surface area), and (2e) After the completion of administration of fluorouracil as described in (2d), administer fluorouracil 2400 mg / m² (body surface area) intravenously on a continuous basis. The series of administrations of (2a), (2b), (2c), (2d), and (2e) are performed at two-week intervals. For the initial dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. Nivolumab is administered intravenously at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks, and is used as a treatment agent for solid tumors, specifically pancreatic cancer with distant metastases, to suppress progression, prevent recurrence, and / or treat the disease.

8. A solid tumor progression inhibitor, recurrence inhibitor and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with a standard therapy and a CD47 inhibitor, wherein the standard therapy is FOLFIRINOX therapy, the immune checkpoint inhibitor is Nivolumab, the CD47 inhibitor is Magrolimab, and the FOLFIRINOX therapy is (2a) Administer oxaliplatin 85 mg / m² (body surface area) intravenously. (2b) Administer 200 mg / m² (body surface area) of levofolinate calcium intravenously. (2c) Administer irinotecan hydrochloride hydrate 180 mg / m² (body surface area) intravenously. (2d) Rapid intravenous administration of fluorouracil 400 mg / m² (body surface area), and (2e) After the completion of administration of fluorouracil as described in (2d), administer fluorouracil 2400 mg / m² (body surface area) intravenously on a continuous basis. The series of administrations of (2a), (2b), (2c), (2d), and (2e) are performed at two-week intervals. For the initial dose, Magrolimab is administered intravenously at a dose of 1 mg / kg (body weight), and from the second dose onward, 15 mg / kg (body weight) to 30 mg / kg (body weight) is administered intravenously at one-week or two-week intervals. Nivolumab is administered intravenously at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks, and is used as a treatment agent for solid tumors, specifically pancreatic cancer with distant metastases, to suppress progression, prevent recurrence, and / or treat the disease.

9. The agent according to claim 7 or 8, characterized in that it is administered as first-line treatment to a patient with pancreatic cancer having distant metastases who has no prior treatment history with systemic anti-cancer agents.

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