CN117460534A

CN117460534A - Methods of cancer treatment based on combinations of CD47 inhibitory substances, immune checkpoint inhibitory substances and standard therapies

Info

Publication number: CN117460534A
Application number: CN202280039953.1A
Authority: CN
Inventors: 冈本达也
Original assignee: Ono Pharmaceutical Co Ltd
Current assignee: Ono Pharmaceutical Co Ltd
Priority date: 2021-06-10
Filing date: 2022-06-09
Publication date: 2024-01-26

Abstract

The problem underlying the present invention is to provide an effective method for the treatment of cancer. The present invention provides a method for treating cancer, which combines a CD47 inhibitor, an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody, etc.), and a standard therapy (e.g., a combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy for colon cancer or rectal cancer that cannot radically cure progress or recurrence of resection, a FOLFIRINOX therapy for pancreatic cancer having distant metastasis, or a reduction regimen thereof). The treatment methods of the present invention are useful in cancer treatment.

Description

Methods of cancer treatment based on combinations of CD47 inhibitory substances, immune checkpoint inhibitory substances and standard therapies

Technical Field

The present disclosure relates to a method of treating cancer (sometimes simply referred to as a method of treating the present invention) or the like based on a combination of a CD 47-inhibitory substance, an immune checkpoint-inhibitory substance and a standard therapy.

Background

CD47 is a 5-time transmembrane glycoprotein, and CD47 expressed in cancer cells binds to signal-regulating protein α (sirpa, signal regulatory protein alpha) expressed in macrophages and dendritic cells, thereby transmitting a "don't-eat me" signal to macrophages, and participating in inhibiting phagocytosis of cancer cells by macrophages. The CD47 inhibitor is considered to be useful for cancer therapy because it binds to CD47 on the cancer cell membrane, inhibits the transmission of "don't eat me" signal to macrophages, and promotes phagocytosis of cancer cells by macrophages (see non-patent documents 1 to 4).

Patent document 1 discloses that a CD47 inhibitor promotes phagocytosis of cancer cells by macrophages, and is useful as a therapeutic agent for cancer (see patent document 1).

On the other hand, in cancer cells and in the microenvironment of cancer, various immune checkpoint molecules exist that interfere with the immune response to cancer. Immune checkpoint inhibitory substances are novel therapeutic methods for activating immune responses to cancers by releasing immune inhibitory mechanisms, and as immune checkpoint inhibitory substances, ipilimumab (ipilimumab) which is an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) antibody, nivolumab (nivolumab) which is an anti-PD-1 (pro grammed cell death-1) antibody, pambrizumab (pembrolizumab) and the like have been approved at home and abroad for cancer treatment.

As standard therapies for colon or rectal cancer that cannot radically cure the progress or recurrence of excision, there are combination therapies in which bevacizumab as a molecular targeting therapeutic agent for Vascular Endothelial Growth Factor (VEGF) or cetuximab or Panitumumab as a molecular targeting therapeutic agent for Epidermal Growth Factor Receptor (EGFR) is added to FOLFOX therapy using fluorouracil (5-FU), levofolinate (Levofolinate) and oxaliplatin.

The main treatments for unresectable pancreatic cancer with distant metastasis are drug therapy, and as standard therapies, there are FOLFIR INOX therapy (hereinafter, sometimes abbreviated as "FFX therapy") in which a regimen comprising fluorouracil (5-FU) is combined with oxaliplatin and irinotecan, rapid administration of fluorouracil is omitted from FFX therapy while toxicity is reduced, and modified FOLFIRINOX (modified FOLFI RINOX) therapy (hereinafter, sometimes abbreviated as "mFFX therapy") in which irinotecan is reduced.

Although certain effects are confirmed in these therapeutic methods, there is an unmet need for treatments that lead to increased survival.

Prior art literature

Patent literature

Patent document 1: WO2009/091601

Non-patent literature

Non-patent document 1: trends in Cell Biology, eleventh roll (3), pages 130-135, 2001

Non-patent document 2: journal of Experimental Medicine, volume 194 (4), pages 541-549, 2001

Non-patent document 3: journal of Immunology, volume 174 (4), pages 2004-2011, 2005

Non-patent document 4: cell, volume 138 (2), pages 286-299, 2009

Disclosure of Invention

Technical problem to be solved by the invention

The technical problem of the present invention is to provide a novel method for treating cancers (e.g., colorectal cancer, pancreatic cancer).

Means for solving the technical problems

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a combination of a CD47 inhibitor and an immune checkpoint inhibitor in a standard therapy can be an effective cancer treatment method.

Accordingly, in one aspect, the present invention provides:

[1] a progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for solid cancer, comprising a CD47 inhibitory substance as an active ingredient, wherein the progression inhibitor, the recurrence inhibitor and/or the therapeutic agent for solid cancer are administered in combination with standard therapy and an immune checkpoint inhibitory substance;

[2] a progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for solid cancer, comprising an immune checkpoint inhibitory substance as an active ingredient, wherein the progression inhibitor, the recurrence inhibitor and/or the therapeutic agent for solid cancer is administered in combination with standard therapy and a CD47 inhibitory substance.

Effects of the invention

The treatment methods of the present invention are useful in cancer treatment.

Drawings

Fig. 1 shows a summary of a multi-facility common non-blind test non-control test for evaluating the tolerance, safety, and effectiveness of Mo Luoli mab, nivolumab, and combination therapy with bevacizumab or cetuximab added to FOLFOX therapy, which will be described later, in a colon cancer or rectal cancer patient who cannot radically cure progress or recurrence of excision.

Fig. 2 shows an outline of a multi-facility common non-blind test non-control test for evaluating the tolerance, safety, and efficacy of the combination of Mo Luoli mab, nivolumab, and mFFX therapy described later, in a pancreatic cancer patient with distant metastasis.

Detailed Description

(1) CD47 inhibiting substance

In the present invention, the CD 47-inhibiting substance is not particularly limited as long as it is a compound having a CD 47-inhibiting effect, and in one embodiment, is an agent (preferably an antibody, more preferably a monoclonal antibody) that inhibits the binding of CD47 to sirpa, and examples thereof include: anti-CD 47 antibodies, anti-sirpa antibodies, and the like, may be antigen-binding fragments of the antibodies (e.g., fv, fab, fab ', (Fab') ₂ scFv, scFv-Fc). Examples of anti-CD 47 antibodies include: mo Luoli mAb (Hu 5F 9-G4), CC-90002, STI-6643, ZL-1201, TAY-018, SGN-CD47M, genSci-059, lezoparlimab (Letaplimab), letelimab (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-01133, letelimab, TQB-2928, AL-008, JMT-601 and DSP-107. Examples of anti-SIRPalpha antibodies include ES-004, CTX-5861, ADU-1805, BI-765063, BYON-4228, FSI-189 and CC-95251. The CD47 inhibitory substances may be used alone or in combination of 1 or more than 2. As the CD 47-inhibiting substance, an anti-CD 47 antibody is preferable, and as the anti-CD 47 antibody, mo Luoli monoclonal antibody (CAS number: 2169232-81-7) is preferable. In addition, antibodies or antigen binding fragments thereof comprising the heavy and light chain Complementarity Determining Regions (CDRs) or Variable Regions (VR) of the known antibodies are also one form of CD47 inhibitory substances. For example, as another embodiment of the anti-CD 47 antibody, an antibody or an antigen-binding fragment thereof comprising the heavy and light chain Complementarity Determining Regions (CDRs) or Variable Regions (VR) of Mo Luoli mab can be exemplified. In addition, as one embodiment of the anti-CD 47 antibody, an antibody that competes with Mo Luoli mab for binding to CD47, an antibody that binds to the same CD47 epitope as Mo Luoli mab, or an antigen-binding fragment thereof can be given.

In the present invention, the CD 47-inhibitory substance can be produced according to a known method, and for example, mo Luoli mab can be produced according to the method described in WO 2011/143624.

The amount of the CD47 inhibitory substance used in the therapeutic method of the present invention may be adjusted to bring about the optimal desired effect depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, and the like.

For example, in one embodiment, a therapeutically effective dose (therapeutic dose) of an anti-CD 47 antibody (e.g., mo Luoli mab) is about 15mg/kg to about 60mg/kg (preferably about 15mg/kg to about 45mg/kg, more preferably about 15mg/kg to about 30mg/kg, and preferred embodiments are about 15mg/kg, about 20mg/kg, about 30mg/kg, about 45 mg/kg). Examples of the administration interval include a half cycle (3 days or 4 days), 1 week, and 2 weeks, and examples of the single administration time include about 60 minutes or more, about 90 minutes or more, about 120 minutes or more, and about 2 hours (+ -30 minutes). As described above, the amount of the drug to be administered varies depending on various conditions, and therefore, there are cases where a smaller amount than the amount of the drug to be administered is sufficient, and there are cases where the drug to be administered is required to be administered beyond the range. Furthermore, in one embodiment, the therapeutic dose may be gradually increased in order to optimize safety and efficacy.

In one embodiment, a priming agent (priming) is administered prior to administration of a therapeutically effective dose of an anti-CD 47 antibody (e.g., mo Luoli mab). Suitable pre-charges comprise a first administered dose of Erythropoiesis Stimulating Agent (ESA) and/or anti-CD 47 antibody (e.g., mo Luoli mab). After administration of the pre-charge, a therapeutic dose of an anti-CD 47 antibody (e.g., mo Luoli mab) is administered after a period effective to confer an increase in reticulocyte production (e.g., after administration of the pre-charge, at least about 3 days later (e.g., at least about 4 days later, at least about 5 days later, at least about 6 days later, at least about 7 days later, at least about 8 days later, at least about 9 days later, or at least about 10 days later). In one embodiment, a given suitable initial dose of anti-CD 47 antibody (e.g., mo Luoli mab) or the like is from about 0.5mg/kg to about 5mg/kg (preferably about 1 mg/kg) and is administered intravenously over a period of from about 2.5 hours to about 6 hours (e.g., about 3 hours to about 4 hours, or about 3 hours (+ -30 minutes)). In one embodiment, as an anti-CD 47 antibody (e.g., mo Luoli mab), about 1mg/kg is administered intravenously at the time of primary administration, and about 15mg/kg to about 30mg/kg (preferably about 20mg/kg or about 30 mg/kg) is administered intravenously at 1-week intervals or 2-week intervals after the secondary administration.

(2) Immune checkpoint inhibitory substance

In the present invention, an immune checkpoint molecule refers to a molecule that exerts an immunosuppressive function by transmitting an inhibitory co-signal (suppresive co-signal). As immune checkpoint molecules, there are known: 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 in hibitory receptor), VISTA (V-domain Ig-containing suppressor of T Cell activa tion), IDO1 (Indoleamine 2, 3-dioxygenase), arginaseI, TIGIT (T Cell immun oglobulin and ITIM domain), CD115, etc. (see Nature Reviews Cancer, pages 252-264, 2012; cancer Cell,27, pages 450-461, 2015) are not particularly limited as long as they have a function consistent with the definition.

In the present invention, an immune checkpoint inhibitory substance is a substance that inhibits the function of an immune checkpoint molecule. The immune checkpoint inhibitor is not particularly limited as long as it can inhibit the function (signal) of the immune checkpoint molecule. The immune checkpoint inhibitor may be used alone or in combination of 1 or more than 2. As the immune checkpoint inhibitory substance, an antibody (preferably a monoclonal antibody) or an antigen-binding fragment thereof (e.g., fv, fab, fab ', (Fab') ₂ 、scFv、scFv-Fc)。

As an immune checkpoint inhibitory substance, such as anti-PD-1 antibodies (e.g., nafiizumab, simipu Li Shan antibodies (REGN-2810), pabolizumab (MK-3475), stbadizumab (PDR-001), tirilizumab (BGB-A317), AMP-514 (MEDI 0680), duodalizumab (ANB 011/TSR-042), terlipu Li Shan antibodies (JS 001), carilizumab (SHR-1210), jenolizumab (Genoliizumab) (CBT-501), sidi Li Shan antibodies (IBI 308), STI-A1110, ENUM D4, ENUM 244C8, GLS010, ruifer Li Shan antibodies (MGA 012), butilizumab (AGEN 2034), CS1003, studi Lu Lishan antibodies (HLX 10), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, jim 021, ji Li Shan, sy Li Shan, XYBX 5, xidelizumab (UK-67), xidelizumab (e.g., TXClu5), XClujiuB-67, xidelizumab (UK-55), XYPABK-55, XYPAUK-55, XYPAL (UK-67) and the like, alcalizumab (RG 7446/MPDL 3280A), averment (PF-06834635/MSB 0010718C), dewaruzumab (MEDI 4736), BMS-936559, STI-1014, enfra Li Shan antibody (KN 035), tadalizumab (LY 3300054), HLX20, SHR-1316, CS1001 (WBP 3155), MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502 (TQB 2450), JS003, CX-072, etc.), or anti-CTLA-4 antibodies (e.g., ipilimumab (MDX-010), zephylum mab (AGEN 1884), tremelimumab, etc.), anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-Ti m-3 antibodies (e.g., MBG 453), anti-LAG-3 antibodies (e.g., BMS-986016, LAG 525), anti-KIR antibodies (e.g., li Ruilu mab), etc. Furthermore, antibodies or antigen binding fragments thereof comprising the heavy and light chain Complementarity Determining Regions (CDRs) or Variable Regions (VR) of the known antibodies are also one mode of immune checkpoint inhibitory substances. For example, as another embodiment of the anti-PD-1 antibody, an antibody or an antigen-binding fragment thereof comprising heavy and light chain Complementarity Determining Regions (CDRs) or Variable Regions (VR) of nivolumab may be mentioned. In addition, as one embodiment of the anti-PD-1 antibody, there may be mentioned an antibody which competes with the Nawuzumab for binding to PD-1, an antibody which binds to PD-1 as with the Nawuzumab, or an antigen-binding fragment thereof.

In the present invention, the immune checkpoint inhibitor is preferably an anti-PD-1 antibody, an anti-PD-L1 antibody or 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 Nawuzumab, simipu Li Shan antibody, pabolizumab, st.Pabolizumab, tirilizumab, terep Li Shan antibody, xindi Li Shan antibody and Carrilizumab, and the anti-PD-L1 antibody is preferably at least one selected from the group consisting of Abilizumab, averment, devaluzumab and BMS-936559, and the anti-CTLA-4 antibody is preferably at least one selected from the group consisting of Ipimab and trametes. Further, as the anti-PD-1 antibody, at least one selected from the group consisting of nivolumab, cimetidine Li Shan antibody and palbociclizumab is more preferable, and nivolumab is further preferable. In the present invention, as the immune checkpoint inhibitory substance, an anti-PD-1 antibody is preferable, and nivolumab is more preferable.

In the present invention, the immune checkpoint inhibitor can be produced by a known method. For example, nivolumab may be produced according to the method described in WO2006/121168, palbociclib may be produced according to the method described in WO2008/156712, BMS-936559 may be produced according to the method described in WO2007/005874, and ipilimab may be produced according to the method described in WO 2001/014424.

Any one or any plurality of these immune checkpoint inhibitory substances may be used in combination with the compounds used in the present invention.

The amount of the immune checkpoint inhibitor used in the therapeutic method of the present invention is adjusted so as to bring about the optimal desired effect, depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, and the like.

For example, as the active ingredient of the immune checkpoint inhibitory substance, intravenous administration (for example, intravenous drip) may be performed at intervals of about 1mg/kg (body weight) to about 10mg/kg (body weight) at a time or about 200mg to about 1200mg at a time and 2 to 4 weeks for about 30 minutes to about 60 minutes or more. Here, examples of the dose in terms of weight per single dose include: 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg or 10mg/kg, and as the amount to be administered per single administration, for example, there may be mentioned: 200mg, 240mg, 250mg, 280mg, 300mg, 320mg, 350mg, 360mg, 400mg, 420mg, 450mg, 480mg, 500mg, 540mg, 560mg, 600mg, 640mg, 700mg, 720mg, 750mg, 800mg, 840mg, 900mg, 1000mg, 1080mg, 1100mg, 1120mg or 1200mg. The administration interval may be, for example, 2 weeks, 3 weeks or 4 weeks, and the single administration time may be, for example, about 30 minutes to about 60 minutes or more.

In the case where the active ingredient is nivolumab as an anti-PD-1 antibody, the following administration is carried out in the following manner and dosage. That is, as nivolumab, for a malignant melanoma patient, intravenous drip administration was performed at a single 3mg/kg (body weight) and 2-week interval or a single 2mg/kg (body weight) and 3-week interval, or intravenous drip was performed at a single 240mg and 2-week interval or a single 480mg and 4-week interval. For each patient of non-small cell lung cancer, renal cell carcinoma, classical hodgkin lymphoma, head and neck cancer, gastric cancer and malignant pleural mesothelioma, a single 3mg/kg (body weight) was administered as nivolumab by intravenous drip at 2-week intervals. In addition, as other usage/dose, for example, 240mg for each patient of malignant melanoma, non-small cell lung cancer, renal cell carcinoma, classical hodgkin lymphoma, head and neck cancer, urothelial carcinoma, MSI-H or dwmr positive colorectal cancer (also including childhood patients over 12 years old), gastric cancer, esophageal cancer, hepatocellular carcinoma, small cell lung cancer and malignant pleural mesothelioma is administered as nivolumab by intravenous drip at 2-week intervals, or 480mg for each patient by intravenous drip at 4-week intervals. In addition, as other usage/dose, for example, in a malignant melanoma patient, in combination with ipilimumab, it is sometimes the case that nivolumab is intravenously instilled at 1mg/kg (body weight) at a time of 3 weeks, then, nivolumab is intravenously instilled at 3mg/kg (body weight) at a time of 2 weeks, or nivolumab is intravenously instilled at 80mg at a time of 3 weeks, then, nivolumab is intravenously instilled at 240mg at a time of 2 weeks or at 480mg at a time of 4 weeks. In addition, for example, in a renal cell carcinoma patient or a colorectal cancer patient, in combination with ipilimumab, intravenous infusion was performed 4 times at a single 240mg and 3-week interval as nivolumab, and then intravenous infusion was performed at a single 240mg and 2-week interval or a single 480mg and 4-week interval as nivolumab.

Furthermore, in the case of the cimiput Li Shan antibody, which is also an anti-PD-1 antibody, 350mg was administered at a single time at 3-week intervals.

In the case of palbociclib as an anti-PD-1 antibody, the same administration was performed in the following manner. That is, as palbociclib, single 200mg intravenous drip administration at 3-week intervals or single 400mg intravenous drip administration at 6-week intervals was performed for each patient of malignant melanoma, non-small cell lung cancer, classical hodgkin lymphoma, head and neck cancer, MSI-H or dwmr positive solid cancer or colorectal cancer, urothelial cancer, cervical cancer, primary mediastinal B cell lymphoma, hepatocellular carcinoma, gastric cancer, and merck cell carcinoma. In addition, as other usage/dose, for example, each patient of classical hodgkin lymphoma, MSI-H or dMMR positive solid cancer or colorectal cancer and primary mediastinal B cell lymphoma in children over 2 years old was given as palbockizumab by intravenous infusion at 3-week intervals at single 2mg/kg (to single 200 mg) of body weight.

In addition, in the case where the active ingredient is avermectin as an anti-PD-L1 antibody, each patient with merck cell carcinoma and urothelial carcinoma is administered as avermectin by intravenous infusion at intervals of 2 weeks at a single dose of 10mg/kg (body weight). Also, atilizumab as a PD-L1 antibody was administered as ati Li Zhushan antibody at single 1200mg and 3 week intervals for each patient of non-small cell lung cancer, urothelial cancer and hepatocellular carcinoma, and as ati Li Zhushan antibody at single 840mg and 2 week intervals for patients with triple negative breast cancer in combination with paclitaxel. In addition, dewaruzumab, which is also a PD-L1 antibody, was intravenously instilled at 2-week intervals at a single dose of 10mg/kg (body weight) as Dewaruzumab for each patient with non-small cell lung cancer and urothelial cancer, and at 1500mg at 4-week intervals as Dewaruzumab for patients with progressive small cell lung cancer.

In addition, in the case of ipilimumab as an anti-CTLA-4 antibody, for patients with malignant melanoma, intravenous infusion was performed at 3-week intervals as ipilimumab single times a day of 3mg/kg (body weight) alone or in combination with nivolumab, and for each patient with renal cell carcinoma and MSI-H or dwmr positive colorectal cancer, intravenous infusion was performed at 3-week intervals as ipilimumab single times of 1mg/kg (body weight) single times of 4-week intervals as ipilimumab in combination with nivolumab, and intravenous infusion was performed at 6-week intervals as ipilimumab single times of 1mg/kg (body weight) for patients with non-small cell lung cancer.

In the present invention, the dosages used may also be used in the methods of treatment of the present invention.

Intravenous drip is preferred as a mode of administration of the immune checkpoint inhibitory substance of the present invention.

(3) Combination therapy incorporating molecular targeting agents (e.g., bevacizumab, cetuximab) in FOLFOX therapy Method (one example of standard therapy)

By "standard therapy" in the present invention is meant a treatment that is most recommended based on scientific basis, confirming the effect, safety, of the treatment based on the results of many clinical trials. The "FOLFOX therapy" in the present invention is a method for treating cancer, which comprises a combination of 3 agents, namely oxaliplatin, calcium levofolinate (hereinafter abbreviated as "levofolinate") and fluorouracil, and in one embodiment, comprises (1 a) oxaliplatin 85mg/m ² ～130mg/m ² (1 b) L-folinate 100mg/m ² ～200mg/m ² (1 c) fluorouracil 400mg/m ² Is administered intravenously (1 d) 600mg/m fluorouracil ² ～2400mg/m ² Is a therapeutic method in which a series of administrations of (1 a), (1 b), (1 c) and (1 d) are carried out at 2-week intervals. The doses in this treatment method are all doses in terms of body surface area per single administration. FOLFOX therapy according to the 3 reagents to be administered dosage, administration method of known various scheme, as a mode, for example, can not be used to carry out the (1 c) fluorouracil rapid intravenous administration, the (1 a) oxaliplatin dosage can be 85mg/m ² 、100mg/m ² 、130mg/m ² Or 85mg/m ² ～130mg/m ² The dosage of the levofolinate of the (1 b) can be 100mg/m ² 、200mg/m ² Or 100mg/m ² ～200mg/m ² Any of the doses, and the dose of fluorouracil (1 d) to be administered continuously intravenously may be 600mg/m ² 、1500mg/m ² 、2400mg/m ² Or 600mg/m ² ～2400mg/m ² Any dosage in between.

In one embodiment, the rapid intravenous administration is performed within 15 minutes.

In one embodiment, for example, FOLFOX therapy, known as FOLFOX4 therapy, comprises: (1a) Oxaliplatin 85mg/m ² And (1 b) levofolinate 100mg/m ² Intravenous administration for 2 hours; (1c) After the administration of oxaliplatin of the (1 a) and levofolinic acid salt of the (1 b) has ended, fluorouracil 400mg/m is administered rapidly intravenously ² The method comprises the steps of carrying out a first treatment on the surface of the (1d) After the fluorouracil administration of (1 c) was completed, 600mg/m of fluorouracil was further administered ² Intravenous administration for 22 hours; then, (1 e) further concentrating the L-folinate 100mg/m ² Intravenous administration for 2 hours; (1f) After the administration of the levofolinate of (1 e) was completed, fluorouracil was added at 400mg/m ² Intravenous administration for 22 hours; and (1 g) after the fluorouracil administration of (1 f) is completed, further adding 600mg/m fluorouracil ² Intravenous administration for 22 hours is a treatment method in which a series of administrations of (1 a), (1 b), (1 c), (1 d), (1 e), (1 f) and (1 g) are carried out at 2-week intervals. The doses in this treatment method are all doses in terms of body surface area per single administration.

In addition, as another embodiment, FOLFOX therapy, referred to as mfofox 6 therapy, comprises: (1a) Oxaliplatin 85mg/m ² And (1 b) L-folinate 200mg/m ² Intravenous administration was performed for 2 hours; (1c) After the administration of oxaliplatin of the (1 a) and levofolinic acid salt of the (1 b) has ended, fluorouracil 400mg/m is administered rapidly intravenously ² The method comprises the steps of carrying out a first treatment on the surface of the And (1 d) after the completion of fluorouracil administration of (1 c), further administering 2400mg/m fluorouracil intravenously for 46 hours ² Is a therapeutic method in which the series of administrations of (1 a), (1 b), (1 c) and (1 d) are carried out at 2-week intervals. The doses in the treatment method are all in terms of body surface area per single administrationDosage of the drug.

In the present specification, FOLFOX therapy includes all methods that are used differently depending on the administration method of each agent, for example, FOLFOX4 therapy, mfofox 6 therapy, and the like.

The interval between the series of administrations of the combination therapy in which the molecular targeting agent is added to the FOLFOX therapy may be set to 2-week intervals, or may be set to 3-week intervals or more (for example, 3-week intervals or 4-week intervals) temporarily or continuously according to the degree of the side effect expression of the patient. Withdrawal, decrement, and resumption of combination therapy with bevacizumab or cetuximab added to FOLFOX therapy was performed at the discretion of the Investigator (investor) or the assistant Investigator (sumevestiator) with reference to the latest package insert.

Examples of the molecular targeting agent include an anti-EGFR antibody (e.g., cetuximab, panitumumab) and an anti-VEGF antibody (e.g., bevacizumab). The molecular targeting agent may be used alone or in combination of 1 or more than 2. In one embodiment, the molecular targeted drug is selected to accommodate the patient taking into account the presence or absence of a RAS gene (KR AS/NRAS gene) mutation. In one embodiment, an anti-EGFR antibody (e.g., cetuximab, panitumumab) is used for RAS gene wild-type colorectal cancer. In one embodiment, an anti-VEGF antibody (e.g., bevacizumab) is used for colorectal cancer of the RAS gene mutant type.

In one embodiment, the initial dose of bevacizumab is set to 5mg/kg (body weight) for patients with RAS genotype, and is instilled intravenously for 90 minutes. When tolerance is good at the first administration, the second administration may be 60 minutes. Furthermore, if the tolerability is also good in the second administration, the administration may be 30 minutes thereafter. The dosing interval may be more than 2 weeks (e.g., 2 weeks, 3 weeks, 4 weeks).

In one embodiment, the starting dose of cetuximab is set at 400mg/m for a RAS gene wild type patient ² (body surface area), intravenous drip for 2 hours. After the second time, 250mg/m is used for 1 hour at a single time per week or at intervals of 2 weeks ² Intravenous drip is performed. In addition, cetuximab may be used as the cetuximab as neededEvery 2 weeks, 500mg/m was infused intravenously over 2 hours ² And is suitably decremented according to the state of the patient.

In one embodiment, as panitumumab, a single intravenous drip of 6mg/kg (body weight) is performed for more than 60 minutes every 2 weeks for patients with wild-type RAS gene. The amount is reduced appropriately according to the state of the patient.

(4) In combination with the addition of molecular targeting agents (e.g., bevacizumab, cetuximab) in FOLFOX therapy Combination of therapies.

In one embodiment, the CD47 inhibitory substance in combination with a combination therapy in which a molecular targeting agent (e.g., bevacizumab, cetuximab) is added to FOLFOX therapy is administered at the dosage described for the use of the CD47 inhibitory substance of (1). In one embodiment, mo Luoli mab, an example of a CD 47-inhibiting substance, is administered intravenously as a primary administration for 3 hours (+ -30 minutes) at 1mg/kg, followed by a single administration of 20mg/kg or 30mg/kg at 1-week intervals or 2-week intervals. In one embodiment, 1mg/kg is administered intravenously as the primary administration of Mo Luoli mab 3 hours (+ -30 minutes) on the first day of the first cycle, followed by a single 20mg/kg or 30mg/kg administration intravenously at 1 week intervals for the first cycle, 2 hours (+ -30 minutes) intervals after the second cycle. Depending on the degree of patient side effect expression, the amount of Mo Luoli mab administered may be reduced stepwise or the administration itself may be discontinued. In addition, administration of Mo Luoli mab may be restarted if the restart criterion is met, and in the case of restart, the dose of Mo Luoli mab may be reduced and restarted at the discretion of the researcher or assistant researcher. In one embodiment, when Mo Luoli mab, a CD47 inhibiting substance, is administered at an initial dose of 30mg/kg, the level 1 decrement is followed by 20mg/kg and the level 2 decrement is followed by 15mg/kg. When Mo Luoli monoclonal antibody as a CD47 inhibiting substance was administered at an initial administration dose of 20mg/kg, the amount was reduced to 15mg/kg.

An immune checkpoint inhibitor in combination with a combination therapy in which a molecular targeting agent (e.g., bevacizumab, cetuximab) is added to FOLFOX therapy, and in one embodiment, is administered at the dose recited in (2) an immune checkpoint inhibitor. Nivolumab as an immune checkpoint inhibitor, in one embodiment, as nivolumab is administered intravenously at 240mg single and 2 week intervals, 360mg single and 3 week intervals, 480mg single and 4 week intervals. Intravenous drip administration as nivolumab at 480mg single and 4 week intervals is preferred. Further preferred is intravenous drip administration of nivolumab at 480mg single dose at 4 week intervals for about 30 minutes. The administration of nivolumab itself may also be discontinued depending on the extent of patient side effect expression. Furthermore, administration of nivolumab may be restarted if the restart criteria are met.

In the therapeutic methods of the invention, when a CD47 inhibitory substance (preferably Mo Luoli mab) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably nivolumab)) are administered in combination (e.g., administered on the same day or starting on the same day) with a combination therapy in which a molecular targeting agent (preferably bevacizumab or cetuximab) is added to the FOLFOX therapy, in one embodiment, the CD47 inhibitory substance and immune checkpoint inhibitor are administered first. In one embodiment, a combination therapy with bevacizumab or cetuximab added to FOLFOX therapy is performed after administration of the CD47 inhibitory substance and the immune checkpoint inhibitor.

(5) FFX therapy or a reduction regimen thereof (another example of standard therapy)

The term "FFX therapy" in the present invention refers to a method of treating cancer using 4 agents, namely oxaliplatin, irinotecan hydrochloride hydrate (hereinafter abbreviated as "irinotecan"), calcium levofolinate (hereinafter abbreviated as "levofolinate"), and fluorouracil, in combination, and includes, as recommended doses, for example: (2a) Oxaliplatin 85mg/m for 2 hours intravenous administration ² Then, (2 b) 200mg/m levofolinate was administered intravenously over 2 hours ² The method comprises the steps of carrying out a first treatment on the surface of the (2c) After 30 minutes from the start of administration of the levofolinic acid salt of (2 b), 180mg/m of irinotecan was intravenously administered over 1.5 hours ² ；(2d) After the completion of the administration of levofolinate of the formula (2 b), fluorouracil was further rapidly administered intravenously at 400mg/m ² The method comprises the steps of carrying out a first treatment on the surface of the And (2 e) after the completion of fluorouracil administration of (2 d), further administering 2400mg/m fluorouracil intravenously for 46 hours ² Is a therapeutic method in which the series of administrations of (2 a), (2 b), (2 c), (2 d) and (2 e) are carried out at 2-week intervals. The doses in this treatment method are all doses in terms of body surface area per single administration.

The "dose reduction schedule" of the FFX therapy means a schedule in which the dose of any one of the 4 agents administered in the FFX therapy is reduced from the initial dose or the administration itself is stopped, or is reduced in any one of the subsequent doses after the second cycle or the administration of any one of the 4 agents is stopped depending on the degree of side effect expression confirmed by any one of the doses after the first cycle. As a mode thereof, for example, rapid intravenous administration of fluorouracil of (2 d) may not be carried out from the initial administration, and the dose of oxaliplatin of (2 a) may be 50mg/m ² 、65mg/m ² Or 50-85 mg/m ² The dose of irinotecan of (2 c) can be 90mg/m ² 、120mg/m ² 、150mg/m ² Or 90-180 mg/m ² Any of the doses, and the dose of fluorouracil to be administered continuously intravenously in (2 e) may be 1200mg/m ² 、1800mg/m ² Or 1200-2400mg/m ² Any dosage in between.

In addition, as another mode of the reduction regimen, in any of the administrations after the second cycle in the FFX therapy, the rapid intravenous administration of fluorouracil of the (2 d) may be stopped depending on the degree of side effect expression of the patient, and the administration amount of oxaliplatin of the (2 a) may be reduced to 50mg/m depending on the degree of side effect expression of the patient ² 、65mg/m ² Or 50-85 mg/m ² Any amount of the drug administered or the drug administration of oxaliplatin is stopped, and the dose of irinotecan of (2 c) can be reduced to 90mg/m according to the degree of the expression of the side effect of the patient ² 、120mg/m ² 、150mg/m ² Or 90-180 mg/m ² Any amount of the intermediate or the termination of the administration of irinotecan, the amount of fluorouracil of (2 e) to be administered can be reduced to 1200mg/m depending on the degree of expression of side effects in the patient ² 、1800mg/m ² Or 1200-2400mg/m ² Any amount of the above or discontinuation of the administration of fluorouracil.

Furthermore, as another mode of this decrement regimen recognized as modified FOLFIRINOX therapy (mFFX therapy), as recommended usage doses, for example, there are included: (2a) Oxaliplatin 85mg/m for 2 hours intravenous administration ² Thereafter, (2 b) 200mg/m levofolinate was administered intravenously over 2 hours ² (2 c) 150mg/m irinotecan intravenously administered 1.5 hours after 30 minutes from the start of administration of levofolinate of (2 b) ² And (2 e) after the completion of the administration of the levofolinate of (2 b), further administering 2400mg/m fluorouracil intravenously for 46 hours ² Is a therapeutic method in which the series of administrations of (2 a), (2 b), (2 c) and (2 e) are carried out at 2-week intervals. The doses in this treatment method are all doses in terms of body surface area per single administration.

As a further reduction regimen of the mFFX therapy, for example, the oxaliplatin of (2 a) may be administered in an amount of 50mg/m from the initial administration ² 、65mg/m ² Or 50-85 mg/m ² The dose of irinotecan of (2 c) can be 120mg/m ² 、140mg/m ² Or 120-140 mg/m ² Any of the doses, and the dose of fluorouracil to be administered continuously intravenously in (2 e) may be 1200mg/m ² 、1800mg/m ² 、2400mg/m ² Or 1200-2400 mg/m ² Any dosage in between.

In addition, in any of the administrations after the second cycle of the mFFX therapy, the amount of oxaliplatin administered in (2 a) can be reduced to 50mg/m depending on the degree of side effect expression in the patient ² 、65mg/m ² Or 50-85 mg/m ² Any amount of the drug administered in between or the administration of oxaliplatin is stopped, and the amount of irinotecan to be administered in (2 c) can be reduced to 90mg/m depending on the degree of the expression of side effects in the patient ² 、120mg/m ² Or 90-150 mg/m ² Any amount of the intermediate administration or the discontinuation of the administration of irinotecan, the amount of fluorouracil to be continuously administered intravenously of (2 e) can be reduced to 1200mg/m depending on the degree of the expression of side effects in the patient ² 、1800mg/m ² Or 1200-2400 mg/m ² Any amount of the above or discontinuation of the administration of fluorouracil.

Furthermore, the interval of the series of administrations of the FFX therapy or the decrement regimen thereof (e.g., mFFX therapy) may be set to a 3-week interval or a 4-week interval temporarily or continuously, depending on the degree of side effect expression of the patient. The cessation, decrement, and resumption of FFX therapy or its decrement regimen (e.g., mFFX therapy) is performed at the discretion of the researcher or assistant researcher with reference to the latest package insert.

(6) Combination with FFX therapy or a reduction regimen thereof

In one embodiment, the CD47 inhibitory substance in combination with FFX therapy or a weight loss regimen thereof (e.g., mFFX therapy) is administered at the dosage of the use described in (1) CD47 inhibitory substance. In one embodiment, mo Luoli mab, an example of a CD 47-inhibiting substance, is administered intravenously for 3 hours (+ -30 minutes) as a primary administration, and then administered intravenously at 1-week intervals or 2-week intervals as a single 20mg/kg or 30mg/kg. In one embodiment, 1mg/kg is administered intravenously as the primary administration of Mo Luoli mab 3 hours (+ -30 minutes) on the first day of the first cycle, followed by a single 20mg/kg or 30mg/kg administration intravenously at 1 week intervals for the first cycle, 2 hours (+ -30 minutes) intervals after the second cycle. Depending on the degree of patient side effect expression, the amount of Mo Luoli mab administered may be reduced stepwise or the administration itself may be discontinued. In addition, administration of Mo Luoli mab may be restarted if the restart criterion is met, and in the case of restart, the dose of Mo Luoli mab may be reduced and restarted at the discretion of the researcher or assistant researcher. In one embodiment, when Mo Luoli mab, a CD47 inhibiting substance, is administered at an initial dose of 30mg/kg, the level 1 decrement is followed by 20mg/kg and the level 2 decrement is followed by 15mg/kg. When Mo Luoli monoclonal antibody as a CD47 inhibiting substance was administered at an initial administration dose of 20mg/kg, the amount was reduced to 15mg/kg.

The immune checkpoint inhibitor in combination with FFX therapy or a reduction regimen thereof, in one embodiment, is administered in a dose recited in (2) the immune checkpoint inhibiting substance. Nivolumab as an immune checkpoint inhibitor, in one embodiment, as nivolumab is administered intravenously at 240mg single and 2 week intervals, 360mg single and 3 week intervals, 480mg single and 4 week intervals. Intravenous drip administration as nivolumab at 480mg single and 4 week intervals is preferred. Further preferred is intravenous drip administration of nivolumab at 480mg single dose at 4 week intervals for about 30 minutes. The administration of nivolumab itself may also be discontinued depending on the extent of patient side effect expression. Furthermore, administration of nivolumab may be restarted if the restart criteria are met.

In the methods of treatment of the invention, when a CD47 inhibitory substance (preferably Mo Luoli mab) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably nivolumab)) are administered in combination (e.g., administered the same day or starting the same day) with FFX therapy or a reduction regimen thereof (e.g., mFFX therapy), in one embodiment, the CD47 inhibitory substance and the immune checkpoint inhibitor are administered first. In one embodiment, FFX therapy or a reduction regimen thereof (e.g., mFFX therapy) is performed after administration of the CD47 inhibitory substance and the immune checkpoint inhibitor.

[ applicable to diseases and patients ]

A suitable disease for the treatment method of the present invention is cancer.

More specifically, examples of the cancer include: leukemia (e.g., acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia), malignant lymphoma (hodgkin's lymphoma, non-hodgkin's lymphoma (e.g., adult T-cell leukemia, follicular lymphoma, diffuse large cell type B-cell lymphoma)), multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal adenocarcinoma, gastric cancer, esophageal gastric-gastric junction cancer, duodenal cancer, large intestine cancer (e.g., colon cancer or rectal cancer), liver cancer (e.g., hepatocellular carcinoma), gall bladder-bile duct cancer, biliary tract cancer, pancreatic cancer (e.g., pancreatic ductal carcinoma, insulinoma, intraductal papillary mucinous tumor of the pancreas with distant metastasis), thyroid cancer, lung cancer (e.g., non-small cell lung cancer (e.g., squamous non-small cell lung cancer, non-squamous non-small cell lung cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer), cervical cancer, uterine body cancer, endometrial cancer, vaginal cancer, vulval cancer, renal cancer (e.g., renal cell carcinoma), renal pelvis ureter cancer, urothelial cancer (e.g., bladder cancer, epithelial carcinoma), penile cancer, prostate cancer, testicular tumor (e.g., embryonic cell tumor), bone and soft tissue sarcoma, malignant bone tumor, skin cancer (e.g., uveal malignant melanoma, mercker cell carcinoma), thymoma, mesothelioma, malignant pleural mesothelioma, glioblastoma, blood cancer, primary unknown cancer, and the like.

As one mode of the disease treated by the treatment method of the present invention, solid cancer is given. Examples of solid cancers include: head and neck cancer, esophageal adenocarcinoma, gastric cancer, esophageal gastric junction cancer, duodenal cancer, colorectal cancer (e.g., colon cancer or rectal cancer), liver cancer (e.g., hepatocellular carcinoma), gall bladder-bile duct cancer, biliary tract cancer, pancreatic cancer (e.g., pancreatic ductal carcinoma, insulinoma, pancreatic ductal papillary tumor, 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 non-small cell lung cancer, non-squamous non-small cell lung cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer), cervical cancer, uterine body cancer, endometrial cancer, vaginal cancer, vulval cancer, renal cancer (e.g., renal cell carcinoma), renal pelvis-ureter cancer, urothelial cancer (e.g., bladder cancer, urothelial cancer), penile cancer, prostate cancer, testicular tumor (e.g., embryonic cell tumor), bone-soft tissue sarcoma, malignant bone tumor, skin cancer (e.g., uveal malignant melanoma, merck cell carcinoma), breast cancer, mesothelioma, malignant mesothelioma, and primary carcinoma.

The disease to which the treatment method of the present invention is applied is preferably colorectal cancer or pancreatic cancer, more preferably colorectal cancer that cannot radically cure progress or recurrence of resection, or pancreatic cancer that has distant metastasis. Further preferred are colon or rectal cancers that fail to radical cure the progression or recurrence of the resection, or pancreatic ductal cancers with distant metastasis.

In the present specification, "treatment" of cancer includes, for example, treatment performed for the purpose of: (i) reducing proliferation of tumor cells, (ii) reducing symptoms caused by cancer, (iii) improving the quality of life of a cancer patient, (iv) reducing the dose of other anti-cancer drugs or cancer treatment aids that have been administered, and/or (v) prolonging survival of a cancer patient, "inhibition of progression" of cancer refers to delaying progression of cancer, stabilizing symptoms associated with cancer, and reversing progression of symptoms. In addition, "recurrence inhibition" of cancer refers to the prophylactic inhibition of recurrence of cancer in a patient whose lesions have been completely or substantially eliminated or removed by cancer treatment or resection surgery.

The methods of treatment of the present invention are sometimes directed to the following cancer patients: (a) Patients with insufficient or insufficient therapeutic effects of anticancer drugs or patients with worsening after treatment with anticancer drugs; (b) Cancer patients who are not radical or resected, metastatic, recurrent, refractory and/or distant metastatic; (c) TPS (Tumor Proportion Score, tumor cell positive proportion score) is 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more of cancer patients; (d) CPS (Combined Positive Score ) of 20% or more, 10% or more, 5% or more, or 1% or more of cancer patients; (e) Cancer patients with dMMR (deficient mismatch repair, mismatch repair deficiency) and/or MSI-H (Microsatellite instability-High, microsatellite highly unstable); or (f) TMB (Tumor Mutational Burden ) is a high frequency cancer patient. In addition, in another aspect, the methods of treatment of the present invention are sometimes further directed to cancer patients: (g) treating the subject undergoing treatment with no anti-cancer drug; (h) Less than 50%, less than 25%, less than 10%, less than 5% or less than 1% of cancer patients with TPS; (i) CPS is less than 20%, less than 10%, less than 5% or less than 1% of cancer patients; (j) Cancer patients without dMMR and/or MSI-H or with MSI-L (Microsatellite instability-Low); or (k) TMB is a low frequency cancer patient. In particular, as a cancer patient for whom the treatment method of the present invention is required, there is a cancer patient who has undergone no treatment by an anticancer drug and/or who cannot radically cure progress or recurrence of resection, particularly a patient with colorectal cancer or pancreatic cancer. In one embodiment, there may be mentioned a patient who has not undergone a treatment for colorectal cancer or a patient who has not undergone a treatment for pancreatic cancer. Patients who have not undergone treatment with a systemic malignant tumor agent against colorectal cancer or patients who have not undergone treatment with a systemic malignant tumor agent against pancreatic cancer can be preferably cited. Further preferred examples include patients who have not undergone treatment with a systemic anti-malignant agent for colorectal cancer that cannot radically cure progress or recurrence of resection, or patients who have not undergone treatment with a systemic anti-malignant agent for pancreatic cancer that has distant metastasis.

As one embodiment, the treatment method of the present invention is used as a primary treatment (primary treatment) for a patient who has not undergone treatment with a systemic anti-malignant agent for colorectal cancer that cannot radically cure the progress of resection or recurrence.

As one mode, the treatment method of the present invention is used as a primary treatment for a patient who has not undergone treatment with a systemic anti-malignant agent for pancreatic cancer with distant metastasis.

As one embodiment, the therapeutic method of the present invention can be applied to the treatment of metastatic cancer and the inhibition of cancer metastasis.

As one mode, the treatment methods of the present invention inhibit recurrence.

As one aspect, in the present invention, treatment refers to the generation of at least one of the following: reduction in tumor size, inhibition of tumor growth (delay or stop), inhibition of tumor metastasis (delay or stop), inhibition of recurrence (prevention or delay), and alleviation of one or more symptoms associated with cancer.

In one embodiment, the therapeutic method of the present invention may be used in combination with other drugs (for example, known anticancer drugs or antiemetics) for (1) supplementation and/or enhancement of therapeutic effects, (2) improvement of dynamic absorption, reduction of administration amount, and/or (3) reduction of side effects.

In the present specification, "about" means that the displayed value can be changed by falling or rising within a range of 10%.

The present invention provides, for example, the following embodiments.

[1] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for solid cancer, comprising a CD47 inhibitory substance as an active ingredient, wherein the progression inhibitor, the recurrence inhibitor and/or the therapeutic agent for solid cancer are administered in combination with standard therapy and an immune checkpoint inhibitory substance.

[3] The agent according to [1] or [2], wherein the standard therapy is a combination therapy in which a molecular targeting agent (preferably a VEGF inhibitor (preferably bevacizumab) or an EGFR inhibitor (preferably cetuximab or panitumumab)) is added to FOLFOX therapy.

[4] The agent according to any one of [1] to [3], wherein the standard therapy is a combination therapy in which bevacizumab or cetuximab is added to folfox therapy.

[5] The agent according to any one of [1] to [4], wherein the solid cancer is colorectal cancer.

[6] The agent according to the above [5], wherein the colorectal cancer is colon cancer or rectal cancer.

[7] The agent according to the item [6], wherein the colon or rectal cancer is a colon or rectal cancer that cannot radically cure progress or recurrence of excision.

[8] The agent according to any one of [1] to [7], which is administered as a primary treatment to a patient who has not undergone treatment with a systemic anti-malignant agent for colon cancer or rectal cancer that cannot radically cure progress of resection or recurrence.

[9] The agent according to any one of [1] to [8], wherein the CD 47-inhibitory substance is an anti-CD 47 antibody.

[10] The agent according to [9], wherein the anti-CD 47 antibody is Mo Luoli mab.

[11] The agent according to [10], wherein as the monoclonal antibody Mo Luoli, 1mg/kg (body weight) is administered intravenously at the time of the initial administration, and 15mg/kg (body weight) to 30mg/kg (body weight) are administered intravenously at 1-week intervals or 2-week intervals after the second administration.

[12] The agent according to [10] or [11], wherein 1mg/kg (body weight) is administered intravenously at the time of the first administration as Mo Luoli mab, 20mg/kg (body weight) is administered intravenously at 1-week intervals or 2-week intervals after the second administration (preferably 1mg/kg (body weight) is administered intravenously at the time of the first administration as Mo Luoli mab, 20mg/kg (body weight) is administered at 1-week intervals in the first cycle after the second administration, and 2-week intervals after the second cycle).

[13] The agent according to [10] or [11], wherein 1mg/kg (body weight) is administered intravenously at the time of the first administration as Mo Luoli mab, 30mg/kg (body weight) is administered intravenously at 1-week intervals or 2-week intervals after the second administration (preferably 1mg/kg (body weight) is administered intravenously at the time of the first administration as Mo Luoli mab, 30mg/kg (body weight) is administered at 1-week intervals in the first cycle after the second administration, and 2-week intervals after the second cycle).

[14] The agent according to any one of [1] to [13], wherein the immune checkpoint inhibitory substance 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 inhibitory substance is an anti-PD-1 antibody.

[16] The agent of [14] or [15], wherein the anti-PD-1 antibody is nivolumab, cimetidine Li Shan antibody, pamglizumab, swadazumab, tirelizumab, AMP-514, doralimab, terprin Li Shan antibody, karilizumab, jernab, singdi Li Shan antibody, STI-a1110, ENUM 388D4, ENUM 244C8, GLS010, refs Li Shan antibody, batirimab, CS1003, s Lu Lishan antibody, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, sym021, jerlow Li Shan antibody, SSI-361, JY034, HX008, ISU106, bragg Li Shan antibody, palol Li Shan antibody, sal Li Shan antibody, CX-188, sirolimumab, or sirolimumab.

[17] The agent according to [14], wherein the immune checkpoint inhibitory substance is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Abelimumab, abamectin, dewaruzumab, BMS-936559, STI-1014, enfra Li Shan, lovalimab, HLX20, SHR-1316, CS1001, MS B2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ 053, CBT-502, JS003 or CX-072.

[18] The agent according to [14], wherein the immune checkpoint inhibitory substance 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 a Pabo Li Zhushan antibody.

[21] The agent according to [15], wherein the anti-PD-1 antibody is a cimrpress Li Shan antibody.

[22] The agent according to [17], wherein the anti-PD-L1 antibody is avilamab.

[23] The agent according to [17], wherein the anti-PD-L1 antibody is an Ab Li Zhushan antibody.

[24] The agent according to [17], wherein the anti-PD-L1 antibody is Dewaruzumab.

[25] The agent according to [18], wherein the anti-CTLA-4 antibody is ipilimumab.

[26] The agent according to the above [19], wherein as nivolumab, administration is performed at a single 3mg/kg (body weight) or a single 240mg and 2-week interval, a single 360mg and 3-week interval or a single 480mg and 4-week interval (preferably, a single 240mg and 2-week interval, a single 360mg and 3-week interval or a single 480mg and 4-week interval).

[27] The agent according to [19], wherein intravenous administration is performed as nivolumab at 480mg at a single time and at 4-week intervals.

[28] The agent according to [19], wherein as nivolumab, intravenous administration is performed at 480mg at a single time and at 4-week intervals for about 30 minutes.

[29] The agent according to [20], wherein as palbociclib, administration is performed at a single dose of 2mg/kg (body weight) or a single dose of 200mg at intervals of 3 weeks or at intervals of 400mg at intervals of 6 weeks.

[30] The agent according to [21], wherein the administration is carried out as a single 350mg and 3-week interval of the cimetidine Li Shan antibody.

[31] The agent according to [22], wherein the drug is administered as the avermectin at a single dose of 10mg/kg (body weight) at 2-week intervals.

[32] The agent according to [23], wherein as the atilizumab, administration is performed at an interval of 3 weeks at 1200mg in a single dose.

[33] The agent according to [24], wherein as Dewaruzumab, administration is performed at a single 10mg/kg (body weight) and 2-week intervals or intravenous administration is performed at a single 1500mg and 4-week intervals for 4 times.

[34] The agent according to [25], wherein as ipilimumab, intravenous administration is performed 4 times at a single 3mg/kg (body weight) or a single 1mg/kg (body weight) and 3-week intervals, or administration is performed at a single 1mg/kg (body weight) and 6-week intervals.

[35] The agent according to any one of [4] to [34], wherein the combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy is a therapy in which (1A-1) bevacizumab or (1A-2) cetuximab, (1B) oxaliplatin, (1C) levocalcium folinate and (1D) fluorouracil are administered in combination.

[36] The agent according to any one of [4] to [35], wherein the combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy is a therapy in which (1A-1) bevacizumab, (1B) oxaliplatin, (1C) calcium levofolinate and (1D) fluorouracil are administered in combination.

[37] The agent according to any one of [4] to [35], wherein the combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy is a therapy in which (1A-2) cetuximab, (1B) oxaliplatin, (1C) calcium levofolinate and (1D) fluorouracil are administered in combination.

[38] The agent according to any one of [4] to [35], wherein the combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy comprises:

(1 x) intravenous administration of bevacizumab 5mg/kg (body weight), or first intravenous administration of cetuximab 400mg/m ² (body surface area) for intravenous administration of 250mg/m after the second time ² (body surface area);

(1a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area);

(1b) Intravenous administration of L-calcium folinate 200mg/m ² (body surface area);

(1c) Rapid intravenous administration of fluorouracil 400mg/m ² (body surface area); and

(1d) After the fluorouracil administration of (1 c) is completed, 2400mg/m of fluorouracil is further continuously administered intravenously ² (body surface area).

[39] The agent according to any one of [4] to [36] and [38], wherein the combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy comprises:

(1 x) intravenous administration of bevacizumab 5mg/kg (body weight);

(1a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area);

(1c) Rapid intravenous administration of fluorouracil400mg/m ² (body surface area); and

[40] The agent according to any one of [4] to [35], [37] and [38], wherein the combination therapy with bevacizumab or cetuximab added to the FOLF OX therapy comprises:

(1 x) first intravenous administration of cetuximab 400mg/m ² (body surface area) for intravenous administration of 250mg/m after the second time ² (body surface area);

(1a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area);

[41] The agent according to any one of [4] to [35] and [38], wherein the combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy comprises:

(1 x) 5mg/kg (body weight) of bevacizumab intravenously administered over 90 minutes, or 400mg/m of cetuximab intravenously administered for 2 hours for the first time ² (body surface area) for 1 hour and then intravenous administration of 250mg/m ² (body surface area);

(1a) Oxaliplatin 85mg/m for 2 hours intravenous administration ² (body surface area);

(1b) At the same time as the administration of oxaliplatin of (1 a), 200mg/m of levo-calcium folinate was administered intravenously for 2 hours ² (body surface area);

(1c) After the completion of the administration of the calcium levofolinate of the item (1 b), further rapid intravenous administration of fluorouracil 400mg/m ² (body surface area); and

(1d) Fluorouracil in (1 c)After the end of the administration, 2400mg/m fluorouracil is continuously further administered intravenously ² (body surface area),

the series of administrations of (1 x), (1 a), (1 b), (1 c) and (1 d) were performed at 2 week intervals in a combination therapy with bevacizumab or cetuximab added to FOLFOX therapy.

[42] The agent according to any one of [4] to [36], [38], [39] and [41], wherein the combination therapy in which bevacizumab or cetuximab is added to FOLFOX therapy comprises:

(1 x) intravenous administration of bevacizumab 5mg/kg (body weight) over 90 minutes;

(1d) After the completion of the administration of fluorouracil of (1 c), 2400mg/m of fluorouracil was further administered intravenously for 46 hours ² (body surface area),

[43] The agent according to any one of [4] to [35], [37], [38], [40] and [41], wherein the combination therapy with bevacizumab or cetuximab added to FOLFOX therapy comprises:

(1 x) first 2 hours intravenous administration of cetuximab 400mg/m ² (body surface area) for 1 hour and then intravenous administration of 250mg/m ² (body surface area);

(1b) Simultaneously with the administration of oxaliplatin of (1 a), levorotatory subleaf is administered intravenously for 2 hours200mg/m calcium carbonate ² (body surface area);

[44] The agent according to any one of [4] to [43], which is a therapy in which administration of bevacizumab or cetuximab, an immune checkpoint inhibitor and a CD47 inhibitor is started on the same day in a FOLF OX therapy.

[45] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for cancer, which comprises a CD47 inhibitory substance as an active ingredient, wherein the progression inhibitor, the recurrence inhibitor and/or the therapeutic agent for cancer are administered in combination with an immune checkpoint inhibitory substance and a combination therapy comprising bevacizumab or cetuximab added to FOLFOX therapy,

(i) The CD47 inhibiting substance is Mo Luoli mAb, as Mo Luoli mAb, 1mg/kg (body weight) is administered intravenously at the time of the first administration, 15mg/kg (body weight) to 30mg/kg (body weight) are administered intravenously at 1-week intervals or 2-week intervals after the second administration,

(ii) The immune checkpoint inhibitory substance is nivolumab administered as nivolumab at 240mg single and 2 week intervals, 360mg single and 3 week intervals, or 480mg single and 4 week intervals (preferably 480mg single and 4 week intervals),

(iii) The combination therapy with bevacizumab or cetuximab added to FOLFOX therapy comprises:

(1 x) (preferably 90 minutes) intravenous administration of bevacizumab 5mg/kg (body weight), or first (preferably 2 hours) intravenous administration of cetuximab 400mg/m ² (body surface area) after the second time (preferably 1 hour) Intravenous administration of 250mg/m ² (body surface area);

(1a) Oxaliplatin 85mg/m for intravenous administration (preferably 2 hours) ² (body surface area);

(1b) Concurrently with the administration of oxaliplatin of (1 a), 200mg/m of calcium levofolinate is administered intravenously (preferably over 2 hours) ² (body surface area);

(1d) After the completion of the administration of fluorouracil of (1 c), 2400mg/m of fluorouracil is further continuously administered intravenously (preferably for 46 hours) ² (body surface area),

[46] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for cancer, which comprises a CD47 inhibitory substance as an active ingredient, wherein the progression inhibitor, the recurrence inhibitor and/or the therapeutic agent for cancer are administered in combination with an immune checkpoint inhibitory substance and a combination therapy comprising bevacizumab or cetuximab added to FOLFOX therapy,

(1 x) (preferably 90 minutes) of bevacizumab administered intravenously at 5mg/kg (body weight);

(1a) Intravenous administration of oxali (preferably 2 hours)Platinum 85mg/m ² (body surface area);

[47] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for cancer, which comprises a CD47 inhibitory substance as an active ingredient, wherein the progression inhibitor, the recurrence inhibitor and/or the therapeutic agent for cancer are administered in combination with an immune checkpoint inhibitory substance and a combination therapy comprising bevacizumab or cetuximab added to FOLFOX therapy,

(1 x) first (preferably 2 hours) intravenous administration of cetuximab 400mg/m ² (body surface area) after the second (preferably 1 hour) intravenous administration of 250mg/m ² (body surface area);

(1a) Oxaliplatin 85mg/m for 2 hours intravenous administration ² (body surface)Area);

[48] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for cancer, which comprises an immune checkpoint inhibitor as an active ingredient, wherein the progression inhibitor, recurrence inhibitor and/or therapeutic agent for cancer is administered in combination with a combination therapy comprising Folfox therapy with bevacizumab or cetuximab and a C D inhibitor,

(1 x) (preferably 90 minutes) intravenous administration of bevacizumab 5mg/kg (body weight), or first (preferably 2 hours) intravenous administration of cetuximab 400mg/m ² (body surface area) after the second (preferably 1 hour) intravenous administration of 250mg/m ² (body surface area);

(1a) Intravenous for 2 hoursAdministration of oxaliplatin 85mg/m ² (body surface area);

[49] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for cancer, which comprises an immune checkpoint inhibitor as an active ingredient, wherein the progression inhibitor, recurrence inhibitor and/or therapeutic agent for cancer is administered in combination with a combination therapy comprising Folfox therapy with bevacizumab or cetuximab and a C D inhibitor,

(1b) The same administration of oxaliplatin as in (1 a) When (preferably 2 hours) 200mg/m of levofolinic acid calcium is administered intravenously ² (body surface area);

[50] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for cancer, which comprises an immune checkpoint inhibitor as an active ingredient, wherein the progression inhibitor, recurrence inhibitor and/or therapeutic agent for cancer is administered in combination with a combination therapy comprising Folfox therapy with bevacizumab or cetuximab and a C D inhibitor,

(1b) At the same time as the administration of oxaliplatin of (1 a), (preferably with 2Hour) intravenous administration of calcium levofolinate 200mg/m ² (body surface area);

[51] The agent according to any one of [36], [39], [42], [46] and [49], wherein the cancer is a RAS gene mutant cancer.

[52] The agent according to any one of [37], [40], [43], [47] and [50], wherein the cancer is a cancer of the RAS gene wild type.

[53] The agent according to any one of [45] to [52], wherein the cancer is colon cancer or rectal cancer that cannot radically cure progress or recurrence of excision.

[54] The agent of [53], which is administered as a primary treatment to a patient who has not undergone treatment with a systemic anti-malignant agent for colon or rectal cancer that cannot radically cure the progress of resection or recurrence.

[55] The agent according to any one of [45] to [54], which is a therapy in which bevacizumab or cetuximab is added to FOL FOX therapy at the same day, and administration of Mo Luoli mab and nivolumab is started.

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

[57] The agent according to any one of [1], [2] and [56], wherein the solid cancer is pancreatic cancer.

[58] The agent according to [57], wherein the pancreatic cancer is a pancreatic cancer having distant metastasis.

[59] The agent according to any one of [1], [2], [56], [57] and [58], which is administered as a primary treatment to a patient who has not undergone treatment with a systemic anti-malignant agent for pancreatic cancer with distant metastasis.

[60] The agent according to any one of [1], [2] and [56] to [59], wherein the CD 47-inhibiting substance is an anti-CD 47 antibody.

[61] The agent according to [60], wherein the anti-CD 47 antibody is Mo Luoli mab.

[62] The agent according to [61], wherein as the monoclonal antibody Mo Luoli, 1mg/kg (body weight) is administered intravenously at the time of the initial administration, and 15mg/kg (body weight) to 30mg/kg (body weight) is administered intravenously at 1-week intervals or 2-week intervals after the second administration.

[63] The agent according to [61] or [62], wherein 1mg/kg (body weight) is administered intravenously at the time of the first administration as Mo Luoli mab, 20mg/kg (body weight) is administered intravenously at 1-week intervals or 2-week intervals after the second administration (preferably 1mg/kg (body weight) is administered intravenously at the time of the first administration as Mo Luoli mab, 20mg/kg (body weight) is administered at 1-week intervals in the first cycle after the second administration, and 2-week intervals after the second cycle).

[64] The agent according to [61] or [62], wherein 1mg/kg (body weight) is administered intravenously at the time of the first administration as Mo Luoli mab, 30mg/kg (body weight) is administered intravenously at 1-week intervals or 2-week intervals after the second administration (preferably 1mg/kg (body weight) is administered intravenously at the time of the first administration as Mo Luoli mab, 30mg/kg (body weight) is administered at 1-week intervals in the first cycle after the second administration, and 2-week intervals after the second cycle).

[65] The agent according to any one of [1], [2] and [56] to [64], wherein the immune checkpoint inhibitory substance 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 inhibitory substance is an anti-PD-1 antibody.

[67] The agent of [65] or [66], wherein the anti-PD-1 antibody is nivolumab, cimetidine Li Shan antibody, pamglizumab, swadazumab, tirelizumab, AMP-514, doralimab, terprin Li Shan antibody, garelizumab, jenomab, singdi Li Shan antibody, STI-a1110, ENUM 388D4, ENUM 244C8, GLS010, refs Li Shan antibody, batirimab, CS1003, s Lu Lishan antibody, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, sym021, jerlow Li Shan antibody, SSI-361, JY034, HX008, ISU106, bragg Li Shan antibody, palol Li Shan antibody, sal Li Shan antibody, CX-188, sirolimumab, or sirolimumab.

[68] The agent according to [67], wherein the immune checkpoint inhibitory substance is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Abelimumab, abamectin, dewaruzumab, BMS-936559, STI-1014, enfra Li Shan, lovalimab, HLX20, SHR-1316, CS1001, MS B2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ 053, CBT-502, JS003 or CX-072.

[69] The agent according to [65], wherein the immune checkpoint inhibitory substance 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 a Pabo Li Zhushan antibody.

[72] The agent according to [66], wherein the anti-PD-1 antibody is a cimrpress Li Shan antibody.

[73] The agent according to [68], wherein the anti-PD-L1 antibody is avilamab.

[74] The agent according to [68], wherein the anti-PD-L1 antibody is an Ab Li Zhushan antibody.

[75] The agent according to [68], wherein the anti-PD-L1 antibody is Dewaruzumab.

[76] The agent according to [69], wherein the anti-CTLA-4 antibody is ipilimumab.

[77] The agent according to [70], wherein as nivolumab, administration is performed at a single 3mg/kg (body weight) or a single 240mg and 2-week interval, a single 360mg and 3-week interval or a single 480mg and 4-week interval (preferably, a single 240mg and 2-week interval, a single 360mg and 3-week interval or a single 480mg and 4-week interval).

[78] The agent according to [70], wherein intravenous administration is performed as nivolumab at 480mg at a single time and at 4-week intervals.

[79] The agent according to [70], wherein as nivolumab, intravenous administration is performed at 480mg at a single time and at 4-week intervals for about 30 minutes.

[80] The agent according to [71], wherein as palbociclib, administration is performed at a single dose of 2mg/kg (body weight) or a single dose of 200mg at intervals of 3 weeks or at intervals of 400mg at intervals of 6 weeks.

[81] The agent according to [72], wherein the administration is carried out as a single 350mg and 3-week interval of the cimetidine Li Shan antibody.

[82] The agent according to [73], wherein the drug is administered as the avermectin at a single dose of 10mg/kg (body weight) at 2-week intervals.

[83] The agent according to [74], wherein as the atilizumab, administration is performed at an interval of 3 weeks at 1200mg in a single dose.

[84] The agent according to [75], wherein as Dewaruzumab, administration is performed at a single 10mg/kg (body weight) and 2-week intervals or intravenous administration is performed at a single 1500mg and 4-week intervals for 4 times.

[85] The agent according to [76], wherein as ipilimumab, administration is performed intravenously at 3mg/kg (body weight) once or 1mg/kg (body weight) once and 3-week intervals, or at 1mg/kg (body weight) once and 6-week intervals.

[86] The agent according to any one of [56] to [85], wherein FOLFIRINOX therapy or a reduction regimen thereof is a therapy in which (2A) oxaliplatin, (2B) calcium levofolinate, (2C) irinotecan hydrochloride hydrate and (2D) fluorouracil are administered in combination.

[87] The agent according to any one of [56] to [86], wherein FOLFIRINOX therapy comprises:

(2a) Oxaliplatin 50-85 mg/m for intravenous administration ² (body surface area) (preferably 50mg/m ² (body surface area), 65mg/m ² (body surface area), 85mg/m ² (body surface area), more preferably 85mg/m ² (body surface area)),

(2b) Intravenous administration of L-calcium folinate 200mg/m ² (body surface area),

(2c) Intravenous irinotecan hydrochloride hydrate 90-180 mg/m ² (body surface area) (preferably 90mg/m ² (body surface area), 120mg/m ² (body surface area), 150mg/m ² (body surface area), 180mg/m ² (body surface area), more preferably 180mg/m ² (body surface area)),

(2d) Rapid intravenous administration of fluorouracil 400mg/m ² (body surface area); and

(2e) After the fluorouracil administration of (2 d) is completed, further continuously administering 1200-2400 mg/m fluorouracil intravenously ² (body surface area) (preferably 1200mg/m ² (body surface area), 1800mg/m ² (body surface area), 2400mg/m ² (body surface area), more preferably 2400mg/m ² (body surface area)).

[88] The agent of any one of [56] to [86], wherein the decrement regimen of FOLFIRINOX therapy comprises:

(2c) Intravenous irinotecan hydrochloride hydrate 120-150 mg/m ² (body surface area) (preferably 150mg/m ² (body surface area)); and

(2e) Intravenous sustained administration fluorouracil 1200-2400 mg/m ² (body surface area) (preferably 1200mg/m ² (body surface area), 1800mg/m ² (body surface area), 2400mg/m ² (body surface area), more preferably 2400mg/m ² (body surface area)).

[89] The agent according to any one of [56] to [88], wherein FOLFIRINOX therapy or a reduction regimen thereof is a therapy in which a series of administrations is carried out at 2 to 4-week intervals (preferably 2-week intervals, 3-week intervals or 4-week intervals, more preferably 2-week intervals).

[90] The agent according to any one of [56] to [87] and [89], wherein,

FOLFIRINOX therapy comprises:

(2a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area),

(2c) Intravenous administration of irinotecan hydrochloride hydrate 180mg/m ² (body surface area),

(2e) After the fluorouracil administration of (2 d) is completed, 2400mg/m of fluorouracil is further continuously administered intravenously ² (body surface area),

the FOLFIRINOX therapy was administered as a series of administrations of the (2 a), (2 b), (2 c), (2 d) and (2 e) at 2 week intervals.

[91] The agent according to any one of [56] to [86], [88] and [89], wherein,

the decrement regimen of FOLFIRINOX therapy comprises:

(2a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area),

(2c) Intravenous irinotecan hydrochloride hydrate 150mg/m ² (body surface area); and

(2e) Intravenous sustained administration of 2400mg/m fluorouracil ² (body surface area),

the decrement regimen of FOLFIRINOX therapy carries out the series of administrations of (2 a), (2 b), (2 c) and (2 e) at 2 week intervals.

[92] The agent according to any one of the above [56] to [87], [89] and [90], wherein,

FOLFIRINOX therapy comprises:

(2a) Oxaliplatin 85mg/m for 2 hours intravenous administration ² (body surface area),

(2b) (preferably 200mg/m of levocalcium folinate administered intravenously 2 hours after the end of oxaliplatin administration of (2 a) ² (body surface area),

(2c) After 30 minutes from the start of administration of the calcium levofolinate of (2 b), 180mg/m of irinotecan hydrochloride hydrate was intravenously administered for 1.5 hours ² (body surface area),

(2d) After the completion of the administration of the calcium levofolinate of the formula (2 b), further rapid intravenous administration of fluorouracil 400mg/m ² (body surface area); and

(2e) After the completion of the administration of fluorouracil of (2 d), 2400mg/m of fluorouracil was further administered intravenously for 46 hours ² (body surface area),

[93] The agent according to any one of [56] to [86], [88], [89] and [91], wherein the decrement regimen of FOLFIRINOX therapy comprises:

(2c) After 30 minutes from the start of the administration of calcium levofolinate of the (2 b), 150mg/m of irinotecan hydrochloride hydrate was intravenously administered for 1.5 hours ² (body surface area); and

(2e) After the completion of the administration of calcium levofolinate of the above (2 b), 2400mg/m fluorouracil was further administered intravenously for 46 hours ² (body surface area),

[94] The agent according to any one of [56] to [93], which is a therapy in which the administration of FOLFI RINOX therapy or a reduction regimen thereof, an immune checkpoint inhibitory substance and a CD47 inhibitory substance is started on the same day.

[95] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for cancer, which comprises a CD47 inhibitory substance as an active ingredient, wherein the progression inhibitor, recurrence inhibitor and/or therapeutic agent for cancer is administered in combination with FOLFIRINOX therapy or a reduction regimen thereof and an immune checkpoint inhibitory substance,

(iii) The FOLFIRINOX therapy comprises:

(2a) Oxaliplatin 85mg/m for intravenous administration (preferably 2 hours) ² (body surface area),

(2b) (preferably after the end of oxaliplatin administration of (2 a)), 200mg/m of calcium levofolinate is administered intravenously (preferably over 2 hours) ² (body surface area),

(2c) (preferably 30 minutes after the start of administration of the calcium levofolinate of (2 b)), 180mg/m of irinotecan hydrochloride hydrate is administered intravenously (preferably over 1.5 hours) ² (body surface area),

(2e) After the completion of the administration of fluorouracil of (2 d), 2400mg/m of fluorouracil is further administered continuously intravenously (preferably for 46 hours) ² (body surface area),

the FOLFIRINOX therapy is carried out by administering a series of administrations of (2 a), (2 b), (2 c), (2 d) and (2 e) at 2-week intervals, or

The decrement regimen of FOLFIRINOX therapy comprises:

(2c) (preferably 30 minutes after the start of administration of the calcium levofolinate of (2 b)), 150mg/m of irinotecan hydrochloride hydrate is administered intravenously (preferably over 1.5 hours) ² (body surface area)

(2e) After the completion of the administration of the calcium levofolinate of (2 b), further intravenous administration of 2400mg/m fluorouracil is continued (preferably for 46 hours) ² (body surface area),

the decrement regimen of FOLFIRINOX therapy carries out a series of administrations of the (2 a), (2 b), (2 c) and (2 e) at 2 week intervals.

[96] A progression inhibitor, a recurrence inhibitor and/or a therapeutic agent for cancer, which comprises an immune checkpoint inhibitory substance as an active ingredient, wherein the progression inhibitor, recurrence inhibitor and/or therapeutic agent for cancer is administered in combination with FOLFIRINOX therapy or a reduction regimen thereof and a CD47 inhibitory substance,

(iii) The FOLFIRINOX therapy comprises:

the FOLFIRINOX therapy is carried out by administering a series of administrations of (2 a), (2 b), (2 c), (2 d) and (2 e) at 2 week intervals,

the decrement regimen of FOLFIRINOX therapy comprises:

[97] The agent according to the above [95] or [96], wherein the cancer is pancreatic cancer having distant metastasis.

[98] The agent of [97], which is administered as a primary treatment to a patient who has not undergone treatment with a systemic anti-malignant agent for pancreatic cancer with distant metastasis.

[99] The agent of any one of [95] to [98], which is a therapy in which FOLFI RINOX therapy or a decrement regimen thereof, administration of Mo Luoli mab and nivolumab, are started on the same day.

Unless defined otherwise, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art.

In this specification, the contents of all patent documents and non-patent documents or references explicitly cited are incorporated herein by reference as part of the present specification.

Examples

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1:non-blind test non-control test: a combination therapy comprising Mo Luoli mab, nivolumab and bevacizumab added to FOLFOX therapy as a standard therapy, as a primary therapy, was used in a subject who had failed to radically cure the progress of excision or had relapsed colon cancer or rectal cancer.

The purpose of this test was to study the tolerance, safety and efficacy of Mo Luoli mab, nivolumab and combination therapy with bevacizumab or cetuximab added to FOLFOX therapy as primary treatment in colon cancer or rectal cancer patients who cannot radically cure progress of resection or relapse. Through the clinical test, the combined effect of the combination of Mo Luoli mab, nivolumab and the combination therapy with bevacizumab or cetuximab added to FOLFOX therapy can be evaluated.

(1) Subject patient

Patients with colon or rectal cancer who cannot radically cure progress or recurrence of excision

(2) Patient selection criteria

At the time of registration, patients satisfying all of the criteria described below were selected. It was clarified that, when the following criteria were not satisfied before the initial administration of the test drug, the clinical test of the drug was stopped without starting the administration of the test drug.

1. Gender: without asking too much.

2. Age (when informed): over 20 years old.

3. Patients (only the tolerability evaluation portion) who could be hospitalized from the day before the start of the test drug administration to the end of the examination at least the fifteenth day after the start of the test drug administration.

4. Histologically pathologically diagnosed with adenocarcinoma of the colon or rectum (except for appendiceal, anal canal cancers) and is not suitable for radical resections.

5. Patients with measurable lesions defined in RECIST guidelines version 1.1 in diagnostic imaging within 28 days prior to administration of the trial drug.

The progress of the patient who received the radiotherapy for the measurable lesions was confirmed in the image diagnosis after the radiotherapy was performed.

6. Patients experiencing no treatment for colon or rectal cancer that could not radically cure the progression of resection or recurrence with systemic anti-malignancy agents.

In the case of performing the preoperative/postoperative adjuvant therapy together with the curative surgery (confirmation of R0 excision), no recurrence was confirmed within 6 months after completion of the adjuvant therapy.

7. Tumor tissue specimens for biomarker inspection can be provided.

Tumor tissue samples were obtained during the screening period. In case of a new tumor biopsy being difficult, a preserved specimen may be used. Wherein the preserved specimens are collected within 180 days prior to administration of the test agent and after final administration of the recent systemic anticancer therapy.

8. Patients scheduled to be treated with a combination therapy of FOLFOX (fluorouracil, levofolinate, oxaliplatin) and bevacizumab (group (Cohort)) in the case of RAS mutant, or FOLFOX (fluorouracil, levofolinate, oxaliplatin) and cetuximab (group 2) in the case of RAS wild-type and primary lesion-occupying site left (descending colon, sigmoid colon, rectum).

Patients with ecog physical performance status (ECOG Performance Status) of 0-1.

10. Patients who survived for 3 months or more can be expected at the time of registration.

11. In the case of females who are likely to be pregnant (including those who have no menstruation for medical reasons such as chemical menopause), patients who have agreed to perform dual contraception during the pregnancy period prescribed in each drug from the time of consent to 5 months after the final administration of the test drug and after the final administration of the standard therapeutic drug. In addition, patients who had agreed to not suckle during the period in which each agent was restricted from suckling, were allowed to gain agreement until 5 months after final administration of the test agent and after final administration of the standard therapeutic agent. Here, women who are likely to become pregnant refer to women who have undergone a beginner or have not undergone sterile surgery (hysterectomy, bilateral tubal ligation, bilateral ovariectomy, etc.), including all non-menopausal women. Menopause is defined as menopause over 12 months in duration, although there is no reason to be specifically given. Women using oral contraceptives or intrauterine contraceptive devices, pessaries are considered women who are likely to become pregnant.

12. In the case of men, the double contraception was agreed from the start of the administration of the test drug to within 4 months after the final administration of the test drug and within the given period of pregnancy of each drug after the final administration of the standard therapeutic drug. Here, in terms of contraception, dual contraception is required by any two of a seminiferous excision of the seminiferous canal of a male patient or male partner or a condom, a tubal ligation of a female patient or female partner, a pessary, an intrauterine contraceptive device, or an oral contraceptive.

13. The most recent clinical examination values performed within 14 days before the start of the administration of the test drug satisfied the patients on the following criteria. The administration or transfusion of a hematopoietic factor preparation such as granulocyte colony-stimulating factor (G-CSF) was not received within 14 days before the examination.

Neutrophil count 1500/mm ³ The above.

Platelet count of 100000/mm ³ The above.

Hemoglobin is 11.0g/dL or more.

AST (GOT) and ALT (GPT) are 3.0 times or less of the upper limit of the facility reference value (wherein, in the case where liver metastasis is present, 5.0 times or less of the upper limit of the facility reference value).

Total bilirubin is 1.5 times or less the upper limit of the baseline value of the facility (wherein, in the case of gilbert syndrome patients, total bilirubin is 3.0 times or less the upper limit of the baseline value of the facility).

Blood creatinine is 1.5 times or less the upper limit of the facility reference value, or creatinine clearance (measured value or estimated value based on cockcroft/Gault expression) is 40mL/min or more.

Albumin at 3.0g/dL or more.

[ group 1 only ] urine protein was 1+ or less. Wherein, in urine examination or urine test paper examination, patients with urine protein more than 2+ accumulate urine for 24 hours and urine protein is less than 1g/24 hours, or urine protein/creatinine ratio (UPCR) is less than 1g/gCr can register.

14. The content of the clinical trial was sufficiently received from a researcher or assistant researcher using a consent document and a description document, and the patients who participated in the clinical trial were consented to by the document according to the discretion.

(3) Patient exclusion criterion

Patients meeting any of the criteria described below were excluded at the time of registration. In the case where the initial administration of the test drug is contradicted by any of the following criteria, the clinical test of the drug is stopped without starting the administration of the test drug.

1. Patients with wild-type RAS/BRAF with primary foci occupying the right side (cecum, ascending colon, transverse colon).

BRAF mutant patients and patients with High frequency microsatellite instability (MSI-High) or impairment of the mismatch repair mechanism (dMMR).

3. Patients with or in need of anticoagulant therapy.

4. Patients with gastrointestinal bleeding above Grade2 were continuously confirmed.

5. Patients with perforation of digestive tract, severe fistula and tracheoesophageal fistula.

6. Patients with unmanageable retention of pericardial fluid, hydrothorax or ascites in medication were identified.

7. Patients with a history of highly allergic reactions to the antibody preparation.

8. Patients on any of the agents of standard therapies used in each group are contraindicated.

Group 1 fluorouracil, levofolinate, oxaliplatin and bevacizumab.

Group 2 fluorouracil, levofolinate, oxaliplatin and cetuximab.

9. Patients with peripheral neuropathy above Grade 2.

10. Patients with complications of autoimmune diseases or a history of chronic or recurrent autoimmune diseases. Among them, patients who have complicated skin diseases (white spots, psoriasis, alopecia, etc.) that do not require systemic therapy or diseases that do not recur in the absence of external causes can be registered.

11. Due to the effects of surgical therapies, researchers or assistant researchers will judge patients who have affected the safety and efficacy assessment of test drugs.

12. Patients with dual cancers. Wherein patients with fully resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intra-mucosal or superficial bladder carcinoma, or other carcinomas not confirmed to recur for more than 3 years, can log in.

13. Brain or meningeal patients with metastatic lesions. Wherein patients who are asymptomatic and do not require treatment can be enrolled.

14. A patient having a complication or history of interstitial lung disease or lung fibrosis diagnosed by image diagnosis or clinical observation.

15 is unable to stably control tumor-associated pain.

16. Patients with a history of hemolytic anemia within 90 days prior to enrollment.

17. Patients with transient ischemic attacks, cerebrovascular attacks, thrombosis or thromboembolism (pulmonary arterial embolism or deep vein thrombosis) and poor control of thrombosis or thromboembolism within 180 days prior to registration. Wherein a central venous catheter-related venous thrombosis is allowed.

18. There are patients with uncontrolled or significant cardiovascular disease as described below.

Acute myocardial infarction within 6 months prior to registration.

Unstable angina or angina in need of treatment.

New York Heart Association (NYHA) heart function classification degree III-degree IV congestive heart failure.

High blood pressure which cannot be managed although being suitable for treatment (systolic blood pressure of 150mmHg or more, diastolic blood pressure of 100mmHg or more, 24 hours or more, etc.).

Inability to control or significant arrhythmia.

19. And uncontrolled diabetic patients are involved.

20. Patients with systemic infections in need of treatment.

21. Patients in need of or having a history of transplantation therapy (excluding autograft).

Patient positive for any of HIV-1 antibody and HIV-2 antibody test, HTLV-1 antibody test, HBs antigen test, HCV antibody test. Further, the HBs antigen test is negative, but the HB s antibody test or the HBc antibody test is positive and the HBV-DNA is quantified to a patient having a detection sensitivity or higher. Note that, even if the HCV antibody is checked to be positive, registration is allowed when the HCV-RNA is negative.

23. Patients who received the following treatments before consent was obtained and before trial administration.

Patients who had a history of drug treatment targeting Mo Luoli mab, CD 47-sirpa pathway.

Patients having a history of treatment comprising anti-PD-1 antibodies, anti-PD-L2 antibodies, anti-CTLA-4 antibodies, or other antibody therapies or cancer vaccines for T cell control purposes in the past.

Patients receiving more than 2 units of red blood cells transfused within 28 days before informed consent.

Patients who received surgical therapy with local anesthesia within 14 days prior to administration of the trial drug.

Patients who received adhesions such as pleura and pericardium within 14 days before administration of the test drug.

Patients who received a systemic adrenocortical hormone (excluding temporary use for examination, local administration, treatment of contrast agent allergic reaction, prevention of edema accompanied by radiotherapy, or the like) or administration of an immunosuppressive substance in an amount of prednisone equivalent to more than 10 mg/day within 14 days before administration of the test drug.

Patients who received mild local radiotherapy within 28 days prior to administration of the trial drug.

Patients who received surgical therapy accompanied by general anesthesia within 28 days prior to administration of the trial drug.

Patients receiving live or attenuated vaccination within 28 days prior to administration of the test drug.

Patients who received administration of the radiopharmaceutical (except for the use of the radiopharmaceutical for examination and diagnosis) within 56 days before administration of the test drug.

Patients who received administration of other non-approved drugs (also including administration of clinical studies, non-approved drug combinations, new dosage forms) within 28 days prior to administration of the trial drug.

24. A patient who is pregnant, lactating, or is likely to be pregnant.

25. A patient who has a status of lacking consent due to complications of dementia or the like is determined.

26. Furthermore, the researcher or assistant researcher determines that the patient is not suitable for the subject of the present clinical trial.

(4) Usage, dose and period of administration

[ Mo Luoli monoclonal antibody ]

On the first day of the first cycle, as the primary administration, mo Luoli mab was administered intravenously at 1mg/kg for 3 hours (+ -30 minutes) and then, in the first cycle, at 2 hours (+ -30 minutes) at 1 week intervals, at 20mg/kg or 30mg/kg single, and, after the second cycle, at 2 hours (+ -30 minutes) at 2 week intervals, at 20mg/kg single or 30mg/kg single, continuing administration until the given dosing discontinuation criteria associated with Mo Luoli mab was met. In the case of Mo Luoli mab, nivolumab, and a combination therapy in which bevacizumab or cetuximab was added to FOLFOX therapy, the administration was started in the order of Mo Luoli mab, nivolumab, and a combination therapy in which bevacizumab or cetuximab was added to FOLFOX therapy.

[ Nawuzumab ]

The administration of 480mg of nivolumab was intravenous at 4 week intervals for 30 minutes and continued until the given discontinuation criteria for nivolumab were met. The administration of nivolumab was performed at least 24 days or more from the last administration and after the twenty-fifth day.

[ combination therapy with bevacizumab or cetuximab added to FOLFOX therapy ]

Regarding the selection of bevacizumab or cetuximab, bevacizumab was used for patients with RAS mutant and cetuximab was used for patients with RAS wild type.

Bevacizumab was given at a starting dose of 5mg/kg (body weight) and was intravenously instilled for 90 minutes. If the tolerance is good at the first administration, the second administration may also be 60 minutes. Further, if the tolerance is also good in the second administration, the administration may be 30 minutes thereafter. The administration interval is more than 2 weeks.

Starting dose of cetuximab is 400mg/m ² (body surface area), intravenous drip for 2 hours. After the second time, 250mg/m is infused intravenously with 1 hour at single or 2 week intervals ² . In addition, as required, cetuximab may be administered singly every 2 weeks, and 500mg/m may be intravenously instilled for 2 hours ² Dosing was at 2 week intervals. The amount is reduced appropriately according to the state of the patient.

(1 x) intravenous administration of (1 a) oxaliplatin 85mg/m after administration of bevacizumab or cetuximab for 2 hours ² (body surface area). (1b) Simultaneous with oxaliplatin, 200mg/m of levorotatory calcium folinate was administered intravenously over 2 hours ² (body surface area). (1c) Ending intravenous administration of calcium levofolinateAfter rapid intravenous administration of fluorouracil 400mg/m ² (body surface area), (1 d) 2400mg/m was then administered intravenously over 46 hours ² (body surface area). The series of administrations of (1 x), (1 a), (1 b), (1 c) and (1 d) were performed at 2-week intervals. The bevacizumab, cetuximab, oxaliplatin, levofolinic acid calcium and fluorouracil were commercially available products, respectively.

[ clinical trial timetable (Clinical trial schedule) ]

The test consisted of screening period, treatment period and post-observation period. An outline of the clinical trial schedule is shown in fig. 1.

The screening period was set to be 28 days or less before administration of the test drug, and the researchers or assistant researchers were enrolled in patients who satisfied the selection criteria and were judged to be suitable as subjects for the present clinical trial without contradiction to the exclusion criteria.

The treatment period was set to 28 days of a cycle, and the initial test drug administration day was set to the first day of cycle 1. The first day of each cycle after the second cycle was set to [28× (cycle number-1) +1] days. For Mo Luoli mab, nivolumab and combination therapy with bevacizumab or cetuximab added to FOLFOX therapy, administration was started according to the above-described usage and dose, and administration was continued according to the administration standard, the decrement standard and the administration amount at the time of decrement concerning Mo Luoli mab, nivolumab and combination therapy with bevacizumab or cetuximab added to FOLFOX therapy, respectively. The end of the treatment period was defined as the end of the time point at which the evaluation was completed when the administration of Mo Luoli mab, nivolumab, and combination therapy with bevacizumab or cetuximab added to FOLFOX therapy was completed (discontinued). Of all subjects to whom the test drug was administered, evaluation at the end of administration (discontinuation) was discontinued or completed for Mo Luoli mab, nivolumab and subjects to whom the combination therapy of bevacizumab or cetuximab was added in FOLFOX therapy, and the period was shifted to the post-observation period. After the end of the post-observation period, a follow-up survey was conducted.

[ benchmark for administration of Mo Luoli mab and nivolumab ]

The subjects must all meet the given dosing criteria at the beginning of each dose, determined by considering the dosing criteria in the clinical trial previously conducted for Mo Luoli mab and nivolumab. When either of these criteria is not met, the administration of the predetermined Mo Luoli mab and nivolumab is stopped. Subjects who have stopped taking the drug are examined at a frequency of not less than one time per week or clinically required, and it is determined whether or not to start the drug administration again.

[ standard for discontinuation of administration of Mo Luoli mab ]

In the treatment period, the administration of Mo Luoli mab was discontinued in subjects who met any of the given administration discontinuation criteria determined in view of the administration discontinuation criteria in the clinical trial previously conducted with respect to Mo Luoli mab.

[ standard for discontinuing administration of Nawuzumab ]

During the treatment period, subjects who met any of the given discontinuation criteria determined in view of the discontinuation criteria in the clinical trial previously conducted for nivolumab discontinued administration.

[ dosing benchmark for combination therapy with bevacizumab or cetuximab added to FOLFOX therapy ]

The subjects must all meet at the beginning of each dose: regarding the combination therapy with bevacizumab or cetuximab added to FOLFOX therapy, the given dosing standard was determined taking into consideration the latest package instructions. The clinical test value is returned to a state satisfying the condition of the standard after the delay of the administration until the administration of the predetermined day, and the administration is performed on the basis of confirmation that the medication is not in compliance with the contraindication.

[ reduction and reduction criterion of combination therapy comprising Bevacizumab or cetuximab added to FOLFOX therapy ]

The decrement is performed according to the latest package insert.

[ reference for discontinuation of combination therapy with bevacizumab or cetuximab added to FOLFOX therapy ]

In the treatment period, the administration of the combination therapy with bevacizumab or cetuximab added to FOLFOX therapy was discontinued to subjects who met any of the given administration discontinuation criteria determined in consideration of the latest package instructions for the combination therapy with bevacizumab or cetuximab added to FOLFOX therapy.

[ evaluation criterion of effectiveness ]

(image diagnosis)

CT/Magnetic Resonance Imaging (MRI) of the chest, abdomen, and pelvis is performed.

Researchers or assistant researchers determine the antitumor effect by measuring the tumor diameter of the target lesion according to RECIST guidelines version 1.1.

(evaluation item)

(1) remission rate (ORR), (2) Disease Control Rate (DCR), (3) total survival (OS), (4) no worsening survival (PFS), (5) remission period (DOR), (6) period of remission (TTR) reached, (7) rate of change of sum of tumor diameters of target lesions, (9) maximum rate of change of sum of tumor diameters of target lesions, (10) passage of tumor markers (CEA and CA 19-9)

(evaluation of target lesions)

Complete remission (complete response CR)

Meaning that all non-lymph node target lesions disappear, and the short diameter of all lymph node lesions selected as target lesions is reduced to less than 10 mm.

Partial remission (partial response: PR)

Meaning that the sum of diameters of target lesions is reduced by more than 30% compared to the sum of diameters of the base lines.

Progress (progressive disease PD)

The sum of diameters of the target lesions is increased by more than 20% and the absolute value of the sum of diameters is also increased by more than 5mm, compared to the smallest sum of diameters in the process.

Stabilization (stabledsease: SD)

There is no reduction in PR, and no increase in PD, compared to the smallest sum of diameters in the process.

Cannot be evaluated (Not Evaluable: NE)

Meaning that inspection is not possible for some reason or that any one of CR, PR, PD or SD cannot be determined.

(1) Rate of remission

Remission rate represents the proportion of subjects whose best overall efficacy is judged to be CR or PR.

(2) Disease control rate

The disease control rate represents the proportion of subjects who are judged to be CR, PR or SD for the optimal overall efficacy.

(3) Total life cycle

The total lifetime is calculated by the following formula.

Total survival (day) = "all cause-induced death date" - "test drug administration start date" +1)

The subject who cannot be tracked or who did not die before the date of expiration of the data set the final survival confirmation date as the expiration date.

(4) Non-worsening lifetime

The non-worsening lifetime is calculated by the following formula.

Non-worsening survival (day) = "date of overall efficacy determined as PD, or date of death due to all causes" - "date of start of test drug administration" +1)

The date on which the last evaluable image diagnosis was performed was set as the expiration date for subjects whose overall efficacy was not determined to be PD and also not dead. Subjects who did not undergo an evaluable image diagnosis and did not die set the administration start date of the test drug as the expiration date. The total efficacy was determined as PD or subjects who received post-treatment for cancer before death, and the date on which the last evaluable image diagnosis before the start of post-treatment for cancer was performed was set as the expiration date.

(5) Remission period

The remission period is calculated from the following formula.

Remission period (day) = "date of initial determination after remission of initial determination of overall efficacy as PD or date of early death due to all causes" - "initial determination date of CR or PR" +1 determined

Furthermore, the evaluation object is a subject showing a determined CR or PR by a clinical test.

(6) Period of time until reaching remission

The period until the relief is achieved is calculated by the following equation.

Period (day) until remission is reached= "initial determination date of CR or PR determined" - "administration start date of test drug" +1

(7) Optimum overall therapeutic effect

The optimal overall efficacy is determined based on the overall efficacy determined prior to the end of the present clinical trial. Among them, CR and PR were determined by continuous evaluation at intervals of 4 weeks (28 days) or more, and were determined based on the criteria of table 1.

TABLE 1

Initial overall evaluation	Subsequent overall evaluation	Optimum overall therapeutic effect
			CR	CR	CR
CR	PR	SD, PD or PR
			CR	SD	SD is the shortest standard of SD, and other cases are PD
CR	PD	Meets the shortest standard of SD as sD, except for the casesThe condition is PD
			CR	NE	When the shortest reference of SD is satisfied, it is sD, and other cases are NE
PR	CR	PR
			PR	PR	PR
PR	SD	SD
			PR	PD	SD is the shortest standard of SD, and other cases are PD
PR	NE	SD is the shortest criterion, but NE is the other criterion
			NE	NE	NE

(8) Tumor diameter and rate of change of target lesions

The change rate of the sum of tumor diameters of the target lesions was calculated using the following calculation formula, with respect to the subjects having the target lesions. Wherein the rate of change of the sum of tumor diameters of the target lesions after post-treatment is not calculated.

[ mathematics 1]

Rate of change (%) = ("sum of tumor diameters at each evaluation time point and-sum of tumor diameters before administration")/("sum of tumor diameters before administration") 100

(9) Maximum rate of change of sum of tumor diameters of target lesions

The maximum rate of change of the sum of tumor diameters of the target lesions is the rate of change of the sum of tumor diameters of the target lesions at the minimum time point. Wherein the overall efficacy is determined as tumor diameter of the target lesion after PD or after post treatment and not used for calculation of the maximum rate of change.

[ math figure 2]

Maximum rate of change (%) = ("minimum tumor diameter after administration and-tumor diameter before administration sum")/("tumor diameter before administration sum") ×100

(10) Change rate of tumor markers (CEA and CA 19-9)

The rate of change of tumor markers was calculated using the following calculation formula. Wherein the rate of change of tumor markers after post-treatment is not calculated.

[ math 3]

Rate of change (%) = ("tumor marker before dose" at each evaluation time point ")/(" tumor marker before dose ") 100

[ evaluation item of safety ]

For the following items, measurement, examination and investigation are performed at a predetermined period by a researcher or the like.

(1) Dose Limiting Toxicity (DLT), (2) adverse events, (3) clinical examination (hematological examination, blood biochemical examination, immunological examination, hormone investigation, blood clotting system examination, urine qualitative examination), peripheral blood smear specimen, (4) vital signs (systolic blood pressure/diastolic blood pressure, pulse rate, body temperature, respiratory rate), percutaneous oxygen saturation (SpO) ₂ ) Weight, 12-lead electrocardiogram, (6) ECOG physical ability status and (7) chest X-ray

[ evaluation result of validity ]

As for the combination therapy of Mo Luoli mab, nivolumab and bevacizumab added to FOLFOX therapy, two cases were determined as PR at the time point of 8 months from the registration of the first subject.

Regarding Mo Luoli mab, nivolumab and combination therapy with cetuximab added to FOLFOX therapy, 3 cases were determined as PR at the time point of 8 months from the registration of the first subject.

Example 2: non-blind test non-control test: pancreatic cancer patients with distant metastasis are treated as primary therapy with Mo Luoli mab, nivolumab and mFFX therapy as standard therapy

The purpose of this test was to investigate the tolerability, safety and efficacy of a combination of Mo Luoli mab, nivolumab and mFFX therapy as primary treatment in pancreatic cancer patients with distant metastasis. Through the clinical test, the combined effect of Mo Luoli monoclonal antibody, nivolumab and mFFX therapy can be evaluated.

(1) Subject patient

Pancreatic cancer patients with distant metastasis

(2) Patient selection criteria

At the time of registration, patients satisfying all of the criteria described below were selected. It was clarified that when the following criteria were not satisfied from the registration to the initial administration of the test drug, the administration of the test drug was not started and the clinical test of the drug was stopped.

1. Gender: without asking too much.

2. Age (when informed): over 20 years old.

4. Patients diagnosed with invasive pancreatic ductal carcinoma of the adenocarcinoma by tissue diagnosis or cellular diagnosis.

5. Patients experiencing distant metastatic pancreatic cancer were not treated with systemic anti-malignancy agents. Among them, in the case of a patient who received chemotherapy, postoperative adjuvant chemotherapy or preoperative adjuvant chemotherapy in the past, it can be registered that the patient has relapsed over 180 days or more from the end of administration of an anti-malignant agent.

6. Patients with measurable lesions defined in RECIST guidelines version 1.1 in diagnostic imaging within 14 days prior to administration of the trial drug. However, in the case of a measurable lesion having only a therapeutic history in which radiation is present, the present invention is limited to a lesion in which deterioration is confirmed in image diagnosis after radiation therapy is performed.

7. Eastern tumor co-operating group (Eastern Cooperative Oncology Group, ECOG) patients with physical status 0 or 1.

8. Patients with survival over 90 days are predicted.

9. A patient of a tumor tissue specimen for biomarker inspection can be provided.

Tumor tissue samples were obtained during the screening period. In case of a new tumor biopsy being difficult, a preserved specimen may be used. Wherein the preservation sample is collected within 180 days before administration of the test drug.

10. In the case of females who are likely to be pregnant (including those who have no menses due to medical reasons such as chemical menopause), the prescribed contraceptive phase in each medicament will agree to perform dual contraception from the time of consent to within 5 months after the final administration of the test medicament and after the final administration of the standard therapeutic medicament. In addition, patients who did not breast feed during the period in which each agent limited breast feed were agreed to after the consent was obtained, to within 5 months after the final administration of the test agent and after the final administration of the standard therapeutic agent. Here, women who are likely to become pregnant refer to women who have undergone a beginner or have not undergone sterile surgery (hysterectomy, bilateral tubal ligation, bilateral ovariectomy, etc.), including all non-menopausal women. Menopause is defined as menopause over 12 months in duration, although there is no reason to be specifically given. Women using oral contraceptives or intrauterine contraceptive devices or contraceptive pessaries are considered women who are likely to become pregnant.

11. In the case of men, the individual agents agree to perform dual contraception within 4 months from the start of administration of the test agent to the end of administration of the test agent and after the end of administration of the standard therapeutic agent during the given pregnancy. Here, in connection with contraception, it is necessary to perform dual contraception by any two of a seminiferous tube excision of a male patient or male partner or a condom, tubal ligation of a female patient or partner, contraceptive pessary, intrauterine contraceptive devices or oral contraceptive drugs.

12. The latest clinical examination values carried out within 14 days before the start of the administration of the test drug satisfy the following criteria. Furthermore, administration or blood transfusion of hematopoietic factor preparations such as granulocyte colony-stimulating factor (G-CSF preparation) was not received within 14 days before the examination day.

Neutrophil count of 2000/mm ³ The above.

Platelet count of 100000/mm ³ The above.

Hemoglobin is 11.0g/dL or more.

Total bilirubin: the upper limit of the facility reference value is 1.5 times or less.

Albumin: 3.0g/dL or more.

Creatinine is 1.5 times or less the upper limit of the facility reference value or creatinine clearance (measured value or estimated value based on Cockc roft/Gault) is 40mL/min or more.

13. The content of the clinical trial was sufficiently received from a researcher or assistant researcher using a consent document and a description document, and the patients who participated in the clinical trial were consented to by the document according to the discretion.

(3) Patient exclusion criterion

Patients considered to meet any of the criteria described below were excluded at the time of registration. When the initial administration of the test drug from the registration was not performed until the initial administration of the test drug was performed, the clinical test of the drug was stopped without starting the administration of the test drug.

1. Patients with oxaliplatin, irinotecan, fluorouracil or calcium levofolinate are contraindicated.

2. Patients with diarrhea (including watery feces) that is clinically problematic were identified.

3. Patients with peripheral motor neuropathy or peripheral Zhou Xinggan sensory neuropathy were identified.

4. Has UDP-glucuronyl transferase A1 (UGT 1A 1) gene polymorphism; patients with homozygotes (UGT 1A1 x 6/6, UGT1A1 x 28/28) or heterozygotes (complex heterozygotes: UGT1A1 x 6/28).

5. Patients with complications or medical history of highly allergic reactions to antibody preparations.

6. Due to the effects of surgical therapies, researchers or assistant researchers will judge patients who have affected the efficacy and safety assessment of test drugs.

7. Patients with complications of autoimmune diseases or a history of chronic or recurrent autoimmune diseases. Among them, patients complicated with type 1 diabetes, hypothyroidism that can be treated by hormone replacement therapy, or skin diseases (leukoplakia, psoriasis, alopecia, etc.) that do not require systemic therapy can be registered.

8. Patients with dual cancers (basal cell carcinoma completely resected, squamous cell carcinoma of stage I, carcinoma in situ, intra-mucosal or superficial bladder cancer, or patients with other cancers not confirmed to recur for more than 3 years) can log in.

9. Brain or meningeal patients with metastatic lesions. Wherein patients who are asymptomatic and do not require treatment can be enrolled.

10. A patient having complications or medical history of interstitial lung disease or lung fibrosis diagnosed by image diagnosis or clinical observation.

11. Patients with diverticulitis or symptomatic peptic ulcer disease.

12. Patients with unmanageable retention of pericardial fluid, hydrothorax or ascites in medication were identified.

13. Patients with unmanageable cancer pain are also associated.

14. Patients with peritoneal high-grade spread, such as continuous retention of ascites, exceeding the pelvic cavity were confirmed.

15. Patients in need of or having a history of transplantation therapy (excluding autograft).

17. Patients with a history of transient ischemic attacks, cerebrovascular attacks, thrombosis or thromboembolism (pulmonary arterial embolism or deep vein thrombosis) within 180 days prior to registration.

18. There are patients with unmanageable or significant cardiovascular disease as described below.

Myocardial infarction within 180 days before registration.

Angina that could not be managed within 180 days before registration.

New York Heart Association (NYHA) congestive heart failure of degree III or degree IV of cardiac functional classification.

High blood pressure which cannot be managed although being suitable for treatment (systolic blood pressure of 150mmHg or more, diastolic blood pressure of 90mmHg or more, 24 hours or more, etc.).

Arrhythmia requiring treatment.

19. And unmanageable diabetic patients.

20. Patients with systemic infections in need of treatment.

21. In the screening test, patients positive for any of HIV-1 antibody and HIV-2 antibody, HTLV-1 antibody, HBs antigen, and HCV antibody (except HCV-RNA negative) were examined. Note that, even if the HCV antibody is checked to be positive, registration is allowed in the case where the HCV-RNA is negative.

22. In the screening test, the HBs antigen test is negative, but the HBs antibody test or the HBc antibody test is positive and HBV-DNA is quantified as a patient with a detection sensitivity of more than that.

Patients who have had a history of treatment with drugs targeting Mo Luoli mab or CD 47-sirpa pathway, nivolumab, anti-PD-1 antibodies, anti-PD-L2 antibodies, anti-CD 137 antibodies, anti-CTLA-4 antibodies or other antibody therapies aimed at T cell modulation or drug therapies containing cancer vaccines.

Patients who received radiation irradiation for the purpose of alleviation within 28 days before administration of the test drug.

Patients who received administration of other non-approved drugs (also including administration of clinical studies, non-approved drug combinations, new dosage forms) within 28 days prior to administration of the test drug (within 90 days in the case of antibody preparations).

24. Patients with germline BRCA gene mutations (lesions or suspected lesions) were identified.

25. A patient who is pregnant, is nursing, or is likely to be pregnant (a patient in nursing is set to be unregisterable even if nursing is interrupted).

26. A patient who has a status of lacking consent due to complications of dementia or the like is determined.

27. Furthermore, researchers or assistant researchers judge patients who are not suitable as clinical trial subjects.

(4) Usage, dose and period of administration

[ Mo Luoli monoclonal antibody ]

On the first day of the first cycle, as the primary administration, mo Luoli mab was administered intravenously at 1mg/kg for 3 hours (+ -30 minutes) and then, in the first cycle, at 2 hours (+ -30 minutes) at 1 week intervals, at 20mg/kg or 30mg/kg single, and, after the second cycle, at 2 hours (+ -30 minutes) at 2 week intervals, at 20mg/kg single or 30mg/kg single, continuing administration until the given dosing discontinuation criteria associated with Mo Luoli mab was met. In the case of Mo Luoli mab, nivolumab, and mFFX therapy, administration was started in the order of Mo Luoli mab, nivolumab, and mFFX therapy.

[ Nawuzumab ]

[ mFFX therapy ]

(2a) Oxaliplatin is administered intravenously for 2 hours at 85mg/m ² (body surface area). (2b) Intravenous administration of 200mg/m of L-calcium folinate over 2 hours ² (body surface area). (2c) Intravenous irinotecan hydrochloride hydrate 150mg/m 1.5 hours after 30 minutes from the start of calcium levofolinate administration ² (body surface area). (2e) 2400mg/m fluorouracil was administered intravenously over 46 hours ² (body surface area). The series of administrations of (2 a), (2 b), (2 c) and (2 e) were carried out at 2-week intervals. Oxaliplatin, irinotecan hydrochloride hydrate, calcium levofolinate and fluorouracil were used as commercial products, respectively.

[ clinical trial timetable ]

The test consisted of screening period, treatment period and post-observation period. A summary of the clinical trial schedule is shown in fig. 2.

The treatment period was set to 28 days of a cycle, and the initial test drug administration day was set to the first day of cycle 1. The first day of each cycle after the second cycle was [28× (cycle number-1) +1] days. For Mo Luoli mab, nivolumab and mFFX therapy, administration was started according to the above-described usage/dose, and administration was continued according to the administration standard, decrement standard and dose at decrement of Mo Luoli mab, nivolumab and mFFX therapy, respectively. The time point at which the evaluation ends when Mo Luoli mab, nivolumab, and mFFX therapy administration ended (discontinued) was taken as the end of the treatment period. Of all subjects to whom the test drug was administered, those who discontinued or ended administration of Mo Luoli mab, nivolumab, and mFFX therapy performed evaluation at the end of administration (discontinuation), shifted to the post-observation period. After the end of the post-observation period, a follow-up survey was conducted.

[ benchmark for administration of Mo Luoli mab and nivolumab ]

[ standard for discontinuation of administration of Mo Luoli mab ]

[ standard for discontinuing administration of Nawuzumab ]

[ administration base of mFFX therapy ]

The subjects must all meet at the beginning of each dose: regarding mFFX therapy, a given dosing standard determined in consideration of the latest package insert is considered. The clinical test value is returned to a state satisfying the condition of the standard after the delay of the administration until the administration of the predetermined day, and the administration is performed on the basis of confirmation that the medication is not in compliance with the contraindication.

[ reduction of mFFX therapy and reduction criterion ]

The decrement is performed according to the latest package insert.

[ reference for suspension of mFFX therapy ]

In the treatment period, administration of mFFX therapy is discontinued for patients who meet any of the given administration discontinuation criteria determined in consideration of the latest package insert for mFFX therapy.

[ evaluation criterion of effectiveness ]

(image diagnosis)

(evaluation item)

(evaluation of target lesions)

Complete remission (complete response CR)

Partial remission (partial response: PR)

Progress (progressive disease PD)

Stabilization (stabledsease: SD)

Cannot be evaluated (Not Evaluable: NE)

(1) Rate of remission

(2) Disease control rate

(3) Total life cycle

The total lifetime is calculated by the following formula.

(4) Non-worsening lifetime

The non-worsening lifetime is calculated by the following formula.

(5) Remission period

The remission period is calculated from the following formula.

(6) Period of time until reaching remission

(7) Optimum overall therapeutic effect

The optimal overall efficacy is determined based on the overall efficacy determined prior to the end of the present clinical trial. Among them, CR and PR were determined by continuous evaluation at intervals of 4 weeks (28 days) or more, and were determined based on the criteria of table 2.

TABLE 2

Initial overall evaluation	Subsequent overall evaluation	Optimum overall therapeutic effect
			CR	CR	CR
CR	PR	SD, PD or PR
			CR	SD	SD is the shortest standard of SD, and other cases are PD
CR	PD	SD is the shortest standard of SD, and other cases are PD
			CR	NE	SD is the shortest criterion, but NE is the other criterion
PR	CR	PR
			PR	PR	PR
PR	SD	SD
			PR	PD	SD is the shortest standard of SD, and other cases are PD
PR	NE	SD is the shortest criterion, but NE is the other criterion
			NE	NE	NE

(8) Tumor diameter and rate of change of target lesions

[ mathematics 4]

(9) Maximum rate of change of sum of tumor diameters of target lesions

[ math 5]

(10) Change rate of tumor markers (CEA and CA 19-9)

[ math figure 6]

[ evaluation item of safety ]

(1) Dosage ofLimiting Toxicity (DLT), (2) adverse events, (3) clinical examination (hematology examination, blood biochemistry examination, immunology examination, hormone investigation, blood clotting system examination, urine qualitative examination), peripheral blood smear specimen, (4) vital signs (systolic blood pressure/diastolic blood pressure, pulse rate, body temperature, respiratory rate), percutaneous oxygen saturation (SpO) ₂ ) Weight, 12-lead electrocardiogram, (6) ECOG physical ability status and (7) chest X-ray

[ evaluation result of validity ]

Regarding the combination therapy of Mo Luoli mab, nivolumab and mFFX therapy, cases judged as PR were 1 at the time point when 10 months elapsed since the first subject was enrolled.

Industrial applicability

The present invention provides novel methods of cancer treatment, which are useful.

Claims

1. A solid cancer progression inhibitor, recurrence inhibitor and/or therapeutic agent comprising a CD47 inhibiting substance as an active ingredient, wherein,

The solid cancer progression inhibitor, recurrence inhibitor and/or therapeutic agent is administered in combination with standard therapy and immune checkpoint inhibiting substances.

2. A solid cancer progression inhibitor, recurrence inhibitor and/or therapeutic agent comprising an immune checkpoint inhibitory substance as an active ingredient, wherein,

the solid cancer progression inhibitor, recurrence inhibitor and/or therapeutic agent is administered in combination with standard therapy and a CD47 inhibiting substance.

3. The agent according to claim 1 or 2, wherein,

standard therapy is combination therapy with bevacizumab or cetuximab added to FOLFOX therapy.

4. The agent according to claim 3, wherein,

combination therapies with bevacizumab or cetuximab added to FOLFOX therapy comprise:

(1a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area);

(1d) After the fluorouracil administration of (1 c) is completed, 2400mg/m of fluorouracil is further continuously administered intravenously ² (body surface area),

5. The agent according to claim 4, wherein,

(1 x) intravenous administration of bevacizumab 5mg/kg (body weight);

(1a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area);

6. The agent according to claim 4, wherein,

(1a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area);

7. The agent according to any one of claims 1 to 6, wherein,

the solid cancer is colon cancer or rectal cancer.

8. The agent according to claim 7, wherein,

colon or rectal cancer is colon or rectal cancer that cannot radically cure the progress or recurrence of resection.

9. The agent according to any one of claims 1 to 8, which is administered as a primary treatment to a patient who has not undergone treatment with a systemic anti-malignant agent for colon or rectal cancer that is unable to radically cure the progression of resection or recurrence.

10. The agent according to claim 1 or 2, wherein,

the standard therapy is FOLFIRINOX therapy or an abatement regimen thereof.

11. The agent according to claim 10, wherein,

FOLFIRINOX therapy comprises:

(2a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area);

(2b) Intravenous administration of L-calcium folinate 200mg/m ² (body surface area);

(2c) Intravenous administration of irinotecan hydrochloride hydrate 180mg/m ² (body surface area);

FOLFIRINOX therapy was performed with a series of administrations of (2 a), (2 b), (2 c), (2 d) and (2 e) at 2 week intervals.

12. The agent according to claim 10, wherein,

the decrement regimen of FOLFIRINOX therapy comprises:

(2a) Intravenous administration of oxaliplatin 85mg/m ² (body surface area);

the decrement regimen of FOLFIRINOX therapy performed a series of administrations of (2 a), (2 b), (2 c) and (2 e) at 2 week intervals.

13. The agent according to any one of claim 1, 2, 10, 11 and 12, wherein,

solid cancers are pancreatic cancers with distant metastasis.

14. The agent of any one of claims 1, 2, 10, 11, 12 and 13, which is administered as a primary treatment to a patient who has not undergone treatment with a systemic anti-malignant agent for pancreatic cancer with distant metastasis.

15. The agent according to any one of claims 1 to 14, wherein,

the CD 47-inhibiting substance is an anti-CD 47 antibody.

16. The agent according to claim 15, wherein,

the anti-CD 47 antibody is Mo Luoli mab.

17. The agent according to claim 16, wherein,

as Mo Luoli, 1mg/kg (body weight) was administered intravenously at the time of the initial administration, and 15mg/kg (body weight) to 30mg/kg (body weight) was administered intravenously at 1-week intervals or 2-week intervals after the second administration.

18. The agent according to claim 16 or 17, wherein,

as Mo Luoli, 1mg/kg (body weight) was administered intravenously at the time of the first administration, and 30mg/kg (body weight) was administered intravenously at 1-week intervals or 2-week intervals after the second administration.

19. The agent according to any one of claims 1 to 18, wherein,

The immune checkpoint inhibitory substance is an anti-PD-1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.

20. The agent according to any one of claims 1 to 19, wherein,

the immune checkpoint inhibitory substance is an anti-PD-1 antibody.

21. The agent according to claim 19 or 20, wherein,

the anti-PD-1 antibody is Nawuzumab, simaroubno Li Shan antibody, pabrizumab, stadazumab, tilapizumab, AMP-514, duotolimab, terlipressin Li Shan antibody, caririzumab, jernomoab, xindi Li Shan antibody, STI-A1110, ENUM 388D4, ENUM 244C8, GLS 010, raffin Li Shan antibody, batilimumab, CS1003, st Lu Lishan antibody, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, sym021, jerlow Li Shan antibody, SSI-361, JY034, HX008, ISU106, bragg Li Shan antibody, paruo Li Shan antibody, sashan Li Shan antibody, CX-188, west lizumab or Paricumab.

22. The agent according to claim 21, wherein,

the anti-PD-1 antibody is nivolumab.

23. The agent according to claim 22, wherein,

as nivolumab, 480mg was administered intravenously at 4 week intervals.