Treatment of metastatic pancreatic adenocarcinoma

Abstract

To provide methods for the treatment of metastatic pancreatic adenocarcinoma and uses of agents.SOLUTION: A method of treating metastatic pancreatic adenocarcinoma in a subject in need thereof is provided. The method comprises administering to the subject a therapeutically effective amount of each of a peptide set forth in a specific sequence, an anti PD-1 and a chemotherapy, thereby treating the metastatic pancreatic adenocarcinoma.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related applications This application is based on U.S. Provisional Patent Application No. 62 / 746,5 filed on October 17, 2018. Claiming the benefit of priority under Patent No. 87, the content of that U.S. provisional patent application, as a whole, is referred to in this It is included in the specification.

[0002] Statements in sequence listings Filing this application simultaneously with the filing of this application, including 1018 bytes, on October 17, 2019. A file named 78928 Sequence Listing.txt was created in [location]. SCII files are incorporated herein by reference.

[0003] In some embodiments, the present invention provides a method for treating metastatic pancreatic adenocarcinoma and Regarding the use of toxic substances. [Background technology]

[0004] Cancer immunotherapy, a new and rapidly growing field of research, aims to fight cancer by utilizing the body's own... We will research the use of therapies that utilize the body's immune system. Tumors have various mechanisms to evade host immune detection. It utilizes the following mechanisms: myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and Tumor-infiltrating immune cells, such as tumor-associated macrophages, actively regulate the tumor microenvironment. There is a mountain of evidence that this response suppresses the effector arm. Cancer immunotherapy The objective of the approach is to suppress the tumor's ability to be detected and eliminated by its own host immune system. The goal is to block it. Several biological mechanisms target a series of immune signaling pathways. Substances, for example, programmed death receptor 1 (PD-1) / programmed death receptor ligand 1 (P D-L1), lymphocyte activation gene 3 (LAG-3), and killer immunoglobulin-like receptors KIR is currently in clinical development for the treatment of various cancers. However, one of the target groups... This is a result of local immunosuppression mediated by stroma cells (mainly fibroblasts). These treatments are ineffective. Activated fibroblasts in tumor stromas are present in several mutilations. It was found to mediate immunosuppression in a cancer model. The basis of this immunosuppression was One suggestion is that fibroblast stromal cells produce the chemokine CXCL12. Hmm. The binding of CXCL12 by T cells leads to their elimination from the vicinity of those cancer cells. T cell elimination occurs despite the presence of cancer-specific CD8+ T cells, and T cell checkpoints It neutralizes the antagonist. Preclinical studies have shown that this immunosuppression is effective in treating CXCL12. The condition is inhibited by the administration of inhibitors of the CXC chemokine receptor 4 (CXCR4), and This leads to the rapid accumulation of T cells among cancer cells, thereby triggering immune checkpoints. We demonstrated the removal of the veil of efficacy of inhibitors.

[0005] BL-8040 BL-8040 (formerly named BKT140, Sequence ID 1) is a highly selective CX It is a CR4 antagonist. The investigational drug has high affinity for CXCR4 (IC). 50 0.5 14, which bind at a density of 4-4.5 nM and inhibit its function, are capped with aromatic rings. It is a cyclic synthetic peptide of residues [1]. Chemokine CXCL12 (SDF-1 stroma The originating factor 1) and its receptor, CXCR4, are involved in the transport of hematopoietic cells to the bone marrow (BM). It plays a central role in [2]. The activity of BL-8040 in various mouse cancer models Animal studies exploring it have shown that, in addition to its activity as a hematopoietic cell mobilizing factor, BL-804 0 exhibits a CXCR4-dependent preferential antitumor effect against malignant cells overexpressing CXCR4[3]. The efficacy of BL-8040 and its analogs for blocking CXCR4 in vitro and in vivo has been demonstrated in a number of preclinical studies, including in vitro and in vivo models for small cell lung cancer, breast cancer, malignant melanoma, neuroblastoma, and pancreatic cancer. As a CXCR4 antagonist, BL- 8040 also affects the transport of immune cells into the tumor microenvironment. Administration of BL-8040 has been found to induce the mobilization of natural killer (NK) cells, T cells, and B cells from the BM and lymph nodes to their periphery. Using a syngeneic cancer model in mice, it has been shown that BL- 8040 removes the immunological barrier and enables the accumulation of immune cells within the tumor microenvironment. In vitro and in vivo models for small cell lung cancer, breast cancer, malignant melanoma, neuroblastoma, and pancreatic cancer are included. 8040 also affects the transport of immune cells into the tumor microenvironment. Administration of BL-8040 has been found to induce the mobilization of natural killer (NK) cells, T cells, and B cells from the BM and lymph nodes to their periphery. Using a syngeneic cancer model in mice, it has been shown that BL-8040 removes the immunological barrier and enables the accumulation of immune cells within the tumor microenvironment. Using a syngeneic cancer model in mice, it has been shown that BL-8040 removes the immunological barrier and enables the accumulation of immune cells within the tumor microenvironment. Using a syngeneic cancer model in mice, it has been shown that BL-8040 removes the immunological barrier and enables the accumulation of immune cells within the tumor microenvironment. It has been shown that BL-8040 can remove the immunological barrier and enable the accumulation of immune cells within the tumor microenvironment.

[0006] Preclinical studies The nonclinical development of BL-8040 includes a number of pharmacodynamic, pharmacokinetic (PK), safety pharmacology, as well as single and repeated dose toxicity studies.

[0007] BL-8040 exhibits CXCR4-dependent selective cytotoxicity to malignant cells both in vivo and in vitro, inducing apoptotic cell death in cancer cells[3-6]. BL- 8040 causes phosphatidylserine externalization, a decrease in mitochondrial membrane potential, caspase activation, subsequent sub-G1 arrest, and DNA double-strand breaks in leukemia cells and multiple myeloma cells[3]. These effects have been shown to be specific; BL- 8040 causes phosphatidylserine externalization, a decrease in mitochondrial membrane potential, caspase activation, subsequent sub-G1 arrest, and DNA double-strand breaks in leukemia cells and multiple myeloma cells[3]. These effects have been shown to be specific; BL-8040 causes phosphatidylserine externalization, a decrease in mitochondrial membrane potential, caspase activation, subsequent sub-G1 arrest, and DNA double-strand breaks in leukemia cells and multiple myeloma cells[3]. These effects have been shown to be specific; BL-8040 causes phosphatidylserine externalization, a decrease in mitochondrial membrane potential, caspase activation, subsequent sub-G1 arrest, and DNA double-strand breaks in leukemia cells and multiple myeloma cells[3]. 8040 did not affect the viability of human keratinocytes or normal human hematopoietic cells. [3] In addition to its mobilization capacity, the nature of this direct apoptotic effect is that of Mozobil / Pl Distinguish BL-8040 from other CXCR4 antagonists such as erixafor. [3] In addition, administration of BL-8040 stimulates NK cells, T cells, and B cells in the BM It also induces the mobilization of lymph nodes to the surrounding areas.

[0008] BL-8040 has shown safety and first-class results in several Phase I and Phase II trials. [Hidalgo MM, Epelbaum R, Semenisty V, Geva R, Golan T,] demonstrating clinical efficacy. Borazanci EH. Evaluation of pharmacodynamic (PD) biomarkers in patients with met astatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist. J Clin Oncol. 2018; 36:88-88. Abstract].

[0009] Pembrolizumab Pembrolizumab is a potent humanized immunoglobulin with high specificity for binding to the PD-1 receptor. It is a robulin G4 (IgG4) monoclonal antibody (mAb), and therefore PD-1 It inhibits the interaction with PD-L1 and PD-L2. Based on preclinical in vitro data. Therefore, pembrolizumab is a high-affinity and potent receptor blocker for PD-1. It is active. Pembrolizumab has an acceptable preclinical safety profile and progresses It is currently in clinical development as an IV immunotherapy for malignant tumors. Keytruda (Registered Trademark) Pembrolizumab is indicated for the treatment of patients across several indications.

[0010] Pharmaceutical and therapeutic background The importance of intact immune surveillance mechanisms in regulating the proliferation of neoplastic transformations has been recognized for decades. It has been known for some time.[7] Accumulation of evidence has shown that tumor-infiltrating lymphocytes in cancer tissue are different. A correlation has been shown with a favorable prognosis in malignant tumors. In particular, the presence of CD8+ T cells The ratio of CD8+ effector T cells to FoxP3+ regulatory T cells (Treg) is in the egg. Cancers of the nephrotic tract, colorectal tract, and pancreas; hepatocellular carcinoma; malignant melanoma; and solid malignancies such as renal cell carcinoma. Tumor-infiltrating lymphocytes correlate with improved prognosis and long-term survival in sexual tumors. It can be grown and reinjected, and provides a persistent objective tumor response in cancers such as melanoma. This induces [8, 9].

[0011] PD-1 receptor-ligand interactions are hijacked by tumors to suppress immunomodulation. This is the main pathway. PD-1 expressed on the cell surface of activated T cells under healthy conditions Its normal function is to downregulate unwanted or excessive immune responses, including autoimmune reactions. This is the case. PD-1 (encoded by the gene Pdcd1) has its ligand (P Binding to D-L1 and / or PD-L2 negatively regulates antigen receptor signaling. Surface antigen classification 28 (CD28) and cytotoxic T lymphocyte-associated antigens have been shown to be related to the following: Immunoglobulin (Ig) superfamily members related to protein 4 (CTLA-4) It is a bar. [10, 11]

[0012] The structure of mouse PD-1 has been elucidated

[12] . PD-1 and its family The members include the Ig variable (IgV type) domain responsible for ligand binding and the signaling molecule. It is a type I transmembrane glycoprotein that contains a cytoplasmic terminal responsible for the binding of offspring. PD-1 cells The tertiary end consists of two tyrosine-dependent signaling motifs, and an immune receptor tyrosine-dependent inhibitory receptor. It contains a control motif and an immune receptor tyrosine-dependent switch motif. PD-1 is a tyrosine phosphatase, and it is used to stimulate the cytoplasm of SHP-1 and SHP-2. It is recruited to the tyrosine-dependent switch motif of the immune receptor in the lateral terminal, and CD3 T cell signals CD3 zeta (CD3ζ) and protein kinase C-C are involved in the signal transduction cascade. Effects such as quaternary zeta (PKCθ) and zeta chain-related protein kinase (ZAP70) It leads to the dephosphorylation of T-cell molecules [11, 13-15]. PD-1 downregulates the T-cell response. The linking mechanism is the mechanism of CTLA-4, and both molecules are involved in a redundant set of signaling pathways. They are similar but different in that they both regulate proteins.[16, 17] Conclusion Therefore, the PD-1 / PD-L1 pathway is an attractive target for therapeutic intervention in pancreatic cancer. ru.

[0013] Preclinical and clinical trials Therapeutic studies in mouse models have shown that it can be used as a monotherapy or in combination with other treatment modalities. Concurrent administration of antibodies that block PD-1 / PD-L1 interaction is used to treat tumor-specific CD. It has been shown to enhance 8+ T cell infiltration and ultimately lead to tumor rejection [18~ 23] Anti-mouse PD-1 antibody or anti-mouse PD-L1 antibody is used for squamous cell carcinoma, pancreatic cancer, black It has shown an antitumor response in models of chromoma, AML, and colorectal cancer [12, 22]. ~25]. In such studies, tumor invasion by CD8+ T cells, and IFN Increased expression of γ, granzyme B, and perforin was observed, and PD-1 checkpoint The underlying mechanism of the antitumor activity of inhibitory receptors is the localization of effector T cells in vivo. This indicates infiltration and activation of its function

[22] . Experiments have shown syngeneic mouse tumors In models, the use of anti-mouse PD-1 antibodies as monotherapy and in combination with chemotherapy. In vivo efficacy has been confirmed (see pembrolizumab IB).

[0014] Chemotherapy: Nanoliposomal irinotecan with fluorouracil and leucovorin (Onivyde (registered trademark) in conjunction with 5-FU / LV) Liposomal irinotecan has pharmacological and clinical effects compared to non-liposomal irinotecan. To overcome limitations, the topoisomerase-1 inhibitor irinotecan was developed for use in liposomes. It is an encapsulated formulation [26, 27]. 5-FU is indicated for the treatment of patients with pancreatic adenocarcinoma. It is a nucleoside metabolism inhibitor.

[28] LV is a chemically reduced derivative of folic acid. It can enhance the therapeutic and toxic effects of 5-FU. Simultaneous administration of LV. It appears that this does not alter the plasma pharmacokinetics of 5-FU. 5-FU is fluorodeo It is metabolized to xyuridylic acid, and this fluorodeoxyuridylic acid is converted into the enzyme thymidylate synthia. It binds to and inhibits enzymes (enzymes important in DNA repair and replication). LV is another enzyme. It is readily converted to protofolate, 5,10-methylenetetrahydrofolate, and its 5,10-methylenetetrahydrofolate Lentetrahydrofolate binds to thymidylate synthase of fluorodeoxyuridylic acid. It works to stabilize the enzyme, thereby enhancing its inhibition.

[29] Posomal irinotecan injection (Onivyde®) is gemcitabine-based In patients with metastatic pancreatic adenocarcinoma that has progressed after treatment, 5-FU and LV( It is approved for use in combination with 5-FU / LV. It is used after gemcitabine-based treatment. Central international collaborative Phase III NAPO in patients with advanced metastatic pancreatic adenocarcinoma In the LI-1 trial, liposomal irinotecan used in combination with 5-FU / LV was 5-F Compared to U / LV controlled therapy, the primary analysis (after 313 events) and the final analysis (38 At the point after two events, the median overall survival (OS) (primary endpoint) It significantly extended the median progression-free survival (PFS) and objective response rate (ORR). Furthermore, the liposomal irinotecan + 5-FU / LV group showed significantly better results than the control group. It was expensive. Combination therapy based on liposomal irinotecan has a manageable safety profile. The most common grade 3 severe TEAEs are actually hematologically and It was the gastrointestinal tract.[26, 27]

[0015] Indications for treatment Pancreatic cancer is a malignant neoplasm of the pancreas with a low early diagnosis rate and poor prognosis. The rate has been rising in recent years, and it now accounts for 1% to 2% of common tumors. Every year, Approximately 185,000 people worldwide have been diagnosed with this condition. Its symptoms are usually nonspecific. Because it is unusual, pancreatic cancer is often not diagnosed until it reaches an advanced stage. The only treatment with a chance of cure is surgical excision. Unfortunately, only 20% of patients... Only tumors in this area are resectable at the time of diagnosis. Those who have undergone resection for pancreatic cancer and have negative margins. Even among those patients, the five-year survival rate is only 10% to 25%.[30, 31] The 5-year overall survival rate among patients is less than 5%, which is the highest among solid malignancies. This corresponds to the mortality rate. The median overall survival time is less than one year from diagnosis, and newer treatments This highlights the need to develop alternatives.

[0016] The anatomical structure of the pancreas is very complex. High interstitial tension and insufficient hemoperfusion in pancreatic tumors. The flow makes them extremely resistant to most chemotherapy drugs. As a result, Conventional systemic IV chemotherapy often fails to reach effective concentrations. The amount may cause serious adverse reactions, and therefore impair the immune system and potentially It reduces the effectiveness of treatment. Failure of clinical procedures in patients with pancreatic ductal adenocarcinoma increases the risk of early metastasis. This is due to proliferation, high levels of drug resistance to standard treatment options, and a high rate of local recurrence. In many cases

[32] .

[0017] Despite recent advances in understanding chemotherapeutic agents and the molecular biology of pancreatic cancer, metastatic Advances in treatment options for the disease are limited. Over the past 40 years, several complications have been discussed. Studies on oral therapy have shown a slight life-extending effect compared to gemcitabine alone, It has shown no life-prolonging effect whatsoever. Combination therapy with gemcitabine and erlotinib has a median survival time. Gemcitabine monotherapy for several years until it was shown to increase the value by two weeks, in the metastatic pancreas It was the standard of care for patients with cancer. However, its moderate life-extending effect was However, this was stifled by its significant side effect profile and high treatment costs. Later, L Multiple drugs including V, 5-FU, irinotecan, and oxaliplatin (FOLFIRINOX) The combination therapy showed an increase in median survival time of 4.3 months; however, its side effects were... Considering the file, it is only available to a selected group of patients with advanced pancreatic cancer. Yes, it is possible. Recently, gemcitabine + nab-paclitaxel combination therapy has shown to reduce the median survival time by 1 It was shown that OS increased over 8 months, and over 1 year and 2 years; AE These were reasonable; they included cytopenia and peripheral neuropathy.

[33] The National Comprehensive Cancer Network recommends good Performance status (i.e., ECOG performance status of 0 or 1) For patients with good pain management, a patent bile duct stent, and adequate nutrition, This suggests that combination chemotherapy is acceptable; these combinations include FOLFIRINOX, Gem Examples include citabine + nab-paclitaxel and gemcitabine + erlotinib. The only recommended option for patients with poor performance status is G This is mucitabine monotherapy. In 2015, Onivyde (registered trademark) released gemcitabine. In patients with metastatic pancreatic adenocarcinoma in a second-line setting after disease progression following treatment, based on the following criteria: For the first time in the US and EU, it has been introduced as a chemotherapy agent to be used in combination with 5-FU and LV for treatment. It was approved.[26,34]

[0018] Additional background technologies include: International Publication No. 2017009843 International publication no. 2017009842. [Overview of the project] [Means for solving the problem]

[0019] According to some embodiments of the present invention, metastatic pancreatic adenocarcinoma in the target population as required. A method for treating the following: the peptide described in SEQ ID NO: 1, anti-PD-1, and chemotherapy The treatment involves administering each therapeutically effective dose to target the patient, thereby treating metastatic pancreatic adenocarcinoma. A method is provided that includes the following.

[0020] According to some embodiments of the present invention, metastatic pancreatic adenocarcinoma in the target population as required. For use in treating, the peptide described in SEQ ID NO: 1, anti-PD-1, and The therapeutically effective doses of each chemotherapy agent are provided.

[0021] According to some embodiments of the present invention, for use in the treatment of metastatic pancreatic adenocarcinoma Therefore, the therapeutic effects of the peptide, anti-PD-1, and chemotherapy described in SEQ ID NO: 1 are as follows: Products containing efficacy are provided.

[0022] According to some embodiments of the present invention, the anti-PD-1 agent is pembrolizumab.

[0023] According to some embodiments of the present invention, chemotherapy comprises a plurality of chemotherapeutic agents.

[0024] According to some embodiments of the present invention, chemotherapy involves irinotecan and fluorouracil. It contains (5-FU) and leucovorin (LV).

[0025] According to some embodiments of the present invention, irinotecan is encapsulated in liposomes.

[0026] According to some embodiments of the present invention, irinotecan is used in Onivyde®. be.

[0027] According to some embodiments of the present invention, the peptide is administered subcutaneously (SC).

[0028] According to some embodiments of the present invention, the peptide is administered at a dose of 1.25 mg / kg. It will be done.

[0029] According to some embodiments of the present invention, anti-PD-1 is administered intravenously (IV).

[0030] According to some embodiments of the present invention, anti-PD-1 is administered in a dose of 200 mg. .

[0031] According to some embodiments of the present invention, chemotherapy is administered intravenously.

[0032] According to some embodiments of the present invention, the treatment involves a period of monotherapy with a peptide, followed by... This includes combination therapies with peptides, anti-PD-1, and chemotherapy.

[0033] According to some embodiments of the present invention, combination therapy with chemotherapy and anti-PD-1 lasts for 8 days. It begins with the eye.

[0034] According to some embodiments of the present invention, combination therapy involves repeating chemotherapy every two weeks. This involves repeating anti-PD-1 therapy every three weeks.

[0035] According to some embodiments of the present invention, combination therapy with peptides is initiated on day 10. , twice a week on non-consecutive days, at least 24 hours after chemotherapy, and 48 hours apart. ru.

[0036] According to some embodiments of the present invention, monotherapy is administered daily on days 1 to 5.

[0037] According to some embodiments of the present invention, the treatment further includes an antihistamine, and optionally , including painkillers.

[0038] According to some embodiments of the present invention, the combination therapy is continued for up to 35 treatments.

[0039] According to some embodiments of the present invention, the subject is a first-line treatment for metastatic pancreatic adenocarcinoma. It was later.

[0040] According to some embodiments of the present invention, the first choice treatment is a chemical treatment based on gemcitabine. Includes therapy.

[0041] According to some embodiments of the present invention, metastatic pancreatic adenocarcinoma is unresectable.

[0042] According to some embodiments of the present invention, metastatic pancreatic adenocarcinoma is pancreatic ductal adenocarcinoma.

[0043] According to some embodiments of the present invention, metastatic pancreatic ductal adenocarcinoma is a pancreatic papillary mucinous neoplasm. include.

[0044] Unless otherwise specified, all technical and / or scientific terms used herein are defined as follows: , having the same meaning as generally understood by those skilled in the art. (as described herein) Similar or equivalent methods and materials may be used in the practice or testing of embodiments of the present invention. This is possible, but illustrative methods and / or materials are listed below. In case of inconsistency, This specification, including its definitions, shall prevail. In addition, its materials, methods, and examples shall be governed by This is merely illustrative and not necessarily limiting.

[0045] Some embodiments of the present invention are described herein only as examples, with reference to the accompanying drawings. It is being done. Currently, I am referring to the drawings in detail, and the details shown are, for example, Therefore, I strongly assert that this is for the purpose of illustrating embodiments of the present invention. In relation to the drawings, the embodiments of the present invention may be put into practice. This will become clear to those skilled in the art. [Brief explanation of the drawing]

[0046] [Figure 1] This figure shows an embodiment of the treatment regimen. [Modes for carrying out the invention]

[0047] In some embodiments, the present invention provides a method and action for the treatment of pancreatic adenocarcinoma. Regarding the use of substances.

[0048] Before describing in detail at least one embodiment of the present invention, let us explain that the present invention is applicable to the following applications. However, this is not necessarily limited to the details shown in the following description or illustrated in the examples. It should be understood that there are no other embodiments of this invention. Other embodiments are possible, or various It can be practiced or implemented in any manner.

[0049] The inventors have developed a novel method for treating metastatic pancreatic adenocarcinoma in human subjects where there is a need. The clinical protocol was developed through painstaking experiments and screenings.

[0050] Therefore, according to an aspect of the present invention, metastatic pancreatic adenocarcinoma can be treated in the target area as needed. A method comprising the peptide, anti-PD-1, and chemotherapy described in SEQ ID NO: 1, respectively. This includes administering a therapeutically effective dose to target the patient, thereby treating metastatic pancreatic adenocarcinoma. A method is provided.

[0051] According to another aspect of the present invention, metastatic pancreatic adenocarcinoma can be treated in the target population where it is needed. For use in the following applications, the peptide described in SEQ ID NO: 1, anti-PD-1, and chemotherapy Each is provided in a therapeutically effective dose.

[0052] According to another aspect of the present invention, for use in the treatment of metastatic pancreatic adenocarcinoma, SEQ ID NO: 1 The therapeutically effective amounts of the peptide, anti-PD-1, and chemotherapy described are provided. .

[0053] As used herein, “metastatic pancreatic adenocarcinoma” means a tumor that has spread outside the pancreas, i.e. If present in lymph nodes or other distal locations, it indicates stages IIb to IV of the disease. vinegar.

[0054] [Table 1-1] [Table 1-2]

[0055] According to certain embodiments, metastatic pancreatic adenocarcinoma is pancreatic ductal adenocarcinoma.

[0056] As used herein, “pancreatic ductal adenocarcinoma” (PDAC) is a type of exocrine pancreatic cancer. These are the cells that line the small tubes in the pancreas called ducts (as shown in the table above). They originate from ductal cells. These then deliver enzyme-containing digestive fluids to the main pancreatic duct, and then... It is transported into the bidenum (the first part of the small intestine). PDAC can grow anywhere in the pancreas. However, it is almost always found in the head of the pancreas.

[0057] According to certain embodiments, PDAC includes intraductal papillary mucinous neoplasms.

[0058] In some embodiments, pancreatic cancer is recurrent pancreatic cancer.

[0059] In some embodiments, pancreatic cancer recurs after remission.

[0060] In some embodiments, individuals are measurable (e.g., by RECIST standards). He has a disease.

[0061] In some embodiments, the individual is examined, for example, by CT scan (or MRI) , having one or more measurable metastatic tumors.

[0062] In some embodiments, the pancreatic cancer is unresectable. In this context, pancreatic cancer is a type of pancreatic cancer that can be surgically removed.

[0063] In some embodiments, pancreatic cancer is borderline resectable.

[0064] In some embodiments, the primary site of pancreatic cancer is the head of the pancreas. In this context, the primary site of pancreatic cancer is the main body of the pancreas. In some embodiments, the primary site of pancreatic cancer The location of residence is the tail of the pancreas.

[0065] As used herein, “subject” refers to a human subject diagnosed with metastatic pancreatic adenocarcinoma. .

[0066] In some embodiments, the subject is female. In some embodiments, the individual The individual is male. In some embodiments, the individual is less than about 65 years old (e.g., about 60 years old) Any of the following: under, under approximately 55 years old, under approximately 50 years old, under approximately 45 years old, or under approximately 40 years old (k) In some embodiments, the subjects are at least about 65 years old (for example, at least They are all approximately 70 years old, at least approximately 75 years old, or at least approximately 80 years old.

[0067] According to certain embodiments, the subjects are at least 18 years of age.

[0068] According to a particular embodiment, the procedure is performed after first-line treatment for pancreatic adenocarcinoma.

[0069] Therefore, the methods, articles, and compositions described herein, as well as the methods, articles, and compositions related to pancreatic cancer If pretreatment fails or is substantially unsuccessful, or if the pancreatic cancer is not treated as a first-line treatment If the patient is substantially resistant, it may be used as a second-line or third-line treatment. In some embodiments, the individual has pancreatic cancer (e.g.) before receiving the treatment described herein. For example, at least one line of treatment (e.g., chemotherapy) to treat metastatic pancreatic cancer. (is receiving immunotherapy). In some embodiments, the patient receives one line of treatment or He is receiving two lines of treatment (for example, one line of chemotherapy or immunotherapy). Therefore, the treatments described herein may be used as second-line treatments. The preceding line of treatment may be the same as the preceding line of chemotherapy or immunotherapy. First-line treatment This may include any of the following: gemcitabine, 5-FU, masitinib, Paclitaxel, trametinib, and / or erlotinib.

[0070] According to a particular embodiment, the first-line treatment is gemcitabine-based chemotherapy, for example For example, gemcitabine under the brand name Gemzar (trademark).

[0071] According to a particular embodiment, the disease is treated with a first-line, for example, gemcitabine-based, chemical The disease progression was observed on X-ray examination after discontinuing treatment with medical therapy.

[0072] As used herein, the term "to treat" means to prevent the progression of a condition, to implement Qualitative inhibition, slowing, or reversal; clinical symptoms of metastatic pancreatic adenocarcinoma. This includes substantially relieving the condition.

[0073] According to a particular embodiment, the subject is diagnosed with metastatic pancreatic adenocarcinoma.

[0074] According to certain embodiments, metastatic pancreatic adenocarcinoma is histologically confirmed (previously (A new biopsy has been performed at either location.)

[0075] According to a particular embodiment, the subject is a response evaluation criterion in solid tumors. Measurable diseases based on Ion Criteria In Solid Tumors (RECIST) v1.1 It has a measurable lesion (≥1).

[0076] According to a particular embodiment, tumor lesions located in a previously irradiated area are such If progression is evident in the lesion, it is considered measurable.

[0077] According to certain embodiments, the subject is histologically confirmed (either previously or newly) Metastatic, unresectable pancreatic adenocarcinoma, including intraductal papillary mucinous neoplasms (biopsy performed at any site). It holds.

[0078] According to a particular embodiment, pancreatic cancer can be acinar cell carcinoma, pancreatic blastoma, or malignant cystic tumor. Whether it is an endocrine neoplasm, squamous cell carcinoma, or a malignant tumor of the duodenum around Vater's and ampulla, It is neither a malignant tumor of the common bile duct.

[0079] According to certain embodiments, the subject does not have intestinal obstruction.

[0080] According to certain embodiments, the subjects are not immunocompromised.

[0081] According to a particular embodiment, the subject has undergone systemic treatment (i.e.,) in the two years prior to this procedure. Treatment requiring the use of disease-modifying agents, corticosteroids, or immunosuppressants. They do not have any known autoimmune diseases.

[0082] According to a specific embodiment, the subject has a history of (non-infectious) pneumonitis requiring steroids. Neither the current pneumonia nor the pneumonia will last.

[0083] According to certain embodiments, the subjects do not have a history of interstitial lung disease.

[0084] As used herein, BL-8040 (formerly known as "BKT140") The peptide described in SEQ ID NO: 1, also known as ), is a novel treatment for cancer. It is a highly selective CXCR4 antagonist. Its peptide has high affinity for CXCR4. I C 50 It binds at a molecular weight of 0.54-4.5 nM and inhibits its function, capped by an aromatic ring. A pinged, 14-residue cyclic synthetic peptide [Tamamura H, Hiramatsu K, Kusano S, Terakubo S, Yamamoto N, Trent JO, et al. Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives Org Biomol Chem 2003;1:3656-3662].

[0085] According to a particular embodiment, BL-8040 is used in water and 0.45% sodium chloride ( A white to off-white powdered synthetic polypeptide that dissolves easily in half saline solution. It is manufactured as a Chido. It is BioConnection BV (formerly MSD) ), Kloosterstraat 9, 5349 AB Oss, Netherlan ds provides the latest Good Manufacturing Practice (cGMP) It is manufactured according to the following.

[0086] PD1 (also known as CD279, programmed death 1) is an Ig gene superfamily It is a 55kDa type I transmembrane glycoprotein that is part of Lee, and is used by activated T cells, B cells, and It is expressed on the surface of several immune cells, including NK cells and myeloid cells. PD- 1 consists of a membrane-proximal immunoreceptor tyrosine repression motif (ITIM) and a membrane-distal tyrosine receptor It contains an Existential Switch Motif (ITSM).

[0087] The presence of ITIM on PD-1 suggests that this molecule is involved in the recruitment of cytoplasmic phosphatases. It has been shown that it functions to attenuate protoreceptor signaling.

[0088] According to a specific embodiment, the PD1 protein is GenBank number NP_00500 This refers to human proteins such as those provided in 9. Two ligands for PD-1, P D-L1 and PD-L2 (also known as B7-DC) have been identified.

[0089] The expression and function patterns of PD1 are cell type-dependent. PD1 expression is an effector. - Induced after T cell activation. Through ligand binding, PD1 is involved in T cell activation. The kinase is inhibited, for example, through the phosphatase SHP2, thereby inhibiting the kinase It transmits nal. Conversely, PD1 is highly expressed on regulatory T cells, and its regulatory T In cells, it can enhance the proliferation of regulatory T cells through ligand binding. PD- 1 also induces other activated non-T lymphocyte subsets, such as B cells and NK cells. It is then guided there, and it is through ligand binding that their antibody production and lysis activity are stimulated. Each transmits a restrictive inhibitory signal [Pardoll (2012) Nature Reviews Cancer 12, [252-264]

[0090] As used herein, "anti-PD-1" refers to a substance that binds to PD-1 and inhibits the biological activity of PD-1. This refers to antibodies that prevent and / or inhibit medical functions.

[0091] According to a particular embodiment, a PD1 antagonist is an immune cell affected by PD1 (for example, To prevent and / or inhibit signaling to T cells, B cells, and NK cells; thereby This suppresses PD1 immunosuppressive activity.

[0092] As used in this invention, the term "antibody" refers to an intact molecule, in addition to (an antigen's epitope). It contains its functional fragment (which has the ability to bind with it).

[0093] As used herein, the term “epitope” means the paratope to which an antibody binds. This refers to any antigenic determinant on the original molecule. Epitope determinants are usually amino acids or carbohydrate side chains. Which molecules consist of chemically active surface groupings, typically with specific three-dimensional structural properties and specific It has the following charge characteristics.

[0094] According to a particular embodiment, the antibody fragment binds to the antigen epitope in an HLA-restrictive manner. It has the ability to do so, single-stranded, Fab, Fab', and F(ab')2 fragments, Fd, Fca b, Fv, dsFv, scFv, diabody, minibody, nanobody, Fab expression Examples include, but are not limited to, single-domain molecules such as Ibrari, VH, and VL. It will not be done.

[0095] Suitable antibody fragments for practicing some embodiments of the present invention include immunoglobulin fragments. Complementarity-determining regions (CDRs) of the chain (referred to herein as "light chains"), immunoglobulin heavy chains ( Complementarity-determining region of the heavy chain (referred to as the "heavy chain" in this specification), variable region of the light chain, variable region of the heavy chain, light Chain, heavy chain, Fd fragment, Fv, single-strand Fv (scFv), disulfide-stabilized Fv (dsF v) Essentially all of the light and heavy chains, such as Fab, Fab', and F(ab')2 Examples include antibody fragments containing a variable region, or antibody fragments containing the Fc region of an antibody.

[0096] As used herein, the terms “complementarity-determining region” or “CDR” refer to the heavy chain and It is interchangeably used to refer to the antigen-binding region found within the variable region of a light chain polypeptide. Generally, antibodies have three CDRs (CDR H1 or H) in each of the VHs. 1; CDR H2 or H2; and CDR H3 or H3) and VL respectively In the case of three CDRs (CDR L1 or L1; CDR L2 or L2; and CDR Includes L3 or L3).

[0097] The identity of amino acid residues in specific antibodies that constitute a variable region or CDR. This can be determined using methods well known in the art, and these methods include Kab at et al. (for example, Kabat et al., 1992, Sequences of Proteins of Immunological Inter) (See est, 5th ed., Public Health Service, NIH, Washington DC) Sequence diversity such as that seen in Chothia et al. (e.g., Chothia et al., Nature 342:877-8) The location of the structural loop region as defined by (see 83, 1989), Oxford M olecular AbM antibody modeling software (currently Accelrys (registered) (Trademark), Martin et al., 1989, Proc. Natl Acad Sci USA. 86:9268; and WorldW (See the Id website www(dot)bioinf-org(dot)uk / abs) A hybrid of Kabat and Chothia, as defined by contact definitions. possible complex crystal structures (see MacCallum et al., J. Mol. Biol. 262:732-745, 1996); and "Definition of three-dimensional structure" (e.g., Makabe et al., Journal of Biological Chemistry, Examples of such methods include (see 283:1156-1166, 2008).

[0098] As used herein, “variable region” and “CDR” refer to a combination of approaches. This includes variable regions and CD as defined by any approach known in the art. This could refer to R.

[0099] Functional antibody fragments containing all or essentially all of the variable regions of the light and heavy chains are as follows: Defined as: (i) Fv, the variable region (VL) of the light chain and the variable region (V) of the heavy chain expressed as two separate chains. It is defined as a genetically modified fragment consisting of H); (ii) Single-stranded Fv ("scFv"), as a single-stranded molecule formed by gene fusion, appropriate poly Genetic components include variable regions of the light chain and heavy chain linked by peptide linkers. A single-stranded molecule that has been manipulated; (iii) Disulfide-stabilized Fv ("dsFv"), genetically modified disulfide bonds Genetically modified antibodies, including variable light chain regions and variable heavy chain regions linked by fusion. body; (iv) The entire antibody is treated with the enzyme papain to remove the intact light chain and the variable heavy chain. It can be obtained by generating a heavy chain Fd fragment consisting of the main and CH1 domains. A fragment of an antibody molecule containing the monovalent antigen-binding portion of the antibody molecule; (v)Fab' is obtained by treating the entire antibody with the enzyme pepsin and then reducing it. This can be achieved (two Fab's are obtained for each antibody molecule), and the monovalent antigenic bond of the antibody molecule is formed. A fragment of an antibody molecule containing a combined portion; (vi)F(ab')2 can be obtained by treating the entire antibody with the enzyme pepsin. A fragment of an antibody molecule (i.e., two disulfides) containing the monovalent antigen-binding portion of the antibody molecule. Dimers of Fab' fragments held together by phytobonds; (vii) Single-domain antibodies or nanobodies that exhibit sufficient affinity for the antigen, It consists of one VH or VL domain; and (viii) FCab, by introducing antigen-binding capability into the Fc region of the antibody, A fragment of an antibody molecule containing the Fc portion, which was developed as the main component.

[0100] Methods for producing polyclonal antibodies and monoclonal antibodies, as well as their fragments, are , which is well known in the art (for example, incorporated herein by reference, Harl ow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New (See York, 1988).

[0101] Exemplary methods for producing antibodies include in vivo induction of antibody molecule production and immunoglobulin therapy. Library screening (Orlandi DR et al., 1989. Proc. Natl. Acad. Sci.) USA 86:3833-3837; Winter G. et al., 1991. Nature 349:293-299), or culture The process involves the production of monoclonal antibody molecules using continuous cell lines. These include hybrids. Human B-cell hybridoma technology, human B-cell hybridoma technology, and Epstein-Barr virus (EBV) technology. )Hybridoma technology is one example, but it is not limited to these (Kohler G. et al., 1975) . Nature 256:495-497;Kozbor D. et al., 1985. J. Immunol. Methods 81:31-42;Cote RJ. et al., 1983. Proc. Natl. Acad. Sci. USA 80:2026-2030;Cole SP. et al. , 1984. Mol. Cell. Biol. 62:109-120).

[0102] When producing antibodies in vivo, the target antigen must be small enough to induce a sufficient immunogenic response. In such cases, such antigens (haptens) are keyhole limpet hemocyanins (KLH ) or antigenically such as serum albumin [e.g., bovine serum albumin (BSA)] carriers It can be connected to a neutral carrier (for example, U.S. Patent No. 5,189,178). (See also Specification No. 5,239,078). Connecting the hapten to the carrier is a part of this technology. It can be brought about in the field using well-known methods. For example, direct linkage to an amino group It may be added, optionally, and then the imino bond formed can be reduced. The carrier is a condensation agent such as dicyclohexylcarbodiimide or other carbodiimide dehydrating agents. Linking can be achieved using an agent. Linker compounds are also used to bring about the linking. This is possible; homobifunctional and heterobifunctional linkers are Pierce Chemi It can be obtained from Cal Company, Rockford, and Ill. Subsequently, the resulting exemption The epidemic-causing complex can be injected into suitable mammalian targets such as mice and rabbits. The protocol follows a schedule that boosts antibody production in the serum, This includes repeated injections of immunogen in the presence of juvant. The titer of the immunoserum is in the art. It can be easily measured using well-known immunoassay procedures.

[0103] The resulting antiserum can be used directly, or the monoclonal antibody can be used as described above. It can be acquired as described.

[0104] Antibody fragments according to some embodiments of the present invention are obtained by protein hydrolysis of the antibody. or the expression of the DNA encoding that fragment in E. coli or mammalian cells (for example, Prepared using Chinese hamster ovary cell culture or other protein expression systems. It is possible.

[0105] Antibody fragments are obtained by conventional methods, specifically by pepsin or papain digestion of the entire antibody. This can be done. For example, antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin. A 5S fragment denoted as F(ab')2 is provided. This fragment is a thiol reducing agent. And optionally, blocking of sulfidyl groups resulting from the cleavage of disulfide bonds. It can be further cleaved using a lig group, yielding a monovalent fragment of 3.5S Fab'. Enzymatic cleavage using pepsin directly yields two monovalent fragments, Fab' and Fc. These methods include, for example, Goldenberg, U.S. 4,036,945 Specification No. 4,331,647 and the references contained herein Further details are provided, and those patents are incorporated herein by reference as a whole. Yes. See also Porter, RR [Biochem. J. 73: 119-126 (1959)]. Chain-heavy chain separation to form heavy chain fragments, further cleavage of fragments, or other enzymatic or chemical processes. Other methods of cleaving antibodies, such as scientific or genetic techniques, also ensure that the fragments remain intact. It can be used as long as it binds to the antigen recognized by the antibody.

[0106] As described above, the Fv fragment includes the association of the VH and VL chains. The same is described in Inbar et al. [Proc. Nat'l Acad. Sci. USA 69:2659-62 (19720)] Thus, they can be non-covalent. Alternatively, their variable chains may be intermolecular disulfides. They can be linked by bonding or crosslinked by chemicals such as glutaraldehyde. In other words, the Fv fragment contains VH and VL chains linked by a peptide linker. These single-chain antigen-binding proteins (sFv) are linked by oligonucleotides. To construct a structural gene containing DNA sequences encoding the VH domain and VL domain, It is prepared by the following. The structural gene is inserted into the expression vector, and then the expression vector The recombinant host cell is introduced into a host cell such as E. coli. Synthesize a single polypeptide chain containing a linker peptide that cross-links the chain. Prepare sFv. A method for doing so is, for example, Whitlo, which is incorporated herein by reference in its entirety. w and Filpula, Methods 2: 97-105 (1991);Bird et al., Science 242:423-426 (1988) Pack et al., Bio / Technology 11:1271-77 (1993); and U.S. 4,946,7 This is described in Specification No. 78.

[0107] Another type of antibody fragment is a peptide that encodes a single complementarity-determining region (CDR). CDR peptides ("minimum recognition units") are genes that encode the CDR of the antibody of interest. Such genes can be obtained by constructing offspring. Such genes are, for example, polymerase. By using a chain reaction, the variable region is synthesized from the RNA of antibody-producing cells, and then prepared. See, for example, Larrick and Fry [Methods, 2: 106-10 (1991)].

[0108] As mentioned, the antibody fragment contains the Fc region of the antibody named "Fcab". It is possible. Such antibody fragments typically contain the CH2-CH3 domain of the antibody. F cab is present in small amounts in the structural loop region of the antibody, that is, in the CH3 region of the heavy chain. It is manipulated to include at least one modification. Such an antibody fragment may be, for example, as follows: It can be fabricated by: including at least one structural loop region (e.g., Fc region). A nucleic acid encoding an antibody is supplied, and at least one nucleic acid of at least one structural loop region The creotide residue was modified, the modified nucleic acid was transferred to the expression system, and the modified antibody was expressed. The modified antibody is brought into contact with the epitope, and it is determined whether the modified antibody binds to the epitope. For example, the United States Patent No. 9,045, which is incorporated herein by reference in its entirety. See specifications No. 528 and Nos. 9,133,274.

[0109] Humanized versions of non-human (e.g., mouse) antibodies are derived from minimal non-human immunoglobulins. immunoglobulins, immunoglobulin chains, or fragments thereof containing columns (e.g., Fv, F ab, Fab', F(ab').sub.2, or other antigen-binding subsequences of the antibody It is a chimeric molecule. Humanized antibodies are derived from residues in the complementarity-determining region (CDR) of the recipient. However, mice, rats, or rabbits, etc., that possess the desired specificity, affinity, and ability. Human immunoglobulins are replaced by residues derived from non-human CDRs (donor antibodies). Contains brin (recipient antibody). In some cases, human immunoglobulin Fv francs. The muwerk residue is replaced by the corresponding non-human residue. Humanized antibodies also, It was also found in the recipient antibody and in the imported CDR or framework sequence. It may contain residues that are not present. Generally, humanized antibodies have at least one, typically two, variable residues. This includes substantially the entire domain, and in a variable domain, all or the entire CDR area of ​​that domain. Qualitatively, they all correspond to those of non-human immunoglobulins, and all or a substantial portion of their FR region. Essentially, all of them are common human immunoglobulin sequences. Humanized antibodies are also optimally , at least a portion of the constant region (Fc) of immunoglobulins, typically human immunoglobulins This includes [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature] , 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)] .

[0110] Methods for humanizing non-human antibodies are well known in this field. Generally, Humanized antibodies are antibodies into which one or more amino acid residues have been introduced from a non-human source. These non-human amino acid residues are often called import residues, and These are typically taken from imported variable domains. Humanization is essentially rodent. By using one or more CDR sequences in place of the corresponding sequences in human antibodies Winter and collaborators [Jones et al., Nature, 321:522-525 (1986); Riechm ann et al., Nature 332:323-327 (1988);Verhoeyen et al., Science, 239:1534-1536 This can be carried out according to the method of (1988). Therefore, such humanized antibodies are A substantially smaller portion than the intact human variable domain is derived from the corresponding sequence of a non-human species. It is a substituted chimeric antibody (U.S. Patent No. 4,816,567). Humanized antibodies typically have some CDR residues and, in some cases, some FR residues. This is a human antibody in which residues derived from similar sites in rodent antibodies have been substituted.

[0111] Human antibodies are also known in the art, including phage display libraries. It can be produced using various technologies [Hoogenboom and Winter, J. Mol. Biol., 22 7:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)]. Cole et al. and B The technology developed by Oerner et al. can also be used for the preparation of human monoclonal antibodies (Cole et al. ., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boer [ner et al., J. Immunol., 147(1):86-95 (1991)]. Similarly, human antibodies are used in human immunoglobulins. Transgenic animals with a brin locus, for example, the endogenous immunoglobulin gene is partially It can be produced by introducing it into mice that have been completely inactivated. Exposure Human antibody production was observed, and it was due to gene rearrangement, assembly, and antibody repertoire —In all respects, including this, it is very similar to what is seen in humans. This approach is, for example U.S. Patent No. 5,545,807; Patent No. 5,545,806; No. 5,5 Specification No. 69,825; Specification No. 5,625,126; Specification No. 5,633,425 ; Specification No. 5,661,016, and the following scientific publication: Marks et al., Bio / Tech nology 10,: 779-783 (1992);Lonberg et al., Nature 368: 856-859 (1994);Morrison , Nature 368 812-13 (1994);Fishwild et al., Nature Biotechnology 14, 845-51 (19 96); Neuberger, Nature Biotechnology 14: 826 (1996); and Lonberg and Huszar, I This is described in ntern. Rev. Immunol. 13, 65-93 (1995).

[0112] An anti-PD1 antibody suitable for use in the present invention is obtained by using a method well known in the art. In particular, it can be manufactured based on the detailed explanation above. Alternatively, in the field of this technology Anti-PD1 antibodies approved in [unspecified field] can be used. An example of an anti-PD1 antibody is, for example, [unspecified field]. This text is incorporated herein by reference as follows: Topalian, et al. NEJM 2012, USA Patent No. 7,488,802 specification; No. 8,008,449 specification; No. 8,609,0 Specification No. 89; Specification No. 6,808,710; No. 7,521,051; and No. 816 Specification No. 8757, U.S. Patent Application Publication No. 20140227262; No. 20100 Specification No. 151492; Specification No. 20060210567; and No. 20060034 Specification No. 826, and International Publication No. 2008156712; 2010 Pamphlet No. 089411; Pamphlet No. 2010036959; No. 201115 Pamphlet No. 9877; Pamphlet No. 2013 / 019906; Pamphlet No. 2014159 Pamphlet No. 562; Pamphlet No. 2011109789; No. 01 / 14557 Brochure; Brochure No. 2004 / 004771; and No. 2004 / 0568 This information is disclosed in pamphlet No. 75.

[0113] Specific anti-PD1 antibodies that can be used according to some embodiments of the present invention are as follows: These include, but are not limited to: Nivolumab (also known as MDX1106, BMS-936558, and ONO-4538) It is commercially available from BMY as Opdivo, and when combined with PD-1, it enhances the regeneration of PD-1. Gando blocks activation by PD-L1 and PD-L2, WHO Drug Information A fully human IgG4 antibody having the structure described in Vol. 27, No. 1, pages 68-69 (2013). ; Pidilizumab (also known as CT-011, hBAT, and hBAT-1) is used in Cure Humanized monoclonal IgG1 antibody (manufactured by Tech) that binds to PD-1 body; AMP-514 (also known as MEDI-0680, AZY and MedImmu A humanized monoclonal IgG4 antibody that binds to PD-1 (manufactured in ne); Humanized antibodies h409Al I, h409A16, and h409A17, International Publication No. 20 It is stated in the 08 / 156712 pamphlet.

[0114] According to a particular embodiment, anti-PD-1 is pembrolizumab (MK-3475, Key Truda, also known as SCH 900475, is manufactured by Merck. It binds to PD1 and blocks its activation by its ligand. This is based on the information provided in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013). This is a humanized monoclonal IgG4 antibody with a specific structure.

[0115] As mentioned, this instruction intends to use chemotherapy for the treatment of disease. This includes gemcitabine, FOLFIRINOX, erlotinib, 5-fluorouracil, and Clitaxel, Nab-paclitaxel, docetaxel, capecitabine, oxaliplatin Cisplatin, FOLFOXIRI, Abraxane, anti-CD40 antibody, olegovomab nelfinavir, cetuximab, tegaflu, leucovorin, irinotecan, and These are some possible combinations, but they are not limited to these.

[0116] According to a particular embodiment, chemotherapy involves a topoisomerase inhibitor, irinotecan That is the case.

[0117] Irinotecan is converted by esterase enzymes into a more active metabolite, SN-38. It is replaced. The chemical name irinotecan is (S)-4,11-diethyl-3,4,12, 14-Tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[4',4': 6,7]-Indolidino[1,2-b]quinoline-9-yl-[1,4'bipiperidine] -1'-carboxylate. Irinotecan hydrochloride trihydrate is also known as CPT-11 and is called by the name and the trade name CAMPTOSAR®.

[0118] The topoisomerase inhibitor can be a camptothecin conjugated with a biocompatible polymer such as cyclodextrin or a cyclodextrin analog (e.g., sulfonated cyclodextrin). For example, the topoisomerase inhibitor can be a cyclodextrin-containing polymer chemically bonded to camptothecin, iri notecan, SN-38, or other topoisomerase 1 inhibitor compounds. The cyclodextrin-camptothecin conjugate type topoisomerase 1 inhibitor can be administered at a pharmaceutically acceptable dose including administration of 6 mg / m2, 12 mg / m2, or 18 mg / m2 per week, or administration of 12 mg / m2, 15 mg / m2, or 18 mg / m2 every other week. The camptothecin- cyclodextrin conjugate topoisomerase 1 inhibitor (e.g., the cyclodextrin-containing polymer conjugate with camptothecin named "CRLX10 1") and related intermediates for preparing the same are disclosed, for example, in Greenwald et al., Bioorg. Me d. Chem., 1998, 6, 551-562, in addition to U.S. Patent Application No. 2010 / 0247668, U.S. Patent Application No. 2011 / 0160159, and U.S. Patent Application No. 2011 / 01890 92. The topoisomerase inhibitor can also be a liposomal formulation of irinotecan, camptothecin, or topotecan. Liposomal irinotecan ([[]] For example, Greenwald et al., Bioorg. Med. Chem., 1998, 6, 551-562, in addition to U.S., Patent Application No. 2010 / 0247668, U.S. Patent Application No. 2011 / 0160159, and U.S. Patent Application No. 2011 / 0189092. Patent Application No. 2011 / 0160159, and U.S. Patent Application No. 2011 / 0189092 are disclosed.

[0119] The topoisomerase inhibitor can also be a liposomal formulation of any topoisomerase inhibitor such as irinotecan, camptothecin, or topotecan. Liposomal irinotecan ( ​​For example, MM-398 (also known as "nal-IRI") is involved in the cell cycle in tumors. Irinotecan and its active metabolite S are delivered to cells with a higher proportion of the more sensitive S phase. A highly stabilized liposomal formulation of irinotecan that provides sustained exposure to N-38. MM-398 has shown promising preclinical and clinical activity in various cancer types. It is a somal irinotecan used in pancreatic disease progression after gemcitabine-based treatment. In patients with metastatic adenocarcinoma, in combination with 5-FU / LV, recently in the United States, Approved. Compared to free irinotecan, nal-IRI has an extended PK profile. It has the ill and causes prolonged local tumor exposure to MM-398 and SN-38. SN- 38 is cleared faster from normal tissue than from tumors, therefore MM-398 Conversely, delaying veliparib administration increases the expected window for maximum irinotecan-induced toxicity. However, it is assumed that this will allow passage in the absence of simultaneous beriparib toxicity. However, the tumor level of SN-38 persisted at the time of subsequent veliparib administration. It is predicted that both drugs will act on the tumor tissue simultaneously, maintaining a synergistic effect. Maintain the ability to do so.

[0120] One suitable liposomal Top1 inhibitor formulation was previously classified as "MM-3" before FDA approval. The brand name is ONIVYDE (registered trademark) (Irinote Kanriposo) (Merrimack Pharmaceuticals, Inc. Cam) Liposomal irinotecan (available from bridge, Mass.), and ONIVY This is a liposomal irinotecan product that is bioequivalent to DE. ONIVYDE / MM -398 (Irinotecan Liposome Injection) is an irinotecan liposome encapsulated for intravenous use. It contains irinotecan as linotecan scrosofate salt. The drug product is a liposome. , an aqueous space containing irinotecan in a gelled or precipitated state as a sucrose salt It is a small, monolayer lipid bilayer vesicle with a diameter of approximately 110 nm that encloses the lipid. The carrier is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). , 6.81 mg / mL; cholesterol, 2.22 mg / mL; and methoxy-terminated poly Ethylene glycol (MW 2000)-distearoylphosphatidylethanolamine It consists of 0.12 mg / mL of (MPEG-2000-DSPE). Per 1 mL, As a buffer, 2-[4-(2-hydroxyethyl)piperazine-1-yl]ethanesulfate Honic acid (HEPES), 4.05 mg / mL; sodium chloride as isotonic reagent, 8.4 It also contains 2 mg / mL, and ONIVYDE / MM-398 is a liposome with a diameter of approximately 100 nm. Approximately 80,000 sucrose sorbates are enclosed within the sucrose in a gelled or precipitated state. It is thought to contain the molecule irinotecan.

[0121] Gemcitabine (e.g., Gemzar®), or albumin-binding paclita Abraxane, Tarceva, or capecitabine (This was used in combination with other drugs such as Xeloda, or in combination with radiation therapy.) Chemotherapy based on gemcitabine (also known as chemoradiotherapy).

[0122] As used herein, "leucovorin" typically refers to Onivyde (registered trademark). Refers to folic acid administered in combination with the label) and 5-FU.

[0123] 5-FU is a thymidylate synthase (TS) inhibitor. Interfering with the action of this enzyme blocks the synthesis of thymidine, a pyrimidine nucleoside required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). Administration of 5-FU causes a deficiency of dTMP, and thus rapidly dividing cancer cells undergo cell death by thymine starvation. Calcium folinate provides an exogenous source of reduced folate, and thus stabilizes the 5-FU-TS complex and therefore enhances the cytotoxicity of 5-FU. 5-FU is sold, among other things, under the brand name Adrucil.

[0124] According to certain embodiments, chemotherapy comprises a plurality of chemotherapeutic agents, for example, at least 2, or at least 3, for example, 2, 3, 4, 5 chemotherapeutic agents.

[0125] According to certain embodiments, chemotherapy comprises irinotecan (e.g., encapsulated in liposomes, for example, Onivyde®), 5-FU, and leucovorin.

[0126] According to certain embodiments, the treatment does not include oxaliplatin.

[0127] The peptides, antibodies, and chemotherapy (the "agents") described above can be administered to a subject, either alone or in a pharmaceutical composition in which it is mixed with a suitable carrier or excipient. Each of the active substances can be formulated in separate preparations, or At least some of these can be combined into a single formulation.

[0128] As used herein, "pharmaceutical composition" refers to a physiologically appropriate carrier and excipient. One or more of the active ingredients described herein, together with any other chemical components. This refers to a preparation of a compound. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0129] In this specification, the term "active ingredient" means a substance that produces a biological effect, for example, Column number 1, pembrolizumab, irinotecan (e.g., encapsulated in liposomes, e.g., This refers to Onivyde®, 5-FU, and leucovorin.

[0130] The following phrases can be used interchangeably: "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" The "carrier" does not cause significant irritation to the organism, and the biological effects of the administered compound are not significant. Adjuvants refer to carriers or diluents that do not inhibit activity or properties. It is included in.

[0131] In this specification, the term "excipient" refers to an excipient added to a pharmaceutical composition to further facilitate the administration of the active ingredient. This refers to the inert substance that is added. Examples of excipients include, but are not limited to, calcium carbonate and calcium phosphate. Calcium, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil, Polyethylene glycol is another example.

[0132] Techniques relating to the formulation and administration of drugs are incorporated herein by reference. “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, lates It can be found in the t edition.

[0133] Appropriate routes of administration include, for example, oral, rectal, transmucosal, especially transnasal, intraintestinal, or non-transnasal. Oral delivery, e.g., intramuscular, intradermal, subcutaneous, and intrathecal injection, in addition to intrathecal and direct intraventricular injections. For example, into the right or left ventricular cavity, into the common coronary artery, within the heart, within the veins, within the abdominal cavity, nasal cavity Possible methods include intraocular or intraocular injection.

[0134] Alternatively, the pharmaceutical composition may be administered locally rather than systemically, for example, in the tissue area of ​​the patient. It can be administered by direct injection of the pharmaceutical composition into the body.

[0135] According to a specific embodiment, the peptide of the present invention or a pharmaceutical composition containing the same is administered subcutaneously. It will be done.

[0136] According to a particular embodiment, an anti-PD-1 antibody (e.g., pembrolizumab) or it The pharmaceutical composition containing the active ingredient is administered intravenously.

[0137] According to certain embodiments, chemotherapy or a pharmaceutical composition containing the same is administered intravenously. .

[0138] Pharmaceutical compositions of several embodiments of the present invention are obtained by processes well known in the art, For example, normal mixing, dissolution, granulation, sugar-coated tablet preparation, gelling, emulsification, encapsulation, capture, Alternatively, it can be manufactured using a freeze-drying process.

[0139] Thus, pharmaceutical compositions for use according to some embodiments of the present invention are pharmaceutically A preparation comprising excipients and auxiliary agents that promote the treatment of the active ingredient with the preparation that can be used. It can be formulated in a conventional manner using one or more physiologically acceptable carriers. The effectiveness of the formulation depends on the chosen route of administration.

[0140] A pharmaceutical composition suitable for use in connection with some embodiments of the present invention contains an active ingredient Examples include compositions containing an effective amount to achieve the intended purpose. Physically, according to a particular embodiment, the therapeutically effective dose is for the treatment of the disease (i.e., metastatic pancreatic adenocarcinoma). The target of preventing, reducing, or relieving the symptoms of ) This refers to the amount of active ingredients that are effective in extending the survival of the organism.

[0141] According to a particular embodiment, the peptide of the present invention or a pharmaceutical composition containing the same is 0.1 to Between 10 mg / kg body weight, between 0.1 and 2 mg / kg body weight, and between 0.1 and 1 mg / kg body weight. During the interval, the dose is administered in the range of 0.3 to 2 mg / kg body weight, between 0.3 and 10 mg / kg body weight.

[0142] According to a specific embodiment, BL-8040 is administered at a dose of 1-2 mg / kg body weight. ru.

[0143] According to a specific embodiment, BL-8040 is administered in doses of 1.25 to 1.5 mg / kg body weight. It is administered as follows.

[0144] According to a specific embodiment, BL-8040 is administered at a dose of 1.25 mg / kg body weight. It can be done.

[0145] According to certain embodiments, BL-8040 is administered subcutaneously (SC).

[0146] According to a particular embodiment, an anti-PD-1 agent, such as pembrolizumab, is present in concentrations of 0.001 to 3 Between 0 mg / kg body weight, between 0.001 and 20 mg / kg body weight, between 0.001 and 10 mg / Between kg body weight, between 0.001 and 1 mg / kg body weight, between 0.01 and 30 mg / kg body weight , between 0.01 and 20 mg / kg body weight, between 0.01 and 10 mg / kg body weight, 0.01 Between 1 mg / kg body weight, between 0.1 and 30 mg / kg body weight, between 0.1 and 20 mg / kg body weight Between 0.1 and 10 mg / kg body weight, between 0.1 and 5 mg / kg body weight, 1 to approximately 30 m Between g / kg, between 1 and approximately 20 mg / kg, or between 2 and approximately 10 mg / kg, 0.5~ Between approximately 30 mg / kg, between 0.5 and approximately 20 mg / kg, between 0.5 and approximately 20 mg / kg, 1 It is administered in doses ranging from approximately 5 mg / kg to 1 to approximately 5 mg / kg.

[0147] According to a specific embodiment, an anti-PD-1 agent, such as pembrolizumab, is administered at a dose of 2.85 mg / It is administered in doses of kg.

[0148] According to a specific embodiment, an anti-PD-1 agent, such as pembrolizumab, is administered in doses of 1 to 500 mg. , 1~400mg, 1~300mg, 1~200mg, 10~500mg, 50~500 The dosage is 100-500 mg, 100-300 mg, or 150-450 mg. To be given.

[0149] According to a particular embodiment, an anti-PD-1 agent (e.g., pembrolizumab) is administered intravenously (IV). It is administered via [method / method].

[0150] According to a particular embodiment, anti-PD-1 is administered in a fixed dose of 200 mg.

[0151] According to certain embodiments, chemotherapy is administered intravenously.

[0152] According to a particular embodiment, chemotherapy is administered in a tolerable dose known in the art. .

[0153] According to a specific embodiment, the dose is 70 mg / m² of Onivyde®. 2 ,B Icovorin 400 mg / m² 2 , and fluorouracil 2400 mg / m² 2 That is .

[0154] The administration regimen may be as follows: 90 minutes of IV Onivyde (registered trademark), followed by 30 minutes of IV Roy Covorin 400mg / m² 2 Subsequently, IV fluorouracil 240 over a period of 46 hours. 0 mg / m² 2 Once every two weeks.

[0155] According to a particular embodiment, the treatment involves a period of monotherapy with the peptide, followed by the peptide This includes combination therapy with thiosulfate, the anti-PD-1 agent, and the chemotherapy agent.

[0156] As used herein, “monotherapy” refers to the use of a single drug to treat cancer. The term refers to other drug therapies used to treat symptoms not related to the disease itself. This does not preclude the use of analgesics and / or antihistamines, as well as / or the use of antiemetic drug therapy may be considered even during the period of monotherapy. During the course of drug therapy, the use of anticancer drugs (as defined therein) will be excluded.

[0157] In certain embodiments, the duration of monotherapy is up to 7 days.

[0158] In certain embodiments, the duration of monotherapy is 5 days (for example, daily).

[0159] As used herein, "combination therapy" means, as in the embodiments of the present invention, multiple This refers to the use of multiple anticancer drugs (peptides, chemotherapy, anti-PD-1).

[0160] According to a particular embodiment, the combination therapy of the chemotherapy and the anti-PD-1 is 6-1 It starts on day 0.

[0161] According to a particular embodiment, the combination therapy of the chemotherapy and the PD-1 is administered on day 8. It will begin.

[0162] According to a particular embodiment, the combination therapy involves repeating the chemotherapy every two weeks, and the anti This involves repeating PD-1 every three weeks.

[0163] According to a particular embodiment, the peptide is administered during a monotherapy period, and then the antibody and Chemotherapy is administered.

[0164] According to a specific embodiment, combination therapy with peptides is initiated on day 10 and separated by 48 hours. Administer twice a week on non-consecutive days (optionally, at least 24 hours after the aforementioned chemotherapy) be.

[0165] According to a specific embodiment, monotherapy is administered daily on days 1 through 5.

[0166] I don't intend to be bound by theory, but cytotoxic chemotherapy induces tumor death and tumor burden. This suggests that it reduces [unclear]. Cytotoxic chemotherapy induces immunogenic cell death, leading to new [unclear]. This can lead to the activation and proliferation of tumor-reactive T cell clones. BL-8040 is this It promotes the infiltration of T cells into the tumor core. BL-8040 promotes T-reg and MDS It reduces C (myelin-derived suppressor cells) and, therefore, reduces the immunosuppressive microenvironment. Mubrolizumab maintains / restores T cell activity within tumors.

[0167] Therefore, the following are specific embodiments of the present invention.

[0168] Pembrolizumab for injection (MK-3475) solution contains 100 mg / 4 mL of pembrolizumab. Zumab (MK-3475) is supplied in a disposable Type I glass vial. It is a sterile, non-pyrogenic aqueous solution. The product is essentially free of foreign particles and preservatives. It is a pear solution.

[0169] Chemotherapy: Onivyde(registered trademark) / 5-FU / LV Onivyde is an injectable drug: a single-dose vial containing a white to yellowish opaque liposomal solution. This is 43 mg / 10 mL of irinotecan free base as a dispersion.

[0170] Fluorouracil injection contains 2.5g / 50mL (50mg / mL) fluorouracil. It is supplied as a pharmacy bulk package in vials containing [the substance].

[0171] Leucovorin calcium for injection is supplied as a sterile, freeze-dried powder. 350 mg The vial contains no preservatives. The inactive ingredient is sodium chloride per 350 mg vial. It contains 140 mg / vial. Sodium hydroxide and / or hydrochloric acid are used during manufacturing, pH It is used to adjust it to approximately 8.1. 1 mg of leucovorin calcium is 0. It contains 0.002 mmol of leucovorin and 0.002 mmol of calcium.

[0172] BL-8040 is administered as monotherapy for 5 days, starting from day 1 and continuing daily until day 5. It is administered by SC injection at a dose of 1.25 mg / kg per day. The target group receives it once a day in the morning. Receive BL-8040 SC injection. Systemic antihistamine with or without analgesics. Premedication with steroids may cause local injection site reactions and / or systemic reactions related to BL-8040. It is administered to minimize the occurrence of a reaction.

[0173] According to certain embodiments, the BL-8040 injection site is suitable for any local injection site reaction. The dosage is rotated to minimize the severity of the symptoms. The reconstituted dose volume is greater than 2 ml. In some cases, the injection is divided so that each injection is less than 2 ml; the treatment is performed by a specialist. At the discretion of the household, a single dose may be divided and injected into more than one site. Depending on the method of administration, the same instructions apply to the duration of combined treatment.

[0174] According to a particular embodiment, BL-8040 injection is administered before the next BL-8040 injection. A significant increase in measured WBC (e.g., WBC > 60,000 / μL) and / or It would be recognized that if there is evidence of leukocyte stagnation, the procedure will be skipped. There are no signs of stagnation and / or a decrease in WBC to a value of ≤60,000 / μL. Under certain conditions, the BL-8040 procedure will be resumed.

[0175] After monotherapy, BL-8040 received pembrolizumab in 3-week cycles, and It is administered as part of a combination therapy with chemotherapy in 2-week cycles. Specific Embodiments According to the information, the medication is as follows:

[0176] During the combination therapy period, BL-8040 should be administered at least 24 hours after chemotherapy, followed by a 48-hour interval. It is administered as an SC injection twice a week in the morning on non - consecutive days.

[0177] Treatment with pembrolizumab begins as part of combination therapy after the monotherapy period. During the combination period, pembrolizumab is administered as a 30 - minute IV infusion at a dose of 200 mg on the first day of each 3 - week treatment cycle. According to certain embodiments, pembrolizumab may be administered within 3 days before or after the first day of each scheduled cycle, for

[0178] administrative reasons. According to certain embodiments, pembrolizumab is administered as a 30 - minute IV infusion at a dose of 200 mg. Considering the variability of the infusion pump, a window of - 5 minutes to + 10 minutes is allowed (i.e., the infusion time is 30 minutes - 5 minutes / +10 minutes).

[0179] According to certain embodiments, when pembrolizumab is administered on the same day as BL - 8040, it will be recognized that BL - 8040 is administered 1 hour (±0.5 hour) after the end of the pembrolizumab infusion.

[0180] According to certain embodiments, when pembrolizumab is administered on the same day as chemotherapy, it will be recognized that pembrolizumab should be administered first, and then chemotherapy should be administered.

[0181] According to certain embodiments, Onivyde is administered before LV and 5 - FU. Every two weeks, Onivyde 70 mg / m 2 is administered as an IV infusion over 90 minutes, then LV 400 mg / m 2 is administered as an IV over 30 minutes, and then 5 - FU 2 400 mg / m is administered over 46 hours.2 IV. UGT1A1 * For 28 alleles, patients who are homozygous are 50 mg / m 2 Start with Onivyde®, and the dosage will be adjusted at a later point in time (for example, If tolerability is observed after 35 cycles, the dosage can be increased.

[0182] Figure 1 shows a specific treatment regimen according to an embodiment of the present invention.

[0183] Efficacy testing may be conducted at any point in the execution of a regimen as described herein, for example. , at least one or two cycles of treatment (for example, as disclosed in Figure 1), Do this after 3, 5, 10, or more cycles. This is possible. To clarify, the cycle is, for example, a 3-week cycle of pembrolizumab. This refers to concomitant treatments based on the treatment schedule.

[0184] Efficacy test Diagnostic imaging evaluation Diagnostic imaging is used to evaluate the response. For example, CT or MRI may be used. The same imaging diagnostic method should be used for each patient throughout the procedure.

[0185] According to a particular embodiment, the image diagnostic evaluation can be performed at the following points in time: The point at which to select the target for treatment. End of monotherapy period, day 5 At the end of cycle 2 of the combined treatment, and thereafter for one year of treatment (cycle 17), 3 months After each cycle, and then every four cycles until the end of the treatment.

[0186] According to certain embodiments, RECIST 1.1 is found in relation to the treatment of immunotherapeutic agents. It is suitable for explaining the unique tumor response characteristics. Pembrolizumab and BL-80 Substances such as 40 produce antitumor effects by enhancing the endogenous cancer-specific immune response. Obtainable. The response patterns observed with such approaches are as follows, as seen with cytotoxic agents. The response may be prolonged beyond the typical time course, following an initial increase in tumor volume or new lesions. Clinical responses can be manifested even after the appearance of: If radiological imaging confirms the initial progressive disease, continue treatment as follows: Regarding this option, a tumor evaluation is repeated at least four weeks later to confirm the progression of the disease. It should be done. • Repeated imaging tests show Nadir, stable, or improved, previous new Lesions (if identified as the cause of the initial progressive disease) and stable / improved non-targeted lesions Less than 20% of tumor volume compared to the lesion (if identified as the cause of the initial progressive disease). If an increase is observed, treatment may be continued / restarted. Repeated imaging studies confirmed a progressive disease in one of the following scenarios: In that case, treatment will be discontinued. • In determining whether tumor volume has increased or decreased, all target lesions, In addition, non-target lesions should be considered.

[0187] Scenarios for cases where a progressive disease is repeatedly confirmed by imaging studies: • Tumor volume is still more than 20% higher compared to Nadia, and at least 5m m remains an absolute increase. • The non-target lesion that initially caused the progressive disease is worsening (qualitative). • The new lesions that caused the initial progressive disease are worsening (qualitative). • Additional new lesions since the last assessment

[0188] In subjects with initial radiological evidence of progressive disease, repeated imaging studies are available. The decision of whether or not to continue treating the patient until [a certain condition is met] is at the discretion of the treating physician. The assessment includes the overall clinical status of the subject, including performance status, clinical symptoms, and laboratory data. It should be based on the bed condition. The subjects are clinical as they are defined by the following criteria. If the condition is stable, treatment can continue while awaiting confirmation of a progressive disease. • No signs or symptoms indicating disease progression. • No decrease in ECOG performance status • No rapid progression of the disease • In critical anatomical areas requiring urgent alternative medical intervention (e.g., spinal cord compression) No uterine tumors

[0189] If possible, the procedure should not be stopped until progression is confirmed. Despite the progression of the disease, this acceptance of continuing treatment is due to the fact that some individuals are undergoing immunotherapy. During the first few months after initiation, there may be a transient tumor flare, but thereafter, a disease response may occur. This observation is being taken into consideration. Patients considered clinically unstable are used to confirm progressive disease. Therefore, repeated imaging tests are not required.

[0190] If the physician assesses the progression of the disease and the patient is clinically stable (as described above), the patient will be treated. Furthermore, imaging should be performed at least four weeks after the first tumor imaging diagnosis indicating a progressive disease. This is at the discretion of the physician. At that time, whether follow-up tumor imaging confirms a progressive disease. To determine this, the physician follows irRECIST. Subjects for whom disease progression was not confirmed are If they meet the conditions detailed above, continue the treatment until progress is confirmed. Subsequently, regular imaging diagnostic schedule intervals may be followed.

[0191] irRECIST evaluation of disease As mentioned above, if tumor imaging shows the initial progression of the disease, then the trial The trial site chose to continue treatment based on irRECIST, and after more than 4 weeks, the image was drawn. Repeated imaging studies can be used to assess the tumor response or confirmed progression.

[0192] Biopsy analysis According to a particular embodiment, a biopsy can be performed at the time of screening, and genes Tumor mutation burden (TMB), PD-L1, and DNA mismatch repair The recovery state is evaluated.

[0193] Blood sampling and processing The samples were used for safety and efficacy analysis, e.g., CBC, anti-drug antibody titer, and BL-8. 040 is collected to determine plasma concentration.

[0194] Some embodiments of the present invention contain, if desired, one active ingredient Alternatively, a pack or dispenser, such as an FDA-approved kit, may contain multiple unit dosage forms. - May be provided in the device. Packing may be, for example, a blister pack or metal foil or May contain plastic foil. Pack or dispenser device may be used for administration. Instructions for use may be included. The pack or dispenser may also be used for the manufacture, use, and Alternatively, a notice attached to the container may be included in the form instructed by the government agency regulating sales, The notification reflects the institutional approval of the composition's form or human or veterinary administration. Such notices are, for example, approved by the U.S. Food and Drug Administration for prescription drugs. This may be a label or an approved product insert. Formulated in a suitable pharmaceutical carrier. Compositions containing the prepared product of the present invention are also prepared as described in more detail above. They may be placed in appropriate containers and labeled with instructions for the prescribed treatment.

[0195] As used herein, the term "approximately" refers to ±10%.

[0196] The terms "comprises," "comprising," and "includes" are all related. "Including," "having," and their conjugations are, It means "includes, but is not limited to."

[0197] The term "consisting of" means "to include or be limited to."

[0198] The term "essentially derived from" means that a composition, method, or structure is derived from an additional component, step, and / or parts may include, however, additional ingredients, steps, and / or parts The claims substantially represent the fundamental and novel properties of the claimed composition, method, or structure. This applies only if no changes are necessary.

[0199] As used herein, the singular forms "a", "an", and "so The "the" can refer to multiple things unless the context clearly indicates otherwise. For example, the term "one compound" or "at least one compound" includes multiple compounds, including mixtures thereof. It may contain the following compounds.

[0200] Through this application, various embodiments of this invention may be presented in scope form. The use of boxed format is solely for convenience and conciseness, and does not offer flexibility within the scope of the present invention. It should be understood that this should not be interpreted as a restriction. Therefore, The enclosed description includes all possible partial ranges, and specifically discloses the individual numerical values ​​within those ranges. It should be considered that it is. For example, a range description such as 1 to 6 should be considered as 1 to 3 Up to, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc. A partial range, in addition to the individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6 It should be considered to have been specifically disclosed. This applies regardless of the scope of disclosure. It can be done.

[0201] Whenever a numerical range is indicated herein, any pull within that indicated range It is intended to include the numerical values ​​used (fractions or integers). The first number shown and the second The phrase "be in the range between / range between" of the indicated number, and the first indicated number The phrase "to the range / range" of the second number indicated, "from", is used in this specification. Used interchangeably with the first and second shown numbers, as well as all fractions in between. It is intended to include integers as well.

[0202] As used herein, the term "method" means a form or means for achieving a given objective. It refers to techniques and procedures, and includes fields such as chemistry, pharmacology, biology, biochemistry, and medicine. Forms, means, techniques, and procedures known to or by practitioners of the Act This includes any of the styles, means, techniques, and procedures that were developed easily, Not limited to this.

[0203] Certain features of the present invention, described in relation to separate embodiments for clarity, are It is also recognized that these may be provided in combination in a single embodiment. Conversely, The various features of the present invention, which are described in terms of a single embodiment for the sake of brevity, are or separately, or in any suitable partial combination, or any other described part of the present invention It may be provided as suitable in the embodiment. It is described in relation to various embodiments. A certain feature is acceptable unless its embodiment cannot function without those elements. These embodiments should not be considered essential features.

[0204] The present invention as described above and as asserted in the claims below. Various embodiments and aspects can be experimentally supported in the following examples. . [Examples]

[0205] The following embodiments are referenced and, together with the above description, illustrate several embodiments of the present invention. The examples are given in a non-restrictive format.

[0206] [Example 1] the purpose The purpose of this study is to study liposomal irinotecan in patients with metastatic pancreatic adenocarcinoma. Onivyde(registered trademark) / 5-Fluorouracil / Leucovorin(5-FU / LV By evaluating the efficacy and safety of BL8040 / pembrolizumab in combination with ) Yes. The mechanism of action of BL-8040 when administered alone and in combination is as follows: blood samples Further research will be conducted using tumor tissue samples.

[0207] Test endpoints Primary endpoint Response Evaluation Criteria in Solid Tumors (R) Response rate (ORR) determined according to ECIST v1.1 criteria RECIST1.1 ) Secondary endpoint Response rate (ORR) determined according to irRECIST criteria irRECIST ) OS PFS Disease management according to RECISIT 1.1 (DC) RECIST1.1 ) is a partial response (PR) Defined as the sum of ), CR, and SD. Safety and tolerability TEAE Clinical laboratory safety data Vital signs ECG Physical examination (PE) Early termination of the trial, both overall and by AE. explorability Changes in tumor markers (CA19-9) from baseline Further tumor tissue analysis

[0208] [Example 2] Test design This is an open-label, single-arm phase IIa trial in patients with metastatic pancreatic adenocarcinoma. This examination consists of the following two periods: • Monotherapy period: Treatment using BL-8040 on days 1-5 for 1 week • Combination therapy: Onivyde(registered trademark) / 5-FU / LV every 2 weeks, pembrolizumab every 3 weeks Once a week, and BL-8040 twice a week.

[0209] Metastatic pancreatic adenocarcinoma that has progressed after first-line treatment with gemcitabine-based chemotherapy The subjects who have the condition are registered and receive 5 days of BL-8040 monotherapy, followed by BL-8040, Patients will receive pembrolizumab and chemotherapy in combination. During the monotherapy period, eligible patients are: From day 1 to day 5, the patient receives daily SC injections of BL-8040 (1.25 mg / kg).

[0210] Starting on day 8, the subjects will begin a combined treatment period consisting of the following: • IV Onivyde® 70 mg / m² over 90 minutes 2 , then 30 minutes Intermittent IV leucovorin (LV) 400 mg / m² 2 Then, a 46-hour IV Fluorouracil (5-FU) 2400 mg / m² 2 , every two weeks Pembrolizumab 200mg once every 3 weeks • Starting on day 10, BL-8040 twice weekly, and at least from chemotherapy administration 24 hours later.

[0211] Combination therapy may be administered for up to 35 treatments (approximately 2 years), or if the disease progresses, or if there is a clinical worsening. It will continue until either it is terminated early, whichever comes first.

[0212] The Independent Data Monitoring Committee (DMC) has established DMC privileges to ensure the well-being of those affected. The accumulated test data is reviewed. Serious adverse events (SAEs) are constantly monitored throughout the trial. It will be monitored.

[0213] The security review of the accumulated data in question will initially target six people, but it may shift to 12 people. The subjects (safety dose-limiting toxicity (DLT) cohort) include monotherapy and combination therapy. Upon completion of the 8-day treatment period, it will be conducted by an independent DMC. Safety DLT cohort The guidelines used by the DMC for the review process are presented below: If 0 out of 6 subjects experience DLT during the first cycle of treatment, The combined treatment is deemed eligible for further evaluation, and the recruitment process will continue without hesitation. If one of the six subjects experiences DLT, the safety DLT cohort is 1 The scope is expanded to include two people. • If two or more of the six subjects experience DLT, DMC will consider the concomitant treatment. Evaluate the risk / benefit ratio and recommend one or more of the following: 1) Safety DLT 1) The hort should be expanded to include 12 participants, and 2) the protocol should be modified. Therefore, 3) the treatment schedule should be changed, or 4) the trial should be discontinued. It should be done. • In the expanded safety DLT cohort, two or fewer out of 12 subjects underwent DLT. If experience is required, recruitment can continue until the proposed full trial size is reached. • In the expanded safety DLT cohort, more than 2 out of 12 subjects experienced DL. If T is experienced, DMC will either stop recruiting or revise the protocol. We will decide whether to continue recruitment based on the information provided.

[0214] Effectiveness data will be evaluated throughout the trial without suspending recruitment. The evaluation will cover all Available data, including imaging studies, biopsies, and safety assessments, are used in conjunction with clinical trials. Evaluate the clinical usefulness of the procedure.

[0215] [Example 3] Test group Men and women aged 18 or older with metastatic unresectable PDAC are enrolled in this clinical trial. The inclusion / exclusion criteria are screening unless otherwise specified within those specific criteria. Evaluation will be conducted during the evaluation period.

[0216] The entry criteria are absolute. Failure to meet one or more inclusion criteria, or 1 Any subject who meets one or more of the exclusion criteria is permitted to enroll in this clinical trial. No. If the criteria specify a limit on the variable, that limit cannot be exceeded. do not have.

[0217] Inclusion Criteria To be eligible to participate in this clinical trial, participants must meet the following criteria: 1. Ages 18 and over 2. Patients must sign a written informed consent form before enrolling in this study. It must be done. 3. Histologically confirmed (either previously or recently, a biopsy was performed), pancreas Metastatic, unresectable pancreatic adenocarcinoma, including intraductal papillary mucinous neoplasms. 4. Measurable based on RECIST v1.1, if determined by the site team. The patient has a disease (one or more measurable lesions). The tumor is located in a previously irradiated area. A lesion is considered measurable if its progression is documented. 5. Previous treatment line Objective X-ray examination after discontinuing treatment with first-line gemcitabine-based chemotherapy The progression of the disease has been demonstrated. Only patients with primary metastatic cancer are allowed to participate. Patients who have previously undergone surgery are not permitted to participate. 6. Unless the tumor is deemed inaccessible, or otherwise, a biopsy should be performed on the patient. Unless it is deemed not to be of the greatest benefit to the patient, preferably from liver metastases, evaluation is possible. I am willing to submit a tumor tissue sample. 7. Complete recovery to grade 1 or less of the toxicity effect of the most recent previous chemotherapy (excluding alopecia). If the subject has undergone major surgery or radiation therapy >30 Gy, they will be affected by the intervention. Patients must have recovered from previous toxicity and / or complications. 8. ECOG status ≤ 1 9. Average life expectancy of at least 3 months 10. Sufficient organ function at baseline as defined below. All clinical tests The evaluation should be conducted within 10 days of the start of treatment. a. Hematology: ·White blood cells (WBC) ≧2,500 / mm 3 • Neutrophil absolute count ≥ 1500 / mm³ 3 ·Platelet count ≧100,000 / mm 3 Hemoglobin ≥ 9 g / dL or ≥ 5.6 mmol / L • Hematocrit ≥ 30% b. Kidney function: • Creatinine ≤ 1.5 × upper limit of normal (ULN), or creatinine level > 1.5 × For patients with facility ULN, measured or calculated creatinine clearance ( Glomerular filtration rate (GFR) can also be used as a substitute for creatinine, (CrC l)≧60mL / min. c.Liver function: • Total bilirubin: Within facility standard range • Aspartate aminotransferase / serum glutamate oxaloacetate trans Alanine aminotransferase (AST / SGOT) and serum glutamic acid Transaminase (ALT / SGPT): ≤2.5 × ULN, or liver For subjects with visceral metastases, ≤5 × ULN d. Coagulation: • INR or PT: ≤ 1.5 × ULN, provided that PT or PTT is the intended anticoagulant. As long as it is within the therapeutic scope of use, if the subject is currently receiving anticoagulant therapy except • aPTT: ≤ 1.5 × ULN, provided that PT or PTT is the intended use of an anticoagulant. As long as it is within the therapeutic range, except when the subject is currently receiving anticoagulant therapy. 11. The subjects must use effective contraception: a. Female subjects must be infertile, or if they are capable of becoming pregnant, the test drug You must have a negative urine or serum pregnancy test result within 72 hours prior to ingesting the substance. If a urine test is positive or cannot be confirmed as negative, a serum pregnancy test is necessary. It is required. A serum pregnancy test must be negative for the subject to be eligible. Possibility is defined as follows (for reasons other than medical reasons): • Over 45 years old, and have not had a menstrual period for more than two years. • Amenorrhea lasting longer than 2 years without hysterectomy or oophorectomy, and pre-trial (screen) Follicle-stimulating hormone (FSH) levels within the postmenopausal range in the evaluation (Ning) • Hysterectomy, bilateral oophorectomy, and bilateral tubal dilation at least 6 weeks prior to screening. After oral surgery or bilateral tubal ligation. Documented hysterectomy or oophorectomy are based on the actual procedure. It must be confirmed by medical records or by ultrasound. Tubal ligation is actually The procedure must be confirmed in the medical records; otherwise, the subject will be screened. Starting from the time of arrival at the hospital and continuing until 120 days after the last dose of the study treatment, throughout the study, two tens We must be willing to accept the use of appropriate barrier methods. For male subjects, the treatment period starts from the first dose of the study treatment and continues until 120 days after the last dose of the study treatment. You must agree to use sufficient contraception until then.

[0218] Exclusion criteria Participants must be excluded from the clinical trial if they meet any of the following criteria: 1. Acinar cell carcinoma, pancreaticoblastoma, malignant cystic neoplasm, endocrine neoplasm, Squamous cell carcinoma, malignant tumors of the duodenum or common bile duct around Vater's and ampulla, The patient has a pancreatic tumor other than cancer. 2. Patients with intestinal obstruction. 3. Having an active infection or an uncontrolled infection that requires systemic treatment. 4. Having an additional known malignant tumor that is progressing or requires aggressive treatment. Outside, well-treated basal cell carcinoma or squamous cell carcinoma that is receiving treatment with the potential for a cure. It is skin cancer or cervical intraepithelial neoplasia. 5. Having an underlying medical condition that is expected to prevent participation in the study. 6. The patient has a disease for which treatment is suitable for administration for curative purposes. 7. You are currently participating in a clinical trial of an investigational drug, receiving or undergoing an investigational treatment. Within four weeks of the first dose, participants who received the investigational treatment or used the investigational device There is. 8. Diagnosed with immunodeficiency or systemic steroid use within 7 days prior to the first dose of the investigational treatment. They are receiving treatment or any other type of immunosuppressive therapy. 9. The patient received prior anti-cancer monoclonal antibody (mAb) treatment within four weeks prior to day 1 of the trial. This includes recovery from an AE caused by an active agent administered more than 4 weeks prior (i.e., ≤ Not at Grade 1 or baseline. 10. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within two weeks prior to day 1 of the trial. Having received therapy or recovered from an adverse event caused by a previously administered active ingredient (i.e., (Not at Grade 1 or baseline.) 11. Systemic treatments (i.e., disease-modifying agents, corticosteroids) during the two years prior to this study. An active autoimmune disease requiring treatment with steroids or immunosuppressants. 12. Transfusion of blood products (e.g., platelets or red blood cells) within 4 weeks prior to Day 1 of the test. or colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF], GM-CSF) They have previously received (or recombinant erythropoietin). 13. A history of (non-infectious) pneumonitis requiring steroids, or current pneumonitis. 14. Has a history of interstitial lung disease. 15. O2 saturation < 92% (in indoor air). 16. Unstable angina, new-onset angina within the past 3 months, myocardial infarction within the past 6 months, And current congestive heart failure New York Heart Association Stage III or higher. Ventricular arrhythmia or control within 6 months prior to the start of the trial. The patient has poor blood pressure or severe arterial thromboembolism. 17. Any condition that may interfere with the results of this clinical trial and prevent the subject from participating in this clinical trial for the entire duration. A principal investigator who has or is treating past or present evidence of medical or laboratory abnormalities. According to this opinion, participation is not in the best interest of the individuals involved. 18. Any known psychiatric or substance abuse disorder that is expected to interfere with the requirements of this trial. It holds. 19. Starting from the time of the screening visit, until 120 days after the last dose of the clinical trial procedure. During the planned period of the trial, if you are pregnant, breastfeeding, or have a child He is either a stay-at-home parent or expecting to become a father. He tested positive within 72 hours of baseline. A woman who has a pregnancy test result. 20. Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents. The subject has previously participated in the Merck MK-3475 clinical trial. case. 21. Positive HIV test at the time of screening or at any point before screening The results are available. Patients without a previous positive HIV test result may not be permitted by local ordinance. Unless otherwise specified, you will be tested for HIV during the screening process. 22. Active hepatitis B (positive hepatitis B surface antigen (HBsAg) at screening) ) Defined as having a test result for hepatitis C (positive at the time of screening) (defined as having an HCV antibody test result or a positive HCV RNA test result) I'm buying it. 23. I know you have a history of chronic hepatitis B or C. 24. You have received a live vaccine within 30 days of the planned start date of the trial treatment. Seasonal influenza vaccines that do not contain the virus are permitted. 25. Active central nervous system (CNS) metastases and / or carcinomatous meningitis are known. Note Meaning: Subjects with previously treated brain metastases should be considered stable (first use of investigational treatment) For at least four weeks prior to the assessment, the same imaging modality, MRI, was used for each evaluation. Evidence of progression from imaging diagnostics using either computed tomography (CT) scans. (No basis, and any neurological symptoms have returned to baseline), new or expanding No evidence of brain metastasis was produced, and for at least 14 days prior to the investigational procedure, steroids were used. Participation is possible on the condition that no drug is used. This exception will be excluded regardless of clinical stability. It does not include carcinomatous meningitis. 26. Severe hypersensitivity to pembrolizumab and / or any of its excipients. It has (≥ Grade 3). 27. The patient has clinically ill ascites requiring treatment.

[0219] Target identification Each consenting participant will be included from the time of screening until the end of the trial, or if the participant is A unique identifier used to identify the subject for all procedures that occur until the end of this test It receives a target number. Each target is assigned only one target number. The target number is, It must not be reused for a different purpose.

[0220] Any subject being screened multiple times will be assigned during their first screening visit. It retains the first target number assigned. If a single target is assigned more than one target number, That is impossible.

[0221] Screening Ineligible Those who do not meet the entrance criteria at any stage during the screening period are This is defined as being ineligible for screening.

[0222] Removal, replacement, or early withdrawal of the subject from treatment or evaluation. The subject is a trial, which can be implemented at any time and without affecting the implementation of further measures. Participants are free to withdraw from the investigational drug and / or their participation in the trial. The principal investigator may, Any subject, if that subject requests to leave, or if in the examination It was determined that continuing would result in a significant safety risk to the subject. If so, the patient must be withdrawn from the trial. If the patient achieves CR, they should be removed early (i.e., 2 The trial treatment can be terminated (within one year). Subjects who discontinue the trial drug will be subject to their Unless you withdraw your consent to continue participating in the trial, you will be ineligible to continue participating in the trial for up to five years. Continue participating in the tracking.

[0223] Patients who withdrew from the study before their baseline visit or before the first injection of any of the study drugs The elephants are replaced.

[0224] If a participant discontinues the clinical trial during the DLT evaluation period for any reason other than safety, a replacement will be provided. Subjects may be registered if deemed appropriate to reach the target number for DLT evaluation. For subjects who discontinued the clinical trial during the DLT period due to progression, the DLT evaluation will be reviewed. They are not; however, they are counted as having progressed in terms of effectiveness analysis. Those being replaced will be assigned a unique procedure / number.

[0225] The use of the test drug may be discontinued for any of the following reasons: ·toxicity ·death • Regulatory body requirements • Requirements of the clinical trial sponsor • Request from the primary care physician or principal investigator: The principal investigator withdraws from the trial. It is determined that this is in the best interest of the subject. • Withdrawal of consent by the subject ·Disease progression • For women who have become pregnant Untrackable • The subject does not comply with the test procedures / test protocols. ·others

[0226] Handling of withdrawal If a participant withdraws from the study, every effort will be made to determine the reason. This information should be recorded in the relevant case report form (CRF). Is it premature to conduct the trial? All subjects who withdrew from the trial, regardless of the reason, were subject to all early termination trial visit procedures and safety follow-up visits. Furthermore, long-term follow-up should be continued regarding survival.

[0227] If withdrawal is triggered by an adverse event (AE) that the principal investigator believes may be related to the investigational drug, If requested, the AE will follow local guidelines and establish an Institutional Review Board / Independent Review Board. It will be reported to the Ethics Board (IRB / IEC).

[0228] All adverse events (AEs) will have their prognosis determined or stabilized according to the clinical judgment of the principal investigator. They will be tracked with appropriate medical management until recovery from the AE. All tracking information will be kept in the relevant CRF until recovery from the AE. It will be recorded.

[0229] Discontinuation of experimental treatment after complete remission Discontinuation of the investigational drug may be considered for subjects who have achieved confirmed complete response (CR): • Treated with combination therapy for at least 24 weeks, • Received at least two treatment cycles of combination therapy beyond the date the first complete response (CR) was declared. .

[0230] [Example 4] Treatment period The treatment period consists of the following two periods: • Monotherapy period: BL-8040 is administered daily from day 1 to day 5. • Combination therapy: Chemotherapy: Onivyde(registered trademark) / 5-FU / LV every two weeks, Pembroliz Mab once every three weeks, and BL-8040 twice a week.

[0231] Monotherapy This period begins immediately after baseline, preferably on the day of baseline assessment, and This lasts for a week. During this period, BL-8040 is administered daily from day 1 to day 5. Systemic antihistamine Premedication with tamins may be associated with local injection site reactions and / or systemic reactions related to BL-8040. Recommended to minimize the occurrence of sexual response.

[0232] Week 1 (Days 1-5) Procedure 1. AE (Airborne Examination) review at each visit. 2. Premedication and concurrent administration 3. Before daily administration on days 1-5, and 4 hours after administration on days 1 and 5. CBC blood smear with differential diagnosis after ±2 hours 4. FAC before administration and 4 hours (±2 hours) after administration on days 1 and 5. Blood for immunophenotype testing by S 5. Specific PE on day 5 (+ up to 3 days, but before the start of the combined period) 6. Vital signs: Before administration of BL-8040 on day 5. Post-administration evaluation is at the discretion of the principal investigator. It can be collected by means of a designated method. 7.12 lead ECG 8. CA 19-9 and C on day 5 (+ up to 3 days, but before the start of the combined use period) Blood about EA 9.CXCR before administration and 4 hours (±2 hours) after administration on days 1 and 5. Blood for 4 and PD-1 expression 10.5 days (+ up to 4 days, but before the start of the combined period) for evaluation of metastasis or Collection of tumor tissue (biopsy) 11. Evaluation of tumor imaging on day 5 (+ up to 4 days, but before the start of the concomitant use period) Biomarker correlation on day 12.5 (+ up to 3 days, but before the start of the concomitant use period) Blood for testing cells, DNA, and RNA 13. Biomarker correlation on day 5 (+ up to 3 days, but before the start of the concomitant use period) Serum (immune cells) for testing

[0233] Combination therapy The cycle is defined by a 3-week cycle schedule of pembrolizumab treatment. .

[0234] Starting on day 8 (+ up to 4 days), the patient will begin a combination therapy period consisting of the following treatments: • IV Onivyde® 70 mg / m² over 90 minutes 2 , then 30 minutes Intermittent IV LV 400mg / m² 2 Subsequently, IV 5-FU 24 over 46 hours 00 mg / m² 2 Every two weeks. IV Pembrolizumab 200 mg, once every three weeks. • Starting on day 10, SC BL-8040 1.25 mg / kg, twice a week, chemotherapy. At least 24 hours after administration.

[0235] Combination therapy should be continued until disease progression, clinical deterioration, or early termination.

[0236] Premedication with systemic antihistamines may reduce local injection site reactions related to BL-8040. Recommended to minimize the occurrence of bi / or systemic reactions.

[0237] The following evaluations will be performed for each cycle (the time frame is ±3 days unless otherwise specified). It should be: 1. Review of pre-medication and concurrent medication at every visit. 2. Review of adverse events (AEs) at every visit. 3. Pre-administration specific PE on day 1, starting from cycle 2. 4. Vital signs were assessed on day 1 of each cycle before administration of the study drug, and after administration. Vital signs may be collected at the discretion of the principal investigator. 5. Body weight is assessed at the beginning of each week during the concomitant treatment period, before the first injection of that week. The dosage of BL-8040 will be adjusted accordingly. 6. ECOG performance status on day 1 of each cycle. 7. Chemistry panel before administration of the study drug on day 1 of each cycle. 8. Treatment / Administration: i.BL-8040 administered twice a week. ii. Pembrolizumab administration on day 1 of each 3-week cycle. iii. Onivyde(registered trademark) / 5-FU / LV every two weeks.

[0238] The following evaluations are performed in a specific cycle (the time frame is ±3 days unless otherwise specified). It should be: 1. CBC blood smear with differential diagnosis a. Cycle 1: Regarding WBC evaluation, the first three doses of BL-8040 were evaluated before administration (BL-8 Regarding CBC before injection (040), the frame is not acceptable). Further evaluation is deemed necessary. It should be implemented if that occurs. Regarding WBC evaluation, for the first three doses of BL-8040, 4 hours after injection ( (±2 hours) b. Cycle 2 and beyond Regarding WBC evaluation, before administration of each BL-8040 in each treatment cycle (BL-8 Regarding CBC before injection (040), the frame is not acceptable). Further evaluation is deemed necessary. It should be implemented if that occurs. 2. Before administration on day 1 of cycle 1, and 4 hours (±2 hours) after concomitant treatment. 2-lead ECG 3. Day 1 of Cycle 1, and thereafter, starting with Cycle 2, and every day of every two cycles. In the eye, pre-administration T3 (total or free), free T4, and TSH 4. Pregnancy test - Starting in cycle 2, and every two cycles using serum or urine. 5. Starting with Cycle 2, CA 19-9 and CEA on Day 1 of every two cycles. Blood 6. Blood for immunophenotyping by FACS: Day 15 of Cycle 1 and Cycle 1 Day 21 of 2 7. CXCR4 and PD- at day 15 of cycle 1 and day 21 of cycle 2 Blood for expression 1 8. Blood for DNA and RNA for biomarker correlation testing: a. Blood for cell, DNA, and RNA correlation tests will be collected during cycle 1 / 2. Day 15 before the start of chemotherapy, and every 21 days starting from cycle 3. It is collected by sight. 9. Tumor imaging assessment should be performed at the end of Cycle 2 and thereafter for one year after the treatment (cycle 17) Every 3 cycles until then, and then at the end of cycle 34 / 4 (2 years) The procedure is performed every four cycles. 10. Serum for biomarker correlation testing: Chemistry of cycle 1 / 2 On day 15 prior to therapy, and on day 21 of every two cycles starting from cycle 3. , collected (immune cells, receptor occupancy, CA 19-9).

[0239] More specific embodiments are outlined below: BL-8040 The clinical trial treatment with BL-8040 involved monotherapy, administered daily for one week, starting on day 1 and continuing until day 5. It is administered by SC injection at a dose of 1.25 mg / kg per day. The target group is those who receive it once a day. I will receive a BL-8040 SC injection in the morning. Systemically, with or without an analgesic. Premedication with antihistamines may cause local injection site reactions and / or other issues related to BL-8040. This is recommended to minimize the occurrence of systemic reactions.

[0240] The BL-8040 injection site is designed to minimize the severity of any local injection site reactions. It is rotated. If the reconstituted dose volume is greater than 2 ml, the injection is a single injection. It should be divided into doses of less than 2 ml per injection; at the discretion of the principal investigator, single dose The dose may be divided and injected into more than one site. The same instructions apply to the combined use of the test. Applies to the usage period.

[0241] BL-8040 injection significantly reduces WBC count measured before the next BL-8040 injection. If there is an increase (WBC > 60,000 / μL) and / or evidence of leukocyte stagnation, skip. The BL-8040 treatment is performed when there are no signs of leukocyte stagnation and / or WBC values ​​≤ The procedure will be resumed on the condition that the concentration decreases to 60,000 / μL.

[0242] After monotherapy, BL-8040 is used in combination with pembrolizumab in 3-week cycles. It is administered as part of the treatment. The administration is as follows: During the combination therapy period, BL-8040 should be administered at least 24 hours after chemotherapy, and 48 hours after chemotherapy. It is administered twice a week as an SC injection in the morning on non-consecutive days.

[0243] Blood sampling and other evaluations should be completed before administration of BL-8040. Actions performed at 0 will, when the action is resumed, follow the same schedule defined within that protocol. Under the condition that it continues in joules, that is, without making up for any missing doses, It can be delayed. More than two consecutive doses can be skipped during the monotherapy period. Or, if more than three consecutive doses (weekly treatments) are skipped during the concomitant use period, The principal investigator assesses the risks and benefits and determines whether the subject can continue participating in the trial. The reason for the interruption should be documented in the relevant test record.

[0244] Pembrolizumab Treatment with pembrolizumab begins as part of combination therapy after a period of monotherapy. During the period, pembrolizumab will be administered in 3-week intervals after all procedures and evaluations are completed. It is administered as a 200 mg dose using a 30-minute IV infusion on the first day of Ikul. Pembrolizumab may be taken 3 days before and 3 days after day 1 of each scheduled cycle for administrative reasons. It may be administered by [date].

[0245] Pembrolizumab is administered as a 200 mg dose using an intravenous infusion over 30 minutes. We make every effort to aim for the injection timing to be as close to 30 minutes as possible. This should be done. However, considering the variability of the injection pump, from -5 minutes A 10-minute window is allowed (i.e., the infusion time is 30 minutes - 5 minutes / +10 minutes). (That is.)

[0246] If pembrolizumab is supplied on the same day as BL-8040, BL-8040 administration is This is 1 hour (±0.5 hours) after the end of pembrolizumab infusion. If pembrolizumab is administered on the same day as chemotherapy, pembrolizumab is administered first, and then, Chemotherapy should be administered.

[0247] Discontinuation of administration is due to medical / surgical events or logistical reasons unrelated to the study treatment (i.e., In the case of selective surgery, unrelated medical events, the subject's leave, or holidays, it is permitted. The patient should be brought back to the trial treatment within three weeks of the scheduled interruption. The reason for the interruption is: This should be documented in the elephant's test records.

[0248] Onivyde / 5-FU / LV Onivyde should be administered before LV and 5-FU. Every two weeks, Onivyde 70 mg / m² was administered as an IV infusion over a 90-minute period. 2 Then, for 30 minutes LV 400mg / m³ 2 IV, followed by 5-FU 2400 mg / m² over 46 hours. 2 IV. UGT1A1 * Patients who are homozygous for 28 alleles are registered in Onivyde (registration). (Trademark) 50 mg / m² 2 It is started at a dose that is tolerable in subsequent cycles. If possible, it can be increased.

[0249] [Example 5] Safety follow-up visit After the hospital visit for completion / early termination, safety follow-up visits should be approximately 30 minutes after the last dose of the final study drug. It will be performed a few days later (or within 7 days before the start of the new anti-cancer treatment, whichever comes first). The elephant will be kept until safety follow-up visits, or until the toxicity is reduced to grade 0-1 or AE is stabilized. AEs are monitored until whichever comes first. SAEs are monitored for 90 days after the end of the exam. If it occurs within 120 days of the end of the trial, and if pregnancy occurs within 120 days of the end of the trial, In either case, if a new anti-cancer treatment is started, within 30 days of discontinuation In such cases, it should be reported.

[0250] The following assessments will be performed during this visit: 1. AE review 2. Review prior and concurrent drug therapies. 3. Anti-cancer treatment received after the trial 4. CBC blood smears requiring differential diagnosis 5. Chemical Panel 6. T3 (total or free), free T4, TSH 7.12 lead ECG

[0251] Long-term survival tracking All subjects, regardless of the reason for termination (i.e., early termination [ET] or after 2 years), They will be contacted by phone every 12 weeks (±4 weeks) to assess their survival status. The agreement will continue for a maximum of five years unless they withdraw their consent to continue participating in the exam. In these calls, the subjects discussed, in particular, their disease status and the anti-cancer treatments they had received after the trial. You will be asked to provide the latest information. All dates will be collected and stored in the CRF. It will be entered.

[0252] Unscheduled visit Unscheduled visits may occur at the request of the patient or if deemed necessary by the principal investigator. This may be done at any time during the trial. The date and reason for any unscheduled visits will be recorded. AE Monitoring and recording of concurrent drug therapy will be performed by the principal investigator. Other procedures And evaluation will be completed if deemed necessary by the principal investigator, and this will include clinical Safety checks, vital signs, and physical examinations are examples (but are not limited to these). do not have).

[0253] Safety evaluation Safety assessment is based on clinical signs reported by the subjects or observed by the principal investigator. Based on the changes in symptoms from baseline, this includes adverse events (AEs), concurrent drug use, and treatment. Compliance, tolerability (e.g., dropout due to adverse events), vital signs, E This includes safety assessments of computer graphics (CG), physical examinations, and clinical tests.

[0254] Adverse events (AEs) Adverse events (AEs) will be evaluated at every trial visit throughout the trial.

[0255] Any new adverse events that occur between scheduled evaluation visits are also the responsibility of the principal investigator. The supervisor should be informed and the information should be recorded on the appropriate CRF page in the relevant medical file. ru.

[0256] AE is defined in the latest National Cancer Institute Common Terminology Criteria for Adverse Events (NCI). mmon Terminology Criteria for Adverse Events (NCI-CTCAE) version Reported and graded according to the current version 4.03, and the latest version of Medical Medical Dictionary for Regulatory Activities (MedDRA) It is coded according to the data management system used.

[0257] Concurrent drug therapy The use of concurrent drug therapies is recorded from baseline to all trial visits.

[0258] Vital signs, height, and weight Vital signs were measured at screening, baseline, and on day 5 of monotherapy treatment. Measured before administration. Post-administration evaluation is performed as deemed necessary by the principal investigator. This may be performed at any time. During the concomitant use period, vital signs will be monitored on day 1 of each cycle. It will be evaluated before administration. Further evaluation may be performed at the discretion of the principal investigator.

[0259] Vital signs include blood pressure, pulse, and oral temperature after a minimum 5-minute rest, as per standard procedures. This includes oxygen saturation and respiratory rate. These criteria meet the definition of an AE and were noticed after the start of the investigational drug. Important findings must be recorded in the AE CRF module.

[0260] Height is recorded only during screening.

[0261] Weight was measured at baseline and at the beginning of each week (combined use period) using BL-8040. The dosage is recorded before administration to calculate the required dose.

[0262] electro-cardiogram ECG is performed at the screening visit and the baseline visit (before administration on day 1). It can be done.

[0263] During the concomitant use period, ECGs were monitored on cycle 1 / 1 day before administration and after the last study drug was administered. It is performed 4 hours (±2 hours) after administration. ECG is performed upon the completion of the visit, and This is performed during optional safety follow-up visits.

[0264] Additional ECGs may be performed at the discretion of the principal investigator. The subjects are those who were present before the measurement was taken. You should take a break for at least 10 minutes.

[0265] The ECG printout must be evaluated and signed by the principal investigator or nominee, and by [date]. An attachment is added and filed in the source documentation file. Clinical significance is possible. If the principal investigator or designated investigator detects any possible findings, a cardiologist will make the final decision. All should seek advice on interpretation and, if necessary, appropriate action. Contacts and diagnoses should be filed in the source documentation file. The principal investigator / designated principal investigator / local cardiologist believes that the ECG findings are clinical They are responsible for determining whether it has significance. All abnormalities must be stabilized or resolved. Therefore, it should be closely monitored. Findings of clinical significance should be noted on the AE CRF page. This should be reported.

[0266] Physical examination and specific physical examination Complete PE is performed at the time of screening and at the time of discontinuation. PE includes the following physical systems Assessments can be given for the following areas: head, neck, thyroid, respiratory, cardiovascular, ophthalmic, gastrointestinal tract, liver, and endocrine system. Metabolic, musculoskeletal, dermatological, lymphatic, nervous system, and, where appropriate, examination schedule Other bodily systems, as shown in the diagram.

[0267] Specific PE occurs on day 5 of monotherapy (±3 days, but before the first dose of the combination therapy), and Starting from Cycle 2, the first day of each cycle (±3 days, however, the maximum number of days when using Cycle 2 concurrently) This is done (before the first dose) (Figure 1). During a specific PE, A may be involved with the drug. We will focus particularly on identifying E and effectively managing these AEs. It should.

[0268] Information regarding PE must be available. Important findings present before the start of the investigational drug test. This must be included in the relevant medical history / current health status CRF. Any significant findings that occur after the initiation of the investigational drug must be recorded in the AE CRF module. stomach.

[0269] Clinical laboratory safety evaluation All clinical laboratory safety assessments listed below are performed at the time of screening and at specific evaluations. Depending on the value, at different time points between monotherapy and combination therapy, by local laboratory The procedure will be carried out. Pre-administration clinical testing procedures may be performed within 4 hours prior to administration.

[0270] Safety clinical laboratory sampling includes the following parameters:

[0271] Clinical tests for hematology, chemistry, urinalysis, and other fields are specified in Table 2. .

[0272] [Table 2]

[0273] If applicable, serum pregnancy tests are collected at baseline and performed at a local laboratory. It can be done.

[0274] If clinically necessary, any abnormal safety clinical laboratory values ​​that occur after administration of the investigational drug should be restored to normal levels. This process is repeated until the condition returns to normal or until the cause is determined and the condition is considered stable. Abnormal clinical laboratory results that the principal investigator deems clinically important are classified as AE CR. It is reported as an AE in module F. Examination abnormalities are considered AEs except in the following cases. Not done: • Intervention is needed • Dosage changes are required (reduction, discontinuation, interruption). • Other procedures / treatments may be required. • Related to other diagnoses

[0275] [Example 6] Effectiveness evaluation Diagnostic imaging evaluation Diagnostic imaging is used to evaluate the response. For example, CT or MRI may be used. The same imaging diagnostic method should be used for each patient throughout the treatment process.

[0276] According to a particular embodiment, the image diagnostic evaluation can be performed at the following point in time: • The point at which the target for the match is selected • End of monotherapy period, day 5 • End of cycle 2 of the combined treatment period, and thereafter for one year of treatment (cycle 17) Then every 3 cycles, and then every 4 cycles thereafter until the end of treatment.

[0277] According to certain embodiments, the unique tumor response characteristics observed with respect to immunotherapy agent treatment are described. RECIST 1.1 is applied to clarify the situation. Pembrolizumab and BL-804 Substances such as 0 can produce antitumor effects by enhancing the endogenous cancer-specific immune response. The response patterns observed with respect to such approaches are similar to those observed with respect to cytotoxic agents. The typical response time course may be prolonged beyond the initial increase in tumor volume or the development of new lesions. Clinical responses can be manifested even after the onset of symptoms: • If radiological imaging demonstrates the initial progressive disease, tumor evaluation should be as follows: With the option of continuing treatment, to confirm the progression of the disease, after 4 weeks or more This should be repeated. • Repeated imaging studies have shown that the previous new lesions were stable or improved (first progression). (When identified as the cause of a circumventive disorder) and stable / improved non-target lesions (initial progressive If the tumor volume shows an increase of less than 20% compared to when it is identified as the cause of the disease The treatment may be continued / restarted. Repeated imaging studies confirm progressive disease in one of the scenarios listed below. In that case, treatment will be discontinued. • In determining whether tumor volume has increased or decreased, all target lesions, in addition Therefore, non-target lesions should be considered.

[0278] Scenarios for cases where a progressive disease is repeatedly confirmed by imaging studies: • The tumor volume is still more than 20% greater and at least 5 mm larger compared to Nadia. It remains an absolute increase. • The non-target lesion that initially caused the progressive disease is worsening (qualitatively). • The new lesions that caused the initial progressive disease are worsening (qualitatively). • Additional new lesions since the last assessment

[0279] In subjects with initial radiological evidence of progressive disease, repeated imaging studies are available. Whether or not to continue treating the subject until [a certain condition is met] is at the discretion of the treating physician. This clinical decision is The overall subject, including performance status, clinical symptoms, and clinical laboratory data. It should be based on the clinical condition. The subjects should be as defined by the following criteria. If the patient is bedridden and stable, treatment can continue while awaiting confirmation of a progressive disease. • No signs or symptoms indicating disease progression. • No decrease in ECOG performance status • No rapid progression of the disease • In critical anatomical sites requiring urgent alternative medical intervention (e.g., spinal cord compression) No progressive tumor

[0280] If possible, the procedure should not be stopped until progression is confirmed. Despite the progression of the disease, this acceptance of continuing treatment is due to the fact that some individuals are undergoing immunotherapy. During the first few months after initiation, there may be a transient tumor flare, but thereafter, a disease response may occur. This observation is being taken into consideration. Patients considered clinically unstable are used to confirm progressive disease. Therefore, repeated imaging tests are not required.

[0281] If the physician assesses the progression of the disease and the patient is clinically stable (as described above), the patient should continue treatment. Furthermore, imaging should be performed at least four weeks after the first tumor imaging diagnosis showing progressive disease. This is at the discretion of the physician. At that time, whether follow-up tumor imaging has confirmed a progressive disease. To make a decision, the physician follows irRECIST. Subjects for whom disease progression was not confirmed are If they meet the conditions detailed above, continue treatment until progress is confirmed. And, it can follow a regular imaging diagnostic schedule interval.

[0282] irRECIST evaluation of disease As mentioned above, if tumor imaging shows the initial progression of the disease, then the size The patient chose to continue treatment, and repeated imaging studies were performed more than 4 weeks later, and irRECI ST can be used to assess the tumor response or progression.

[0283] Planned biopsy analysis According to certain embodiments, biopsies can be performed at the time of screening, and tumor mutations can be detected. The quantity (TMB), PD-L1, and DNA mismatch repair status are evaluated.

[0284] Blood sampling and processing The samples were used for safety and efficacy analysis, anti-drug antibody titers, and BL-8040 plasma concentration analysis. These are collected for the purpose of making a decision.

[0285] [Example 7] Identity of the clinical trial product BL-8040 BL-8040 is a novel investigational treatment for cancer. Developed jointly by apeutics, Ltd. and BioLineRx Ltd. It is a highly selective CXCR4 antagonist.

[0286] BL-8040 is a white to off-white powdered synthetic polypeptide that is used in water. It dissolves easily in 0.45% sodium chloride (half physiological saline). Connection BV (formerly MSD), Kloosterstraat 9 ,5349 AB Oss, Netherlands, the latest Good Manu Manufactured in accordance with Manufacturing Practice (cGMP).

[0287] Pembrolizumab Injectable pembrolizumab (MK-3475) solution contains 100 mg / 4 mL of pembrolizumab. Zumab (MK-3475) is supplied in a disposable Type I glass vial. It is a sterile, non-pyrogenic aqueous solution. The product is essentially free of foreign particles and preservatives. It is a pear solution.

[0288] Chemotherapy: Onivyde(registered trademark) / 5-FU / LV Onivyde is an injectable drug: a single-dose vial containing a white to yellowish opaque liposomal solution. This is 43 mg / 10 mL of irinotecan free base as a dispersion.

[0289] Fluorouracil injection contains 2.5g / 50mL (50mg / mL) fluorouracil. It is supplied as a pharmacy bulk package in vials containing [the substance].

[0290] Leucovorin calcium for injection is supplied as a sterile, freeze-dried powder. 350 mg The vial contains no preservatives. The inactive ingredient is sodium chloride per 350 mg vial. It contains 140 mg / vial. Sodium hydroxide and / or hydrochloric acid are used during manufacturing, pH It is used to adjust it to approximately 8.1. 1 mg of leucovorin calcium is 0. It contains 0.002 mmol of leucovorin and 0.002 mmol of calcium.

[0291] [Example 8] Pembrolizumab and chemotherapy in patients with metastatic pancreatic adenocarcinoma (PDAC) Phase 2a clinical trial to evaluate the safety and efficacy of BL-8040 in combination background Current treatment options for PDAC are limited. PD-1 / PD-L1 antagonist While Nist has shown promising results in other cancer types, this approach is particularly effective in PDAC. It was ineffective. In Cohort 1 of the COMBAT trial, BL-8040 (CXCR The dual combination of 4 inhibitors and pembrolizumab is safe and is used in second-line (2L) patients. This study showed a promising median overall survival (OS) of 7.5 months (Hidalgo, A., et al., AP). hase 2a Trial to Assess the Safety and Efficacy of BL-8040 and Pembrolizumab in Patients with Metastatic Pancreatic Adenocarcinoma (PDAC). Annals of Oncology, 2 018. 29: p. viii400-viii441). BL-8040 is an efferent that expresses granzyme B. By increasing the level of dermatological CD8 cells, in addition, myeloid suppressor cells (MDS) By reducing the level of C), the tumor microenvironment (TME) is modified.

[0292] These encouraging results, in addition to BL-8040, pembrolizumab, and chemotherapy Based on preclinical data supporting the combination of the two drugs, this study will test BL-8040 and pembroliz A combination group consisting of mab and chemotherapy (Onivyde / 5-FU / LV) (cohort The expanded cohort was to include (2). Preclinical efficacy of BL-8040 in this expanded cohort. Sex and safety data are provided below.

[0293] method Phase 2a trial, Cohort 2, treatment regimen: 5 days of BL-8040 monotherapy, Afterwards, Onivyde / 5-FU / LV every two weeks, pembrolizumab every three weeks, The treatment consists of BL-8040 administered twice a week. Eligibility criteria are based on gemcitabine. After first-line chemotherapy, the disease is progressing, as described in Example 3, and is measurable. This includes patients with metastatic PDAC who have other diseases.

[0294] result As of September 2019, 22 patients had been enrolled, of which 15 were evaluable. (i.e., receiving at least one dose of concomitant therapy and having a post-baseline CT). Year Median age 68 years, ECOG ≤ 1, and 60% male. 15 SAEs in 10 patients. It was reported that the two subjects were discontinued by SAE. RE for evaluable populations The best response according to CISTv1.1 (Example 6) was a partial response (PR) in 4 patients and 8 patients The study included 12 out of 15 patients with stable disease (SD) whose disease was under control. This showed that the median PFS and OS had not yet been reached. In particular, SD and PR All patients with this condition experienced an initial increase in CA 19-9, followed by a decrease. Tumor reduction. This began during a transient increase in CA 19-9.

[0295] conclusion Ongoing COMB with triple combination therapy of BL-8040, pembrolizumab, and chemotherapy Preliminary data from AT trial cohort 2 show promising overall response rates (ORR) (4 / 15) and This shows the disease control rate (DCR) (12 / 15).

[0296] The present invention is described in conjunction with its specific embodiments, but many alternatives, modifications, and It is obvious that the variations are obvious to those skilled in the art. Therefore, the attached claims The spirit of the scope and all such substitutes, modifications, and variations within that broad scope It is intended to include .

[0297] All publications, patents, and patent applications referenced in this specification are as if each individual publication If any works, patents, or patent applications are specifically and individually indicated and incorporated herein by reference... It is incorporated into this specification by reference to the same extent as if it were incorporated in whole. In addition, any citation or identification of references in this application is prohibited. The referenced literature should not be interpreted as an acknowledgment that it can be used as prior art for the present invention. Within the scope in which section headings are used, they are not necessarily interpreted as limiting. It shouldn't be done.

[0298] In addition, any priority documents of this application are incorporated herein by reference in their entirety. This application also relates to the following aspects. (1) A method for treating metastatic pancreatic adenocarcinoma in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of the peptide, anti-PD-1, and chemotherapy described in SEQ ID NO: 1, thereby treating the metastatic pancreatic adenocarcinoma. (2) The therapeutically effective doses of the peptide, anti-PD-1, and chemotherapy described in SEQ ID NO: 1, respectively, for use in treating metastatic pancreatic adenocarcinoma in patients requiring treatment. (3) A product containing therapeutically effective amounts of the peptide described in SEQ ID NO: 1, anti-PD-1, and chemotherapy, for use in the treatment of metastatic pancreatic adenocarcinoma. (4) The method, therapeutically effective amount, or product described in any one of the above (1) to (3), wherein the anti-PD-1 is pembrolizumab. (5) The method or therapeutically effective amount or product according to any one of the claims (1) to (4) above, wherein the chemotherapy comprises a plurality of chemotherapeutic agents. (6) The chemotherapy comprising irinotecan, fluorouracil (5-FU), and leucovorin (LV), according to the method or therapeutically effective amount or product described in any one of (1) to (5) above. (7) The method or therapeutically effective amount or product according to any one of the above (1) to (6), wherein the irinotecan is encapsulated in liposomes. (8) The method or therapeutically effective amount or product according to any one of the above (1) to (7), wherein the irinotecan is Onivyde®. (9) The method or therapeutically effective amount or product according to any one of (1) to (8) above, wherein the peptide is administered subcutaneously (SC). (10) The method or therapeutically effective dose according to any one of the above (1) to (9), wherein the peptide is administered at a dose of 1.25 mg / kg. (11) The method or therapeutically effective dose according to any one of the above (1) to (10), wherein the anti-PD-1 is administered intravenously (IV). (12) The method or therapeutically effective dose according to any one of the above (1) to (11), wherein the anti-PD-1 is administered in a dose of 200 mg. (13) The method or therapeutically effective dose of the chemotherapy administered intravenously according to any one of the claims (1) to (12) above. (14) The method or therapeutically effective dose according to any one of (1) to (13), wherein the treatment comprises a period of monotherapy with the peptide, followed by combination therapy with the peptide, the anti-PD-1, and the chemotherapy. (15) The method or therapeutically effective dose according to any one of the claims (1) to (14), wherein the combination therapy with the chemotherapy and the anti-PD-1 is initiated on day 8. (16) The method according to (14) or (15) or a therapeutically effective dose, wherein the combination therapy comprises repeating the chemotherapy every two weeks and repeating the anti-PD-1 every three weeks. (17) The method according to (15) or a therapeutically effective dose wherein the combination therapy with the peptide is initiated on day 10 and administered twice a week on non-consecutive days separated by 48 hours. (18) The method or therapeutically effective dose of the monotherapy described in any one of the above (1) to (17), wherein the monotherapy is administered daily on days 1 to 5. (19) The method according to (18) or a therapeutically effective amount, wherein the treatment further comprises an antihistamine and, optionally, an analgesic. (20) The combination therapy described above is performed in a manner consistent with any one of the methods described in (1) to (19) above, or in a therapeutically effective dose, for up to 35 treatments. (21) The method or therapeutically effective dose according to any one of the items (1) to (20), wherein the subject has undergone first-line treatment for the metastatic pancreatic adenocarcinoma. (22) The first-line treatment is the method according to (21) or a therapeutically effective dose, comprising gemcitabine-based chemotherapy. (23) The method or therapeutically effective dose according to any one of the above (1) to (21), wherein the metastatic pancreatic adenocarcinoma is unresectable. (24) The method or therapeutically effective dose according to any one of the above (1) to (21), wherein the metastatic pancreatic adenocarcinoma is pancreatic ductal adenocarcinoma. (25) The method according to (24) or a therapeutically effective amount, wherein the metastatic pancreatic ductal adenocarcinoma includes an intraductal papillary mucinous neoplasm.

[0299] Table 3-1

[0300] Table 3-2

[0301] Table 3-3

[0302] Table 3-4

Claims

1. The peptide described in SEQ ID NO: 1, Anti-PD-1 antibody, and, A formulation comprising one or more therapeutically effective amounts of each chemotherapeutic agent, A pharmaceutical composition intended for use in treating metastatic pancreatic cancer in the target population, The above treatment is the first-choice treatment. The one or more chemotherapeutic agents are gemcitabine and nab-paclitaxel. Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the peptide is administered subcutaneously (SC).

3. The pharmaceutical composition according to claim 1 or 2, wherein the peptide is administered at a dose of 1.25 mg / kg.

4. The pharmaceutical composition according to any one of claims 1 to 6, wherein the anti-PD-1 antibody is administered in a dose of 150-450 mg.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the combination therapy with the peptide is initiated on the 8th day and administered twice a week on non-consecutive days separated by 48 hours.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the monotherapy is administered on days 1 to 5.

7. The treatment comprises a period of monotherapy with the peptide, followed by combination therapy using the peptide, the anti-PD-1 antibody, and the chemotherapeutic agent or active substance. The combination therapy with the aforementioned chemotherapeutic agent or active substance and the aforementioned anti-PD-1 antibody is initiated on day 8. A pharmaceutical composition according to any one of claims 1 to 4.

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