CN112915203A

CN112915203A - Pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody

Info

Publication number: CN112915203A
Application number: CN202011385436.9A
Authority: CN
Inventors: 葛琪; 张喜全; 李百勇; 王训强; 金小平; 于鼎
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2019-12-06
Filing date: 2020-12-01
Publication date: 2021-06-08

Abstract

There is provided a pharmaceutical combination of a quinoline derivative and PD-1 mab which comprises a tyrosine kinase inhibitor and an immune checkpoint inhibitor, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof. The medicine composition has excellent activity of resisting digestive tract tumor, urinary system tumor or neuroendocrine tumor.

Description

Pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody

Technical Field

The application belongs to the technical field of medicines and relates to a combined treatment for resisting tumors. In particular, the application relates to a combination based on quinoline derivatives and PD-1 monoclonal antibodies and application thereof in resisting digestive tract tumors, urinary system tumors and neuroendocrine tumors.

Background

Tyrosine kinases are a group of enzymes catalyzing phosphorylation of tyrosine residues of proteins, play important roles in signal transduction in cells, participate in regulation, signal transmission and development of normal cells, and are closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases are involved in tumor formation and are classified into Epidermal Growth Factor Receptor (EGFR), platelet-derived growth factor receptor (PDGFR), Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor (FGFR), and the like according to their extracellular domain structures.

Anlotinib (Anlotinib) is a quinoline derivative tyrosine kinase inhibitor, and plays a role in influencing tumor angiogenesis and proliferation signal transduction as a multi-target Tyrosine Kinase Inhibitor (TKI), and main targets comprise: receptor tyrosine kinases Vascular Endothelial Growth Factor Receptors (VEGFR)1 to 3, Epidermal Growth Factor Receptors (EGFR), Fibroblast Growth Factor Receptors (FGFR)1 to 4, Platelet Derived Growth Factor Receptors (PDGFR) α and β, and Stem Cell Factor Receptors (SCFR)7, 8, and 9. A phase 2 trial showed that erlotinib improved progression-free survival with potential benefits for overall survival (Han B, et al Br J cancer.2018; 118 (5): 654-. A multicenter, double-blind, phase 3 randomized clinical trial showed that, among Chinese patients, Arotinib resulted in prolonged overall and progression-free survival, which indicated that Arotinib was well tolerated and is a potential three-line or further treatment for advanced NSCLC patients (Han B, et al, JAMA Oncol.2018 Nov; 4 (11): 1569-.

Document WO2008112407 discloses in example 24 a quinoline derivative tyrosine kinase inhibitor 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine and a process for its preparation, which has the formula shown in formula I:

PD-1(programmed death-1) is a key immune checkpoint receptor expressed by activated T and B lymphocytes and mediates immunosuppression, and its ligands include at least PD-L1 and PD-L2. PD-L1(Programmed death-ligand 1), also known as CD274 or B7-H1, is a 40kDa type 1 transmembrane protein encoded by the CD274 gene and is a ligand for PD-1. Both PD-L1 and PD-1 belong to the immunoglobulin superfamily and both consist of two extracellular Ig domains, an N-terminal V domain and a C-terminal constant domain. The binding interface of PD-L1 to programmed death receptor-1 (PD-1) and B7-1(CD80) is on an IgV-like domain (Lin et al (2008) PNAS 105: 3011-3016). PD-L1 contains a conserved short intracellular tail region (about 30 amino acids), and PD-1 contains two cytoplasmic tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switching motif (ITSM). Following T cell stimulation, PD-1 recruits the tyrosine phosphatase SHP-2 to the ITSM motif in its cytoplasmic tail, resulting in dephosphorylation of effector molecules involved in the CD3+ T cell signaling cascade, such as CD3 ζ, PKC θ and ZAP70 (Freeman et al (2000) J Exp Med 192: 1027-34; Latchman et al (2001) Nat Immunol 2: 261-8; Carter et al (2002) Eur J Immunol 32: 634-43). PD-L1 is widely distributed not only on leukocytes and nonhematopoietic cells in lymphoid and non-lymphoid tissues, but also in various cancer cells, is highly expressed on the surface of various tumor cells, and the degree of malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1. There are clinical data indicating that high tumor expression of PD-L1 is associated with increased tumor invasiveness and poor prognosis. The formation of the PD-1/PD-L1 complex transmits inhibitory signals and negatively regulates T cell immune responses; it inhibits TCR-mediated T cell activation, cytokine production and T cell proliferation (Fife et al (2011) Nature Immunology 10: 1185-1193); induction of depletion or anergy in cognate antigen-specific T cells (Hofmeyer et al (2011) Journal of Biomedicine and Biotechnology 2011: 1-9); promote the differentiation of Th1 cells into Foxp3+ regulatory T cells (Armanath et al (2011) Science TransMed 3: 1-13; Francisco et al (2009) J. exp. Med.206: 3015-; and inducing apoptosis of effector T cells. Disruption of the PD-L1 gene resulted in an upregulated T cell response and the generation of autoreactive T cells (Latchman et al (2004) PNAS 101: 10691-10696). Antibody blockade of PD-1 or PD-L1 resulted in increased anti-tumor immunity (Iwai et al (2002) PNAS 99: 12293-12297).

Chinese patent document CN106977602A discloses a PD-1 monoclonal antibody 14C12H1L1, which can effectively block the combination of PD1 and PDL1 and shows good antitumor activity.

The biggest challenge in the course of tumor immunotherapy in foreigners is poor treatment due to tumor immune tolerance and escape. Therefore, the small-molecule anti-tumor compound and the anti-PD-1/PD-L1 antibody are used in combination to break the immune tolerance established by the body to the tumor cells, and the method has important theoretical significance and application value.

Disclosure of Invention

It is an object of the present invention at least to provide a pharmaceutical combination comprising a tyrosine kinase inhibitor and a human PD-1 antibody, said human PD-1 antibody comprising a light chain and a heavy chain, wherein said light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, said light chain complementarity determining regions consisting of the amino acid sequences shown in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively, and wherein said heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, said heavy chain complementarity determining regions consisting of the amino acid sequences shown in SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6, respectively.

In some embodiments, the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof, and in some particular embodiments, the tyrosine kinase inhibitor is a hydrochloride salt of a compound of formula I, i.e., angutinib hydrochloride.

In some embodiments, the human PD-1 antibody comprises a light chain variable region as set forth in amino acid sequence SEQ ID NO. 7 and a heavy chain variable region as set forth in SEQ ID NO. 8.

In some embodiments, the human PD-1 antibody is 14C12H1L 1.

In some embodiments, the compound of formula I may be present as a pharmaceutically acceptable salt or a pharmaceutically acceptable formulation thereof, preferably as its hydrochloride salt.

In some embodiments, the compound is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, namely, nilotinib hydrochloride.

In some embodiments, the pharmaceutical combination comprises: a compound of formula I or a hydrochloride salt thereof (e.g., dihydrochloride); and 14C12H1L1 monoclonal antibody or antigen-binding fragment thereof.

It is also an object of the present invention at least to provide the use of a pharmaceutical combination comprising a tyrosine kinase inhibitor and a human PD-1 antibody, said human PD-1 antibody comprising a light chain and a heavy chain, wherein said light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, said light chain complementarity determining regions consisting of the amino acid sequences shown in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively, and wherein said heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, said heavy chain complementarity determining regions consisting of the amino acid sequences shown in SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6, respectively, for the treatment of a tumor.

In some embodiments, the tyrosine kinase inhibitor is a compound of formula I or a hydrochloride salt thereof.

In some embodiments, the human PD-1 antibody comprises a light chain variable region as set forth in amino acid sequence SEQ ID NO. 7 and a heavy chain variable region as set forth in SEQ ID NO. 8. In some embodiments, the human PD-1 antibody is 14C12H1L 1.

The invention also provides a method for treating a subject having a tumor of the digestive tract, or a tumor of the urinary system, or a neuroendocrine tumor, comprising administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor and a therapeutically effective amount of a human PD-1 antibody, said human PD-1 antibody comprising a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 consisting of the amino acid sequences set forth in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 consisting of the amino acid sequences set forth in SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6, respectively. In some embodiments, the tyrosine kinase inhibitor is a compound of formula I or a hydrochloride salt thereof. In some embodiments, the human PD-1 antibody comprises a light chain variable region as set forth in amino acid sequence SEQ ID NO. 7 and a heavy chain variable region as set forth in SEQ ID NO. 8. In some embodiments, the human PD-1 antibody is 14C12H1L 1.

The invention also provides a combination therapy for treating a subject having a tumor of the digestive tract, or a tumor of the urinary system, or a neuroendocrine tumor, the method comprising administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor alone and a therapeutically effective amount of a human PD-1 antibody alone, the human PD-1 antibody comprising a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3, the light chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID No. 1, SEQ ID No. 2 and SEQ ID No. 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, the heavy chain complementarity determining regions consisting of the amino acid sequences set forth in SEQ ID No. 4, SEQ ID No. 5 and SEQ ID No. 6, respectively.

The present invention also provides a method of treating a subject having a cancer or tumor, the cancer or tumor being a tumor of the digestive tract, or a tumor of the urinary system, or a neuroendocrine tumor, the method comprising: (i) measuring the level of PD-1 and/or PD-L1 in a sample of the subject, wherein the subject is PD-1 and/or PD-L1 positive, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 and/or PD-L1 antibody or antigen-binding portion thereof.

The invention also provides a method for treating a subject having a cancer or tumor. In certain embodiments, the subject is a patient diagnosed with a tumor of the digestive tract, or a tumor of the urinary system, or a neuroendocrine tumor, such as a patient diagnosed with a cancer of the biliary tract, or intrahepatic cholangiocellular carcinoma, or extrahepatic cholangiocellular carcinoma, or gallbladder cancer, or colorectal cancer, or a gastric or gastroesophageal junction (GEJ) adenocarcinoma, or urothelial carcinoma.

In some versions of the invention, the subject has previously undergone surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has re-developed disease progression after achieving complete remission following surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has failed to complete remission or failed to partial remission following surgery, chemotherapy, and/or radiation therapy.

In some embodiments of the invention, the subject has not previously received systemic chemotherapy. In some embodiments, the subject has previously received surgical treatment, radiation therapy, induction chemotherapy and/or adjuvant chemotherapy, or the subject has received concurrent chemotherapy. In some embodiments, the subject has not previously received systemic chemotherapy, but has received surgical treatment, radiation therapy, induction chemotherapy and/or adjuvant chemotherapy, or will receive concurrent chemotherapy. In some embodiments, the subject has complete remission following surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy before disease progression occurs again. In some embodiments, the subject has failed to complete remission or failed to partial remission following surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject undergoes metastasis following surgical treatment, radiation treatment, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.

In some embodiments, the use of treating a tumor is treating a tumor of the digestive tract. In some embodiments, the tumor of the digestive tract has previously failed first-line or more chemotherapy. In some embodiments, the gut tumor has mismatch repair gene deletion (dMMR) or high microsatellite instability (MSI-H). In some embodiments, the tumor of the digestive tract is not amenable to surgical resection. In some embodiments, the is a recurrent or metastatic gut tumor. In some embodiments, the tumor of the digestive tract is a tumor of the digestive tract that has not been previously treated for recurrence or metastasis.

In some embodiments, the tumor of the digestive tract is a cancer of the biliary tract. In some embodiments, the biliary tract cancer is a non-surgically resectable biliary tract cancer or a metastatic biliary tract cancer. In some embodiments, the biliary tract cancer has previously failed first line or more chemotherapy. In some embodiments, the biliary tract cancer is cholangiocellular carcinoma. In some embodiments, the biliary system cancer is intrahepatic cholangiocellular carcinoma (IHCC), or extrahepatic cholangiocellular carcinoma (EHCC), or gallbladder cancer (GBC). In some embodiments, the biliary cancer is intrahepatic cholangiocellular carcinoma (IHCC), or extrahepatic cholangiocellular carcinoma (EHCC), or gallbladder cancer (GBC) that has failed previous first-line or beyond chemotherapy. In some embodiments, the extrahepatic cholangiocellular carcinoma includes hepatoportal cholangiocarcinoma (also known as Klatskin tumor) and distal cholangiocarcinoma. In some embodiments, the biliary system cancer comprises adenocarcinoma-type gallbladder cancer, adenocarcinoma-type intrahepatic cholangiocellular carcinoma, or adenocarcinoma-type extrahepatic cholangiocellular carcinoma. In some embodiments, the biliary tract cancer is diffuse invasive adenocarcinoma of the bile duct.

In some embodiments, the tumor of the digestive tract is colorectal cancer. In some embodiments, the colorectal cancer has mismatch repair gene deletion (dMMR) or high microsatellite instability (MSI-H). In some embodiments, the colorectal cancer is not amenable to surgical resection. In some embodiments, the colorectal cancer is relapsed or metastatic colorectal cancer. In some embodiments, the colorectal cancer is a colorectal cancer that has not previously received treatment for recurrence or metastasis. In some embodiments, the tumor of the digestive tract is an intestinal cancer. In some embodiments, the tumor of the digestive tract is metastatic intestinal cancer.

In some embodiments, the tumor of the digestive tract is a gastric or gastroesophageal junction (GEJ) adenocarcinoma. In some embodiments, the tumor of the digestive tract is metastatic or recurrent adenocarcinoma of the gastric or gastroesophageal junction. In some embodiments, the tumor of the digestive tract is a gastric or gastroesophageal junction adenocarcinoma that has not previously received treatment for recurrence or metastasis.

In some embodiments, the use for treating a tumor is for treating a urinary system tumor. In some embodiments, the urological tumor is not suitable for surgical resection. In some embodiments, the urinary system tumor is a locally progressing or metastatic urinary system tumor. In some embodiments, the urological neoplasm is a urological neoplasm that has failed treatment with at least one systemic standard chemotherapy regimen. In some embodiments, the urinary system tumor is urothelial cancer. In some embodiments, the urinary system tumor is a urothelial cancer of bladder, or ureter, or renal pelvis, or urinary tract origin. In some embodiments, the urological tumor is a locally progressing or metastatic urothelial cancer. In some embodiments, the urological neoplasm is urothelial cancer that has failed treatment with at least one systemic standard chemotherapy regimen.

In some embodiments, the use of treating a tumor is for treating a neuroendocrine tumor. In some embodiments, the neuroendocrine tumor is a low grade (G1) or intermediate grade (G2) advanced neuroendocrine tumor. In some embodiments, the neuroendocrine tumor cannot be surgically resected. In some embodiments, the neuroendocrine tumor is a locally advanced or distant metastatic neuroendocrine tumor. In some embodiments, the neuroendocrine tumor is a neuroendocrine tumor that has previously received at least one treatment with a systemic antineoplastic treatment against an advanced neuroendocrine tumor, preferably, the systemic antineoplastic treatment includes treatment with an mTOR inhibitor, chemotherapy, a long-acting somatostatin analog, an interferon, PRRT (peptide receptor radionuclide), or the like.

In some embodiments, the neuroendocrine tumor is a gastrointestinal pancreatic neuroendocrine tumor. In some embodiments, the gastrointestinal neuroendocrine tumor is a low grade (G1) or intermediate grade (G2) advanced gastrointestinal neuroendocrine tumor. In some embodiments, the gastroenteropancreatic neuroendocrine tumor cannot be surgically resected. In some embodiments, the gastrointestinal neuroendocrine tumor is a locally advanced or distant metastatic gastrointestinal neuroendocrine tumor. In some embodiments, the gastroenteropancreatic neuroendocrine tumor is a gastrointestinal pancreatic neuroendocrine tumor that has previously received at least one treatment with a systemic antineoplastic agent against advanced gastrointestinal pancreatic neuroendocrine tumor, preferably, the systemic antineoplastic agent treatment includes treatment with mTOR inhibitors, chemotherapy, long-acting somatostatin analogs, interferons, PRRT (peptide receptor radionuclides), and the like.

In some embodiments of the present application, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

In some embodiments of the present application, the pharmaceutical combination is a non-fixed combination. In some embodiments, the human PD-1 antibody and the compound of formula I in the non-fixed combination are each in the form of a pharmaceutical composition.

It is also an object of the present application to at least provide a pharmaceutical pack comprising separately packaged pharmaceutical compositions in separate containers, wherein in one container a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof is contained and in a second container a pharmaceutical composition comprising a human PD-1 antibody is contained.

In some embodiments of the present application, the pharmaceutical composition comprises a compound of formula I in an amount of 6-168 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount selected from 6mg, 8mg, 10mg, 12mg, 15mg, 20mg, 30mg, 50mg, 56mg, 70mg, 84mg, 112mg, 140mg, 168mg, or any range formed by any of the foregoing. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount from 10mg to 12 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount of 10 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula I in an amount of 12 mg.

In some embodiments, the human PD-1 antibody is administered in one or more uniform doses effective to treat the cancer. In some embodiments, the uniform dose is in the range of about 10mg to about 1000mg of human PD-1 antibody. In some embodiments, the unitary dose is selected from about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, or about 1000mg of the human PD-1 antibody. In some embodiments, the unitized dose is selected from about 200mg of human PD-1 antibody.

In some embodiments, the treatment for administration of the human PD-1 antibody is administered intravenously to the human PD-1 antibody on the first day (D1) of each cycle for 2 weeks (14 days) or 3 weeks (21 days). That is, the anti-PD-1 antibody is administered at a frequency of once every two weeks (q2w) or once every three weeks (q3 w).

It is also an object of the present application to provide a unit formulation, wherein the unit formulation comprises: a compound component, 6-12 mg of a compound of formula I or a hydrochloride thereof; and an antibody component, 50-350mg of a human PD-1 antibody or antigen-binding fragment thereof; wherein the compound component and the antibody component are packaged separately.

In some embodiments, the unit formulation comprises: compound component, 8mg, 10mg or 12mg of a compound of formula I or its hydrochloride salt; and an antibody component, 100mg or 200mg of a human PD-1 antibody or antigen-binding fragment thereof; wherein the compound component and the antibody component are packaged separately.

It is also an object of the present application to provide a method for preventing or treating cancer or tumor, wherein one or more of the above-described unit preparations are administered to a subject in need thereof. Preferably, the compound component and the antibody component of the unit formulation are each administered separately. Preferably, the cancer or tumor is a tumor of the digestive tract, or a tumor of the urinary system, or a neuroendocrine tumor.

In some embodiments of the present application, the administration of erlotinib in combination with 14C12H1L1, every 21 days for one treatment cycle, is administered as follows: D1-D14 administered 10 mg/time or 12 mg/time of Arotinib, D1 administered 14C12H1L 1200 mg.

In some embodiments of the present application, the administration of erlotinib in combination with 14C12H1L1, wherein the administration of the erlotinib hydrochloride capsule is 1 time daily, 12mg or 10mg each time. The injection is orally administered for 2 weeks and stopped for 1 week, i.e. 3 weeks (21 days) are a treatment period, and the 14C12H1L1 injection is administered by 1 time and 200 mg/time every 3 weeks and is administered by intravenous infusion for 60 + -10 min.

The pharmaceutical combination of the invention shows superior efficacy compared to prior therapies in urothelial cancer patients who relapse or metastasize after surgery and/or chemotherapy, such as doxorubicin and/or gemcitabine in combination with cisplatin, an example of ureteral cancer being urothelial cancer, bladder cancer, etc., and metastases, such as bone metastases.

The pharmaceutical combination of the invention shows superior efficacy compared to existing therapies in rectal cancer patients who relapse or metastasize after surgery and/or chemotherapy, such as tegafur, temozolomide and/or octreotide acetate treatment, which metastasis may be multiple metastasis, such as multiple liver metastasis.

The pharmaceutical combination of the invention shows superior efficacy compared to existing therapies in colon cancer patients who relapse or metastasize after surgery and/or chemotherapy, such as tegafur, temozolomide and/or octreotide acetate treatment, which metastasis may be multiple metastasis, such as multiple liver metastasis.

The pharmaceutical combination of the invention shows superior efficacy compared to existing therapies in gastric cancer patients who relapse or metastasize after surgery and/or chemotherapy, which can be multiple metastases, such as duodenal metastases.

The pharmaceutical combination of the invention shows superior efficacy compared to prior therapies in patients with cholangiocellular carcinoma or gallbladder carcinoma who relapse or metastasize after surgery and/or chemotherapy, such as capecitabine, oxaliplatin in combination with capecitabine therapy, paclitaxel in combination with tegafur, or paclitaxel in combination with capecitabine, which can be multiple metastases, such as liver, peritoneal lymph nodes, mesenteric lymph nodes, kidney, or bone metastases.

Arotinib

As used herein, the chemical name of said nilotinib (i.e., the compound of formula I) is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the following structural formula:

as used herein, the nilotinib includes its non-salt forms (e.g., free acid or free base), as well as its pharmaceutically acceptable salts, which are all included within the scope of the present application. For example, the pharmaceutically acceptable salt of the nilotinib can be the hydrochloride salt or the dihydrochloride salt. The dosage of the nilotinib or salt thereof referred to herein is calculated based on the free base of the nilotinib, unless otherwise indicated.

14C12H1L1

As used herein, 14C12H1L1 or14C12H1L1 monoclonal antibody,is an anti-PD-1 monoclonal antibody, and the sequence and the structure of the monoclonal antibody can be found in the literature (CN 106977602A). In the 14C12H1L1 monoclonal antibody, LCDR1 comprises the sequence QDINTY (SEQ ID NO:1), LCDR2 comprises the sequence RAN (SEQ ID NO:2), LCDR3 comprises the sequence LQYDEFPLT (SEQ ID NO:3), HCDR1 comprises the sequence GFAFSSYD (SEQ ID NO:4), HCDR2 comprises the sequence ISGGGRYT (SEQ ID NO:5), and HCDR3 comprises the sequence ANRYGEAWFAY (SEQ ID NO: 6).

The amino acid sequence of the light chain variable region is as follows:

DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK(SEQ ID NO:7)。

the amino acid sequence of the heavy chain variable region is as follows:

EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS(SEQ ID NO:8)。

definitions and explanations

The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to its corresponding commodity, composition, or active ingredient thereof.

As used herein, the term "antibody" refers to an antigen binding protein having at least one antigen binding domain. The antibodies and fragments thereof of the present application can be whole antibodies or any fragment thereof. Thus, the antibodies and fragments thereof of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab 'fragments, f (ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof can also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgG1, IgG2, IgG3, or IgG4 isotype.

The term "isotype" refers to the class of antibodies encoded by the heavy chain constant region gene. In one embodiment, the anti-PD-1/PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The anti-PD-1/PD-L1 antibodies and fragments thereof of the present application may be derived from any species, including but not limited to mouse, rat, rabbit, primate, llama, and human. The PD-1/PD-L1 antibody and fragments thereof may be chimeric, humanized or fully human.

The term "humanized antibody" refers to antibodies in which the antigen binding site is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may comprise substitutions in the framework regions such that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.

By "isolated antibody" is meant an antibody that: it is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds PD-1/PD-L1 is substantially free of antibodies that specifically bind antigens other than PD-1/PD-L1). However, an isolated antibody that specifically binds PD-1/PD-L1 may have cross-reactivity with other antigens (such as PD-1/PD-L1 molecules from different species). Furthermore, the isolated antibody may be substantially free of other cellular material and/or chemicals.

An "antigen-binding portion" (also referred to as an "antigen-binding fragment") of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen bound by an intact antibody.

As used herein, the term "derived" when used in reference to a molecule or polypeptide relative to a reference antibody or other binding protein means a molecule or polypeptide that is capable of specifically binding the same epitope as the reference antibody or other binding protein.

As used herein, the term "EC 50" refers to the effective concentration, 50% of the maximal response of an antibody. As used herein, the term "IC 50" refers to the inhibitory concentration, 50% of the maximal response of an antibody. Both EC50 and IC50 may be measured by ELISA or FACS analysis or any other method known in the art.

The term "treatment" generally refers to an act of obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic, in terms of preventing the disease or its symptoms, in whole or in part; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) preventing a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed as having the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

As used herein, the term "systemic treatment" refers to treatment in which a drug substance is transported through the bloodstream to reach and affect cells throughout the body.

As used herein, the term "systemic chemotherapy" refers to systemic chemotherapy that does not include chemotherapy for locally advanced disease as one of the links of multimodal treatment, wherein chemotherapy for locally advanced disease includes induction chemotherapy, concurrent chemotherapy with radiotherapy, and adjuvant chemotherapy.

As used herein, the term "subject" means a mammal, such as a rodent, feline, canine, and primate. Preferably, the subject according to the present application is a human.

By "administering" is meant physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, e.g., by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered by a non-parenteral route, and in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.

As used herein, an "adverse event" (AE) is any adverse and often unintended or undesirable sign (including abnormal laboratory findings), symptom or disease associated with the use of medical therapy. For example, an adverse event can be associated with activation of the immune system or expansion of cells of the immune system (e.g., T cells) in response to a treatment. The medical treatment may have one or more related AEs, and each AE may have the same or different severity level. Reference to a method capable of "altering an adverse event" refers to a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.

As used herein, "dosing interval" refers to the amount of time that elapses between multiple doses of a formulation disclosed herein administered to a subject. The dosing interval may thus be indicated as a range.

The term "dosing frequency" as used herein means the frequency of doses administered of a formulation disclosed herein over a given time. The frequency of administration may be indicated as the number of administrations per given time, e.g. 1 or 1 in 2 weeks per week.

The use of the term "flat dose" refers to a dose that is administered to a patient without regard to the weight or Body Surface Area (BSA) of the patient. Thus, a uniform dose is defined as the absolute amount of the agent (e.g., anti-PD-1 antibody) rather than the mg/kg dose. For example, a 60kg human and a 100kg human will receive the same dose of antibody (e.g., 240mg anti-PD-1 antibody).

The use of the term "fixed dose" in reference to a composition of the present application means that two or more different antibodies in a single composition are present in the composition in a specific (fixed) ratio to each other. In certain embodiments, the fixed dose is based on the weight of the antibody (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the antibody (e.g., mg/ml). In certain embodiments, the ratio of mg of the first antibody to mg of the second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 1: 8:1, about 1:1, about 5: 7, about 1:1, about 1: 6:1, about 1:1, about, About 4:1, about 3:1, or about 2: 1. For example, a 3:1 ratio of primary and secondary antibodies may mean that the vial may contain about 240mg of primary and 80mg of secondary antibody, or about 3mg/ml of primary and 1mg/ml of secondary antibody.

The term "weight-based dose" as referred to herein refers to a dose administered to a patient that is calculated based on the weight of the patient. For example, when a patient with a weight of 60kg requires 3mg/kg of anti-PD-1 antibody and 1mg/kg of anti-CTLA-4 antibody, one can extract appropriate amounts of anti-PD-1 antibody (i.e., 180mg) and anti-CTLA-4 antibody (i.e., 60mg) at a time from a 3:1 ratio fixed dose formulation of anti-PD-1 antibody and anti-CTLA-4 antibody.

The term "immunotherapy" means the treatment of a subject having a disease or at risk of infection or of suffering from a relapse of a disease by a method that includes inducing, enhancing, suppressing or otherwise altering an immune response. By "treatment" or "therapy" of a subject is meant any type of intervention or process performed on the subject, or the administration of an active agent to a subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, severity, or recurrence of a symptom, complication, or condition, or biochemical indicator associated with the disease.

As used herein, "PD 1/PD-L1 positive" may be used interchangeably with "at least about 1% PD-1/PD-L1 expression". In one embodiment, PD-1/PD-L1 expression may be used by any method known in the art. In another embodiment, PD-1/PD-L1 expression is measured by automated IHC. In certain embodiments, "PD-1/PD-L1 positive" means that there are at least 100 cells expressing PD-1/PD-L1 on the cell surface.

"programmed death receptor-1 (PD-1)" means an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo and binds to both ligands PD-L1 and PD-L2. The term "PD-1" as used herein includes variants, homologs, and species homologs of human PD-1(hPD-1), hPD-1, and analogs having at least one common epitope with hPD-1.

"programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that down-regulates T cell activation and cytokine secretion upon binding to PD-1.

"subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject," "subject," and "patient" are used interchangeably herein in certain contexts.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes disease regression as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free stages, or prevention of injury or disability caused by the affliction of the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predicting efficacy for humans, or by determining the activity of the agent in an in vitro assay.

As used herein, a "sub-therapeutic dose" refers to a dose of a therapeutic compound (e.g., an antibody) that is lower than the usual or typical dose of the therapeutic compound when administered alone for the treatment of a hyperproliferative disease (e.g., cancer).

As an example, an "anti-cancer drug" promotes cancer regression in a subject or prevents further tumor growth. In certain embodiments, the therapeutically effective amount of the drug promotes regression of the cancer to the point of eliminating the cancer. By "promoting cancer regression" is meant the administration of an effective amount of a drug, alone or in combination with an anti-neoplastic agent, resulting in the reduction of tumor growth or size, necrosis of the tumor, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of disease symptom-free stages, or the prevention of injury or disability resulting from the affliction of the disease. Furthermore, the terms "effective" and "effectiveness" with respect to treatment include pharmacological effectiveness and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety means the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ and/or organism level resulting from drug administration.

As an example for treating a tumor, a therapeutically effective amount of an anti-cancer agent can inhibit cell growth or tumor growth by at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% relative to an untreated subject, or, in certain embodiments, relative to a patient treated with standard of care therapy. In other embodiments of the present application, tumor regression may be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these final measures of therapeutic effectiveness, the evaluation of immunotherapeutic drugs must also take into account "immune-related" response patterns.

By "immune-related" response pattern is meant the clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce an anti-tumor effect by inducing a cancer-specific immune response or by altering the innate immune process. This response pattern is characterized by beneficial therapeutic effects following an initial increase in tumor burden or the appearance of new lesions, which would be classified as disease progression and would be synonymous with drug failure in the evaluation of traditional chemotherapeutic agents. Thus, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effect of these agents on the target disease.

A therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of drug that inhibits the occurrence or recurrence of cancer when administered, alone or in combination with an anti-neoplastic agent, to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of cancer recurrence. In certain embodiments, the prophylactically effective amount completely prevents the occurrence or recurrence of cancer. By "inhibiting" the occurrence or recurrence of cancer is meant reducing the likelihood of occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.

A "recurrent" cancer is one that regenerates at the primary site or a distant site in response to an initial treatment (e.g., surgery). A "locally recurrent" cancer is one that occurs at the same location after treatment as a previously treated cancer.

A "non-resectable" cancer is one that cannot be removed by surgery.

"metastatic" cancer refers to cancer that spreads from one part of the body (e.g., the lungs) to another part of the body.

The use of alternatives (e.g., "or") should be understood to refer to either, both, or any combination of alternatives. The indefinite articles "a" or "an" as used herein shall be understood to mean "one or more" of any listed or enumerated component.

By "failure of treatment with a platinum-containing chemotherapeutic regimen" is meant disease progression or toxic side effects that are not tolerated during or after treatment with first-line chemotherapy or radiotherapy with a platinum-containing regimen.

The definition of "failure of a systemic standard chemotherapy" is: disease progression during or after the last treatment, or intolerance during treatment due to toxic side effects.

The definition of "failure of chemotherapy at or above one line" is: disease progression during or after the last treatment; or is intolerable in the treatment process due to toxic and side effects.

Low grade (G1) defined as nuclear fission image number <2/10 high power field [ HPF ] and/or Ki-67 differentiation index < 3%; the medium grade (G2) is defined as the number of nuclear fission images 2-20/10 high power field [ HPF ] and/or Ki-67 differentiation index 3-20%. If the nuclear division image and the Ki-67 index of the same tumor tissue correspond to different grades, the compliance is higher.

The terms "about," about, "or" consisting essentially of mean a value or composition within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about," about, "or" consisting essentially of can mean within 1 or more than 1 standard deviation, as practiced in the art. Alternatively, "about" or "consisting essentially of may refer to a range that differs by up to 10% or 20% (i.e., ± 10% or ± 20%) from the parameter or value modified thereby. For example, about 3mg may include any number between 2.7mg to 3.3mg (for 10%) or between 2.4mg to 3.6mg (for 20%). Furthermore, particularly with respect to biological systems or processes, the term may refer to up to an order of magnitude or up to at most 5 times the numerical value. Where a particular value or composition is provided in the application and claims, unless otherwise stated, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable error range for that particular value or composition.

As used herein, the terms "about once per week", "about once per two weeks" or any other similar dosing interval term refer to approximations. "about once per week" may include every 7 days ± 1 day, i.e., every 6 days to every 8 days. "about once every two weeks" may include every 14 days ± 3 days, i.e., every 11 days to every 17 days. Similar approximations apply, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In certain embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to that a first dose may be administered on any day of the first week, and then a second dose may be administered on any day of the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to administration of a first dose on a particular day of the first week (e.g., monday) followed by administration of a second dose on the same day of the sixth or twelfth week (i.e., monday), respectively. Similar principles apply to phrases including, but not limited to, "about 1 every 2 weeks," "about 1 every month," etc. … ….

As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the recited range, and when appropriate, to include fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated.

Unless specifically stated otherwise, "about" or "approximately" in this application means within + -5% of the specified numerical range given, preferably within + -2% of the specified numerical range given, and more preferably within + -1% of the specified numerical range given. For example, a pH of about 5.5 means a pH of 5.5. + -. 5%, preferably a pH of 5.5. + -. 2%, more preferably a pH of 5.5. + -. 1%.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" includes salts of the base ion with the free acid or salts of the acid ion with the free base, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt and the like. In the present application, when forming a pharmaceutically acceptable salt, the molar amount of free acid to base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1: 8. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free base to the acid ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1: 8.

The term "fixed combination" means that the active ingredients (e.g. an anti-PD-1 antibody or a compound of formula I) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

The term "non-fixed combination" means that two or more active ingredients are administered to a subject as separate entities (e.g. pharmaceutical compositions, formulations) simultaneously, concurrently or sequentially and without specific time constraints, wherein the active ingredients are administered to the subject to a therapeutically effective amount level. An example of an unfixed combination is cocktail therapy, e.g. 3 or more active ingredients are administered. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as a completely separate pharmaceutical composition. The term "non-fixed combination" also includes the use of "fixed combinations" in between, or "fixed combinations" in combination with, any one or more of the individual entities of the active ingredients.

As used herein, "in combination" or "in combination" means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially in any order as a single formulation.

The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application (e.g., an anti-PD-1 antibody or a compound of formula I) or a pharmaceutical combination thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application, or a pharmaceutical combination thereof, to a subject.

The term "synergistic effect" refers to a simple addition of two or more components (e.g., an anti-PD-1 antibody or a compound of formula I) that produces an effect (e.g., inhibiting the growth of colon cancer, or ameliorating symptoms of colon cancer) that is greater than the effect of the components when administered alone.

Mode of administration

The following is not intended to limit the mode of administration of the pharmaceutical combinations of the present application.

The components of the pharmaceutical combination of the present application may be formulated separately from each other or some or all of them may be co-formulated. In one embodiment, the pharmaceutical combination of the present application may be formulated as a pharmaceutical composition suitable for single or multiple administration.

The components of the pharmaceutical combination of the present application may each be administered separately, or some or all of them may be co-administered. The components of the pharmaceutical combination of the present application may be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.

The components of the pharmaceutical combination of the present application may be administered independently of each other, or some or all of them together in a variety of routes as appropriate, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application may be administered orally or parenterally, such as intravenously or intraperitoneally, each independently, or together with some or all of them.

The components of the pharmaceutical combination of the present application may each independently, or some or all of them together be in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms for sustained release formulations for oral or non-oral administration.

The components of the pharmaceutical combination of the present application may each independently, or some or all of them together, contain a pharmaceutically acceptable carrier and/or excipient.

The pharmaceutical combination of the present application may also comprise additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art.

The application also includes the following scheme:

1. a pharmaceutical combination comprising:

a) a human PD-1 antibody that comprises a light chain and a heavy chain, wherein the light chain comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 consisting of the amino acid sequences set forth in SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, respectively, and wherein the heavy chain comprises heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 consisting of the amino acid sequences set forth in SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively, and

b) a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof,

2. the pharmaceutical combination according to item 1, wherein the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, preferably the dihydrochloride.

3. The pharmaceutical combination of any one of the preceding, wherein the human PD-1 antibody comprises a light chain variable region as set forth in amino acid sequence SEQ ID NO. 7 and a heavy chain variable region as set forth in SEQ ID NO. 8.

4. The pharmaceutical combination of any one of the preceding, wherein the human PD-1 antibody is 14C12H1L 1.

5. The pharmaceutical combination of any one of the preceding claims, which is a non-fixed combination.

6. The pharmaceutical combination of any one of the preceding, wherein the human PD-1 antibody and the compound of formula I, or a pharmaceutically acceptable salt thereof, in the non-fixed combination are each in the form of a pharmaceutical composition.

7. Use of the pharmaceutical combination of any of the preceding claims for the treatment or prevention of a tumor of the digestive tract, or a tumor of the urinary system, or a neuroendocrine tumor.

8. Use according to any one of the preceding claims, for the treatment of a tumour of the digestive tract, or of the urinary system, or of a neuroendocrine tumour, which is not suitable for surgical resection, or which is recurrent or metastatic, or which has failed, or has progressed locally, by first or second line or beyond chemotherapy.

9. Use according to any one of the preceding claims, for the treatment of biliary tract cancer, or diffuse invasive adenocarcinoma of the bile duct, or cholangiocellular carcinoma, or intrahepatic cholangiocellular carcinoma, or extrahepatic cholangiocellular carcinoma, or gallbladder cancer, or intestinal cancer, or colorectal cancer, or adenocarcinoma of the stomach or gastroesophageal junction, or urothelial carcinoma.

10. The use of any one of the preceding claims, for the treatment of biliary tract cancer that is not surgically resectable or metastatic, or that has failed prior first or second line chemotherapy.

11. Use of any of the preceding, for the treatment of colorectal cancer that is deficient in mismatch repair genes or highly microsatellite unstable, or that has relapsed, or that is metastatic, or that has not been previously treated for relapse or metastasis.

12. The use of any of the preceding claims, in combination with a medicament for the treatment of recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that has not previously been treated for recurrence or metastasis.

13. Use according to any one of claims 7 to 9, for the treatment of urothelial cancer of local progression, or metastatic, or failed to have been treated at least by one standard systemic chemotherapy regimen, or of bladder, or ureter, or renal pelvis, or of urethral origin.

14. The use of any of the foregoing in combination for the treatment of a low-grade, or mid-grade, or advanced, or non-surgically resectable, or locally advanced, or distant metastatic tumor, or a gastrointestinal-pancreatic neuroendocrine tumor that has been previously treated with at least one systemic antineoplastic agent directed against an advanced gastrointestinal-pancreatic neuroendocrine tumor.

15. The use according to any one of the preceding claims, wherein the pharmaceutical combination comprises the hydrochloride salt of the compound of formula I administered at a bolus dose of about 10 mg/dose or about 12 mg/dose and 14C12H1L1 administered at a bolus dose of about 200 mg/dose.

16. The use according to any one of the preceding claims, wherein the hydrochloride salt of the compound of formula I is administered 1 time a day, 12mg or 10mg each time, 2 weeks for 1 week on continuous oral administration, and the 14C12H1L1 injection is administered 1 time every 3 weeks, 200 mg/time.

17. An article of manufacture comprising a container containing a fixed dose of a hydrochloride salt of a compound of formula I selected from about 8mg, about 10mg, and about 12mg, and a 14C12H1L1 antibody, a fixed dose of 14C12H1L1 antibody selected from about 100mg and about 200 mg.

Detailed Description

The present application is further described below with reference to specific examples, which, however, are only for illustration and do not limit the scope of the present application. Likewise, the present application is not limited to any particular preferred embodiment described herein. It should be understood by those skilled in the art that equivalent substitutions for the technical features of the present application or corresponding improvements are still within the scope of the present application. The reagents used in the following examples are commercially available products, and the solutions can be prepared by techniques conventional in the art, except where otherwise specified.

TABLE 1 abbreviation table

"14C 12H1L1 injectable solution" refers to a medical formulation for injection containing the 14C12H1L1 monoclonal antibody, which is usually administered to a patient by intravenous infusion route. In a particular embodiment, the expression "injection of 14C12H1L1, 200 mg/time" may be understood in the usual manner in the art as a liquid injectable medical formulation containing 200mg of 14C12H1L1 monoclonal antibody per administration to a patient.

Example a clinical study protocol-study criteria and endpoints

1.1 inclusion exclusion criteria

And (3) inclusion standard: the following candidates can be put into the test

1) All conditions of any one of the following queues are met:

a first queue:

a) pathohistologically confirmed subjects who are inoperable or metastatic biliary tract cancer, including intrahepatic cholangiocellular carcinoma (IHCC), extrahepatic cholangiocellular carcinoma (EHCC), and gallbladder cancer (GBC);

b) past first or more lines of chemotherapy failed. Failure of chemotherapy with one line or more than one line is defined as: disease progression during or after the last treatment; or is intolerable in the treatment process due to toxic and side effects.

And a second queue:

pathohistologically confirmed, recurrent or metastatic colorectal cancer unsuitable for surgical resection with MSI-H or dMMR is present. Systemic treatment for recurrent or metastatic colorectal cancer has not been previously accepted.

And a queue III:

metastasis or recurrent gastroesophageal junction (GEJ) adenocarcinoma diagnosed by pathological tissue. PD-L1 expression was ≧ 1% (CPS) since it had not received systemic treatment for metastatic or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinomas.

And a queue four:

locally advanced or metastatic urothelial cancer (including bladder, ureter, renal pelvis, and urethral origin) that is not amenable to surgical total resection, as determined by histopathology. At least 1 systemic standard chemotherapy regimen failed treatment. Failure of 1 systemic standard chemotherapy was defined as: disease progression during or after the last treatment, or intolerance during treatment due to toxic side effects.

And a fifth queue:

a) pathological tissue confirmed subjects with low and medium grade (G1 or G2) advanced (local advanced or distant metastasis that cannot be surgically resected) gastrointestinal-pancreatic neuroendocrine tumors (NET).

b) More than or equal to 1 systemic antitumor drug aiming at late NET is received in the past: including mTOR inhibitors, chemotherapy, long acting somatostatin analogs, interferons, PRRT (peptide receptor radionuclides), and the like. Patients who are late stage treatment who cannot accept or refuse to accept the treatment can also be grouped;

c) patients had evidence of imagewise confirmed disease progression within 12 months prior to first administration.

2) Year 18; ECOG physical condition: 0-1 min; the expected life span exceeds 3 months;

3) measurable focus defined by RECIST 1.1 standard exists, the focus is considered as measurable focus only when the prior irradiation focus has definite progress after radiotherapy and is not the only focus;

4) the major organs function normally.

5) Patients voluntarily join the study and sign informed consent, and compliance is good.

Exclusion criteria: subjects presenting any of the following subjects would not be able to enter the study

1) The patients who have received local radiotherapy before can be grouped if the following conditions are met: radiotherapy end over 4 weeks from study treatment initiation (brain radiotherapy over 2 weeks); the target focus selected in the research is not in the radiotherapy area; or the target lesion is located within the area of radiotherapy, but progression has been confirmed.

2) Brain metastases with symptoms or symptom control time of less than 2 months.

3) The patient has suffered from other malignant tumors before or simultaneously within 5 years. Except for the following two cases: other malignant tumors treated by a single operation reach no disease production (DFS) for 5 years continuously; curative carcinoma of the cervix in situ, skin cancer without melanoma and superficial bladder tumors [ Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor-infiltrating basement membrane) ].

4) Those with various factors affecting oral medication (e.g., inability to swallow, post-gastrointestinal resection, chronic diarrhea, ileus, etc.);

5) imaging (CT or MRI) shows that the tumor invades the great vessels or is poorly demarcated from the vessels;

6) significant surgical treatment, incisional biopsy or overt traumatic injury was received within 28 days prior to the first dose;

7) patients with arterial/venous thrombotic events, such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis and pulmonary embolism, occurring within 6 months prior to the first administration;

8) those who have a history of abuse of psychotropic drugs and are unable to abstain or have a psychotic disorder;

9) other clinical trials were enrolled within four weeks;

10) at the discretion of the investigator, there are concomitant diseases that seriously compromise patient safety or affect the patient's completion of the study.

1.2 Exit Standard

1) Disease progression occurred and the investigator judged that the subject would not benefit from continued treatment;

2) adverse events occurred, were not tolerated, not alleviated;

3) subjects who had a severe adverse event and were not eligible to continue the study;

4) those who deviate or violate a protocol severely and impact drug safety or efficacy assessments;

5) subject withdrawal of informed consent;

6) follow-up cannot be continued on time for various reasons.

1.3 study endpoint

The first stage is as follows: safe lead-in period

Primary end point:

safety and tolerability of first cycle

Secondary endpoint:

objective Remission Rate (ORR), Disease Control Rate (DCR), duration of remission (DOR), Progression Free Survival (PFS), Overall Survival (OS), and the like.

And a second stage: official test

Primary endpoint

Objective Remission Rate (ORR)

Secondary endpoint

Disease Control Rate (DCR), duration of remission (DOR), Progression Free Survival (PFS), Total survival (OS), and the like

The incidence and severity of Adverse Events (AEs) and Severe Adverse Events (SAEs), and abnormal laboratory test indices.

Example two clinical trial design

Single arm, open, multi-cohort, multi-center phase II clinical trials were employed.

2.1 sample size

There were 5 queues in the study, each queue was grouped in 20-30 cases (adjusted for specific test results).

2.2 image evaluation design

The primary efficacy endpoint of this study was ORR, using results assessed by researchers at various study centers. An independent imaging group is additionally arranged in the research to carry out imaging curative effect evaluation and recheck.

2.3 dosing regimen design

The subjects were all patients enrolled in cohorts one to five of example one.

The study is divided into two phases:

the first phase is a one-armed study, the safe lead-in period.

Patients will receive an erlotinib combination 14C12H1L1 therapy. Every 21 days for a treatment cycle, safety information was collected to determine whether the combination of erlotinib with 14C12H1L1 was successful in performing official trials after RP2D in patients with digestive tract tumors, urologic tumors, neuroendocrine tumors. The lead-in period included the following 2 dose groups:

dose group a: arotinib 10mg D1-D14 in combination with 14C12H1L1 once every 3 weeks 200mg

Dose group B: arotinib 12mg D1-D14 in combination with 14C12H1L1 once every 3 weeks 200mg

Each dose group was scheduled for 3-6 patients and the safety of the combination was observed. Based on the safety data from the previous large sample size clinical study of the anirtinib capsules, the lead-in phase schedule began dose exploration from the dose group a dosing regimen (if 3-6 patients in dose group a were well tolerated in the first cycle, 3-6 patients in dose group B would be explored). After the introduction test is finished, the main researchers and the application consult to determine RP2D of the combination of the Arotinib and 14C12H1L1 in patients with digestive tract tumor, urinary system tumor and neuroendocrine tumor.

The second phase is the official trial, with patients receiving an erlotinib combination 14C12H1L 1:

anrotinib hydrochloride capsules:

the administration is 1 time daily (recommended to start infusion at 14C12H1L1 injection + -60min with internal abdominal administration), 12mg each time (final dose is determined by safe lead-in period, 12mg is tentatively determined). 2 weeks and 1 week, i.e. 3 weeks (21 days) for a treatment period. If the administration period is missed, the time for next administration is shorter than 12 hours, and the medicine is not taken again.

14C12H1L1 injecta:

administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. The infusion time was 60. + -.10 min.

The medication period is as follows:

every 21 days is a treatment period, and other anti-tumor treatments can not be carried out during the administration period; patients in disease control (CR + PR + SD) and with tolerable adverse effects continue to be dosed until disease progression or intolerance.

Efficacy was assessed every 2 cycles and every 4 cycles after 16 cycles. Patients with disease control (CR + PR + SD) and tolerable adverse reactions continue to take their medications until clinical benefit is lost, toxicity is not tolerable, efficacy is assessed as PD, and the study is concluded when the investigator deems it inappropriate to continue taking medications.

Adjusting the dosage of the hydrochloric acid Arotinib capsule:

during the study, the patient may downregulate the aritinib hydrochloride dose due to drug related adverse events (12mg-10mg-8mg are downregulated sequentially, not allowing for cross-dose adjustments), and if the patient is intolerant at the 8mg dose level, the study should be terminated. For patients with the Arotinib hydrochloride capsule with the dosage being adjusted down to 10mg or 8mg, after the drug is taken for a period of time, if researchers judge that the disease is possible to progress and the safety of the patients is stable, the dosage can be adjusted up once. Each patient can only make one dose up-regulation at most and cannot adjust across dose groups.

14C12H1L1 injection fixed dose, without a dose down-regulation scheme.

2.4 methods of combination administration

14C12H1L1 injecta:

200mg was diluted to 100mL with physiological saline and infused for 60 + -10 min. The administration was once every 21 days. The instillation time started at the beginning of the instillation of 14C12H1L1, and ended at the end of the instillation of 14C12H1L1 and the end of the flushing of the physiological saline (20 mL of physiological saline is recommended). For subjects who cannot tolerate a 60min infusion, the infusion time can be extended up to 120 minutes (+ -15 minutes).

Anrotinib hydrochloride capsules:

1 daily (oral on empty stomach before breakfast) 1 capsule (12mg) each time (final dose determined by safe lead-in period, temporary 12mg), is recommended to be infused starting in 14C12H1L1 injection ± 60min for administration in empty stomach. 2 weeks and 1 week, i.e. 3 weeks (21 days) for a treatment period. Without special circumstances, it is recommended to take the medicine at a fixed time every day. On the day of blood sampling or safety inspection, the medicine is taken after blood sampling. If the administration period is missed, the time for next administration is shorter than 12 hours, and the medicine is not taken again.

The medication period is as follows:

The subjects were all patients enrolled in cohorts one to five of example one.

2.5 delayed administration and dose adjustment

Adverse events with 14C12H1L1 injections resulted in delayed dosing, which failed to resume over 12 weeks, and treatment with 14C12H1L1 injections should be terminated permanently. The treatment of adverse events caused by 14C12H1L1 injection is suggested in the treatment of immune related adverse events caused by immune checkpoint inhibitor treatment. The 14C12H1L1 injection allows for delayed dosing without dose adjustment.

The ambrtinib hydrochloride capsule generates adverse reactions related to the ambrtinib within the administration period (1-14 days) per cycle, and the delay time can not exceed 5 days at most when the administration needs to be delayed. If the drug can not be taken continuously for more than 5 days, the residual Arotinib in the period is not used any more. Patients who can not take the anitinib (including reduced dose) for more than 2 weeks at the beginning of the next cycle, such as when the drug can be delayed due to adverse reactions, and the drug can not be taken for more than 2 weeks, need to stop the anitinib permanently (except for the event caused by non-safety reasons). The aritinib hydrochloride capsules may be delayed or dose adjusted during the study if desired.

During the study, downregulation of the dose was allowed when adverse events associated with nilotinib occurred, 12mg → 10mg and 10mg → 8 mg. At the 8mg level, discontinuation of the drug regimen is still not tolerated. After a period of time of down-dosing, the dose can be up-dosed to the original level, allowing for the possibility of progression of the disease and for controlled safety, from the next cycle on.

2.6 disease progression and efficacy assessment

In the period of clinical application of the same kind of 14C12H1L1 injection, the subjects have false progress, and the therapeutic effect evaluation standard of the study is based on RECIST 1.1 (therapeutic effect evaluation standard of solid tumors). The efficacy was also confirmed using the irrecist criteria (tumor immunotherapy-related evaluation criteria). That is, subjects judged to be disease Progression (PD) according to RECIST 1.1 criteria were further confirmed according to irrecist criteria to determine whether to further observe the drug.

Efficacy was assessed every 2 cycles, 16 cycles, and 4 cycles, starting on the first day of the first cycle, until subject development of tumor-image confirmed disease progression, which did not change the frequency of assessment as subjects delayed or discontinued treatment. If the subject terminates study treatment for reasons other than disease progression, it is still necessary to continue receiving the frequent tumor imaging assessments until the subject begins new anti-tumor therapy, or imaging-evidence of disease progression, or the subject actively withdraws, or the subject dies, whichever comes first.

The imaging evaluation mode of the tumor can adopt CT or MRI, but the evaluation method, machine and technical parameters are consistent during the whole research period; if no contraindications are indicated, contrast agents should be used. If tumor assessments were made within 14 days prior to the first dose and the same procedure was used in the same hospital, this could be taken as a baseline tumor assessment. Baseline tumor assessments should include CT or MRI of the chest, abdomen and pelvic cavities. During the screening period, craniocerebral flat scan and enhancement/enhancement MRI examination are required. All suspicious lesion sites should be examined imagewise. For patients with bone metastases, bone scans should be used to follow up on the lesions. For patients with bone metastasis, if no clinical symptoms are aggravated, the tumor evaluation is not required to be performed for recheck every time, and if the clinical symptoms are aggravated, the patient should be rechecked in time. For cases suspected of disease progression before the start of the next evaluation in the plan, an unplanned tumor assessment should be performed. During the test period, only the imaging examination of the focus part is performed, and during the test period, the image of the corresponding part can be examined if the suspicious part exists.

EXAMPLE III Collection of biological samples

3.1 serum anti-14C 12H1L1 antibody (ADA) assay

The immunogenicity monitoring time point is based on the administration time of the 14C12H1L1 injection; when 14C12H1L1 was given late, there was a corresponding delay in immunogenic blood sampling. If the subject is detected to be positive for ADA, the neutralizing antibody is measured.

Collection was taken before dosing (-60min) at cycles 1, 2, 4, 8 and every 6 cycles thereafter. Simultaneous collection was done 30min (+ -5 min) after the end of infusion in cycle 1 and cycle 8 and 30 days (+ -7 days), 90 days (+ -7 days) after the last dose. 5mL of venous blood is required to be collected each time, the venous blood is placed in a blood collection tube containing procoagulant separation gel for 30min at room temperature, after natural coagulation, 3000g of the venous blood is centrifuged for 10min, the venous blood is averagely distributed into 4 freezing storage tubes (3 parts of detection tubes and 1 part of backup tube, wherein each detection tube is not less than 0.5mL), and serum is taken as a marker and then stored in a refrigerator at the temperature of-40 to-80 ℃ for detecting immunogenicity and 14C12H1L1 blood concentration.

Unexpected adverse events related to immunity occurred during the test, and additional 1 blood sampling was required to test immunogenicity and 14C12H1L1 blood concentration after the adverse event was confirmed, but the time from the last blood sampling was less than 24H and the sampling could not be performed.

Note that: based on the ADA results, neutralizing antibodies are subsequently tested if necessary.

3.2 biomarker assays

Participation in this study required the provision of tumor tissue specimens for biomarker studies, including PD-L1 expression, mismatch repair/microsatellite instability (MMR/MSI) detection, and the like.

The samples for biomarker detection were selected from fresh biopsy samples within 1 month prior to group entry. When a fresh tissue sample is taken, 1 needle or more is punctured through the skin. If a fresh biopsy tissue sample cannot be obtained, the biopsy tissue sample can be collected, used and filed, 10 unstained pathological tissue slices (anti-alopecia) are taken, the thickness is 4-6 mu m, white slices prepared by fresh cutting are taken, and wax sealing treatment is needed if the white slices cannot be sent out in time (within one month).

Example four evaluation of effectiveness and safety

4.1. Analysis of the main efficacy index

4.1.1. Objective Remission Rate (ORR):

the ratio of the number of objective remission cases (PR + CR) in each group to the total number of cases in each group and 95% CI were calculated. The 95% CI for ORR was calculated based on the exact binomial method of F distribution.

4.1.2. Analysis of secondary efficacy index

4.1.2.1. Progression Free Survival (PFS)

And estimating the median PFS by adopting a Kaplan-Meier method, and drawing a survival curve graph.

4.1.2.2. Overall lifetime (OS)

And estimating the median OS by adopting a Kaplan-Meier method, and drawing a survival curve graph.

4.1.2.3. Duration of remission (DOR)

The median PFS and 95% CI thereof are estimated by adopting a Kaplan-Meier method, and a survival curve graph is drawn.

4.1.2.4. Disease Control Rate (DCR):

the ratio of the number of disease control cases (CR + PR + SD) to the total number of cases and 95% CI were calculated. The 95% CI for the DCR was calculated based on the exact binomial method of F distribution.

4.2. Evaluation of safety

4.2.1. Drug exposure and compliance

The drug exposure is described by mean, standard deviation, maximum, minimum, median.

Summary of subject exposure to study drug treatment, patient cycle count, dose adjustments during treatment, cumulative number of doses adjusted during treatment, etc.

Statistical descriptions of study drug treatment time, study drug total dose and daily average dose and study drug dose compliance over the treatment period are presented.

Study drug dose compliance will be calculated based on the actual daily study drug total dose and the regimen prescribed study drug total dose recorded by the eCRF.

The comparison of the treatment time of each study drug, the total dose and the daily average dose of the study drug and the study drug dose compliance adopts one-factor analysis of variance, and the comparison of the compliance classification adopts chi-square test or Fisher accurate probability method.

4.2.2. Adverse events

Summary adverse events, adverse events prior to first administration, adverse events during treatment, unexpected adverse events during treatment, significant adverse events during treatment, adverse events of particular interest during treatment, adverse events of grade 3 and above during treatment, severe adverse events during treatment, adverse events related to study drug during treatment, SAEs related to study drug during treatment, instances, number of instances, and incidence of adverse events that lead to dose adjustments during treatment, permanent cessation of treatment, termination of trial, patient death were categorized and summarized according to SOC, PT.

Adverse events with incidence rate of more than or equal to 5% during treatment and drug-related adverse events are summarized according to PT classification.

Drug-related adverse events with CTC AEs graded as grade 3 or 4 during treatment were summarized by PT classification.

Adverse events with incidence rate of more than or equal to 10% during treatment and drug-related adverse events are summarized according to PT classification.

The median first occurrence time of adverse events of particular concern.

4.2.3. Vital signs

Mean ± standard deviation, maximum, minimum, median are used to describe the measurements and changes before and after treatment.

4.2.4. Laboratory test index

Table 2 examination item table

The measured values and the changed values before and after treatment are described by mean values +/-standard deviation, maximum values, minimum values and median values for blood routine, blood biochemistry, thyroid function, blood coagulation function, amylase and lipase, and the paired t test is adopted for group comparison. And describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

The routine of urine: and describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

And (3) conventionally: and describing normal and abnormal change conditions before and after treatment by adopting a cross classification table.

Describes the proportion of "abnormal, clinically significant" in subjects with abnormal changes, where the presence or absence of an abnormality is judged by the investigator.

4.2.5. Electrocardiogram

Electrocardiogram: according to the normal and abnormal conditions judged by the researchers, the change conditions of the normal and abnormal conditions before and after treatment are described.

The heart rate, PR interval, QRS interval, QT interval and QTc describe the measured values and the variation values before and after administration by using the mean value plus or minus standard deviation, the maximum value, the minimum value and the median. The electrocardiogram total evaluation result adopts a cross classification table to describe normal and abnormal change conditions before and after administration. The proportion of "clinically significant" abnormalities in subjects who describe abnormal changes, where the presence or absence of abnormalities is judged by the investigator. The list presents a post-administration exception list.

4.2.6. Physical examination

The changes of normal and abnormal before and after treatment are described.

EXAMPLE V clinical applications

1. The patients: c01012 urothelial cancer

The past medical history: a 63 year old female, with lower abdominal CT on 5, 14 months in 2019: left ureter dilates. Further progression to urinary CTU: left lower ureteral tumor (approximately 16 x 20mm) soft tissue density), considering ureteral cancer potential; left hydronephrosis. 2019-5-29 laparoscopic left ureter cancer radical treatment, ureteroscope examination and perirenal adhesion relaxation. Postoperative pathology: (left kidney + left ureter + partial bladder) high-level urothelial cancer with -like local differentiation, and partial area with mucus-like stroma, infiltrates the outer fibrous adventitial tissue of the muscular layer, and infiltrates deepest 0.75 cm. 2019-5-31- -2019-07-18 Rou is infused seven times (the specific amount is not detailed) compared with the bladder of the same star without chemotherapy contraindications. The postoperative gemcitabine + cisplatin regimen assisted chemotherapy for 6 cycles from 14 days 8/2019 to 29 days 11/2019, specifically: gemcitabine 1.0g d1, 8Ivgtt, cisplatin 30mg d2-4 Ivgtt for 21 days as a cycle. 2020-08-15 flat scan of thoracico-abdominal CT: the thorax is symmetrical, and soft tissue shadows with the diameter of about 45cm are seen at the entrance of the left thorax; the transillumination of the double lung fields is slightly enhanced, the wall of the bronchial tube is thickened, and the large one is positioned in the middle lobe of the right lung and about 10 × 7.5mm, and a small amount of real images are seen in the small mixed ground glass nodules; the two lungs have many hair streaks. Flat scanning of the whole abdomen by CT: the liver is normal in size and shape, and has a few slightly low-density images with the diameter of less than 17 mm. Several soft tissue nodule shadows with the diameter of 20mm are seen behind the peritoneum, and the edges are rough. The left acetabulum becomes shallow, the shapes of the left femoral head and the left neck are irregular, and the left femur moves upwards; the soft tissue around the left hip joint is swollen. Consider a transfer. The pathological prompt of the puncture of the tumor in the left neck of 2020-08-24 is in accordance with the metastasis of the urothelial cancer.

Beginning with 1 oral administration of 12mg of an erlotinib hydrochloride capsule 1 time a day for 10 days 9 months in 2020, stopping for 1 week for 2 weeks, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The tolerance of the patient is good during the medication period, and the medication can be continued.

And (3) pathological report: 2020-09-02 left cervical puncture pathology: high grade urothelial cancer.

The dosage is as follows: arotinib hydrochloride: 12mg, 14C12H1L 1:200 mg of

And (3) evaluating the curative effect:

and (3) screening period: target lesion: 68 mm; non-target lesions: is absent.

After cycle 2 dosing: target lesion: 27 mm; non-target lesions: is absent.

2. The patients: c01012 rectal cancer

The past medical history: for a 44-year-old male, the finding of an enteroscope of a 2018-2-10 patient shows that: rectal cancer; 2018-2-13 pathological diagnosis: (rectal) high grade takes adenocarcinoma into account, low differentiation. 2018-2-24 imaging diagnosis of pelvic rectum nuclear magnetic examination: the lower middle section of the rectum, which penetrates the outer membrane, invades the prostate. 2018-2-26 enteroscopy endoscopy diagnosis; rectal cancer (approximately 4cm from the anal verge), involves the anal canal. Chest-abdomen basin enhanced CT imaging diagnosis: the middle and lower segment of rectum cancer invades the external membrane surface, invades the prostate, and has many low-density focuses on the liver, and the metastatic tumor is considered. The nodes of the left lung inferior lobe, high vigilance of lung metastasis. 2018-2-28 biopsy pathology suggests that neuroendocrine tumors are accompanied by necrosis, and the Ki-67 proliferation index is lower, and conforms to NET G2, Ki-67 (15%), SSTR2(3+), PD-L (+, 5%). 2018-3-5 diagnosis by abdominal magnetic imaging: liver multiple metastases. 6 cycles of chemotherapy between 2018-3-11 and 2018-8 in the last ten days, the specific scheme is as follows: tegafur 60mg Bid 1-14; temozolomide 250mg po d 10-14; this was repeated for 21 days. 2018-4-26 to 2018-7-25, 20mg of octreotide acetate microspheres are administered for intramuscular injection once a month; 2018-9 review of CT results suggests that the treatment is effective. Single dose S1 maintenance treatment for 6 cycles 2018-11 to 2019-9, the specific schedule is: tegafur 60mg po bid 1-14; the treatment is repeated for 21 days, the traditional Chinese medicine is taken intermittently for conditioning, and the CT evaluation after chemotherapy has stable curative effect evaluation. 2020-5-25 enhanced CT shows: the left superior lobar lingual segment nodules are about 0.4cm larger than the anterior ones. 2020-6-2 abdominal nuclear magnetic display: the liver is usually with multiple metastases, larger than the former, and the larger is located in the lower right posterior segment of the liver. The liver scatters in the abnormal signal nodules, which increase earlier, indicating the progression of the tumor.

On 19/6/2020, 10mg of erlotinib hydrochloride capsule is initially orally administered 1 time a day for 2 weeks and 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance.

And (3) pathological report: 2018-2-28 biopsy pathology: neuroendocrine tumors are accompanied by necrosis, with a lower Ki-67 proliferation index, consistent with NET G2, Ki-67 (15%), SSTR2(3+), PD-L (+, 5%).

The dosage is as follows: arotinib hydrochloride: 10mg, 14C12H1L 1:200 mg of

And (3) evaluating the curative effect:

and (3) screening period: target lesion: 42 mm; non-target lesions: liver metastasis, lung metastasis, and rectal lesions.

After cycle 2 dosing: target lesion: 40 mm; non-target lesions: NCR/NPD.

After cycle 4 dosing: target lesion: 38 mm; non-target lesions: NCR/NPD.

3. The patients: c 01007-poorly differentiated cholangiocellular carcinoma/biliary tract carcinoma

The past medical history: 65 year old male, 2019-5-31 MRI: malignant cholangiocarcinoma is considered as the tumor at the junction of the left and right lobes of the liver. 2019-6-11 rows liver V segment + segment IV segment + cholecystectomy. 2019-6-12, and the pathological diagnosis is low differentiation cholangiocellular carcinoma. 2019-08-20 to 2019-10-26 for oxaliplatin in combination with capecitabine chemotherapy for 3 cycles. The specific scheme is as follows: oxaliplatin 190mg, capecitabine 1000g bid po d1-14, q21 d. 2020-07-20 thoraco-abdominal basin enhanced CT prompting: nodules are frequently generated in the liver, multiple swollen lymph nodes in the abdominal cavity and retroperitoneum, and multiple bone changes occur in the spine and pelvis.

On 7/8/2020, 1 oral administration of 10mg of erlotinib hydrochloride capsules is started daily for 2 weeks and stopped for 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance.

And (3) pathological report: 2019-6-12 postoperative pathology: low-differentiation cholangiocarcinoma (partial area is in the form of fusiform cells, accounting for about 30%), focal necrosis and massive lymphocyte infiltration, the maximum diameter of the tumor is 3.6cm, and angioma embolism can be seen. The tumor did not involve liver capsule. The basal margin of the liver is not cancerous. Peripheral liver tissue sink areas are accompanied by significant inflammatory cell infiltration. Cystic hyperplasia of the gallbladder with myoma of the glands accompanied by active epithelial hyperplasia and cystic dilatation of the glands. Lymph node metastatic cancer 2/4, without involvement of lymph node extramembranous. Gastric left paravascular lymph node 1/1, 12, group 13 lymph nodes 1/1, 7, 8, 9 lymph nodes 0/1, group 12P lymph node 0/1, staging: PT2N 1. Immunohistochemical results show that: CK18(2+), CK19(3+), CK7 (foci 1+), GPC3(-), hepatplocyte (-), AFP (-), CA19.9(1+), CD34 (vascular endothelial +), Ki-67(+, 60%). The in situ hybridization results show that: EBER (-).

The dosage is as follows: arotinib hydrochloride: 10mg, 14C12H1L 1:200 mg of

And (3) evaluating the curative effect:

and (3) screening period: target lesion: 68 mm; non-target lesions: multiple lymph node metastasis; liver metastasis.

After cycle 2 dosing: target lesion: 53 mm; non-target lesions: NCR/NPD.

4. The patients: c 01010-invasive urothelial carcinoma

The past medical history: 69 year old male, 2012 month 5, CT prompt: 1. the high density of the lower section of the left ureter is accompanied by left hydrops and the expansion of the middle and upper sections of the left ureter, and the occupation possibility is considered to be high. 2. The left kidney has poor perfusion and excretion functions. 3. The left kidney has multiple cysts. Urine cytology examination found suspicious cancer cells, considering no ureteral tumors. Line 2012-5 "left ureter full length and left nephrectomy", postoperative pathology: transitional cell carcinoma of the left ureter. 2013-3-17 biopsy pathology: papillary urothelial tumors of low malignant potential. 2013-3-21 line "bladder tumor electrostomy", postoperative pathological return: transitional cell carcinoma (bladder), grade II. Line 2014-3-1, "transurethral bladder tumor electrostomy", pathology: transitional cell carcinoma (bladder), grade II. Postoperative "pirarubicin" bladder perfusion chemotherapy. 2014-5-17 pathology: a little degeneration squeezes badly deformed tumor tissue. "transurethral bladder tumor electrosurgery" at line 2014-5-24, and "Pirarubicin" bladder perfusion chemotherapy at postoperative line. 2016-9-7CT suggests more space occupation of the posterior wall of the bladder. Cystoscopy pathology: (trigone vesicae) glandular cystitis is considered. 2017-2-20 CT: left renal postoperative change, right hydronephrosis, right ureteral dilatation, bladder posterior wall space occupying lesion, involvement of the right uretero bladder entrance. 2017-2-27 line "transurethral bladder tumor electrosection + right D-J tube implantation", postoperative pathology: (right ureteral opening, trigone area, posterior bladder wall) were all high grade invasive urothelial carcinoma. 2019-5-22 conclusion of whole-body bone scan: multiple bone metastases occur throughout the body. 2019-6-19- -2019-12-14 gemcitabine and docetaxel are given for 6 cycles of systemic chemotherapy, tegafur is given for 2 cycles of oral maintenance chemotherapy, and zoledronic acid is given for anti-bone metastasis therapy. The best curative effect SD. 2020-1-4 imaging indicates stable disease condition, and the blood test tumor marker is increased earlier, indicating the tumor progression trend. 2020-1-7- -2020-1-14 chemotherapy with gemcitabine and docetaxel for 1 cycle, zoledronic acid is used for the treatment of bone metastasis. Chemotherapy day 6 blood routinely shows leukopenia, thrombocytopenia, complement diagnosis: inhibiting bone marrow function, stopping chemotherapy, and promoting leukocyte and platelet. 2020-2-13- -2020-7-28 Tegaoopo 120mg d2-14 and zoledronic acid 4 cycles. The best curative effect SD. 2020-7-13CT report: left side ureter tumour postoperative, right abdominal wall fistulization postoperative changes. The possibility of multiple cysts in the right kidney is similar to that in the former. Bilateral groins have multiple small lymph nodes, similar to the former. The two lungs have multiple hair strands and micro nodules, which are similar to the former. And (4) emphysema. The aortic and coronary vessel walls are calcified more frequently. Bilateral pachynsis of pleura. The bones at the level of the scan are of abnormal density, with no exception of metastases.

1/9/2020, starting 1 oral administration of 12mg of erlotinib hydrochloride capsule 1 time a day for 2 weeks and 1 week for 2 weeks, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance.

And (3) pathological report: 2017-07-27 postoperative pathology: (right ureteral opening, trigone area, posterior bladder wall) were all high grade invasive urothelial carcinoma.

The dosage is as follows: arotinib hydrochloride: 12mg, 14C12H1L 1:200 mg of

And (3) evaluating the curative effect:

and (3) screening period: target lesion: 10 mm; non-target lesions: foci of bone metastasis, pulmonary nodules.

After cycle 2 dosing: target lesion: 7.4 mm; non-target lesions: NCR/NPD.

5. The patients: c 01014-differentiated adenocarcinoma in common bile duct terminal/biliary tract cancer

The past medical history: for a 72-year-old female, 12 months in 2017, the patient performs B-mode ultrasonography and laboratory examination on the abdomen, and the lower end of the bile duct is suggested to occupy space and obstructive jaundice. PTCD jaundice treatment is performed in 2017-12-27, and liver function and jaundice indexes are obviously improved after puncture drainage. The 'pancreas duodenectomy' is performed in 2018-01-09, the operation process is smooth, and the postoperative recovery is good. 2018-01-10 postoperative pathology suggestion: adenocarcinoma was differentiated in the terminal of common bile duct, and no chemoradiotherapy was performed after the operation. Epigastric discomfort reappears in 3 months in 2020, and the CT prompts the occupying of the gallbladder fossa. The whole body albumin paclitaxel + capecitabine 10 cycles starting from 15/4/2020 to 29/7/2020, the specific scheme is as follows: 100mg d1 q21d + capecitabine 2.5g d1-7 and q21d of albumin paclitaxel, and has no serious adverse reaction. The best curative effect SD, 2020-08-13 full abdomen and pelvic cavity enhancement CT prompts: 1. changes after cholangiocarcinoma and cholecystectomy: the superior mesenteric artery has multiple lymph nodes of different sizes, which are considered to be metastatic, enlarged compared with the anterior one, and necrosis is seen in the focus, please follow the clinical course. 2. Annular thickening and strengthening of the common hepatic duct wall: inflammatory lesions. 3. Swelling of the right lobe of the liver. 4. The right side of the kidney is wrapped with effusion in front of the anterior fascia, which is smaller than the anterior part. 5. Lumbar 1 vertebral hemangioma. CT prompts progress.

On 18 months 9 in 2020, 1 oral administration of 12mg of erlotinib hydrochloride capsule is started daily for 2 weeks and stopped for 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The patient has good overall tolerance during taking the medicine, does not have adverse events of III DEG or above, and can continue taking the medicine.

And (3) pathological report: 2018-01-10 postoperative pathology: adenocarcinoma differentiated in the terminal of common bile duct, with a tumor size of about 1.5 × 1x0.8cm; cancer infiltrates the whole layer of the bile duct wall and invades the pancreas and duodenum wall; no clear intravascular cancer embolus is seen, and nerve invasion can be seen; visible cancer of peripancreatic lymph nodes (1/4); the perigastric lymph nodes are not cancerous (0/7); the incisal margin is not cancerous; (lymph node 8) lymph node not yet cancerous (0/1); (gallbladder) gallbladder not yet having cancer; stage of tumor pathology pT3N 1. Immunohistochemistry results: CDX-2(-), cK19(+), CK20(+), CK7(+), MUC-1(-), MUC-2(-), KI-67 (hot zone 80% +).

The dosage is as follows: arotinib hydrochloride: 12mg, 14C12H1L 1:200 mg of

And (3) evaluating the curative effect:

and (3) screening period: target lesion: 69 mm; non-target lesions: is absent.

After cycle 2 dosing: target lesion: 59 mm; non-target lesions: is absent.

6. The patients: c01013 metastatic intestinal cancer

The past medical history: a27-year-old female, 2019-3-12 patients suffer from abdominal pain and diarrhea for 1 half month and fever for 1 week, and the pathological diagnosis: (sigmoid colon) adenocarcinoma. 2019-3-21 for loosening intestinal adhesion, removing rectal cancer, and removing pelvic abscess to achieve good recovery; 2019-3-27 pathological diagnosis after operation: the ulcer mucus adenocarcinoma of (rectum) invades the soft tissue outside the serosa, and no nerve invasion or cancer embolism in the vessel occurs; 2020-7-28CT flat scan: double lung nodules, hepatic right lobe cyst, pelvic space occupation. 2020-7-31 pelvic MRI: 1. pelvic space occupying lesion 2, pelvic effusion. The 2020-8-6 laparotomy exploration, intestinal adhesion loosening, left ovarian cyst stripping, pelvic tumor biopsy and postoperative pathology prompt metastatic intestinal cancer.

Starting to treat 1 oral aritinib hydrochloride capsule 12mg 1 time a day on 11 days 9/2020, stopping for 1 week for 2 weeks, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The whole tolerance of the patient is good during taking the medicine, and the medicine can be continuously taken.

And (3) pathological report: 2020-8-6 postoperative pathology: (pelvic tumor) metastatic intestinal cancer, immunohistochemical CK7 and Pax-8 suggest Lynch syndrome, suggesting the examination of uterus and ovary. Immunohistochemistry: CK20(+), CK7 (cooker +). PAX-8 (Range +), Ki-67(+, 80%), CDX2(+), Villin (+), ER (+ +), PR (+ +).

The dosage is as follows: arotinib hydrochloride: 12mg, 14C12H1L 1:200 mg of

And (3) evaluating the curative effect:

and (3) screening period: target lesion: 75 mm; non-target lesions: is absent.

2020-9-27 unplanned: target lesion: 67 mm; newly-developed lesions: the right adnexal mass is 42 mm; total remission assessment: IUPD.

After cycle 2 dosing: target lesion: 49 mm; newly-developed lesions: the right adnexal mass is 42 mm; total remission assessment: IUPD.

7. The patients: S06001/C06001-differentiation cholangiocellular carcinoma/biliary tract cancer

Patient 2017.09 presented with no apparent cause of right upper abdominal pain, row 2018.02.23 chest CT: double lung multiple nodules, considered metastases, intrahepatic occupancy, 2018.02.24 epigastric CT: according with the CT expression of liver right lobe megaloblastic liver cancer and lymph node transfer in liver, abdominal cavity and retroperitoneal, 2018.03.08 pathological results show: adenocarcinoma is differentiated in the right lobe of the liver, and immunohistochemistry is combined, so that the cancer conforms to the cancer of the middle differentiated bile duct cell. The gemcitabine + oxaliplatin chemotherapy was given multiple times post. 2019.05.05 general thorax + full abdomen enhancement CT: 1. both lung and multinodular foci, considered metastases: 2. double lung lower lobe fiber focus. 3. The method accords with the multiple lymph node metastasis CT performance after the peritoneum of the liver tumor well: right portal branch cancer embolus: the esophageal and gastric fundus veins are circuitous and thick. Hepatic artery chemoembolization (drug loaded microspheres) + splenic artery embolization under local anesthesia in the ductal room at 2019.05.13. The postoperative patient had no obvious discomfort and was discharged from the hospital. Chest flat scan + whole abdomen CT on 6 months and 12 days in 2019: 1. the compound conforms to the CT performance of the double-lung multiple metastasis tumor, and is similar to the previous step: 2. double lung lower lobe fiber focus. 3. The medicine accords with the change after liver tumor treatment, has obvious lesion necrosis and is scattered in a few strengthening areas: right portal branch cancer embolus: 4. periportal and left-sided ovarian varices are responsible. 5. And (4) infarction of the spleen. 6. Uterine fibroids are considered. 2020.04.20 CT: 1. the compound is in line with the CT performance of double lung multiple metastasis tumor, and is heavier than the front panel: 2. double lung lower lobe fiber focus. 3. The change after treatment of liver tumor is met, the range is similar to increase compared with the front panel, and multiple lymph node metastasis occurs in the abdominal cavity and the retroperitoneal cavity: right portal branch cancer embolus: 4. varicose periportal veins. 5. And (4) infarction of the spleen. 2020.04.22 Lang of bronchial artery chemotherapy drug and hepatic artery chemoembolization (drug-loaded microspheres), the postoperative recovery was good.

The dosage is as follows: arotinib hydrochloride: 10mg, 14C12H1L 1:200 mg of

The first medication time: 2020.06.18 Anrotinib hydrochloride capsules 12mg treatment 1 time daily, 2 weeks stop for 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The whole tolerance of the patient is good during taking the medicine, and the medicine can be continuously taken.

And (3) evaluating the curative effect: and (3) screening period: target lesion: 214.2 mm; non-target lesions: multiple metastasis of lung, peritoneum and liver

After cycle 2 dosing: target lesion: 183.5 mm; non-target lesions: presence, absence of progression

After cycle 4 dosing: target lesion: 173.3 mm; non-target lesions: presence, absence of progression

After cycle 6 dosing: target lesion: 180.7 mm; non-target lesions: presence, absence of progression

8. The patients: S06002/C06002-gastric cancer

The patient has no obvious induction of anorexia, feelings of hypodynamia, eructation, acid regurgitation and heartburn, and has no symptoms of nausea, vomiting and the like 1 year ago. Gastroscopy in 2019 and 5 months shows that huge irregular bulges are formed on the front wall, the rear wall and the small curve side of the antrum and adenocarcinoma is pathologically indicated. Gastroscopy at 2019.8.5: gastric cancer, reflux esophagitis. Upper abdomen lower abdomen CT of chest (2019.8.5): gastric carcinoma with multiple metastasis to lymph nodes: left lung micronodule foci: bone is often found in high density foci. Abdominal ultrasound display: cholecystokinin multiple crystals: the left lateral wall of the bladder is solidly convex. Displaying the heart color ultrasound: degenerative changes in the aortic valve, reduced left ventricular diastolic function. In order to treat the 'palliative gastric cancer resection', no obvious metastasis of liver, spleen, abdominal cavity and pelvic cavity can be seen in the operation, the cancer is positioned at the small bent side of the stomach body, the size is about 8 × 7 × 6cm, the cancer penetrates through a serosal layer, and multiple swollen lymph nodes can be seen in the groups 2, 4, 6, 7 and 8. Cancer is localized in the pancreas and is dense in the mesentery of part of the transverse colon. The lymph nodes in the groups 1, 2, 3, 4, 5, 6, 7, 8 and 11 are removed in the operation, the operation process is smooth, blood transfusion is carried out in the operation, and the pathological result after the operation shows that: the low-differentiation adenocarcinoma in the gastric sinus ulcer type and the immunohistochemical result are as follows: anaplastic adenocarcinoma in antral gastric ulcer. Tumor size: 3 x 2.8 x0.8cm, cancer tissue invaded and serosal layer, no obvious cancer embolus in vessel, no cancer tissue on incisal margin and omentum majus of upper and lower operation, cancer metastasis 1/4 in lymph node of large bending side, no cancer metastasis 0/12 in lymph node of small bending side. The patient underwent an upper abdominal lower abdominal MRI examination (2020.5.27) at 26, 5/2020 due to "abdominal discomfort": 1. abdominal and retroperitoneal occupancy, considering the possibility of lymphatic metastasis: 2. cyst of the left lobe of the liver. Gastroscopy (2020.5.28) shows: 1. esophageal squamous papillomatosis: 2. reflux esophagitis (severe): 3. residual gastritis: 4. bile reflux: 5. gastric retention. History of the past: the traditional 'diabetes' history is more than 16 years, and the hypoglycemic agent is regularly taken, so that the blood sugar is well controlled. The patient has more than 10 years of 'hypertension' history and can be controlled by the medicine. Has a history of 'premature beat' and no obvious symptoms after taking the traditional Chinese medicine for conditioning.

The dosage is as follows: arotinib hydrochloride: 10mg, 14C12H1L 1:200 mg of

The first medication time: 2020.06.19 Anrotinib hydrochloride capsules 12mg treatment 1 time daily, 2 weeks stop for 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The whole tolerance of the patient is good during taking the medicine, and the medicine can be continuously taken.

And (3) evaluating the curative effect: and (3) screening period: target lesion: 25.5 mm; non-target lesions: descending metastasis of duodenum

After cycle 2 dosing: target lesion: 19.6 mm; non-target lesions: NCR/NPD

After cycle 4 dosing: target lesion: 19.6 mm; non-target lesions: NCR/NPD

After cycle 6 dosing: target lesion: 19.3 mm; non-target lesions: NCR/NPD

9. The patients: S06004/C06003-biliary tract cancer

The patient has abdominal distension after drinking the wine, accompanied by symptoms such as poor tolerance, acid regurgitation, eructation, diarrhea and the like more than 2 years ago, and the MR shows that: abnormal morphology and signals of the middle and lower segments of the common bile duct correspond to the bile duct cancer, expansion and manifestation of biliary system and multiple cysts in liver. 2018.06.07 laparoscopic pancreaticoduodenectomy, 2018.06.12 postoperative pathology report: (left half liver) intrahepatic cholangiocarcinoma (tumor area: 4.5 x 3cm), cancer cells are moderately differentiated and are close to the liver capsule, intravascular cancer emboli and nerve invasion are not detected, and cancer cells are not detected at liver incisional margin and hepatic duct incisional margin. The other is that the liver tissue biopsy is sent to check that the cholangiocellular carcinoma is found in the tissue, and the gallbladder is not found. Post 2019. oral tegafur treatment started in 11 months of the year. 2020.03.29 parallel abdominal sweeps CT, the results show: 1. the bile duct cancer is found in the abdominal cavity through the postoperative reexamination. 2. No obvious abnormality was seen in the CT flat scan of the chest. Patients complained of tikitikao. 2020.06.23 Row Abdominal Reinforcement CT results show: 1. biliary duct cancer is seen after postoperative review. 2. Consistent with peritoneal metastasis and peritoneal fluid accumulation.

The dosage is as follows: arotinib hydrochloride: 10mg, 14C12H1L 1:200 mg of

The first medication time: 2020.07.31 Anrotinib hydrochloride capsules 12mg treatment 1 time daily, 2 weeks stop for 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The whole tolerance of the patient is good during taking the medicine, and the medicine can be continuously taken.

And (3) evaluating the curative effect: and (3) screening period: target lesion: 37.5 mm; non-target lesions: peritoneal, retroperitoneal metastasis

After cycle 2 dosing: target lesion: 37.2 mm; non-target lesions: NCR/NPD

10. The patients: S06005/C06004 cholangiocarcinoma/biliary tract cancer

The patient repeatedly suffered from epigastric pain with yellow skin and sclera and dark brown urine 1 year ago, and has no obvious symptoms of fever, shivering, diarrhea and the like. 2019.04.10 Row Abdominal enhancement MRI show: gallbladder volume increase, wall thickening: the intrahepatic and extrahepatic bile ducts are widely expanded, and the upper sections of the left and right hepatic ducts and the common hepatic duct are obviously narrowed. According with the hepatic portal area space occupying lesion (the upper sections of the left hepatic duct, the right hepatic duct and the common hepatic duct) and the hepatoportal area and the portal space swollen lymph nodes according with the representation of the cholangiocarcinoma; it is consistent with the manifestations of cholecystitis. 2019.04.12 bile duct cancer radical treatment and right hemihepatectomy are carried out on the trachea cannula on the lower part of the hepatic portal due to general anesthesia, the operation is smooth, and the pathological result is 2019.04.18; and (left hepatic duct) cholangiocarcinoma, wherein cancer cells are in medium-low degree differentiation, invade the muscular layer and penetrate the serosa, the invasion of the right hepatic duct and the invasion of the submucous membrane to the muscular layer and the serosa are accumulated, the gallbladder and the right hepatic tissue are not accumulated, the hepatic common duct incisal margin and the gallbladder incisal margin are negative, 1 lymph node is found at the left hepatic duct, and the cancer cells are not found. Chronic cholecystitis, cholecystopancreatosis. Oral tegafur 6 cycle therapy was administered at 2019.05.11-2020.03 months after surgery. 2020.04.19 Row Abdominal Reinforcement CT results show: 1. liver right lobe postoperative change, liver left lobe low density foci, considered metastasis; 2. after cholecystectomy; 3. hyperplasia of prostate; 2020.04.26 Row upper abdomen (or lower abdomen) magnetic resonance flat scan + enhanced liver examination results show: 1. portal area bile duct MT postoperative change; multiple nodules in the liver, considered metastases. The abnormal marginal strengthening focus of the left inner lobe of the liver considers that the possibility of metastasis is high. 2. Consider the accessory spleen; complaints 2020.06.15-2020.07.12 were taken from capecitabine 1 cycle. 2020.07.21 chest + full abdomen examination results show: 1. no obvious abnormality is seen in the CT flat scan of the lung; 2. the liver right lobe is changed after operation, the liver has more occupation, and the number of metastatic tumor is considered and increased compared with the former number; portal vein cancer embolus formation is considered. 3. After cholecystectomy; 4. hyperplasia of prostate gland.

The dosage is as follows: arotinib hydrochloride: 10mg, 14C12H1L 1:200 mg of

The first medication time: 2020.08.11 Anrotinib hydrochloride capsules 12mg treatment 1 time daily, 2 weeks stop for 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The whole tolerance of the patient is good during taking the medicine, and the medicine can be continuously taken.

And (3) evaluating the curative effect: and (3) screening period: target lesion: 42.8 mm; non-target lesions: multiple liver metastases, mesenteric lymph node metastases

After cycle 2 dosing: target lesion: 41.7 mm; non-target lesions: iUPD

11. The patients: S06007/C06006-bile duct diffuse infiltrative adenocarcinoma/biliary tract cancer

2017.09.07 Row Abdominal Flat Scan MR examination results show: the expansion MR and MRCP performance of the occupation of the lower end of the common bile duct and the biliary obstruction is met. The results of parallel lung scan + whole abdominal enhancement CT show: 1. double lung with fibrous nodules. 2. The lung was slightly changed in interstitial property. 3. The common bile duct and the cystic duct occupy the space and the internal and external bile ducts and the pancreatic duct of the liver are expanded. 4. Chronic cholecystitis. 5. Liver bunions are considered. 6. Thrombosis of the dry abdominal wall of the abdominal cavity. The pancreaticoduodenectomy is performed under a laparoscope, the operation is smooth, and the pathology after the operation is shown as follows: diffuse invasive adenocarcinoma of bile duct, low differentiation, invasion of serosa, negative bile duct resection, pancreatic duct cauliflower type papillary adenocarcinoma, low-medium differentiation, invasion of duodenal muscle layer, one cancer nodule, and lymph node 0/31. Tegafur 20mg oral bid chemotherapy was given starting with 2017.11.02 post-surgery and discontinued after 2019.03 discontinuation after two cycles of intermittent oral intolerance.

The dosage is as follows: arotinib hydrochloride: 12mg, 14C12H1L 1:200 mg of

The first medication time: 2020.09.09 Anrotinib hydrochloride capsules 12mg treatment 1 time daily, 2 weeks stop for 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The whole tolerance of the patient is good during taking the medicine, and the medicine can be continuously taken.

And (3) evaluating the curative effect: and (3) screening period: target lesion: 38.9 mm; non-target lesions: metastasis of liver, peritoneum, clavicle lymph node

After cycle 2 dosing: target lesion: 38.7 mm; non-target lesions: iUPD

12. The patients: S06008/C06007-intrahepatic bile duct cell carcinoma

The abdomen ultrasonic prompt liver space occupying lesion is performed before 1 year of physical examination, and the MR examination prompts: hepatic left lobe space occupying lesion, taking neoplastic lesion into account; pulmonary right lobular microangioma. The ascending abdominal enhancement CT results show: the liver left lobe space occupying lesion considers the possibility of malignancy, and the bile duct source traveling possibility is high; small hemangioma of the lower right posterior lobe of the liver. At 2019.07.30, the left half hepatectomy of laparoscope is performed under general anesthesia, the operation is smooth, and the pathology after the operation is shown as follows: medium-low differentiated adenocarcinoma, corresponding to intrahepatic cholangiocellular carcinoma, with a size of about 5.5 × 4.5 × 4cm, cancer invasion to peripheral liver tissue, focal involvement of liver capsule; cancer is visible at the surgical margin; nerve invasion is visible, and a plurality of satellite nodules are visible in the peripheral liver tissue. Immunohistochemistry results: PMS2(+), MSH2(+), MSH6(+), MLH1(+), PD-1 (tumor cell-, lymphocyte approximately 2% +), CK7(+), CK20 (individual +), CK19 (weak +), P53 (wild type), Ki-67 (50%). The oxaliplatin + gemcitabine chemotherapy was given at 2019.09-2020.02 post-surgery, the specific chemotherapy cycle was unknown, and the lung/mediastinum/chest wall CT image results at 2020.02.10 post-surgery are shown: the two lungs have multiple lesions, and the lesion of the upper lobe of the right lung is larger than that of the front lung. Bilateral pleural focal thickening. Left lobe of liver postoperative change. Considering the increased metastasis, 2020.02 changed the chemotherapy regimen paclitaxel + tegafur, during which paclitaxel was discontinued, but oral tegafur chemotherapy, the specific date and cycle of chemotherapy were not detailed. 2020.08.12 Thegiloo was discontinued.

The dosage is as follows: arotinib hydrochloride: 12mg, 14C12H1L 1:200 mg of

The first medication time: 2020.09.16 Anrotinib hydrochloride capsules 12mg treatment 1 time daily, 2 weeks stop for 1 week, 14C12H1L 1: administered 1 time every 3 weeks at 200 mg/time, and administered by intravenous infusion. Every 3 weeks for 1 treatment cycle until disease progression or intolerance. The whole tolerance of the patient is good during taking the medicine, and the medicine can be continuously taken.

And (3) evaluating the curative effect: and (3) screening period: target lesion: 71.3 mm; non-target lesions: hepatic portal lymph node metastasis

After cycle 2 dosing: target lesion: 44.4 mm; non-target lesions: NCR/NPD

While the compositions and methods of this application have been described in terms of preferred embodiments in light of the present disclosure, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the application.

The disclosures of all documents cited herein are incorporated by reference herein, to the extent that they provide exemplary, procedural and other details supplementary to those set forth herein.

Sequence listing

<110> Ningda Ningqing pharmaceutical industry group, Inc

<120> pharmaceutical composition of quinoline derivative and PD-1 monoclonal antibody

<130> 2020.11.27

<160> 8

<170> SIPOSequenceListing 1.0

<210> 1

<211> 6

<212> PRT

<213> Synthetic sequence

<400> 1

Gln Asp Ile Asn Thr Tyr

1 5

<210> 2

<211> 3

<212> PRT

<213> Synthetic sequence

<400> 2

Arg Ala Asn

1

<210> 3

<211> 9

<212> PRT

<213> Synthetic sequence

<400> 3

Leu Gln Tyr Asp Glu Phe Pro Leu Thr

1 5

<210> 4

<211> 8

<212> PRT

<213> Synthetic sequence

<400> 4

Gly Phe Ala Phe Ser Ser Tyr Asp

1 5

<210> 5

<211> 8

<212> PRT

<213> Synthetic sequence

<400> 5

Ile Ser Gly Gly Gly Arg Tyr Thr

1 5

<210> 6

<211> 11

<212> PRT

<213> Synthetic sequence

<400> 6

Ala Asn Arg Tyr Gly Glu Ala Trp Phe Ala Tyr

1 5 10

<210> 7

<211> 107

<212> PRT

<213> Synthetic sequence

<400> 7

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Phe Thr Cys Arg Ala Ser Gln Asp Ile Asn Thr Tyr

20 25 30

Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile

35 40 45

Tyr Arg Ala Asn Arg Leu Val Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Gln Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Met Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 8

<211> 118

<212> PRT

<213> Synthetic sequence

<400> 8

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr

20 25 30

Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val

35 40 45

Ala Thr Ile Ser Gly Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Asn Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Asn Arg Tyr Gly Glu Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

Claims

1. A pharmaceutical combination comprising:

2. the pharmaceutical combination according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, preferably the dihydrochloride.

3. The pharmaceutical combination of any one of claims 1-2, wherein the human PD-1 antibody comprises a light chain variable region having an amino acid sequence as set forth in SEQ ID No. 7 and a heavy chain variable region as set forth in SEQ ID No. 8.

4. Use of the pharmaceutical combination according to any one of claims 1 to 3 for the treatment or prevention of tumors of the digestive tract, or of the urinary system, or of neuroendocrine tumors.

5. Use according to claim 4, for the treatment of biliary tract cancer, or cholangiocellular carcinoma, or diffuse invasive adenocarcinoma of the bile duct, or intrahepatic cholangiocellular carcinoma, or extrahepatic cholangiocellular carcinoma, or gallbladder cancer, or intestinal cancer, or colorectal cancer, or adenocarcinoma of the stomach or gastroesophageal junction, or urothelial carcinoma.

6. The use according to any one of claims 4 to 5, for the treatment of biliary tract cancer that is not surgically resectable or metastatic, or that has failed prior first or second line chemotherapy.

7. Use according to any one of claims 4 to 6, for the treatment of colorectal cancer in the presence of mismatch repair gene deletion or high microsatellite instability, or recurrence, or metastasis, or colorectal cancer that has not been treated for recurrence or metastasis, or metastatic intestinal cancer.

8. The use according to any one of claims 4 to 7, for the treatment of recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that has not been treated for recurrence or metastasis.

9. Use according to any one of claims 4 to 8, for the treatment of urothelial cancer of local progression, or metastatic, or failed to have been treated at least by one standard systemic chemotherapy regimen, or of bladder, or ureter, or renal pelvis, or of urethral origin.

10. The use according to any one of claims 4 to 9, for the treatment of a low-grade, or medium-grade, or advanced, or non-surgically resectable, or locally advanced, or distant metastatic, or a gastrointestinal-pancreatic neuroendocrine tumor that has been previously at least treated with one systemic antineoplastic agent against advanced gastrointestinal-pancreatic neuroendocrine tumors.