Use of paclitaxel cationic liposomes for treating tumors - Patent Application 20070122997

Abstract

The present invention provides a use of paclitaxel cationic liposomes in the manufacture of a medicament for treating terminal solid cancer, a use of paclitaxel cationic liposomes and a systemic therapeutic agent in the manufacture of a medicament for treating terminal solid cancer, and a method for treating terminal solid cancer, in which a therapeutically effective amount of paclitaxel cationic liposomes is administered to a patient with terminal solid cancer, or a therapeutically effective amount of paclitaxel cationic liposomes and a systemic therapeutic agent is administered to a patient with terminal solid cancer.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This disclosure claims priority to and the benefit of Chinese Patent Application No. 202310046953.0, filed on January 31, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] [Technical field] The present invention belongs to the field of antitumor, and specifically relates to the use of a combination therapy of arterial infusion of paclitaxel cationic liposomes and systemic treatment, and a single arterial infusion of paclitaxel cationic liposomes in the manufacture of drugs for treating tumors, particularly late-stage solid cancers such as gastric cancer, pancreatic cancer, and liver metastasis from colorectal cancer. [Background technology]

[0003] Paclitaxel is a tricyclic diterpenoid, originally isolated from the bark of Pacific yew (Taxus brevifolia) by Wani et al., and its chemical structure was identified. Paclitaxel is a microtubule inhibitor that can induce and promote microtubule assembly, polymerize and stabilize microtubules, interfere with microtubule rearrangement, and stop mitosis, thereby inhibiting tumor cell proliferation.

[0004] Cationic liposomes are a novel form of drug delivery, and cationic paclitaxel-based drugs are not commercially available worldwide. A similar drug, Endo TAG-1, is currently undergoing clinical studies.

[0005] Gastric cancer is a malignant tumor of epithelial origin that originates in the stomach. According to the latest data from China in 2020, gastric cancer has the third highest incidence and mortality rate among various malignant tumors. Approximately 1.2 million new cases of gastric cancer occur worldwide each year, with China accounting for approximately 40% of these. The rate of early-stage gastric cancer in China is very low, at only about 20%, and most cases are already in an advanced stage by the time they are discovered, resulting in an overall five-year survival rate of less than 50%.

[0006] The incidence and mortality rates of colorectal cancer in China rank third and fifth, respectively, among all malignant tumors, with 376,000 new cases and 191,000 deaths. The incidence rate of colon cancer is much higher in urban areas than in rural areas, and has increased significantly. Most patients are already in the mid- to late-stage stages at the time of diagnosis, with the five-year survival rate for late-stage rectal cancer being less than 10%.

[0007] According to 2021 statistical data from the China National Cancer Center, pancreatic cancer ranks seventh in incidence of malignant tumors in men and 11th in women in China, and sixth in malignant tumor-related mortality.

[0008] Ovarian cancer is one of the common malignant tumors in women, but because it has no typical symptoms or signs, when it is discovered, it is usually in the mid- to late-stage, with a very short survival time. In 2020, there were 55,342 new cases of ovarian cancer in China, and 37,519 new deaths, ranking third in incidence and second in mortality among malignant tumors of the female reproductive system.

[0009] Cholangiocarcinoma (Choleduct Carcinoma) is a common malignant tumor of the biliary tract, accounting for approximately 15-20% of primary hepatobiliary cancers, mostly occurring in people over the age of 50, with a 5-year survival rate of less than 25%.

[0010] Prostate cancer is one of the most common malignant tumors of the male genitourinary system, ranking third in incidence after breast cancer and lung cancer, with 3.8% of deaths from malignant tumors throughout the body and the eighth highest mortality rate. In 2015, prostate cancer ranked sixth among male malignant tumors in China in incidence and tenth in mortality rate.

[0011] Lung cancer is the malignant tumor with the highest incidence rate in China over the past 30 years. In 2015, lung cancer caused 630,000 deaths in China, of which 433,000 were men and 197,000 were women, accounting for 27.0% of all malignant tumor deaths. The 5-year survival rate for lung cancer in Europe, China, and developing countries is estimated to be only 8.9%.

[0012] Primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of tumor-related death in China, posing a serious threat to the lives and health of the Chinese people. According to the National Cancer Institute's SEER database, the average five-year survival rate for HCC (hepatocellular carcinoma) patients in the United States is 19.6%, but the average five-year survival rate for late-stage metastatic disease is a low 2.5%.

[0013] "Systemic therapy" (also known as systemic therapy) refers to treatments administered orally, intramuscularly, or intravenously, including molecular targeted drug therapy, immunotherapy, chemotherapy, and traditional Chinese medicine. This includes, but is not limited to, oncology therapies recommended by the CSCO (Clinical Oncology Society). For example, XELOX therapy (also known as CAPEOX therapy, capecitabine plus oxaliplatin) is the first-line treatment for advanced gastric, colorectal, and pancreatic cancer. Research has shown that after first-line treatment with XELOX therapy, patients with colorectal cancer had a median PFS of 8.0 months and a median OS of 19.8 months. FOLFOX therapy (5-fluorouracil, calcium folinate, and oxaliplatin) is used for systemic chemotherapy of bile duct cancer. Platinum-based and fluorouracil-based chemotherapy is used for systemic chemotherapy of esophageal cancer. Carboplatin and gemcitabine are used for systemic chemotherapy of ovarian cancer. Sorafenib is used for systemic chemotherapy of hepatocellular carcinoma. PD-1 inhibitors are used for systemic treatment of lung cancer.

[0014] The liver is the most common site of metastasis for gastrointestinal tumors as they progress. Systemic chemotherapy is often ineffective against liver metastases. For patients with primary hepatocellular carcinoma (HCC), where surgical treatment is not possible due to the liver's unique anatomical structure, interventional therapies such as transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are often used as local treatments. Due to their remarkable effectiveness, these therapies are recommended in the CSCO guidelines, and the development of these technologies is relatively mature. The guidelines for gastric, colorectal, and pancreatic cancer from the National Health Commission of the People's Republic of China also recommend the use of interventional therapies, including HAIC, for liver metastases from these tumors.

[0015] Arterial infusion combines multiple effective chemotherapy drugs, uses catheter technology to identify the tumor's blood supply arteries, and injects the anticancer drugs directly into the tumor tissue or tumor bed, thereby achieving a "first-pass" effect for drug therapy, significantly increasing local drug concentrations in the tumor. After arterial infusion, the chemotherapy drugs also circulate throughout the body via the bloodstream, simultaneously providing a degree of systemic chemotherapy benefit. The effectiveness of hepatic arterial infusion chemotherapy has been proven in multiple clinical studies, and the 2022 CSCO guidelines for hepatocellular carcinoma (HCC) position HAIC as a back-line treatment for locally advanced hepatocellular carcinoma (HCC). Arterial infusion administration is expected to achieve efficacy in patients with liver metastases, improving their quality of life and prolonging their survival.

[0016] Prior art documents References Non-Patent Document 1: Principles of application of transcatheter arterial infusion of chemotherapy drugs - Consensus among experts on tumor intervention in China, Journal of Interventional Radiology, November 2017, Vol. 26, No. 11, J Intervent Radiol 2017, Vol. 26, No. 11 Non-patent document 2: Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil / folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer.J Clin Oncol.2008 Apr 20;26(12):2006-12. Non-patent document 3: S. Strieth, MEEichhorn, B. Sauer, etal. Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature. Int. J. Cancer, 110:117-124 (2004) Non-patent literature 4: Ma WW, Hidalgo M. The winning formulation: the development of paclitaxel in pancreatic cancer. Clin Cancer Res. 2013 Oct 15; 19(20): 5572-9. doi: 10.1158 / 1078-0432. CCR-13-1356. Epub 2013 Aug 5. PMID: 23918602. Non-patent document 5: Camacho LH, Kurzrock R, Cheung A, Barber DF, Gupta S, Madoff DC, Wallace MJ, Kim EE, Curley SA, Hortobagyi GN, Mavligit G. Pilot study of regional,hepatic intra-arterial paclitaxel in patients with breast carcinoma metastatic to the liver.Cancer.2007 Jun 1;109(11):2190-6. Summary of the Invention

[0017] The present invention provides the use of paclitaxel cationic liposomes in the manufacture of a medicament for treating advanced solid cancer.

[0018] The present invention further provides a use of paclitaxel cationic liposomes and a systemic therapeutic agent in the manufacture of a medicament for treating advanced solid cancer, preferably the systemic therapeutic agent is capecitabine and oxaliplatin, or cisplatin, or gemcitabine, or capecitabine.

[0019] The present invention further provides the use of paclitaxel cationic liposomes in the manufacture of a medicament for improving the efficacy of a systemic therapeutic agent for advanced solid cancer.

[0020] The present invention provides a method for treating terminal solid cancer, which comprises administering a therapeutically effective amount of paclitaxel cationic liposomes to a patient with terminal solid cancer.

[0021] The present invention provides a method for treating terminal solid cancer, comprising administering therapeutically effective amounts of paclitaxel cationic liposomes and a systemic therapeutic agent to a patient with terminal solid cancer, preferably administering therapeutically effective amounts of paclitaxel cationic liposomes, capecitabine, and oxaliplatin to a patient with terminal solid cancer, or preferably administering the paclitaxel cationic liposomes by arterial infusion.

[0022] The present invention provides a method for improving the effectiveness of a systemic therapeutic agent for advanced solid cancer, which comprises administering a systemic therapeutic agent to a patient and then further administering a therapeutically effective amount of paclitaxel cationic liposome, preferably wherein the systemic therapeutic agent is capecitabine and oxaliplatin, or cisplatin, or gemcitabine, or capecitabine.

[0023] In some embodiments, the late-stage solid cancer includes, but is not limited to, gastrointestinal tumors (gastric cancer, esophageal cancer, pancreatic cancer, colorectal cancer, bile duct cancer, liver cancer), lung cancer, gynecological tumors (ovarian cancer, endometrial cancer, cervical cancer), prostate cancer, bladder cancer, and liver metastasis.

[0024] In some embodiments, the advanced solid cancer comprises gastric cancer, pancreatic cancer, and colorectal cancer liver metastasis.

[0025] In some embodiments, the end-stage solid cancer comprises untreated liver metastasis, including, but not limited to, gastric cancer liver metastasis, colorectal cancer liver metastasis, and pancreatic cancer liver metastasis.

[0026] The above "systemic treatment" includes, but is not limited to, tumor therapies recommended by CSCO. For example, XELOX therapy (also known as CAPEOX therapy, capecitabine + oxaliplatin) is the first-line treatment for late-stage gastric cancer, colorectal cancer, and pancreatic cancer. FOLFOX therapy (5-fluorouracil, calcium folinate, oxaliplatin) is used for systemic chemotherapy of bile duct cancer. Platinum-based and fluorouracil-based drugs are used for systemic chemotherapy of esophageal cancer. Carboplatin and gemcitabine are used for systemic chemotherapy of ovarian cancer. Sorafenib is used for systemic chemotherapy of hepatocellular carcinoma. PD-1 inhibitors are used for systemic treatment of lung cancer. The present invention further provides a method for improving the efficacy of a combination of capecitabine and oxaliplatin for the treatment of terminal solid cancers such as terminal gastric cancer, colorectal cancer, and pancreatic cancer, which comprises administering capecitabine and oxaliplatin to a patient and then co-administering a therapeutically effective amount of paclitaxel cationic liposomes.

[0027] The present invention further provides a method for improving the efficacy of a platinum-based or fluorouracil-based drug against esophageal cancer, which comprises administering a platinum-based or fluorouracil-based drug to a patient and then co-administering a therapeutically effective amount of paclitaxel cationic liposomes.

[0028] The present invention further provides a method for improving the efficacy of carboplatin or gemcitabine against ovarian cancer, which comprises administering carboplatin or gemcitabine to a patient and then co-administering a therapeutically effective amount of paclitaxel cationic liposomes.

[0029] The present invention further provides a method for improving the efficacy of sorafenib against hepatocellular carcinoma, which comprises administering sorafenib to a patient and then co-administering a therapeutically effective amount of paclitaxel cationic liposomes.

[0030] The present invention further provides a method for improving the efficacy of a PD-1 inhibitor against lung cancer, which comprises administering a PD-1 inhibitor to a patient and then co-administering a therapeutically effective amount of paclitaxel cationic liposomes.

[0031] Preferably, the paclitaxel cationic liposome according to the present invention is in the form of an injectable powder or a liquid injection. When the paclitaxel cationic liposome is in the form of a liquid injection, it contains 0.05 to 1 mg / ml, preferably 0.2 to 0.3 mg / ml, and more preferably 0.25 mg / ml of the active ingredient, calculated as paclitaxel.

[0032] Preferably, the therapeutically effective amount of the paclitaxel cationic liposome is 5 to 100 mg / m in terms of paclitaxel. 2 and preferably 5 to 80 mg / m 2 , and more preferably 11 to 55 mg / m 2 , or more preferably 24 to 70 mg / m 2 or any value within the range. Specifically, for example, 11 mg / m 2 , 22 mg / m 2 , 24 mg / m 2 , 33 mg / m 2 , 36 mg / m 2 , 44 mg / m 2 , 48 mg / m 2 , 55 mg / m 2 , 60 mg / m 2 , 70 mg / m 2 Preferably, the paclitaxel cationic liposome is administered by intra-arterial infusion, and the administration cycle is preferably once every three weeks.

[0033] In some embodiments, the paclitaxel cationic liposomes of the present invention comprise paclitaxel, dioleoylphosphatidylcholine (DOPC), (2,3-dioleoyloxypropyl)trimethylammonium chloride (DOTAP), and trehalose.

[0034] Preferably, for the paclitaxel cationic liposome, each preparation (or preparation unit) contains 5 to 10 mg of paclitaxel, 72 to 144 mg of DOPC, 68 to 136 mg of DOTAP, and 1500 to 2500 mg of trehalose.

[0035] Most preferably, each formulation (or formulation unit) contains 10 mg paclitaxel, 144 mg DOPC, 136 mg DOTAP, and 2500 mg trehalose, or each formulation (or formulation unit) contains 5 mg paclitaxel, 72 mg DOPC, 68 mg DOTAP, and 2000 mg trehalose, or each formulation (or formulation unit) contains 5 mg paclitaxel, 72 mg DOPC, 68 mg DOTAP, and 1500 mg trehalose.

[0036] The paclitaxel cationic liposomes of the present invention can be prepared by a conventional method in the art, and may be paclitaxel cationic liposomes prepared by any method disclosed in the prior art, for example, by using the formulation and method disclosed in US Pat. No. 7,794,747B.

[0037] All doses of the paclitaxel cationic liposomes according to the present invention are calculated in terms of paclitaxel. [Effects of the Invention]

[0038] The animal experiments of the present invention have demonstrated that the combination of paclitaxel cationic liposomes with other drugs or therapeutic means, such as cisplatin, gemcitabine, or capecitabine, can significantly improve the antitumor effect, and the effect is significantly better than that of the same dose of paclitaxel injection solution Taxol.

[0039] The combined use of arterial infusion therapy of paclitaxel cationic liposomes and XELOX therapy in patients with gastric cancer, pancreatic cancer, and colorectal cancer liver metastases improves the efficacy of XELOX therapy in patients with gastric cancer, pancreatic cancer, and colorectal cancer liver metastases, increases the disease remission rate, particularly the complete remission rate (CR rate) and partial remission rate (PR rate), and inhibits disease progression, while being safe, well-tolerated, and with few toxic side effects.

[0040] By administering paclitaxel cationic liposomes to patients with advanced solid cancer, or by co-administering paclitaxel cationic liposomes with systemic therapeutic agents, the efficacy of systemic therapeutic agents for tumor patients can be improved, the disease remission rate can be increased, and the progression of disease can be inhibited, while the administration is safe, well-tolerated, and has few toxic side effects. [Brief explanation of the drawings]

[0041] [Figure 1] 1 shows the drug-related AE grade distribution for the treatment of Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0042] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the invention.

[0043] [Example 1] Preparation of paclitaxel cationic liposomes The formulation of paclitaxel cationic liposomes is as follows: [Table 1]

[0044] The manufacturing method was as follows. (1) Predetermined amounts of paclitaxel, DOPC, and DOTAP were weighed and dissolved in absolute ethanol to obtain an organic phase. (2) Trehalose was dissolved in water for injection to obtain a 10 to 12.5% ​​trehalose solution as the aqueous phase. (3) The oil phase and the water phase were mixed in a certain ratio to form liposomes. (4) The liposomes obtained in step “3” were sized to obtain liposomes with a more uniform particle size. (5) The liposomes obtained in step “4” were dialyzed, and the trehalose solution obtained in step “2” was used as the dialysate. (6) The liposome solution obtained in step “5” was freeze-dried or spray-dried to obtain a solid powder.

[0045] Before use, the solid powder was redissolved to obtain a paclitaxel cationic liposome injection so that the osmotic pressure of the resulting injection was equal to that of plasma. The "paclitaxel cationic liposome injection" used in the following examples was all obtained by redissolving the product of Example 1, and Formulations 1-1, 1-2, and 1-3 had substantially the same physicochemical properties and pharmacological and clinical effects.

[0046] Examples 2 to 4 were obtained by remelting the product 1-2 of Example 1, and are simply referred to as "A1." Examples 5 and 6 were obtained by remelting the product 1-1 of Example 1, and are simply referred to as "A2."

[0047] [Example 2] Inhibitory effect of injectable cationic liposome paclitaxel and cisplatin (DDP) in combination on RM-1 mouse prostate cancer tumor transplants Test animals: female C57 / BL6 mice (provided by Beijing Vital River Laboratory Animal Technology Co.).

[0048] Test method: Mouse prostate RM-1 cells were subcutaneously inoculated into female C57 / BL6 mice, and on the sixth day after inoculation, the average tumor volume was 140 mm 3When the DPP level reached 100%, the animals were divided into groups (day 0). Administration was performed on days 0, 2, 4, 6, 8, and 10 (all intravenous administration except for intraperitoneal administration of DDP) for a total of six doses, and the study was terminated on day 15. In the A1 high-dose group, the first three doses were administered at 12 mg / kg, and the last three doses were administered at 6 mg / kg, for a cumulative dose of 54 mg / kg. In the A1 low-dose group, all six doses were administered at 6 mg / kg, for a cumulative dose of 36 mg / kg. In the DPP group, all six doses were administered at 1 mg / kg, for a cumulative dose of 6 mg / kg. The vehicle control group received 5% glucose injection (equivalent volume to the A1 high-dose group). In the A1+DDP-1 group, A1 was administered six times at a dose of 6 mg / kg for a cumulative dose of 36 mg / kg; DPP was administered six times at a dose of 1 mg / kg for a cumulative dose of 6 mg / kg; in the A1+DDP-2 group, A1 was administered for the first three times at a dose of 12 mg / kg and for the last three times at a dose of 6 mg / kg for a cumulative dose of 54 mg / kg; DPP was administered six times at a dose of 1 mg / kg for a cumulative dose of 6 mg / kg. During the study, the body weight and tumor volume of the animals were measured three times a week to calculate tumor volume (TV), relative tumor volume (RTV), and relative tumor volume growth rate (T / C). The formula for this calculation is as follows: Tumor volume (TV) = 1 / 2 × a × b 2 (In the formula, a and b represent the long and short diameters of the tumor, respectively.) RTV=TV t / TV0 (where TV0 is the tumor volume measured at the time of group administration (i.e., d0), and V t is the tumor volume at each measurement.) T / C (%) = (TRTV / CRTV) × 100% (TRTV: treatment group RTV, CRTV: solvent control group RTV).

[0049] Preparation method of test drugs: A1: First, add water for injection and dissolve, then dilute with glucose sodium chloride injection to the desired concentration. DDP powder was dissolved in 5% glucose injection and sonicated to the desired concentration.

[0050] Test results: Compared to the vehicle control group, all treatment groups significantly inhibited the growth of mouse prostate cancer RM-1 tumors (P<0.05). The groups administered high and low doses of A1 in combination with DDP had significantly stronger tumor inhibitory effects than the group administered DDP alone (P<0.01). Detailed results are shown in Table 1.

[0051] [Table 2]

[0052] remarks: * indicates p<0.05, and ** indicates p<0.01, and these were results compared with the vehicle group. # indicates p<0.05, ## indicates p<0.01, and the results were compared with the same dose of A1. ★ indicates p<0.05, ★★ indicates p<0.01, and the results were compared with the same dose of DDP.

[0053] [Example 3] Inhibitory effect of injectable paclitaxel cationic liposomes on human pancreatic cancer CFPAC-1 tumors transplanted into mice Test animals: female Nu / Nu nude mice (provided by Beijing Vital River Laboratory Animal Technology Co.).

[0054] Test method: Female Nu / Nu nude mice were subcutaneously inoculated with human pancreatic cancer CFPAC-1 cells. On the fifth day, the average tumor volume was 228 mm 3At day 0, the mice were divided into seven groups: a vehicle control group (5% glucose injection), an A1 6 mg / kg group, a combination of A1 3 mg / kg or 6 mg / kg with injectable gemcitabine (GEM) 20 mg / kg groups, a paclitaxel injection (Taxol) 6 mg / kg group, a combination of Taxol 6 mg / kg and GEM 20 mg / kg, and a GEM 20 mg / kg group. Each group consisted of 10 mice. The mice were administered six times on days 0, 3, 6, 9, 13, and 16 (all intravenous administrations except for GEM, which was administered intraperitoneally five times (the first five time points)). Observation continued for 11 days after the final administration (i.e., day 27) before the study was terminated. During the test, the body weight and tumor volume of the animals were measured twice a week to calculate the tumor volume (TV), and at the end of the test, the tumor weight was measured to calculate the tumor weight inhibition rate. The formula for this calculation is as follows: Tumor volume (TV) = 1 / 2 × a × b 2 (In the formula, a and b represent the long and short diameters of the tumor, respectively.) Tumor weight inhibition rate (%) = (1 - tumor weight in treatment group / tumor weight in solvent control group) x 100%.

[0055] Preparation method of test drugs: A1 was prepared in the same manner as in Example 2. Gemcitabine for injection was prepared to the desired concentration using physiological saline. Paclitaxel injection (Taxol) was prepared to the desired concentration using physiological saline.

[0056] Test results: Compared to the vehicle control group, administration of 6 mg / kg of A1 alone significantly inhibited the growth of human pancreatic cancer CFPAC-1 tumors (P<0.01), and the combination of A1 with gemcitabine had a stronger tumor-inhibiting effect than administration of A1 or gemcitabine alone (P<0.01). Compared to paclitaxel injection (Taxol) under the same administration conditions, administration of 6 mg / kg of A1 alone or in combination with gemcitabine had a significantly stronger tumor-inhibiting effect (P<0.01). Detailed results are shown in Table 2.

[0057] [Table 3]

[0058] remarks: * indicates p<0.05, and ** indicates p<0.01, and these were results compared with the vehicle group. △ indicates p<0.05, compared with the same dose of Taxol. ★ indicates p<0.05, and ★★ indicates p<0.01, compared with GEM. ## indicates p<0.01, and is the result of comparing A1+GEM with the same dose of A1.

[0059] [Example 4] Inhibitory effect of injectable paclitaxel cationic liposomes on human triple-negative breast cancer MDA-MB-231 tumors transplanted into mice Test animals: female NOD / SCID mice (provided by Beijing Vital River Laboratory Animal Technology Co.).

[0060] Test method: Female NOD / SCID mice were subcutaneously inoculated with human triple-negative breast cancer MDA-MB-231 cells. On the 7th day, the average tumor volume was 120-130 mm. 3 On day 0, the animals were divided into seven groups: the vehicle control group (5% glucose injection), the Al 6 mg / kg group, the Al 3 mg / kg and 6 mg / kg combination groups with capecitabine (CAP) 400 mg / kg, the paclitaxel injection (Taxol) 6 mg / kg group, the Taxol 6 mg / kg combination group with capecitabine (CAP) 400 mg / kg, and the cap 400 mg / kg group. Capecitabine (CAP) was administered intragastrically twice weekly, while the other drugs were administered intravenously twice weekly for a total of seven doses (d0, d3, d7, d10, d14, d17, and d21). The study was terminated on day 28. Animal body weights and tumor volumes were measured twice weekly to calculate tumor volume (TV). Tumor weights were measured at the end of the study to calculate tumor weight inhibition rates. The formula for this calculation is as follows: Tumor volume (TV) = 1 / 2 × a × b 2 (In the formula, a and b represent the long and short diameters of the tumor, respectively.) Tumor weight inhibition rate (%) = (1 - tumor weight in treatment group / tumor weight in solvent control group) x 100%.

[0061] Preparation method of test drugs: CAP was diluted to a desired concentration with water for injection, and the remaining drugs were the same as in Example 3.

[0062] Test results: Compared with the vehicle control group, A1 6 mg / kg alone significantly inhibited the growth of human triple-negative breast cancer MDA-MB-231 tumors (P<0.05), and the combination of A1 and capecitabine had a stronger tumor-inhibiting effect than A1 or capecitabine alone (P<0.05). Compared with paclitaxel injection (Taxol) under the same administration conditions, A1 6 mg / kg alone or in combination with capecitabine had a significantly stronger tumor-inhibiting effect (P<0.05). Detailed results are shown in Table 3.

[0063] [Table 4]

[0064] remarks: * indicates p<0.05, and ** indicates p<0.01, and these were results compared with the vehicle group. △ indicates p<0.05, △△ indicates p<0.01, and is a result compared to Taxol. ★ indicates p<0.05, and ★★ indicates p<0.01, and is a result compared to CAP. # indicates p<0.05, ## indicates p<0.01, and the results were compared between A1+CAP and the same dose of A1.

[0065] [Example 5] Clinical study of first-line therapy for gastric cancer, pancreatic cancer, and colorectal cancer liver metastasis by arterial infusion of paclitaxel cationic liposome injection This study was a single-arm, open, single-center investigator-initiated clinical study (IIT) that enrolled patients with untreated liver metastases, including but not limited to, gastric cancer, colorectal cancer, and pancreatic cancer, with the primary site confirmed by histopathology or cytology, and administered arterial infusion of different doses of paclitaxel cationic liposome injection and fixed-dose XELOX therapy. The objectives of the study were to investigate the safety and tolerability of the combination therapy, determine the optimal administration dose of paclitaxel cationic liposome injection in the combination therapy, evaluate its efficacy, and observe its pharmacokinetic properties.

[0066] I. Study Design The study was divided into a dose-escalation phase and a dose-expansion phase.

[0067] 1. Dose Escalation Phase (1) Study design The study included a screening section, a treatment section and an end-of-study examination. After signing informed consent, eligible subjects who completed all baseline examinations in the screening section entered the treatment section. Eligible subjects received paclitaxel cationic liposome injection in combination with XELOX therapy. The dose of paclitaxel cationic liposome injection was gradually increased from the low dose group to the high dose group. Subjects received the same dose as they were receiving or planning to receive at the time of study entry. The drug regimen was once every 3 weeks. The first cycle of the treatment section was a dose-limiting toxicity (DLT) observation period. Subjects who completed the 3-week treatment and observation period could continue receiving the next cycle until recurrence / progression, death, a request by the subject or their legal representative to withdraw from the study, application of other treatment options, or termination of the entire study (whichever occurred first). A total of 6 to 8 cycles of treatment was anticipated. During the treatment period, efficacy assessments were conducted every 2 cycles (6 weeks). All subjects were required to have PK (pharmacokinetic) blood samples taken at different time points before and after dosing as per the protocol, and to undergo relevant tests to monitor safety and tolerability throughout the study. A post-study examination was conducted 30 days after the final dose.

[0068] (2) Dose-escalation regimen Paclitaxel cationic liposome: 11mg / m 2 was the initial dose (paclitaxel equivalent), and 11 mg / m 2 , 22 mg / m 2 , 33 mg / m 2 , 44 mg / m 2 , 55 mg / m 2 A total of five dose groups were designed. Subjects who experienced DLTs were managed by the investigators according to the clinical practice protocol and could be maintained at their original dose or progressed to the next treatment cycle at a reduced dose level. Dose escalation in the same subject was not permitted. XELOX therapy: i.e., oxaliplatin, 130 mg / m 2 , intravenous infusion, D1; capecitabine, 1000 mg / m 2, orally, D1-D14.

[0069] (3) Extending treatment after the DLT observation period Subjects experiencing DLT were managed by the investigator according to the clinical practice protocol and could be delayed for up to 2 weeks, maintained at the original dose, or progressed to the next treatment cycle at a reduced dose level. Dose escalation in the same subject was not permitted. If the maximum tolerated dose (MTD) of paclitaxel cationic liposome injection was explored, the MTD was selected as the recommended phase 2 dose (RP2D). If the maximum tolerated dose (MTD) of paclitaxel cationic liposome injection was not explored, the RP2D was determined through internal discussion among investigators based on the results of the DLT observation period in the dose escalation phase. The dose of the RP2D was selected and expanded in the dose expansion phase.

[0070] 2. Dose expansion phase Dose expansion was performed as needed based on safety, tolerability, and efficacy data obtained from dose escalation studies. Dose expansion was performed by selecting 1 to 3 tumor types, including, but not limited to, gastric cancer liver metastasis, colorectal cancer liver metastasis, pancreatic cancer liver metastasis, etc. The specific cohorts to be expanded were determined through internal discussions by the researchers after determining the expansion dose, and each cohort was expanded to 5 to 15 cases.

[0071] II. Test Subjects (1) Registered Standards Subjects who meet all of the following criteria can be enrolled in this study. 1. Ages 18-75 (inclusive), regardless of gender. 2. Subjects with untreated liver metastases, including but not limited to gastric cancer, colorectal cancer, and pancreatic cancer, with a histopathologically or cytologically confirmed primary site. 3. If liver metastasis was a single measurable target lesion, the diameter of the single target lesion had to be 2 cm or greater. If liver metastasis was two or more target lesions, at least two target lesions had to be 1 cm or greater in diameter. 4. ECOG physical condition score: 0 to 2 points. 5. Expected survival is greater than 3 months.

[0072] III. Effectiveness evaluation index The patients were evaluated by CT / MRI according to RECIST1.1 / mRECIST standard.

[0073] 1. Primary efficacy endpoint Overall response rate (ORR) was defined as the proportion of subjects in the study who had a best overall response of CR or PR as assessed by the investigator according to RECIST v1.1 / mRECIST. The disease control rate (DCR) was defined as the proportion of subjects who achieved a best response of CR, PR, and stable disease (SD) (i.e., CR + PR + SD) as assessed according to RECIST 1.1 / mRECIST standards from the start of study drug administration until study discontinuation.

[0074] 2. Exploratory efficacy evaluation indicators Percent change in target lesions in the arterial blood supply area: In accordance with RECIST v1.1 / mRECIST, all measurable lesions in the blood supply area of ​​the arterial blood vessels were measured (if there was only one target lesion in the blood supply area of ​​the arterial blood vessel, it must have a diameter of 2 cm or more; if there were two or more target lesions, at least two target lesions must have a diameter of 1 cm or more). The sum of the diameters of the target lesions in the blood supply area was calculated as baseline data, and the percentage change in the sum of the diameters of the target lesions in the vascular supply area at each efficacy evaluation was calculated. If a lesion in the vascular supply area shrank and then expanded again, the percentage change from the sum of the smallest diameter of the target lesions in the vascular supply area was calculated.

[0075] 3.Safety indicators AEs (Adverse Events) and SAEs (Serious Adverse Events / Reactions) were used as safety endpoints.

[0076] IV.Research results The combination of arterial infusion of paclitaxel cationic liposomes with systemic treatment (e.g., XELOX therapy) has shown favorable effects in the treatment of liver metastases from late-stage solid cancers (e.g., gastric cancer, pancreatic cancer, and colorectal cancer), improving therapeutic efficacy and reducing the incidence of adverse events, and is expected to be clinically applicable.

[0077] In this example, five patients were enrolled: one with gastric cancer and four with colorectal cancer, none of whom had previously received systemic treatment for metastatic disease. One patient with colon cancer and liver metastasis was undergoing pre-screening for necessary tests (the last patient in Table 4, subject number not yet determined). Details are shown in Table 4.

[0078] [Table 5]

[0079] [Table 6]

[0080] As shown in Table 5, the efficacy could be evaluated in a cumulative total of 4 cases, with the best efficacy being SD in 2 cases and PR in 2 cases (01003 and 01004 achieved CR according to mRECIST), i.e., ORR was 50% and DCR was 100%.

[0081] Safety and tolerability: 11–33 mg / m 2 No DLTs occurred in any dose group. Safety and tolerability were favorable, with no unusual safety signals identified. All currently reported drug-related AEs were grade 1-2 (see Figure 1, where the ordinate indicates the number of occurrences) and resolved with symptomatic treatment. Related AEs (including those that may be unrelated) included decreased lymphocyte count, increased calcitoninogen, fever, nausea, increased white blood cell count, and decreased lymphocyte count.

[0082] Note: Adverse events in clinical trials are classified into five grades. Grade 1: Mild; no or mild symptoms; clinical or laboratory findings only; no treatment required. Grade 2: Moderate; minimal / local / non-invasive treatment required; limitation of activities of daily living other than self-care appropriate for age. Grade 3: Severe or medically significant, but not immediately life-threatening; requiring hospitalization or prolonged hospitalization; incapacitating; limiting self-care activities of daily living. Grade 4: Life-threatening; emergency treatment required. Grade 5: Death due to AE.

[0083] [Example 6] Clinical study of treatment of advanced solid cancer by arterial infusion of paclitaxel cationic liposome injection This study was a single-arm, open, multicenter phase 1 study in which patients with terminal solid cancer confirmed by histopathology or cytology were enrolled and administered different doses of paclitaxel cationic liposome injection via arterial infusion. The objectives were to investigate the safety and tolerability of paclitaxel cationic liposome monotherapy via arterial infusion, as well as to evaluate its efficacy and observe its pharmacokinetic properties.

[0084] I. Study Design The study was divided into a dose-escalation phase and a dose-expansion phase.

[0085] 1. Dose Escalation Phase (1) Study design The dose escalation phase included a screening section (within 28 days), a treatment section, and a PFS follow-up section. After subjects signed informed consent in the screening section, those who completed all baseline examinations entered the treatment section. The dose of injectable paclitaxel cationic liposome was gradually escalated from the low dose group to the high dose group, with each cycle consisting of 3 weeks (21 days). DLTs were observed during the first treatment cycle. Patients underwent protocol-specific PK blood samples at different time points before and after treatment, and completed relevant protocol-specified tests to monitor safety, tolerability, and efficacy during treatment. Only one treatment dose and administration schedule was applied to each subject throughout the study period. Six to eight treatment cycles were expected. Efficacy assessments were conducted every two cycles (6 weeks) during the treatment period.

[0086] (2) Dose-escalation regimen Paclitaxel cationic liposome: 24 mg / m 2 was the initial dose (paclitaxel equivalent), and 24 mg / m 2 , 36 mg / m 2 , 48 mg / m 2 , 60 mg / m 2 , 70 mg / m 2 A total of five dose groups were designed. Subjects who experienced DLTs were managed by the investigators according to the clinical practice protocol and could be maintained at their original dose or progressed to the next treatment cycle at a reduced dose level. Dose escalation in the same subject was not permitted.

[0087] (3) Extending treatment after the DLT observation period Subjects experiencing DLT were managed by the investigator according to the clinical practice protocol and could be delayed for up to 2 weeks, maintained at the original dose, or progressed to the next treatment cycle at a reduced dose level. Dose escalation in the same subject was not permitted. When the maximum tolerated dose (MTD) of paclitaxel cationic liposome injection was explored, the MTD was selected as the recommended phase 2 dose (RP2D). When the maximum tolerated dose (MTD) of paclitaxel cationic liposome injection was not explored, the RP2D was determined through internal discussion based on the results of the DLT observation period in the dose escalation phase. The RP2D dose was selected and expanded in the dose expansion phase.

[0088] 2. Dose expansion phase Dose expansion was performed as necessary based on safety, tolerability, and efficacy data obtained from dose escalation studies. Dose expansion was performed on one to three selected tumor types, including, but not limited to, gastric cancer liver metastasis, colorectal cancer liver metastasis, and pancreatic cancer liver metastasis. The specific cohorts to be expanded were determined through internal discussions by the investigators after the expansion dose was determined, and each cohort was expanded to 5 to 15 patients.

[0089] II. Test population (1) Registered Standards Subjects who meet all of the following criteria can be enrolled in this study. 1. Ages 18-75 (inclusive), regardless of gender. 2. Subjects with histopathologically or cytologically confirmed advanced solid cancer, including but not limited to the following tumor types: Gastrointestinal tumors (including but not limited to gastric cancer, liver cancer, bile duct cancer, pancreatic cancer, colorectal cancer, etc.); gynecological tumors (including but not limited to ovarian cancer, endometrial cancer, etc.); lung cancer; Liver metastases. 3. Target lesion requirements: In the blood supply area of ​​the arterial infusion vessel, there was required to be only one target lesion, with the diameter of the single target lesion being 2 cm or more. In the blood supply area, there were required to be two or more target lesions, with at least two target lesions being 1 cm or more in diameter. 4. ECOG physical condition score: 0 to 2 points. 5. Expected survival is greater than 3 months.

[0090] III. Evaluation Metrics The patients were evaluated by CT / MRI according to RECIST 1.1 standard.

[0091] Planned number of patients enrolled in this study The number of cases enrolled in the dose-escalation studies ranged from approximately 18 to 24. The number of patients enrolled in the dose-expansion study was determined through internal discussion among the investigators.

[0092] Efficacy evaluation Primary efficacy endpoint Overall response rate (ORR) was defined as the proportion of subjects in the study who had a best overall response of CR or PR as assessed by the investigator according to RECIST v1.1. The disease control rate (DCR) was defined as the proportion of subjects who achieved a best response of CR, PR, and stable disease (SD) (i.e., CR + PR + SD) as assessed according to RECIST 1.1 standards from the start of study drug administration to study discontinuation. Progression-free survival (PFS) was defined as the time from the start of study drug administration to the date of first documented disease progression (PD) or death (whichever occurred first). Duration of remission (DoR) was defined as the time from when the tumor was first assessed as CR or PR to when it was first assessed as PD or death from any cause.

[0093] Safety evaluation index AEs (Adverse Events) and SAEs (Serious Adverse Events / Reactions) were used as safety endpoints.

[0094] IV.Research results Arterial infusion of paclitaxel cationic liposomes has shown good efficacy in the treatment of late-stage solid cancers such as gastric cancer, pancreatic cancer, and liver metastasis of colorectal cancer, improving therapeutic efficacy and reducing the incidence of adverse events, and is expected to be applied clinically.

[0095] [Example 7] Clinical study of the safety, tolerability, and pharmacokinetic properties of injectable paclitaxel cationic liposomes in the treatment of patients with terminal solid cancer via transcatheter arterial infusion

[0096] I. Primary and Secondary Objectives and Endpoints

[0097] 1.Main purpose (1) To evaluate the safety and tolerability of transcatheter arterial infusion of injectable paclitaxel cationic liposomes in the treatment of advanced solid cancer. (2) To determine the maximum tolerated dose (MTD) and / or recommended dose in dose escalation phase (RDE) of injectable cationic liposome paclitaxel via transcatheter arterial infusion in the treatment of advanced solid cancers.

[0098] Primary endpoint (1) Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) (based on NCI CTCAE5.0). (2) Incidence of dose-limiting toxicities (DLTs).

[0099] 2. Secondary Objectives (1) To evaluate the pharmacokinetic (PK) characteristics of transcatheter arterial infusion of injectable paclitaxel cationic liposomes in the treatment of advanced solid cancer. (2) To evaluate the preliminary antitumor activity of transcatheter arterial infusion of injectable paclitaxel cationic liposomes in the treatment of advanced solid cancer.

[0100] Secondary endpoints (1) Pharmacokinetic parameters: PK parameters included, but were not limited to, AUC0-t, AUC0-∞, Cmax, Kel, Tmax, Vd, t1 / 2, and CL. (2) Efficacy endpoints: overall remission rate (ORR), disease control rate (DCR), duration of remission (DOR), progression-free survival (PFS), and overall survival (OS).

[0101] II. Overall Study Design The study included two phases: Phase Ia (dose escalation and expansion phase) and Phase Ib (cohort expansion phase).

[0102] The dose escalation phase included a screening section (days 0-28), a treatment section (DLT observation period, subsequent treatment period), and a follow-up section (safety follow-up, survival follow-up). The first cycle (21 days) in which participants received the study drug was the DLT observation period. If participants did not experience DLTs at the end of the DLT observation period, they entered the subsequent treatment period. The dose expansion and cohort expansion phases included a screening section (days 0-28), a treatment section, and a follow-up section (safety follow-up, survival follow-up). Paclitaxel cationic liposome was administered by arterial infusion on day 1 of each cycle, with one treatment cycle occurring every 3 weeks. Participants who met the screening criteria received four to six cycles of study treatment. Treatment could be terminated early if any of the following conditions occurred during treatment: disease progression, unacceptable toxicity, initiation of a new antitumor therapy, withdrawal of informed consent, loss to follow-up, or death (whichever occurred first). If a participant experiences a first disease progression, and if the investigator assesses that the participant would still benefit from continuing treatment and the participant wishes, they may continue with one to two cycles of study treatment until a second disease progression is confirmed.

[0103] During the study, participants were assessed for efficacy every 6 weeks ± 7 days after the first dose. Participants who discontinued treatment due to non-progression were required to continue tumor assessments until disease progression or initiation of new anti-tumor treatment, participant withdrawal of informed consent, loss to follow-up, or death (whichever occurred first).

[0104] 1. Dose Escalation Phase The starting dose of injectable paclitaxel cationic liposome is tentatively set at 22 mg / m 2The dose may be adjusted appropriately based on the data obtained from the preliminary study of arterial infusion of this product after discussion with the SMC (Scientific Review Committee established for this study). Currently, the maximum dose is set at 66 mg / m. 2 If this dose is tolerated safely, the investigator can discuss with the sponsor whether to attempt a higher dose. If participants in the low-dose group do not experience a DLT during the DLT observation period and the safety and tolerability are good, they can subsequently receive a higher dose of the study drug, subject to discussion with the SMC. The specific dose groups for the dose escalation phase were determined based on the modified Fibonacci method and are shown in the table below.

[0105] [Table 7]

[0106] In addition to the escalation of doses other than the starting dose, whether to proceed to the next dose group and whether the dose or administration regimen of other dose groups needs to be adjusted can be decided through discussion between the investigator and sponsor based on the obtained drug safety and PK data, etc.

[0107] The first dose group in this study adopted an accelerated dose-escalation protocol, while subsequent dose groups followed a "3 + 3" dose-escalation protocol. DLTs of paclitaxel cationic liposome were observed during the first cycle (within 21 days). If a participant in the accelerated dose-escalation group experienced moderate toxicity (drug-related AEs of the following grades requiring action: one other grade 3 AE not included in the DLT, or two grade 2 or higher AEs), this and all subsequent dose groups followed the "3 + 3" principle.

[0108] The "3+3" dose escalation rule Three patients were enrolled in each dose group, and after completing DLT observation, the following rules were used to determine whether to proceed to the next dose group study. (1) The first dose group (or specific dose group) enrolled three participants and completed DLT observation. (2) If none of the three participants in a dose group developed a DLT, they were escalated to the next dose group. (3) If two or more of three participants in a dose group developed DLT, they were tapered to the previous dose group. (4) If one of three participants in a dose group developed a DLT, three more participants were added to this dose group; if one-sixth of participants developed a DLT, the group was escalated to the next dose group; if two-sixths or more of participants developed a DLT, the group was escalated to the previous dose group. (5) When tapering to a previous dose group, if there were only three participants in this dose group, three more participants were added. If there were already six participants in this dose group, the dose escalation study was terminated and this dose became the MTD.

[0109] Maximum tolerated dose (MTD) The MTD was defined as the highest dose at which DLT occurred in 33% or less of participants. Typically, if two or more of three participants at a dose level experienced a DLT, the dose immediately preceding this dose was defined as the MTD. If one of three participants at a dose level experienced a DLT, and after three more participants at the same dose experienced a DLT, the dose immediately preceding this dose was defined as the MTD. If necessary, a new dose can be selected and explored between the previous dose and the "unacceptable dose."

[0110] 2. Dose expansion phase Based on the PK, safety, tolerability, and efficacy data obtained from the dose-escalation study, 1 to 3 recommended dose groups may be selected and expanded to 15 to 30 patients per group (including participants in the same dose group during the dose-escalation phase).

[0111] 3. Cohort Expansion Phase After determining the recommended dose (RDE) for the dose expansion phase, the cohort was expanded by selecting 1 to 3 tumor types, including but not limited to liver cancer, liver metastasis, pancreatic cancer, lung cancer, etc. The specific indication population and sample size could be determined by the SMC after thorough discussion.

[0112] III. Dose-Limiting Toxicity (DLT) Dose-limiting toxicity was defined as an adverse event (according to NCI CTCAE 5.0) occurring during the first dosing cycle (21 days) in the dose-escalation phase, related to Paclitaxel Cationic Liposome for Injection (including definitely related, likely related, or possibly related), and meeting one of the following severity levels: Except for concomitant drug and treatment prohibited by the protocol, the study should follow clinical practice protocols, and sufficient and appropriate symptomatic supportive care was provided in a timely manner. [Table 8]

[0113] If any of the following conditions were met during the DLT observation period, the DLT observation period was considered incomplete and case replenishment was required. - If the administered dose falls below 75% of the planned total dose due to reasons other than DLT. - Treatment termination due to non-DLT reasons

[0114] IV. Test Subjects Number of groups and participants Dose escalation phase: 15 to 30 cases. Dose expansion phase: 1 to 3 dose groups were selected and enrollment was expanded to 15 to 30 participants per group (including participants in the same dose group in the dose escalation phase). Cohort expansion phase: TBD (will be decided through discussion with the SMC based on data obtained during the dose escalation and expansion phases).

[0115] Registration Standards 1. Age 18 or older. 2. Subjects with histologically or cytologically diagnosed late-stage solid cancer suitable for arterial infusion chemotherapy, including but not limited to the following tumor types: Gastrointestinal tumors (including, but not limited to, gastric cancer, liver cancer, bile duct cancer, pancreatic cancer, colorectal cancer, etc.) Gynecological tumors (including but not limited to ovarian cancer, endometrial cancer, etc.) ·Non-small cell lung cancer Liver metastasis 3. At least one measurable lesion in the arterial infusion area according to RECIST 1.1. 4. The presence of a limited number of lesions outside the arterial infusion territory at baseline is acceptable if the primary life-threatening lesion is within the arterial infusion territory. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 6. Expected survival time is at least 3 months. 7. Laboratory tests meet the following criteria and organ function is adequate (no blood transfusion or hematopoietic stimulating factor therapy within 14 days): a. Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L b. Platelet count (PLT) ≧100×10 9 / L c. Hemoglobin (Hb) ≥ 90g / L d. Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), and TBIL ≤ 2 × ULN in patients with liver metastasis or hepatocellular carcinoma. e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 × ULN; in patients with liver metastasis or liver cancer, ALT, AST ≤ 5 × ULN. f. Creatinine clearance (Ccr) > 50 mL / min (based on the Cockcroft-Gault formula) g. Activated partial thromboplastin time (APTT) ≤ 1.5 x ULN, international normalized ratio (INR) ≤ 1.5 x ULN. 8. Eligible individuals (men and women) of childbearing age must agree to use reliable contraception (hormonal contraception, barrier methods, or abstinence) with their partner throughout the study and for at least 6 months after the final dose. Women of childbearing age must have a negative blood pregnancy test within 7 days prior to enrollment. 9. Have received a full explanation of this clinical trial and voluntarily sign the informed consent form.

[0116] Exclusion criteria 1. Have received anti-tumor therapy such as chemotherapy, radiation therapy, biological therapy, endocrine therapy, targeted therapy, or immunotherapy within 4 weeks prior to the first dose of the study drug, or within 4 weeks or 5 half-lives of the drug administered in another clinical trial, whichever is shorter. 2. Clinically confirmed symptomatic central nervous system or meningeal metastases, or other evidence of uncontrolled central nervous system or meningeal metastases in an individual who is deemed ineligible for enrollment by the investigator. 3. Adverse events from previous anti-tumor treatment have not resolved to CTCAE 5.0 grade 1 or less (excluding toxicities such as alopecia that the investigator determines do not pose a safety risk). 4. Concurrently participating in other clinical trials (excluding observational (non-interventional) clinical trials or the follow-up period of interventional trials). 5. Persons who have undergone major surgery or invasive interventional therapy within 28 days prior to the first dose. 6.Those who have used Chinese herbal medicines or herbal preparations made from Chinese herbal medicines (regardless of type of cancer) with anti-cancer activity approved by the National Medical Products Administration (NMPA) of China within 14 days prior to the first administration.

[0117] V. Research results Arterial infusion of paclitaxel cationic liposomes has shown good efficacy in the treatment of late-stage solid cancers such as gastric cancer, pancreatic cancer, and colorectal cancer liver metastasis, improving therapeutic efficacy and reducing the incidence of adverse events, and is expected to be clinically applicable.

[0118] The above is merely a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and all modifications and alternatives that can be easily conceived by a person skilled in the art within the scope of the present invention are intended to be included within the scope of the present invention. Therefore, the scope of the present invention is determined by the scope of the claims.

Claims

1. Use of paclitaxel cationic liposomes in the manufacture of a drug for treating advanced solid cancer.

2. 10. Use of paclitaxel cationic liposomes and a systemic therapeutic agent in the manufacture of a medicament for treating advanced solid cancer, wherein preferably said systemic therapeutic agent is capecitabine and oxaliplatin, or cisplatin, or gemcitabine, or capecitabine.

3. A method for treating terminal solid cancer, comprising administering a therapeutically effective amount of paclitaxel cationic liposomes to a patient with terminal solid cancer.

4. A method for treating terminal solid cancer, comprising administering therapeutically effective amounts of paclitaxel cationic liposomes and a systemic therapeutic agent to a patient with terminal solid cancer, preferably administering therapeutically effective amounts of paclitaxel cationic liposomes, capecitabine, and oxaliplatin to a patient with terminal solid cancer, or preferably administering the paclitaxel cationic liposomes by arterial infusion.

5. A method for improving the effectiveness of a systemic therapeutic agent against tumors, comprising administering a systemic therapeutic agent to a patient and then further administering a therapeutically effective amount of paclitaxel cationic liposomes, wherein the systemic therapeutic agent is preferably capecitabine and oxaliplatin, or cisplatin, or gemcitabine, or capecitabine.

6. A method for improving the effectiveness of a combination of capecitabine and oxaliplatin for terminal solid cancers, including terminal gastric cancer, colorectal cancer, and pancreatic cancer, which comprises administering capecitabine and oxaliplatin to a patient and then further administering a therapeutically effective amount of paclitaxel cationic liposomes in combination.

7. The use according to claim 1 or 2, or the method according to any one of claims 3 to 6, wherein the terminal solid cancer comprises gastrointestinal tumors including gastric cancer, esophageal cancer, pancreatic cancer, colorectal cancer, bile duct cancer, and liver cancer; lung cancer; gynecological tumors including ovarian cancer, endometrial cancer, and cervical cancer; prostate cancer; bladder cancer, and liver metastasis.

8. The terminal solid cancer includes gastric cancer, pancreatic cancer, and liver metastasis of colorectal cancer; Preferably, the end-stage solid cancer comprises untreated liver metastasis, including liver metastasis from gastric cancer, liver metastasis from colorectal cancer, and liver metastasis from pancreatic cancer.

9. The therapeutically effective amount of the paclitaxel cationic liposome is 5 to 100 mg / m2 in terms of paclitaxel. ２ , preferably 5 to 80 mg / m ２ , more preferably 11 to 55 mg / m ２ or more preferably 24 to 70 mg / m ２ or 11 mg / m ２ , 22 mg / m ２ , 24 mg / m ２ , 33 mg / m ２ , 36 mg / m ２ , 44 mg / m ２ , 48 mg / m ２ , 55 mg / m ２ , 60 mg / m ２ , 70 mg / m ２ and any value within the range including, preferably, the administration method of the paclitaxel cationic liposome is administration by arterial infusion, preferably, the administration cycle is once every three weeks, and the administration is performed for 6 to 8 cycles.

10. The use according to claim 1 or 2, or the method according to any one of claims 3 to 8, wherein the paclitaxel cationic liposome comprises paclitaxel, dioleoylphosphatidylcholine (DOPC), (2,3-dioleoyloxypropyl)trimethylammonium chloride (DOTAP) and trehalose, preferably each formulation of the paclitaxel cationic liposome comprises 5 to 10 mg of paclitaxel, 72 to 144 mg of dioleoylphosphatidylcholine, 68 to 136 mg of (2,3-dioleoyloxypropyl)trimethylammonium chloride and 1500 to 2500 mg of trehalose.

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