Application of paclitaxel cationic liposome in tumor treatment

Abstract

The invention provides an application of a paclitaxel cationic liposome in preparation of a medicine for treating advanced solid tumors, an application of the paclitaxel cationic liposome and a system treatment medicine in preparation of the medicine for treating the advanced solid tumors, and a method for treating the advanced solid tumors, a therapeutically effective amount of paclitaxel cationic liposome is administered to a patient with the advanced solid tumor, or a therapeutically effective amount of paclitaxel cationic liposome and a systemic therapeutic drug are administered to the patient with the advanced solid tumor.

Description

Application of paclitaxel cationic liposomes in treating tumors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefits of Chinese Patent Application No. 202310046953.0, filed on January 31, 2023, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention belongs to the field of anti-tumor treatment, and specifically relates to a paclitaxel cationic liposome arterial infusion combined with systemic treatment regimen and a paclitaxel cationic liposome single-drug arterial infusion regimen, and their use in preparing drugs for treating tumors, particularly advanced solid tumors, such as gastric cancer, pancreatic cancer, and colorectal cancer liver metastases. Background Art

[0004] Paclitaxel is a tricyclic diterpenoid compound first isolated and chemically structured by Wani et al. from the bark of Taxus brevifolia. Paclitaxel is an antimicrotubule drug that induces and promotes microtubule assembly, polymerizing and stabilizing microtubules. It interferes with microtubule rearrangement, leading to mitotic arrest and thus inhibiting tumor cell growth.

[0005] Cationic liposomes are a novel drug delivery method. Cationic paclitaxel drugs are not yet available globally. A similar drug, Endo TAG-1, is currently in clinical research.

[0006] Gastric cancer refers to a malignant epithelial tumor that originates in the stomach. According to the latest data from China in 2020, gastric cancer ranks third in both incidence and mortality among all malignant tumors. Globally, approximately 1.2 million new cases of gastric cancer occur annually, with China accounting for approximately 40% of these cases. The proportion of early-stage gastric cancer in my country is very low, at only approximately 20%. Most cases are already advanced by the time they are discovered, and the overall five-year survival rate is less than 50%.

[0007] Colorectal cancer morbidity and mortality rates in my country rank third and fifth among all malignant tumors, respectively, with 376,000 new cases and 191,000 deaths. The incidence rate in urban areas is much higher than in rural areas, and the incidence of colon cancer has increased significantly. Most patients are diagnosed in the advanced stages of the disease, and the five-year survival rate for advanced rectal cancer is less than 10%.

[0008] Statistics from the National Cancer Center of China in 2021 show that pancreatic cancer ranks 7th in the incidence of malignant tumors among men and 11th in women in my country, and accounts for 6th in malignant tumor-related mortality.

[0009] Ovarian cancer is a common malignant tumor in women. Due to the lack of typical symptoms and signs, once discovered, it is often in the middle or late stages, with a very short survival time. In 2020, there were 55,342 new cases of ovarian cancer and 37,519 new deaths in my country. Ovarian cancer ranks third in incidence and second in mortality among malignant tumors of the female reproductive system.

[0010] Cholangiocarcinoma is a common malignant tumor of the bile duct, accounting for about 15-20% of all primary hepatobiliary cancers. It mostly occurs in people over 50 years old, and the 5-year survival rate is less than 25%.

[0011] Prostate cancer is one of the most common malignant tumors of the male genitourinary system, with an incidence rate ranking third after breast cancer and lung cancer. Prostate cancer accounts for 3.8% of all malignant tumors in China, and its mortality rate ranks eighth. In 2015, prostate cancer incidence in my country ranked sixth among male malignant tumors, and its mortality rate ranked tenth.

[0012] Lung cancer is the malignant tumor with the fastest increasing incidence in my country over the past 30 years. In 2015, there were 630,000 deaths from lung cancer in China, including 433,000 males and 197,000 females, accounting for 27.0% of all deaths from malignant tumors. The five-year survival rate of lung cancer in Europe, China and developing countries is estimated to be only 8.9%.

[0013] Primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of cancer-related death in my country, posing a serious threat to the lives and health of the Chinese people. According to the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results database, the average five-year survival rate for HCC patients in the United States is 19.6%, but for advanced metastatic disease, the average five-year survival rate can be as low as 2.5%.

[0014] The so-called "systemic therapy", or systemic therapy, refers to a treatment method that is mainly administered orally, intramuscularly or intravenously, including molecular targeted drug therapy, immunotherapy, chemotherapy and traditional Chinese medicine treatment. Including but not limited to tumor treatment regimens recommended by CSCO, such as the XELOX regimen (also known as the CAPEOX regimen, capecitabine + oxaliplatin) is a first-line treatment for advanced gastric cancer, colorectal cancer, and pancreatic cancer. Research results show that after first-line treatment with the XELOX regimen, the median PFS of colorectal cancer patients was 8.0 months and the median OS was 19.8 months. The FOLFOX regimen (5-fluorouracil, folinic acid, oxaliplatin) can be used for systemic chemotherapy of bile duct cancer, platinum and fluorouracil can be used for systemic chemotherapy of esophageal cancer, carboplatin and gemcitabine can be used for systemic chemotherapy of ovarian cancer, sorafenib can be used for systemic chemotherapy of hepatocellular carcinoma, and PD-1 inhibitors can be used for systemic treatment of lung cancer.

[0015] In the advanced stage of digestive tract tumors, the most common site of metastasis is the liver. Systemic chemotherapy is often ineffective for liver metastases. Due to the special anatomy of the liver, for patients with primary hepatocellular carcinoma who cannot be treated surgically, local treatment often uses interventional methods such as transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC). The significant efficacy has been recommended by the CSCO guidelines, and the development of this technology is relatively mature. In the guidelines of the National Health Commission for gastric cancer, colorectal cancer, and pancreatic cancer, interventional treatment, including HAIC, is also recommended for liver metastasis of these tumors.

[0016] Arterial infusion can combine several effective chemotherapy drugs. Using catheter technology, it locates the tumor's blood supply artery and injects anticancer drugs directly into the tumor tissue or tumor bed, achieving a "first-pass effect" of drug treatment, significantly increasing local drug concentration in the tumor. At the same time, after arterial infusion, the chemotherapy drugs will also circulate throughout the body through the blood, thus also having a certain degree of systemic chemotherapy effect. Multiple clinical studies have demonstrated the effectiveness of hepatic arterial infusion chemotherapy. The 2022 CSCO liver cancer guidelines include HAIC as a second-line treatment for locally advanced hepatocellular carcinoma (HCC). Through arterial infusion, the administration method is expected to achieve therapeutic effects in patients with liver metastases, improve patients' quality of life, and prolong their survival.

[0017] List of cited documents

[0018] Non-patent literature 1: Principles of transcatheter arterial infusion of chemotherapy drugs - Consensus of Chinese tumor intervention experts. Journal of Interventional Radiology 2017, Vol. 26, No. 11, November 2017

[0019] Non-patent literature 2: Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén 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.

[0020] Non-patent document 3: S. Strieth, MEEichhorn, B. Sauer, et al. Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature. Int. J. Cancer, 110: 117-124 (2004)

[0021] 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.

[0022] Non-patent literature 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.

[0023] Summary of the Invention

[0024] The present invention provides use of paclitaxel cationic liposomes in preparing a medicine for treating advanced solid tumors.

[0025] The present invention also provides the use of paclitaxel cationic liposomes and systemic therapeutic drugs in preparing drugs for treating advanced solid tumors. Preferably, the systemic therapeutic drugs are capecitabine and oxaliplatin, or cisplatin, or gemcitabine, or capecitabine.

[0026] The present invention also provides use of paclitaxel cationic liposomes in preparing a drug for improving the efficacy of systemic therapeutic drugs on advanced solid tumors.

[0027] The present invention provides a method for treating advanced solid tumors, characterized by administering a therapeutically effective amount of paclitaxel cationic liposomes to patients with advanced solid tumors.

[0028] The present invention provides a method for treating advanced solid tumors, characterized by administering a therapeutically effective amount of paclitaxel cationic liposomes and a systemic therapeutic drug to a patient with advanced solid tumors. Preferably, a therapeutically effective amount of paclitaxel cationic liposomes, capecitabine and oxaliplatin are administered to the patient with advanced solid tumors. Alternatively, preferably, the paclitaxel cationic liposomes are administered by arterial infusion.

[0029] The present invention also provides a method for improving the efficacy of systemic therapeutic drugs for advanced solid tumors, characterized in that: on the basis of administering systemic therapeutic drugs to patients, a therapeutically effective amount of paclitaxel cationic liposomes is further administered. Preferably, the systemic therapeutic drugs are capecitabine and oxaliplatin, or cisplatin, or gemcitabine, or capecitabine.

[0030] In some embodiments, the aforementioned advanced solid tumors include but are not limited to digestive tract 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 metastases.

[0031] In some embodiments, the advanced solid tumors include gastric cancer, pancreatic cancer, and colorectal cancer liver metastases.

[0032] In some embodiments, the advanced solid tumor comprises untreated liver metastases, including but not limited to gastric cancer liver metastases, colorectal cancer liver metastases, and pancreatic cancer liver metastases.

[0033] The above-mentioned "systemic treatment" includes, but is not limited to, tumor treatment regimens recommended by CSCO, such as the XELOX regimen (also known as the CAPEOX regimen, capecitabine + oxaliplatin), which is a first-line treatment for advanced gastric cancer, colorectal cancer, and pancreatic cancer. The FOLFOX regimen (5-fluorouracil, folinic acid, oxaliplatin) can be used for systemic chemotherapy of bile duct cancer, platinum-based and fluorouracil-based drugs can be used for systemic chemotherapy of esophageal cancer, carboplatin and gemcitabine can be used for systemic chemotherapy of ovarian cancer, sorafenib can be used for systemic chemotherapy of hepatocellular carcinoma, and PD-1 inhibitors can be used for systemic treatment of lung cancer.

[0034] The present invention also provides a method for improving the efficacy of the combination of capecitabine and oxaliplatin in treating advanced solid tumors, such as advanced gastric cancer, colorectal cancer, and pancreatic cancer, characterized in that, on the basis of administering capecitabine and oxaliplatin to the patient, a therapeutically effective amount of paclitaxel cationic liposomes is further administered in combination.

[0035] The present invention also provides a method for improving the efficacy of platinum or fluorouracil drugs on esophageal cancer, characterized in that: on the basis of administering platinum or fluorouracil drugs to the patient, a therapeutically effective amount of paclitaxel cationic liposomes is further administered in combination.

[0036] The present invention also provides a method for improving the efficacy of carboplatin or gemcitabine on ovarian cancer, characterized in that: on the basis of administering carboplatin or gemcitabine to the patient, a therapeutically effective amount of paclitaxel cationic liposomes is further administered in combination.

[0037] The present invention also provides a method for improving the efficacy of sorafenib on hepatocellular carcinoma, characterized in that: on the basis of administering sorafenib to the patient, a therapeutically effective amount of paclitaxel cationic liposomes is further administered in combination.

[0038] The present invention also provides a method for improving the efficacy of PD-1 inhibitors on lung cancer, characterized in that: on the basis of administering PD-1 inhibitors to patients, a therapeutically effective amount of paclitaxel cationic liposomes is further administered in combination.

[0039] Preferably, the paclitaxel cationic liposomes of the present invention are in the form of an injectable powder or a liquid injection. When the paclitaxel cationic liposomes are in the form of a liquid injection, the active ingredient is contained in an amount of 0.05-1 mg / ml, preferably 0.2-0.3 mg / ml, and more preferably 0.25 mg / ml, calculated as paclitaxel.

[0040] Preferably, the therapeutically effective amount of paclitaxel cationic liposomes is 5-100 mg / m 2 , preferably 5-80 mg / m 2 , further preferably 11-55 mg / m 2 , or more preferably 24-70 mg / m 2 , or any value within the range. For example, 11 mg / m 2 , 22mg / m 2 , 24 mg / m 2 , 33mg / m 2 , 36mg / m 2 , 44 mg / m 2 , 48mg / m 2 , 55mg / m 2 , 60mg / m 2, 70mg / m 2 Preferably, the paclitaxel cationic liposomes are administered by arterial infusion. Preferably, the administration cycle is once every 3 weeks.

[0041] In some embodiments, the paclitaxel cationic liposomes of the present invention contain paclitaxel, dioleoylphosphatidylcholine (DOPC), (2,3-dioleyloxypropyl)trimethylammonium chloride (DOTAP) and trehalose.

[0042] Preferably, each preparation (or preparation unit) of the paclitaxel cationic liposome contains 5-10 mg of paclitaxel, 72-144 mg of DOPC, 68-136 mg of DOTAP, and 1500-2500 mg of trehalose.

[0043] Most preferably, each preparation (or preparation unit) contains 10 mg of paclitaxel, 144 mg of DOPC, 136 mg of DOTAP, and 2500 mg of trehalose, or each preparation (or preparation unit) contains 5 mg of paclitaxel, 72 mg of DOPC, 68 mg of DOTAP, and 2000 mg of trehalose, or each preparation (or preparation unit) contains 5 mg of paclitaxel, 72 mg of DOPC, 68 mg of DOTAP, and 1500 mg of trehalose.

[0044] The paclitaxel cationic liposomes of the present invention can be prepared by conventional methods in the art, and can be prepared by any method disclosed in the prior art, for example, by the formulation and method disclosed in US Pat. No. 7,794,747B.

[0045] The dosage of the paclitaxel cationic liposomes of the present invention is calculated based on paclitaxel. Beneficial effects

[0046] Animal experiments of the present invention have shown that the combination of paclitaxel cationic liposomes with other drugs or treatments, such as cisplatin, gemcitabine, or capecitabine, can significantly enhance the anti-tumor efficacy, and the effect is significantly better than the same dose of paclitaxel injection Taxol.

[0047] By combining paclitaxel cationic liposome arterial infusion with the XELOX regimen for patients with gastric cancer, pancreatic cancer, and colorectal cancer liver metastases, the efficacy of the XELOX regimen for these patients can be improved, the disease remission rate, especially the complete remission rate (CR rate) and partial remission rate (PR rate) of the disease can be increased, the progression of the disease can be controlled, and it is safe, tolerable, and has few toxic side effects.

[0048] Administration of paclitaxel cationic liposomes to patients with advanced solid tumors, or administration of paclitaxel cationic liposomes in combination with systemic therapeutic drugs, can improve the efficacy of systemic therapeutic drugs on tumor patients, increase the disease remission rate, and control the progression of the disease with safety, tolerance, and minimal toxic side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] FIG1 shows the distribution of drug-related AE grades for the treatment regimen of Example 5. DETAILED DESCRIPTION

[0050] The following examples are provided to illustrate the present invention in detail and are not intended to limit the scope of the present invention.

[0051] Example 1 Preparation of Paclitaxel Cationic Liposomes

[0052] The formulation of paclitaxel cationic liposomes is as follows

[0053] The preparation method is as follows:

[0054] (1) Weigh the prescribed amount of paclitaxel, DOPC, and DOTAP and dissolve them in anhydrous ethanol to obtain an organic phase;

[0055] (2) dissolving trehalose in injection water to obtain a 10-12.5% ​​trehalose solution as the aqueous phase;

[0056] (3) mixing the oil phase and the water phase in a certain proportion to form liposomes;

[0057] (4) The liposomes obtained in step 3 are subjected to a particle size reshaping operation to obtain liposomes with relatively uniform particle size;

[0058] (5) dialyzing the liposomes obtained in step "4" using the trehalose solution obtained in step "2" as the dialysate;

[0059] (6) The liposome solution obtained in step 5 is freeze-dried or spray-dried to obtain a solid powder.

[0060] During use, the solid powder is reconstituted to obtain a paclitaxel cationic liposome injection, and the osmotic pressure of the resulting injection is equal to the plasma osmotic pressure. The "paclitaxel cationic liposome injection" used in the subsequent examples is obtained by reconstitution of the product in Example 1. Formulations 1-1, 1-2, and 1-3 have essentially the same physicochemical properties and pharmacological and clinical effects.

[0061] Example 2-4 uses the product obtained by re-dissolving the product of Example 1-2, which is simplified as "A1".

[0062] Example 5-6 uses the product obtained by re-dissolving the product 1-1 in Example 1, which is simplified as "A2".

[0063] Example 2 Inhibitory Effect of Paclitaxel Cationic Liposomes for Injection Combined with Cisplatin (DDP) on RM-1 Prostate Cancer Xenografts in Mice

[0064] Experimental animals: Female C57 / BL6 mice were provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0065] Experimental method: Female C57 / BL6 mice were subcutaneously inoculated with mouse prostate RM-1 cells. On the 6th day after inoculation, the average tumor volume was 140 mm 3 The mice were divided into groups at d0. The drugs were administered on d0, d2, d4, d6, d8 and d10 (except DDP intraperitoneally, the others were intravenously administered), for a total of 6 doses, and the experiment was terminated on d15. The A1 high-dose group received a dose of 12 mg / kg for the first three doses and 6 mg / kg for the next three doses, with a cumulative dose of 54 mg / kg; the A1 low-dose group received a dose of 6 mg / kg for all six doses, with a cumulative dose of 36 mg / kg, and the DPP group received a dose of 1 mg / kg for all six doses, with a cumulative dose of 6 mg / kg; the solvent control group received 5% glucose injection (equal volume to that of the A1 high-dose group); the A1+DDP-1 group received a dose of 6 mg / kg for all six doses of A1, with a cumulative dose of 36 mg / kg, and DPP was administered 6 times at a dose of 1 mg / kg, with a cumulative dose of 6 mg / kg; the A1+DDP-2 group received a dose of 12 mg / kg for the first three doses of A1, with a dose of 6 mg / kg for the next three doses, with a cumulative dose of 54 mg / kg, and DPP was administered 6 times at a dose of 1 mg / kg, with a cumulative dose of 6 mg / kg. During the experiment, the animal body weight and tumor volume were monitored three times a week, and the tumor volume (TV), relative tumor volume (RTV), and relative tumor volume proliferation rate (T / C) values ​​were calculated.

[0066] Related calculation formula: tumor volume (TV) = 1 / 2 × a × b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0067] RTV=TV t / TV0. TV0 is the tumor volume measured at the time of administration (i.e., d0), TV t is the tumor volume at each measurement.

[0068] T / C (%) = (TRTV / CRTV) × 100% (TRTV: RTV of the drug-treated group; CRTV: RTV of the solvent control group). Test drug preparation method: A1: Dissolve the drug in water for injection, then dilute with glucose and sodium chloride injection to the desired concentration; dissolve DDP powder in 5% glucose injection, sonicate, and adjust to the desired concentration.

[0069] Results: Compared with the vehicle control group, all treatment groups significantly inhibited the growth of RM-1 prostate cancer cells in mice (P < 0.05). The combination of high and low doses of A1 and DDP significantly enhanced the tumor inhibition compared to the DDP alone group (P < 0.01). See Table 1 for detailed results.

[0070] Table 1: Inhibitory effect of combined use with DDP on mouse prostate cancer RM-1 transplanted tumors ( n=9)

[0071] * p<0.05, ** p<0.01 compared with the Vehicle group;

[0072] # p<0.05, ## p < 0.01, compared with the same dose of A1;

[0073] ★ p<0.05, ★★ p<0.01, compared with the same dose of DDP

[0074] Example 3 Inhibitory Effect of Paclitaxel Cationic Liposomes for Injection on Human Pancreatic Cancer CFPAC-1 Mice Transplanted Tumors

[0075] Experimental animals: Female Nu / Nu nude mice were provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0076] Experimental method: Female Nu / Nu nude mice were subcutaneously inoculated with human pancreatic cancer CFPAC-1 cells. On the 5th day, the average tumor volume was 228 mm 3The animals were divided into seven groups (d0): a solvent control group (5% glucose injection), an A1 6 mg / kg group, an A1 3 mg / kg and 6 mg / kg group combined with gemcitabine (GEM) injection at 20 mg / kg, a paclitaxel injection (Taxol) 6 mg / kg group, a Taxol 6 mg / kg group combined with GEM injection at 20 mg / kg, and a GEM 20 mg / kg group. Each group consisted of 10 animals. Dosing was performed on d0, d3, d6, d9, d13, and d16 (all doses were intravenous, except for the first five time points where gemcitabine (GEM) injection was administered intraperitoneally), for a total of six doses. The experiment was terminated after 11 days of observation after the last dose (d27). Animal body weight and tumor volume were monitored twice weekly throughout the experiment, and tumor volume (TV) was calculated. Tumor weight was weighed after the experiment, and the tumor weight inhibition rate was calculated.

[0077] Related calculation formula: tumor volume (TV) = 1 / 2 × a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. Tumor weight inhibition rate (%) = (1 - tumor weight of the drug group / tumor weight of the solvent control group) × 100%.

[0078] Preparation of test drugs: A1 was prepared in the same manner as in Example 2; gemcitabine for injection was prepared with normal saline to the desired concentration, and paclitaxel injection (Taxol) was diluted with normal saline to the desired concentration.

[0079] Results: Compared with the solvent control group, A1 (6 mg / kg) alone significantly inhibited the growth of human pancreatic cancer CFPAC-1 tumors (P < 0.01). The combination of A1 and gemcitabine exhibited a stronger inhibitory effect than either A1 or gemcitabine alone (P < 0.01). Compared with paclitaxel injection (Taxol) under the same dosing conditions, A1 (6 mg / kg) alone or in combination with gemcitabine significantly enhanced its tumor inhibitory effect (P < 0.01). Detailed results are shown in Table 2.

[0080] Table 2: Inhibitory effect on human pancreatic cancer CFPAC-1 transplanted tumors ( n=10)

[0081] *p<0.05, **p<0.01, compared with the Vehicle group;

[0082] △ p < 0.05, compared with the same dose of Taxol; ★ p<0.05, ★★ p < 0.01, compared with GEM;

[0083] ## p<0.01, comparison between A1+GEM and equal dose of A1

[0084] Example 4 Inhibitory Effect of Paclitaxel Cationic Liposomes for Injection on Human Triple Negative Breast Cancer MDA-MB-231 Mice Xenografts

[0085] Experimental animals: Female NOD / SCID mice were provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0086] Experimental method: Female NOD / SCID mice were subcutaneously inoculated with human triple-negative breast cancer MDA-MB-231 cells. On day 7, the average tumor volume was 120-130 mm 3 Seven groups were divided into groups (d0), namely solvent control group (5% glucose injection), A1 6mg / kg group, A1 3mg / kg, 6mg / kg combined with capecitabine injection (CAP) 400mg / kg group, paclitaxel injection (Taxol) 6mg / kg group, Taxol 6mg / kg combined with CAP 400mg / kg group, CAP 400mg / kg group. Capecitabine injection (CAP) was administered orally twice a week, and other drugs were administered intravenously twice a week for a total of 7 times (d0, d3, d7, d10, d14, d17 and d21). The experiment was terminated on d28. During the experiment, the body weight and tumor volume of the animals were monitored twice a week, and the tumor volume (TV) was calculated. After the experiment, the tumor weight was weighed and the tumor weight inhibition rate was calculated.

[0087] Related calculation formula: tumor volume (TV) = 1 / 2 × a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. Tumor weight inhibition rate (%) = (1 - tumor weight of the drug group / tumor weight of the solvent control group) × 100%.

[0088] Test drug preparation method: CAP was diluted with water for injection to the required concentration. The other drugs were as shown in Example 3.

[0089] Results: Compared with the solvent control group, A1 (6 mg / kg) alone significantly inhibited the growth of triple-negative breast cancer MDA-MB-231 tumors (P < 0.05). Combination therapy with capecitabine demonstrated a stronger inhibitory effect than either A1 or capecitabine alone (P < 0.05). Compared with paclitaxel injection (Taxol) under the same dosing conditions, A1 (6 mg / kg) alone or in combination with capecitabine significantly enhanced its inhibitory effect (P < 0.05). Detailed results are shown in Table 3.

[0090] Table 3: Inhibitory effect on human triple-negative breast cancer and pancreatic cancer MDA-MB-231 transplanted tumors ( n=10)

[0091] *p<0.05, **p<0.01, compared with the Vehicle group;

[0092] △ p<0.05, △△ p < 0.01, compared with Taxol; ★ p<0.05, ★★ p < 0.01, compared with CAP;

[0093] # p<0.05, ## p<0.01, comparison of A1+CAP with equal dose of A1

[0094] Example 5. Clinical study of intra-arterial infusion of paclitaxel cationic liposome injection as a first-line treatment for gastric cancer, pancreatic cancer, and colorectal cancer liver metastases

[0095] This study is a single-arm, open-label, single-center investigator-led clinical study (IIT) that enrolls patients with untreated liver metastases, including but not limited to gastric cancer liver metastases, colorectal cancer liver metastases, and pancreatic cancer liver metastases, whose primary lesions are confirmed by histopathology or cytology. Patients are given intra-arterial infusion of different doses of paclitaxel cationic liposome injection and a fixed-dose XELOX regimen. The aim is to explore the safety and tolerability of the combination regimen, determine the optimal dose of paclitaxel cationic liposome injection in the combination regimen, evaluate the efficacy, and observe the pharmacokinetic characteristics.

[0096] 1. Experimental Design

[0097] The study was divided into a dose escalation phase and a dose expansion phase

[0098] 1. Dose escalation phase

[0099] (1) Experimental design

[0100] The study consisted of a screening period, a treatment period, and an end-of-study visit.

[0101] After signing the informed consent form and completing all baseline examinations during the screening period, qualified subjects will enter the treatment period and receive paclitaxel cationic liposome injection combined with the XELOX regimen. The dose of paclitaxel cationic liposome injection will be gradually increased from the low-dose group to the high-dose group. The subject's dose is the dose of the drug currently being used or to be used at the time of entry into this study. The dosing schedule is once every 3 weeks. The first cycle of the treatment period is the DLT (dose-limiting toxicity) observation period. Subjects who complete 3 weeks of treatment and observation can continue to receive the next cycle of dosing until relapse / progression, death, the subject or their legal representative requests to withdraw from the study, other treatment methods are used, or the entire study is completed (whichever occurs first). The expected dosing period is 6-8 cycles. Efficacy evaluation will be performed once every 2 cycles (6 weeks) during the treatment period. All subjects will be required to collect PK (pharmacokinetics) blood samples at different time points before and after dosing as specified in the protocol, and relevant tests will be completed during the study to observe safety and tolerability. The end-of-treatment visit will be conducted 30 days after the last dose.

[0102] (2) Dose escalation regimen

[0103] Paclitaxel cationic liposomes: 11 mg / m 2 As the initial dose (calculated as paclitaxel), 11 mg / m 2 , 22mg / m 2 , 33mg / m 2 , 44mg / m 2 , 55mg / m 2 There were 5 dose groups in total.

[0104] Subjects who experience DLT will be managed by the investigator according to clinical diagnosis and treatment guidelines. The original dose may be maintained or the dose may be reduced by one level before continuing with the next cycle. Dose increases are not permitted for the same subject.

[0105] XELOX regimen: oxaliplatin, 130 mg / m 2 , intravenous drip, D1; capecitabine, 1000 mg / m 2 , oral, D1-D14.

[0106] (3) Extended dosing after completion of the DLT observation period

[0107] Subjects who experience DLT will be managed by the investigator according to clinical diagnosis and treatment guidelines. Dosing may be delayed for up to 2 weeks, maintained at the original dose, or reduced by one dose level to continue with the next cycle. Dose increases are not permitted for the same subject.

[0108] If the MTD (maximum tolerated dose) of paclitaxel cationic liposome injection is found, the MTD will be selected as the RP2D (recommended Phase II dose). If the MTD of paclitaxel cationic liposome injection is not found, the RP2D will be determined by internal discussion among investigators based on the results of the DLT observation period during the dose-escalation phase. The RP2D dose will be selected for dose expansion during the dose-expansion phase.

[0109] 2. Dose expansion phase

[0110] Dose expansion can be performed if necessary based on the safety, tolerability, and efficacy data obtained from the dose escalation study:

[0111] Select 1-3 tumor types for dose expansion, including but not limited to gastric cancer liver metastasis, colorectal cancer liver metastasis, pancreatic cancer liver metastasis, etc. The specific expansion cohort can be decided after internal discussion among researchers after the expansion dose is determined, and each cohort will be expanded to 5-15 cases.

[0112] 2. Trial Population

[0113] (1) Selection criteria

[0114] Only subjects who meet all of the following criteria can be included in this study:

[0115] 1. Applicants must be between 18 and 75 years old (inclusive), regardless of gender.

[0116] 2. Untreated liver metastases, including but not limited to liver metastases from gastric cancer, colorectal cancer, and pancreatic cancer, with the primary lesion confirmed by histopathology or cytology.

[0117] 3. If the liver metastasis is a single measurable target lesion, the diameter of the single target lesion must be ≥2 cm; if the liver metastasis is ≥2 target lesions, at least 2 target lesions must have a diameter ≥1 cm.

[0118] 4.ECOG performance status score: 0 to 2 points.

[0119] 5. The expected survival time is more than 3 months.

[0120] 3. Efficacy evaluation indicators

[0121] Evaluation was performed using CT / MRI according to RECIST1.1 / mRECIST criteria.

[0122] 1. Main efficacy indicators:

[0123] The overall response rate (ORR) was defined as the proportion of subjects in the study who achieved a best overall response of CR or PR as assessed by the investigator according to RECIST v1.1 / mRECIST.

[0124] Disease control rate (DCR): defined as the proportion of patients with CR, PR, or stable disease (SD) (i.e., CR+PR+SD) at the best time point, as evaluated according to RECIST 1.1 / mRECIST standards, from the start of study drug use to study exit.

[0125] 2. Exploratory efficacy indicators:

[0126] Change rate of target lesions in the arterial perfusion territory: According to RECIST v1.1 / mRECIST, all measurable lesions in the arterial perfusion territory (the arterial perfusion territory is required to have only a single target lesion with a diameter ≥2 cm; if there are ≥2 target lesions, at least two target lesions must have a diameter ≥1 cm) are measured. The sum of the target lesion diameters in the supply territory is calculated as the baseline data, and the rate of change in the sum of the target lesion diameters in the supply territory is calculated at each efficacy evaluation. When a lesion in the supply territory increases again after shrinking, the rate of change relative to the minimum sum of the target lesion diameters in the supply territory is calculated.

[0127] 3. Safety indicators

[0128] AE (Adverse Event) and SAE (Serious Adverse Event / Reaction) were used as safety evaluation indicators.

[0129] IV. Research Results

[0130] Paclitaxel cationic liposome arterial infusion combined with systemic therapy (such as the XELOX regimen) has a good effect on the treatment of liver metastases from advanced solid tumors (such as gastric cancer, pancreatic cancer, and colorectal cancer). It can improve the effectiveness of treatment, reduce the incidence of adverse reactions, and has good clinical application prospects.

[0131] In this example, a total of five patients were enrolled (the first five in Table 4), including one with gastric cancer liver metastasis and four with colorectal cancer liver metastasis. None had previously received systemic treatment for metastatic disease. One patient with colorectal cancer liver metastasis was undergoing preliminary screening (the last patient in Table 4, subject number pending). For more information, see Table 4.

[0132] Table 4

[0133] The results are shown in Table 5. A total of 4 cases were evaluable for efficacy, with the best efficacy being SD in 2 cases and PR in 2 cases (01003 and 01004 both achieved CR by mRECIST evaluation), that is, ORR was 50% and DCR was 100%.

[0134] Safety and tolerance: 11-33 mg / m 2No DLT occurred in any dose group; the safety and tolerability were good, and no abnormal safety signals were found; the currently reported drug-related AEs were all grade 1-2 (see Figure 1, the vertical axis indicates the number of occurrences), which were recoverable after symptomatic treatment; related AEs (including those that may be unrelated) included decreased platelet count, increased procalcitonin, fever, nausea, increased white blood cell count, and decreased lymphocyte count.

[0135] Note: Adverse events in clinical trials are divided into five levels:

[0136] Grade 1: Mild, asymptomatic or mild, only clinical or diagnostic observations; no treatment required.

[0137] Grade 2: Moderate, requiring minor, local or noninvasive treatment, with age-appropriate limitation in instrumental activities of daily living.

[0138] Grade 3: Severe or medically significant but not immediately life-threatening, leading to hospitalization or prolonged hospitalization, disability, and limitation of self-care and life activities.

[0139] Grade 4: Life-threatening, medical treatment required.

[0140] Grade 5: Death related to AE.

[0141] Example 6 Clinical Study on Paclitaxel Cationic Liposome Injection for the Treatment of Advanced Solid Tumors by Arterial Infusion

[0142] This study is a single-arm, open-label, multicenter, phase 1 study that enrolled patients with advanced solid tumors confirmed by histopathology or cytology. Patients were given different doses of paclitaxel cationic liposome injection via arterial infusion. The study aimed to explore the safety and tolerability of paclitaxel cationic liposome monotherapy via arterial infusion, while also evaluating its efficacy and observing its pharmacokinetic characteristics.

[0143] 1. Experimental Design

[0144] The study was divided into a dose-escalation phase and a dose-expansion phase.

[0145] 1. Dose escalation phase

[0146] (1) Experimental design

[0147] The dose escalation phase includes a screening period (within 28 days), a treatment period, and a PFS follow-up period. The subjects signed an informed consent form and completed all baseline examinations during the screening period. Qualified subjects will enter the treatment period, and the dosage of paclitaxel cationic liposome injection will gradually increase from the low-dose group to the high-dose group. Each 3W (21 days) is a cycle, and DLT will be observed in the first dosing cycle. PK blood samples will be collected from subjects at different time points before and after administration according to the protocol, and relevant examinations specified in the protocol will be completed during the treatment process to observe safety, tolerability, and efficacy. The same subject can only receive one dose of treatment and dosing schedule during the study. 6-8 cycles of administration are expected. Efficacy evaluation will be performed once every 2 cycles (6 weeks) during the treatment period.

[0148] (2) Dose escalation regimen

[0149] Paclitaxel cationic liposomes: 24 mg / m 2 As the initial dose (calculated as paclitaxel), 24 mg / m 2 , 36mg / m 2 , 48mg / m 2 , 60mg / m 2 , 70mg / m 2 There were 5 dose groups in total.

[0150] Subjects who experience DLT will be managed by the investigator according to clinical diagnosis and treatment guidelines. The original dose may be maintained or the dose may be reduced by one level before continuing with the next cycle. Dose increases are not permitted for the same subject.

[0151] (3) Extended dosing after completion of the DLT observation period

[0152] Subjects who experience DLT will be managed by the investigator according to clinical diagnosis and treatment guidelines. Dosing may be delayed for up to 2 weeks, maintained at the original dose, or reduced by one dose level to continue with the next cycle. Dose increases are not permitted for the same subject.

[0153] If the MTD (maximum tolerated dose) of paclitaxel cationic liposome injection is found, the MTD will be selected as the RP2D (recommended Phase II dose). If the MTD of paclitaxel cationic liposome injection is not found, the RP2D will be determined by internal discussion among investigators based on the results of the DLT observation period during the dose-escalation phase. The RP2D dose will be selected for dose expansion during the dose-expansion phase.

[0154] 2. Dose expansion phase

[0155] Based on the safety, tolerability, and efficacy data obtained from the dose-escalation study, dose expansion can be performed if necessary: ​​1-3 tumor types will be selected for dose expansion, including but not limited to gastric cancer liver metastasis, colorectal cancer liver metastasis, pancreatic cancer liver metastasis, etc. The specific expanded cohorts can be decided after internal discussion among researchers after the expansion dose is determined, and 5-15 cases will be expanded in each cohort.

[0156] 2. Trial Population

[0157] (1) Selection criteria

[0158] Only subjects who meet all of the following criteria can be included in this study:

[0159] 1. Applicants must be between 18 and 75 years old (inclusive), regardless of gender.

[0160] 2. Advanced solid tumors confirmed by histopathology or cytology, including but not limited to the following tumor types:

[0161] Digestive tract tumors (including but not limited to gastric cancer, liver cancer, bile duct cancer, pancreatic cancer, colorectal cancer, etc.);

[0162] Gynecological tumors (including but not limited to ovarian cancer, endometrial cancer, etc.);

[0163] Lung cancer;

[0164] Liver metastases;

[0165] 3. Requirements for target lesions: If there is only a single target lesion in the arterial perfusion vessel supply area, the diameter of the single target lesion must be ≥2cm; if there are ≥2 target lesions in the supply area, at least 2 target lesions must have a diameter ≥1cm.

[0166] 4.ECOG performance status score: 0 to 2 points.

[0167] 5. The expected survival time is more than 3 months.

[0168] 3. Evaluation Indicators

[0169] Evaluation by CT / MRI according to RECIST1.1 criteria

[0170] The planned number of patients to be enrolled in this study is:

[0171] The dose escalation study enrolled approximately 18-24 patients;

[0172] Enrollment in the dose expansion study will be determined after internal discussion among investigators;

[0173] Efficacy evaluation:

[0174] Main efficacy indicators:

[0175] The overall response rate (ORR) was defined as the proportion of subjects in the study who achieved a best overall response of CR or PR as assessed by the investigator according to RECIST v1.1.

[0176] Disease control rate (DCR): defined as the proportion of patients with CR, PR, or stable disease (SD) (i.e., CR+PR+SD) at the best time point, as evaluated according to RECIST 1.1 standards, from the start of study drug use to study exit.

[0177] Progression-free survival (PFS): defined as the time from the start of study drug to the date of first documented disease progression (PD) or death, whichever occurs first.

[0178] Duration of response (DoR) was defined as the time from the first assessment of CR or PR to the first assessment of PD or death from any cause.

[0179] Safety evaluation indicators

[0180] AE (Adverse Event) and SAE (Serious Adverse Event / Reaction) were used as safety evaluation indicators.

[0181] IV. Research Results

[0182] Arterial infusion of paclitaxel cationic liposomes has a good effect on the treatment of advanced solid tumors, such as gastric cancer, pancreatic cancer, and colorectal liver metastases. It improves the effectiveness of treatment, reduces the incidence of adverse reactions, and has good clinical application prospects.

[0183] Example 7 Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Paclitaxel Cationic Liposomes for Injection in Patients with Advanced Solid Tumors by Transcatheter Arterial Infusion

[0184] 1. Primary and secondary objectives and endpoints

[0185] 1. Main Purpose

[0186] (1) To evaluate the safety and tolerability of cationic liposome paclitaxel for injection via catheter arterial infusion in the treatment of advanced solid tumors.

[0187] (2) To determine the maximum tolerated dose (MTD) and / or recommended dose for extension (RDE) of cationic liposome paclitaxel for injection via catheter arterial infusion for the treatment of advanced solid tumors.

[0188] Primary endpoint

[0189] (1) The frequency and severity of adverse events (AEs) and serious adverse events (SAEs) (according to NCI CTCAE5.0).

[0190] (2) The frequency of dose-limiting toxicity (DLT).

[0191] 2. Secondary Purpose

[0192] (1) To evaluate the pharmacokinetic (PK) characteristics of cationic liposome paclitaxel for injection in the treatment of advanced solid tumors via catheter arterial infusion

[0193] (2) To evaluate the preliminary antitumor activity of cationic liposome paclitaxel for injection via catheter arterial infusion in the treatment of advanced solid tumors

[0194] Secondary endpoints

[0195] (1) Pharmacokinetic indicators: PK parameters include but are not limited to AUC 0-t , AUC 0-∞ 、C max , K el 、T max 、Vd、t 1 / 2 and CL et al.

[0196] (2) Efficacy indicators: overall response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

[0197] 2. Overall Experimental Design

[0198] This study consists of two phases: Phase Ia (dose escalation and expansion phase) and Phase Ib (cohort expansion phase).

[0199] The dose-escalation phase consists of a screening period (0-28 days), a treatment period (DLT observation period, subsequent treatment period), and a follow-up period (safety follow-up, survival follow-up). The first 21-day cycle of study drug treatment is the DLT observation period. After the DLT observation period, participants who do not experience a DLT will enter the subsequent treatment period. The dose-expansion and cohort-expansion phases consist of a screening period (0-28 days), a treatment period, and a follow-up period (safety follow-up, survival follow-up). Paclitaxel cationic liposomes are administered by intra-arterial infusion on day 1 of each cycle, with each treatment cycle consisting of 3 weeks. Qualified participants will receive 4-6 cycles of study treatment. Treatment may be terminated early if the following conditions occur during treatment: disease progression, unacceptable toxicity, initiation of new anti-cancer therapy, withdrawal of informed consent, loss to follow-up, death, or other conditions eligible for treatment termination (whichever occurs first). If a participant experiences a first disease progression, and the investigator assesses that the participant still benefits from continued treatment and the participant wishes to continue, they may continue for 1-2 cycles of study treatment until disease progression recurs.

[0200] During the study, participants underwent efficacy assessments every 6 weeks ± 7 days after the first dose. Participants who discontinued treatment for reasons other than disease progression should continue to undergo tumor assessments until disease progression, initiation of new anti-tumor treatment, withdrawal of informed consent, loss to follow-up, or death (whichever occurred first).

[0201] 1. Dose escalation phase

[0202] The initial dose of paclitaxel cationic liposome injection is tentatively set at 22 mg / m 2 The dose may be adjusted appropriately after discussion by the SMC (Scientific Review Committee established for this trial) based on the data obtained from the previous studies on arterial infusion therapy of this product. The current preset maximum dose is 66 mg / m 2 If the dose is safe and tolerable, the investigator and the sponsor may discuss and decide whether to explore a higher dose. Participants in the low-dose group did not experience DLT during the DLT observation period and were well-tolerated. Following discussion with the SMC, higher doses of the study drug may be considered.

[0203] The specific dose group setting in the dose escalation phase is based on the modified Fibonacci method and is shown in the table below:

[0204] Table 6 Dose group settings in the dose escalation phase (administered once every 3 weeks)

[0205] Except for the starting dose, the remaining escalating doses can be discussed by the investigator and the sponsor based on the obtained drug safety and PK data to decide whether to proceed to the next dose group and whether the dose or dosing regimen of other dose groups needs to be adjusted.

[0206] The first dose cohort of this study will utilize an accelerated dose titration schedule, and subsequent dose cohorts will follow a "3+3" dose escalation schedule. Paclitaxel cationic liposomes will be observed for DLTs within the first cycle (21 days). If a participant in the accelerated titration group experiences moderate toxicity (including drug-related AEs requiring management of the following: one occurrence of a Grade 3 AE not classified as a DLT, or two occurrences of a Grade 2 or higher AE), this and subsequent dose cohorts will follow the "3+3" schedule.

[0207] “3+3” dose escalation rule:

[0208] Each dose group will enroll 3 patients. After completing the DLT observation, the following rules will be used to determine whether to proceed to the next dose group trial:

[0209] (1) Three participants in the first dose group (or specific dose group) completed DLT observation;

[0210] (2) If none of the three participants in a dose group experienced DLT, the dose was escalated to the next dose group;

[0211] (3) If two or more of the three participants in a dose group experienced DLT, the dose was de-escalated to the previous dose group;

[0212] (4) If one of the three participants in a dose group developed DLT, three more participants were added to that dose group. If 1 / 6 participants developed DLT, the dose group was increased to the next dose group. If ≥2 / 6 participants developed DLT, the dose group was decreased to the previous dose group.

[0213] (5) When decreasing to the previous dose group, if there are only 3 participants in this dose group, 3 more participants will be added.

[0214] If there are 6 participants in this dose group, the dose escalation trial ends and this dose is the MTD.

[0215] Maximum tolerated dose (MTD):

[0216] MTD: Defined as the highest dose in which ≤33% of participants experience DLT. Generally, if 2 or more of 3 participants at a dose level experience DLT, the dose immediately preceding that dose is considered the MTD. If 1 of 3 participants at a dose level experiences DLT, and 3 more participants are added at the same dose, if ≥2 / 6 participants experience DLT, the dose immediately preceding that dose is considered the MTD.

[0217] If necessary, a new dose can be selected between the previous dose and the "intolerable dose" for exploration.

[0218] 2. Dose expansion phase

[0219] Based on the PK, safety, tolerability and efficacy data obtained from the dose-escalation study, 1-3 recommended dose groups can be selected and the enrollment can be expanded to 15-30 participants in each group (including participants in the same dose group in the dose-escalation phase).

[0220] 3. Queue expansion phase

[0221] After determining the recommended dose for extension (RDE), 1-3 potentially effective tumor types will be selected for cohort expansion, including but not limited to liver cancer, liver metastases, pancreatic cancer, lung cancer, etc. The specific indication population and sample size can be determined after full discussion by the SMC.

[0222] 3. Dose-limiting toxicity (DLT)

[0223] Dose-limiting toxicity is defined as an adverse event occurring during the first 21-day dosing cycle of the dose escalation phase and related to paclitaxel cationic liposome injection (including definitely related, probably related, and possibly related) and meeting the following severity levels (according to NCI CTCAE 5.0). Except for concomitant medications and treatments prohibited by the protocol, clinical diagnosis and treatment protocols should be followed in the study, and adequate and appropriate symptomatic supportive care should be provided in a timely manner.

[0224] During the DLT observation period, if the following circumstances occur, the DLT observation period will be deemed to have not been completed and case replacement will be required:

[0225] - The dose administered was less than 75% of the planned total dose due to non-DLT reasons;

[0226] - Discontinuation of dosing due to reasons other than DLT.

[0227] IV. Trial Population

[0228] Number of groups and participants

[0229] Dose escalation phase: 15-30 patients;

[0230] Dose expansion phase: Select 1-3 recommended dose groups and expand enrollment to 15-30 participants per group (including participants in the same dose group in the dose escalation phase);

[0231] The cohort expansion phase is to be determined (based on the data obtained from the dose escalation and expansion phases, to be decided by the SMC after discussion).

[0232] Inclusion criteria:

[0233] 1. Aged ≥ 18 years;

[0234] 2. Advanced solid tumors diagnosed by histology or cytology that are suitable for intra-arterial chemotherapy, including but not limited to the following tumor types:

[0235] Digestive tract tumors (including but not limited to gastric cancer, liver cancer, bile duct cancer, pancreatic cancer, colorectal cancer, etc.);

[0236] Gynecological tumors (including but not limited to ovarian cancer, endometrial cancer, etc.);

[0237] Non-small cell lung cancer;

[0238] Liver metastases;

[0239] 3. According to RECIST 1.1, there is at least one measurable lesion in the arterial perfusion area;

[0240] 4. If the primary life-threatening lesion is within the arterial perfusion territory, the presence of a limited lesion outside the arterial perfusion territory at baseline is acceptable;

[0241] 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 points;

[0242] 6. The expected survival period is at least 3 months;

[0243] 7. Have adequate organ function and laboratory tests meet the following criteria (have not received blood transfusion or hematopoietic stimulating factor treatment within 14 days):

[0244] a. Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L

[0245] b. Platelet count (PLT) ≥ 100 × 10 9 / L

[0246] c. Hemoglobin (Hb) ≥ 90 g / L

[0247] d. Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); TBIL ≤ 2 × ULN for individuals with liver metastasis or HCC

[0248] e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 × ULN; ALT, AST ≤ 5 × ULN for individuals with liver metastasis or HCC

[0249] f. Creatinine clearance (Ccr) > 50 mL / min (calculated according to the Cockcroft-Gault formula)

[0250] g. Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; international normalized ratio (INR) ≤ 1.5 × ULN

[0251] 8. Eligible individuals (male and female) of childbearing potential must agree to use reliable contraceptive methods (hormonal contraceptives, barrier methods, or abstinence) with their partners during the trial and for at least 6 months after the last medication. Female individuals of childbearing age must have a negative blood pregnancy test within 7 days before enrollment;

[0252] 9. Fully understand this clinical trial and voluntarily sign a written informed consent.

[0253] Exclusion criteria:

[0254] 1. Patients who have received chemotherapy, radiotherapy, biological therapy, endocrine therapy, targeted therapy, immunotherapy or other anti-tumor treatment within 4 weeks before the first use of the study drug, or have participated in other clinical trials and received treatment within 4 weeks or 5 half-lives of the drug, whichever is shorter;

[0255] 2. Patients with known clinical symptoms of central nervous system metastasis or meningeal metastasis, or other evidence indicating that individual central nervous system metastasis or meningeal metastasis has not been controlled, and are judged by the researchers to be unsuitable for inclusion;

[0256] 3. The adverse reactions of previous anti-tumor treatment have not recovered to CTCAE 5.0 grade ≤1 (excluding toxicities such as alopecia that the researcher judges to have no safety risks);

[0257] 4. Participating in another clinical trial at the same time, unless it is an observational (non-interventional) clinical trial or in the follow-up period of an interventional trial;

[0258] 5. Individuals who have undergone major surgery or invasive intervention within 28 days before the first use of the drug;

[0259] 6. Any Chinese herbal medicine or Chinese patent medicine with anti-cancer activity approved by the China National Medical Products Administration (NMPA) within 14 days before the first medication (regardless of the type of cancer);

[0260] V. Research Results

[0261] Arterial infusion of paclitaxel cationic liposomes has a good effect on the treatment of advanced solid tumors, such as gastric cancer, pancreatic cancer, and colorectal liver metastases. It improves the effectiveness of treatment, reduces the incidence of adverse reactions, and has good clinical application prospects.

[0262] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. Use of paclitaxel cationic liposomes in the preparation of drugs for treating advanced solid tumors.

2. Use of paclitaxel cationic liposomes and systemic therapeutic drugs in the preparation of drugs for treating advanced solid tumors, preferably, the systemic therapeutic drugs are capecitabine and oxaliplatin, or cisplatin, or gemcitabine, or capecitabine.

3. A method for treating advanced solid tumors, characterized in that: A therapeutically effective amount of cationic liposome paclitaxel is administered to a patient with an advanced solid tumor.

4. A method for treating advanced solid tumors, characterized in that: A therapeutically effective amount of paclitaxel cationic liposomes and a systemic therapeutic drug are administered to patients with advanced solid tumors. Preferably, a therapeutically effective amount of paclitaxel cationic liposomes, capecitabine and oxaliplatin are administered to patients with advanced solid tumors. Alternatively, preferably, the paclitaxel cationic liposomes are administered by arterial infusion.

5. A method for improving the efficacy of systemic therapeutic drugs on tumors, characterized in that: On the basis of administering systemic therapeutic drugs to the patient, a therapeutically effective amount of paclitaxel cationic liposomes is further administered. Preferably, the systemic therapeutic drugs are capecitabine and oxaliplatin, or cisplatin, or gemcitabine, or capecitabine.

6. A method for improving the efficacy of capecitabine and oxaliplatin combined with treatment of advanced solid tumors, including advanced gastric cancer, colorectal cancer, and pancreatic cancer, characterized in that: On the basis of administering capecitabine and oxaliplatin to the patient, a therapeutically effective amount of paclitaxel cationic liposome is further administered in combination.

7. The use according to claim 1 or 2, or the method according to any one of claims 3 to 6, characterized in that The advanced solid tumors include digestive tract tumors, including gastric cancer, esophageal cancer, pancreatic cancer, colorectal cancer, bile duct cancer, liver cancer, lung cancer, gynecological tumors, including ovarian cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, and liver metastases.

8. The use according to claim 1 or 2, or the method according to any one of claims 3 to 6, characterized in that The advanced solid tumors include gastric cancer, pancreatic cancer, and colorectal cancer liver metastases. Preferably, the advanced solid tumor includes untreated liver metastases, including gastric cancer liver metastases, colorectal cancer liver metastases, and pancreatic cancer liver metastases.

9. The method according to any one of claims 3 to 8, characterized in that In terms of paclitaxel, the therapeutically effective amount of the paclitaxel cationic liposome is 5-100 mg / m 2 , preferably 5-80 mg / m 2 , further preferably 11-55 mg / m 2 , or more preferably 24-70 mg / m 2 , or any value within the range, including, 11 mg / m 2 , 22mg / m 2 , 24 mg / m 2 , 33mg / m 2 , 36mg / m 2 , 44mg / m 2 , 48mg / m 2 , 55mg / m 2 , 60mg / m 2 , 70mg / m 2 Preferably, the administration method of paclitaxel cationic liposomes is arterial infusion. Preferably, the administration cycle is once every 3 weeks for 6-8 cycles.

10. The use according to claim 1 or 2, or the method according to any one of claims 3 to 8, characterized in that The paclitaxel cationic liposomes contain: paclitaxel, dioleoylphosphatidylcholine (DOPC), (2,3-dioleyloxypropyl)trimethylammonium chloride (DOTAP) and trehalose; preferably, each preparation of the paclitaxel cationic liposomes contains 5-10 mg of paclitaxel, 72-144 mg of dioleoylphosphatidylcholine, 68-136 mg of (2,3-dioleyloxypropyl)trimethylammonium chloride and 1500-2500 mg of trehalose.

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