Combined administration of irinotecan lipidosome for treating colorectal cancer

Abstract

The invention relates to irinotecan liposome combined administration for treating colorectal cancer. Specifically, the invention relates to application of irinotecan lipidosome combined with oxaliplatin, 5-fluorouracil, calcium folinate and bevacizumab in preparation of medicines for treating colorectal cancer, and the irinotecan lipidosome contains hydrogenated soybean lecithin, polyethylene glycol 2000-distearoyl phosphatidyl ethanolamine and cholesterol.

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to the use of irinotecan liposomes in combination with oxaliplatin, 5-fluorouracil, calcium folinate and bevacizumab in the preparation of a drug for treating colorectal cancer. Background Art

[0002] Globally, colorectal cancer (CRC) is the third most common malignant tumor and the second most common cause of death from malignant tumors, and has become a major global public health issue. In my country, with the continuous improvement of living standards and changes in lifestyle, the incidence of colorectal cancer has also increased, ranking second in urban malignant tumor incidence (33.17 / 100,000) and fourth in mortality (15.98 / 100,000), and fifth in rural malignant tumor incidence (19.71 / 100,000) and mortality (9.68 / 100,000). In addition, since the early symptoms of CRC are not obvious, about 30% of patients have progressed to the late stage or metastasis when diagnosed, and more than 50% of early CRC patients will eventually relapse and metastasize, resulting in a large base of late or metastatic CRC patients and a heavy disease burden. Improving survival status has always been an important goal of late-stage CRC treatment.

[0003] The National Comprehensive Cancer Network (NCCN) guidelines strongly recommend the use of FOLFOX (fluorouracil, oxaliplatin, leucovorin), FOLFIRI (fluorouracil, irinotecan, leucovorin), or XELOX (capecitabine, oxaliplatin) as first-line treatment for patients with unresectable advanced colorectal cancer. In addition, the NCCN guidelines recommend the selection of targeted therapy drugs based on tumor location and RAS / BRAF gene status, such as biologics targeting vascular endothelial growth factor (VEGF) (bevacizumab) and biologics targeting epidermal growth factor receptor (EGFR) (such as cetuximab).

[0004] According to reported data, the median progression-free survival (PFS) of FOLFOX / FOLFIRI / XELOX combined with bevacizumab as first-line treatment for patients with unresectable advanced colorectal cancer is approximately 9.5 months, and the median overall survival (OS) is less than two years, and there is still much room for improvement in efficacy.

[0005] Clinical studies have shown that the combination of irinotecan + oxaliplatin + fluorouracil (FOLFOXIRI) combined with bevacizumab for the first-line treatment of advanced mCRC has improved efficacy compared with the standard two-drug regimen, but the incidence of severe neutrophil count decrease and diarrhea is significantly increased, which may lead to treatment interruption or intolerance of related toxicity, and its clinical application is relatively limited. The 2022 version of the NCCN guidelines only recommends the combination of irinotecan + oxaliplatin + fluorouracil + bevacizumab as the first-line standard treatment for unresectable advanced CRC with excellent performance; the 2022 version of the Chinese Society of Clinical Oncology (CSCO) colorectal cancer diagnosis and treatment guidelines does not use the FOLFIRINOX / FOLFOXIRI three-drug combination as the preferred first-line standard treatment for the palliative treatment group of advanced CRC.

[0006] Irinotecan is a semi-synthetic derivative of camptothecin and a cycle-specific anticancer drug that acts in the S phase. The current commercially available preparations are irinotecan hydrochloride injection and its lyophilized powder injection preparation. After intravenous administration, the free drug is directly in an alkaline physiological environment, and the lactone ring in its structure is easily hydrolyzed and converted into a carboxylate form, thereby losing its activity and reducing the efficacy of the drug; and the preparation has significant toxic and side effects, mainly manifested as severe neutropenia and severe delayed diarrhea. Summary of the invention

[0007] The present invention discloses an irinotecan liposome, and uses the irinotecan liposome in combination with oxaliplatin, 5-fluorouracil, calcium folinate and bevacizumab in preparing a drug for treating colorectal cancer. The irinotecan liposome contains hydrogenated soybean lecithin, polyethylene glycol 2000-distearoylphosphatidylethanolamine and cholesterol.

[0008] In some embodiments, the liposomes contain the following ingredients in the following weight ratios:

[0009]

[0010] In some embodiments, the weight ratio of cholesterol to hydrogenated soy lecithin is 1:4.

[0011] In some embodiments, the liposomes contain the following ingredients in the following weight ratios:

[0012]

[0013] The weight ratio of cholesterol to hydrogenated soy lecithin is 1:4.

[0014] The liposomes disclosed herein can be prepared according to conventional liposome preparation methods in the art, for example, using an ion gradient method. When using the ion gradient method, there is an ion gradient formed by a buffer between the internal aqueous phase and the external aqueous phase of the liposome, for example, the internal aqueous phase of the liposome has an ion gradient with a high ion concentration than the external aqueous phase, which can improve the particle size stability of the liposome during storage and better maintain the drug efficacy, which can control the average particle size of the liposome to be small and uniform, and can minimize the change of the liposome particle size during the storage period.

[0015] In some embodiments, the method for generating the ion gradient of the aqueous phase inside and outside the liposome membrane of the present disclosure is: replacing the aqueous phase outside the blank liposome to generate an ion gradient between the aqueous phase inside the liposome and the aqueous phase outside the liposome; for example, using a phosphate buffer with a pH of 5.0-7.0 as the replacement medium of the liposome; the phosphate buffer is selected from one or more Li + , K + 、Na + , Fe 2+ , Ca 2+ Mg 2+ , Ba 2+ , Mn 2+ NH4 + or H + Ionic salts.

[0016] The liposomes may further contain charged phospholipids, which are selected from one or more of dilauroylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dioleoylphosphatidylserine, dioleoylphosphatidylglycerol, dilauroylphosphatidic acid, dimyristoylphosphatidic acid or distearoylphosphatidic acid, and the weight ratio of the charged phospholipids to the neutral phospholipids is 1:5 to 1:100.

[0017] The present disclosure also provides a liposome injection containing the liposome. When the liposome is prepared into an injection suitable for use, it is beneficial to add a stabilizer, the stabilizer is selected from one or more of ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid dicalcium salt, and ethylenediaminetetraacetic acid calcium sodium salt, and the addition ratio of the stabilizer is 0% to 0.5w / v% and the lower limit is not 0%.

[0018] The injection may be in the form of an injection solution or a freeze-dried powder injection. The preparation may contain an osmotic pressure regulator, which is selected from one or more of glucose, sucrose, sorbitol, mannitol, sodium chloride, glycerol, histidine and its hydrochloride, glycine and its hydrochloride, lysine, serine, glutamic acid, arginine or valine, and the addition ratio of the osmotic pressure regulator is 0% to 5w / v% and the lower limit is not 0%.

[0019] In some embodiments, the liposome injection further contains an antioxidant, which can be selected from a water-soluble antioxidant or an oil-soluble antioxidant, the oil-soluble antioxidant is selected from α-tocopherol, α-tocopheryl succinate, α-tocopheryl acetate or a mixture thereof, the water-soluble antioxidant is selected from ascorbic acid, sodium bisulfite, sodium sulfite, sodium metabisulfite, L-cysteine ​​or a mixture thereof, and the added ratio of the antioxidant is 0% to 0.5w / v% and the lower limit is not 0%.

[0020] For the preparation in the form of freeze-dried powder, the injection further contains a freeze-dried protective agent, and after freeze-drying, a liposome freeze-dried powder injection is obtained. The freeze-dried protective agent is selected from one or more of glucose, sucrose, trehalose, mannitol, dextran or lactose.

[0021] In some embodiments, the injectable liposome contains the following ingredients in a weight ratio:

[0022]

[0023] The weight ratio of cholesterol to hydrogenated soy lecithin is 1:4.

[0024] In some embodiments, the colorectal cancer is selected from colon or rectal adenocarcinoma.

[0025] In some embodiments, the colorectal cancer is metastatic colorectal cancer, such as unresectable metastatic colorectal cancer.

[0026] In some embodiments, the colorectal cancer is unresectable metastatic colorectal cancer that has not received any previous systemic anti-tumor treatment.

[0027] In some embodiments, the dosage of irinotecan liposomes administered to a subject is selected from 10 to 150 mg / m 2 , for example 30-70 mg / m 2 , for example 36 mg / m 2 、48 / m 2 , 60mg / m 2 , non-limiting examples include: 10 mg / m 2 , 20mg / m 2 , 30mg / m 2 , 40mg / m 2 , 50mg / m 2 , 60mg / m 2 , 70mg / m 2 , 80mg / m 2 , 90mg / m 2 , 100mg / m 2 , 120mg / m 2 , 130mg / m2 , 140mg / m 2 , 150mg / m 2 Or any value between any two numbers, the administration frequency is once every 2 weeks.

[0028] In some embodiments, the dosage of oxaliplatin administered to the subject is selected from 10 to 150 mg / m 2 , for example 30-100 mg / m 2 , for example 51 mg / m 2 , 68mg / m 2 , 85mg / m 2 , non-limiting examples include: 10 mg / m 2 , 20mg / m 2 , 30mg / m 2 , 40mg / m 2 , 50mg / m 2 , 60mg / m 2 , 70mg / m 2 , 80mg / m 2 , 85mg / m 2 , 90mg / m 2 , 100mg / m 2 , 120mg / m 2 , 130mg / m 2 , 140mg / m 2 , 150mg / m 2 Or any value between any two numbers, the administration frequency is once every 2 weeks.

[0029] In some embodiments, the 5-FU is administered to the subject at a dose selected from 500 to 5000 mg / m 2 , for example 1500~3000mg / m 2 , for example 1680mg / m 2 , 1920mg / m 2 , 2400 / m 2 , 2800mg / m 2 , non-limiting examples include: 500 mg / m 2 , 550mg / m 2 , 1000mg / m 2 , 1100mg / m 2 , 1200mg / m 2 , 1300mg / m 2 , 1400mg / m 2 , 1500mg / m 2 , 1600mg / m 2 , 1700mg / m2 , 1800mg / m 2 , 1900mg / m 2 , 2000mg / m 2 , 2100mg / m 2 , 2200mg / m 2 , 2300mg / m 2 , 2400mg / m 2 , 2500mg / m 2 , 2800mg / m 2 , 3000mg / m 2 , 3500mg / m 2 4000mg / m 2 4500mg / m 2 , 5000mg / m 2 Or any value between any two numbers, the administration frequency is once every 2 weeks.

[0030] In some embodiments, the dosage of calcium folinate administered to the subject is selected from 50 to 500 mg / m 2 , for example 100-450 mg / m 2 , for example 400 mg / m 2 , non-limiting examples include: 50 mg / m 2 , 100mg / m 2 , 110mg / m 2 , 120mg / m 2 , 130mg / m 2 , 140mg / m 2 , 150mg / m 2 , 160mg / m 2 , 170mg / m 2 , 180mg / m 2 , 190mg / m 2 , 200mg / m 2 , 210mg / m 2 , 220mg / m 2 , 230mg / m 2 , 240mg / m 2 , 250mg / m 2 , 260mg / m 2 , 270mg / m 2 , 280mg / m 2 , 290mg / m 2 , 300mg / m 2 , 350mg / m 2 , 400mg / m 2 , 450mg / m2 , 500mg / m 2 Or any value between any two numbers, the administration frequency is once every 2 weeks.

[0031] In some embodiments, the dosage of bevacizumab administered to the subject is selected from 0.1-100 mg / kg, for example 5 mg / kg, non-limiting examples include: 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 12.5 mg / kg, 12 mg / kg, 15 mg / kg, 17.5 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg or any value in between, and the dosage frequency is once every 2 weeks.

[0032] In the present disclosure, the particle size of the irinotecan liposome is selected from 50 nm to 120 nm, such as 80 nm to 100 nm.

[0033] In another aspect, the present disclosure also provides a method for treating colorectal cancer, comprising co-administering effective amounts of irinotecan liposomes, oxaliplatin, bevacizumab, 5-FU, and LV to a patient.

[0034] In some embodiments, the calcium folinate described in the present disclosure is in the form of a racemate.

[0035] In some embodiments, the dosage of liposome irinotecan described in the present disclosure is based on irinotecan free base.

[0036] The "combination" and "co-administration" described in the present disclosure are a mode of administration, which refers to the administration of at least one dose of irinotecan liposomes, at least one dose of oxaliplatin, at least one dose of bevacizumab, at least one dose of 5-FU and at least one dose of LV within a certain time limit, wherein these substances all show pharmacological effects. The time limit can be within a dosing cycle, such as within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, such as within 12 hours. Irinotecan liposomes, oxaliplatin, bevacizumab, 5-FU and LV can be administered simultaneously or sequentially. This period includes such treatments, in which irinotecan liposomes, oxaliplatin, bevacizumab, 5-FU and LV are administered by the same route of administration or different routes of administration. The combined administration mode described in the present disclosure is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.

[0037] The content of irinotecan hydrochloride in the irinotecan liposome or the pharmaceutical composition containing irinotecan liposome described in the present disclosure is calculated as irinotecan hydrochloride trihydrate.

[0038] The "intolerance" mentioned in the present disclosure refers to: 1) hematological toxicity: grade III neutropenia accompanied by fever >38.5°C, grade III thrombocytopenia with bleeding symptoms, and other grade IV and above hematological toxic reactions; 2) non-hematological toxicity: grade III and above non-hematological toxic reactions; 3) when the above-mentioned toxic reactions are achieved, the researcher judges that it is not suitable to continue the original treatment plan.

[0039] The "treatment failure" mentioned in the present disclosure refers to the subject having measurable tumor lesions at baseline, which is disease progression (PD) or intolerance according to RECIST1.1 efficacy evaluation criteria.

[0040] Overall survival (OS) refers to the period from randomization to death from any cause. For subjects who are still alive at the last follow-up, their OS is counted as data loss based on the last follow-up time. For subjects who are lost to follow-up, their OS is counted as data loss based on the last confirmed survival time before loss of follow-up. OS with data loss is defined as the time from randomization to censoring.

[0041] Objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain level and remain shrinking for a certain period of time, including cases of CR and PR. The solid tumor response evaluation criteria (RECIST 1.1 standard) are used to assess the objective response of tumors. Subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to the RECIST 1.1 standard.

[0042] Complete remission (CR): All target lesions disappear and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm.

[0043] Partial response (PR): The sum of target lesion diameters decreased by at least 30% compared with the baseline level.

[0044] Disease progression (PD): The minimum value of the sum of all target lesion diameters measured during the entire experimental study is used as a reference, and the relative increase in the sum of diameters is at least 20% (if the baseline measurement value is the smallest, the baseline value is used as a reference); in addition, the absolute value of the sum of diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0045] Stable disease (SD): The target lesions have not decreased to the level of PR, nor have they increased to the level of PD, but are somewhere in between. The minimum value of the sum of diameters can be used as a reference for research.

[0046] Progression-free survival (PFS) is measured from randomization to the date of the first recorded objective tumor progression or death from any cause, whichever occurs first. It is evaluated according to the RECIST 1.1 standard, and the analysis of this indicator includes the tumor evaluation results during the study treatment and follow-up period. If a patient has several indicators that can be judged as PD, such as recurrence, new lesions, or death, the first indicator to appear is used for PFS analysis; if the patient changes to other treatment options or anti-tumor treatment for target lesions, it is also considered as tumor progression and is used as deleted data.

[0047] Time to treatment failure (TTF) was defined as the period from randomization to disease progression or death or study discontinuation due to toxicity, including patient withdrawal. DETAILED DESCRIPTION

[0048] The present invention is further described below with reference to the examples, but these examples are not intended to limit the scope of the present invention. The irinotecan liposomes disclosed herein are prepared according to the method in patent CN102271659B, which is cited in its entirety, wherein the content of irinotecan hydrochloride is calculated as irinotecan hydrochloride trihydrate.

[0049] Example 1 A randomized, double-blind, parallel-controlled, multicenter phase II / III clinical study of irinotecan liposomes combined with oxaliplatin, 5-fluorouracil, leucovorin, and bevacizumab versus FOLFOX combined with bevacizumab as first-line treatment for advanced colorectal cancer

[0050] 1. Inclusion criteria

[0051] 1. Aged ≥18 and ≤75 years old, both male and female;

[0052] 2. Patients with histopathologically confirmed unresectable metastatic colon or rectal adenocarcinoma (i.e., stage IV according to the UICC / AJCC TNM staging system (8th edition, 2017));

[0053] 3. Patients with unresectable metastatic disease have not received any systemic anti-tumor treatment (including but not limited to systemic chemotherapy, molecular targeted drug therapy, immunotherapy, biological therapy, and other research therapeutic drugs, etc.);

[0054] 4. For subjects who have previously received neoadjuvant or adjuvant therapy, the first date of progression must be ≥6 months apart from the last date of neoadjuvant or adjuvant therapy administration.

[0055] 2 Experimental drugs

[0056] Irinotecan hydrochloride liposome injection: produced by Jiangsu Hengrui Medicine Co., Ltd., specification 8mL: 37.66mg (according to C 33 H 38 N4O6);

[0057] Commercially available 5-fluorouracil injection (5-FU), commercially available folinic acid injection (LV), commercially available oxaliplatin for injection, and commercially available bevacizumab injection.

[0058] 3 Dosage regimen

[0059] One treatment cycle is two weeks. If the patient is intolerant to the drug due to toxicity or side effects, the dosage can be adjusted according to the actual situation.

[0060] 3.1 Treatment groups

[0061] Bevacizumab: 5 mg / kg, given on D1, once every 2 weeks.

[0062] Oxaliplatin: 85 mg / m 2 , given on D1, once every 2 weeks.

[0063] Liposomal irinotecan: 60 mg / m 2 , given on D1, once every 2 weeks.

[0064] LV: 400 mg / m 2 , given on D1, once every 2 weeks.

[0065] 5-FU: 2400 mg / m 2 , given on D1, once every 2 weeks.

[0066] Order of administration: bevacizumab, oxaliplatin, liposomal irinotecan, LV and 5-FU were given in sequence.

[0067] 3.2 Control group

[0068] Bevacizumab: 5 mg / kg, given on D1, once every 2 weeks.

[0069] Oxaliplatin: 85 mg / m 2 , given on D1, once every 2 weeks.

[0070] Placebo: irinotecan liposome mimetic, administration method is the same as irinotecan liposome;

[0071] LV: 400 mg / m 2 , given on D1, once every 2 weeks.

[0072] 5-FU: 2800 mg / m 2 , given on D1, once every 2 weeks.

[0073] Dosage order: bevacizumab, oxaliplatin, placebo, LV and 5-FU were given in sequence.

[0074] Imaging assessment was performed every 8 weeks (±7 days) to examine the disease progression of the patients.

[0075] 3 Test results

[0076] Currently, 36 patients have been enrolled in the treatment group. Among them, 36 subjects achieved PR with BOR, and the ORR was 72.22%. In terms of efficacy, the ORR of the treatment group was 72.22%, which was higher than the objective response rate of previous irinotecan-related studies, showing good anti-tumor activity of the combination drug; in terms of safety, the treatment group showed good tolerability. In summary, the treatment group has great clinical potential for first-line treatment of advanced colorectal cancer.

[0077] Table 1. Summary of efficacy of objective response rate

[0078] Efficacy Dose Group 2 n 36 PR, n 26 SD, n 5 PD, n 1 NE, n 4 ORR, % 72.22％ DCR,% 86.11％

[0079] Table 2: Summary of TRAEs of grade 3 or above by system organ and preferred terminology

[0080]

Claims

1. Use of irinotecan liposomes in combination with oxaliplatin, 5-fluorouracil, calcium folinate and bevacizumab in the preparation of a drug for treating colorectal cancer, wherein the irinotecan liposomes contain hydrogenated soybean lecithin, polyethylene glycol 2000-distearoylphosphatidylethanolamine and cholesterol.

2. The method according to claim 1, wherein the liposome contains the following ingredients in a weight ratio:

3. The use according to claim 1 or 2, wherein the weight ratio of cholesterol to hydrogenated soybean lecithin is 1:

4.

4. The use according to any one of claims 1 to 3, wherein the liposome is prepared by an ion gradient method.

5. The use according to claim 4, wherein there is an ion gradient formed by a buffer between the intra-liposome aqueous phase and the external aqueous phase. The liposome according to claim 5 , wherein the internal aqueous phase of the liposome has an ion gradient with a high ion concentration compared to the external aqueous phase.

7. The use according to any one of claims 1 to 6, wherein the liposome further contains a charged phospholipid, which is selected from one or more of dilauroylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dioleylphosphatidylserine, dioleoylphosphatidylglycerol, dilauroylphosphatidic acid, dimyristoylphosphatidic acid or distearoylphosphatidic acid, and the weight ratio of the charged phospholipid to hydrogenated soybean lecithin is 1:5 to 1:

100.

8. The use according to any one of claims 1 to 7, wherein the liposome is an injection.

9. The use according to claim 8, wherein the injection contains a stabilizer, the stabilizer is selected from one or more of ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, dicalcium ethylenediaminetetraacetic acid, and sodium calcium ethylenediaminetetraacetic acid, the addition ratio of the stabilizer is 0% to 0.5w / v% and the lower limit is not 0%, preferably disodium ethylenediaminetetraacetic acid or sodium calcium ethylenediaminetetraacetic acid.

10. The use according to claim 8, wherein the injection is an injection solution or a lyophilized powder injection.

11. The use according to claim 8, wherein the injection contains an osmotic pressure regulator, which is selected from one or more of glucose, sucrose, sorbitol, mannitol, sodium chloride, glycerol, histidine and its hydrochloride, glycine and its hydrochloride, lysine, serine, glutamic acid, arginine or valine, and the addition ratio of the osmotic pressure regulator is 0% to 5w / v% and the lower limit is not 0%.

12. The use according to claim 8, wherein the injection further contains an antioxidant, the antioxidant is selected from a water-soluble antioxidant or an oil-soluble antioxidant, the oil-soluble antioxidant is selected from α-tocopherol, α-tocopheryl succinate, α-tocopheryl acetate or a mixture thereof, the water-soluble antioxidant is selected from ascorbic acid, sodium bisulfite, sodium sulfite, sodium metabisulfite, L-cysteine ​​or a mixture thereof, and the addition ratio of the antioxidant is 0% to 0.5 w / v% and the lower limit is not 0%.

13. The use according to claim 10, wherein the injection is a freeze-dried powder injection, which contains a freeze-dried protective agent and is a liposome freeze-dried powder injection prepared by freeze drying.

14. The use according to claims 8-13, wherein the liposome injection contains the following ingredients in a weight ratio:

15. The use according to any one of claims 1-14, wherein the colorectal cancer is metastatic colorectal cancer, preferably unresectable metastatic colorectal cancer, more preferably unresectable metastatic colorectal cancer that has not received any systemic anti-tumor treatment in the past.

16. The use according to any one of claims 1 to 15, wherein the dosage of irinotecan liposome is selected from 10 to 150 mg / m 2 , preferably 30-70 mg / m 2 , more preferably 60 mg / m 2 .

17. The use according to any one of claims 1 to 16, wherein the dosage of oxaliplatin is selected from 10 to 150 mg / m 2 , preferably 30-100 mg / m 2 , more preferably 85 mg / m 2 .

18. The use according to any one of claims 1 to 17, wherein the dosage of 5-fluorouracil is selected from 500 to 5000 mg / m 2 , preferably 1500~300mg / m 2 , more preferably 2400 mg / m 2 .

19. The use according to any one of claims 1 to 18, wherein the dosage of calcium folinate is selected from 50 to 500 mg / m 2 , preferably 100-450 mg / m 2 , more preferably 400 mg / m 2 .

20. The use according to any one of claims 1-19, wherein the dosage of bevacizumab is selected from 0.1-100 mg / kg, preferably 5 mg / kg.

21. The use according to any one of claims 1 to 20, wherein the particle size of the irinotecan liposome is selected from 50 nm to 120 nm, preferably 80 nm to 100 nm.

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