Use of docetaxel-albumin composition in treatment of gastric cancer or gastroesophageal junction cancer

Abstract

Use of a docetaxel-albumin composition in the preparation of a drug for treating gastric cancer or gastroesophageal junction cancer, a method for treating gastric cancer or gastroesophageal junction cancer using the docetaxel-albumin composition, and a drug or kit comprising the docetaxel-albumin composition for treating gastric cancer or gastroesophageal junction cancer. The docetaxel-albumin composition can treat gastric cancer or gastroesophageal junction cancer.

Description

Use of docetaxel albumin combination for the treatment of gastric cancer or gastroesophageal junction cancer

[0001] Related applications

[0002] This application claims priority and related interests in Chinese Patent Application No. 202410572391.8, filed on May 10, 2024, and Chinese Patent Application No. 202510037621.5, filed on January 10, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application belongs to the pharmaceutical field and specifically relates to the use of a docetaxel albumin composition for the treatment of gastric cancer or gastroesophageal junction cancer. Background Technology

[0004] Gastric cancer is a malignant tumor originating from lesions of the gastric mucosal epithelium. According to statistics from the International Agency for Research on Cancer (IARC) of the World Health Organization, in 2018, there were 1.033 million new cases of gastric cancer globally (accounting for 5.7%), and 783,000 deaths (accounting for 8.2%), ranking fifth in incidence and third in mortality among malignant tumors. China is a high-incidence area for gastric cancer. The latest data from the China Cancer Registry Center estimates that in 2015, there were approximately 679,000 new cases of gastric cancer in China, including 478,000 men and 201,000 women; and approximately 498,000 deaths, including 339,000 men and 159,000 women. China accounts for 42.6% of global gastric cancer cases and 45.0% of global deaths, both ranking second among all malignant tumors. The incidence of gastric cancer shows significant regional differences, with East Asia having a much higher incidence rate than other regions. In my country, the incidence rate of gastric cancer is significantly higher in the northwest and eastern coastal areas than in the southern regions. Stomach cancer typically occurs in individuals over 50 years of age, with a male-to-female ratio of 2:1. However, rapid economic development, severe environmental pollution, changes in dietary habits, and Helicobacter pylori infection are contributing factors, leading to a trend of stomach cancer affecting younger individuals. Stomach cancer can occur in any part of the stomach, with more than half developing in the antrum. The greater curvature, lesser curvature, and anterior and posterior walls of the stomach can all be affected. In recent years, there has been a trend towards higher sites of onset for stomach cancer, but the antrum remains the most common primary site for advanced-stage stomach cancer.

[0005] In recent years, the incidence of gastroesophageal junction cancer has shown a rapid upward trend. Especially in Western countries, adenocarcinoma of the esophagogastric junction (AEG) has become one of the fastest-growing tumors. The widely accepted classification method for AEG is the Siewert classification. The Siewert classification defines AEG cancer as cancer centered at the esophagogastric junction (EGJ) and within 5 cm proximal and distal to it, and further subdivides it into three types: Type I: distal esophageal cancer, with the tumor centered 1-5 cm above the EGJ; Type II: cardia cancer, with the tumor centered 1 cm above and 2 cm below the EGJ; and Type III: subcardia cancer, with the tumor centered 2-5 cm below the EGJ. The Siewert classification lays the foundation for rational surgical treatment plans; different surgical approaches and treatment strategies should be adopted for different types of AEG cancer.

[0006] The vast majority of gastric cancers and gastroesophageal junction cancers are adenocarcinomas. Early stages often present with no obvious symptoms, or nonspecific symptoms such as upper abdominal discomfort and belching, which are easily mistaken for symptoms of chronic diseases like gastritis and gastric ulcers. Therefore, the early diagnosis rate of gastric cancer and gastroesophageal junction cancer in my country remains low. Most patients are diagnosed at middle or late stages, losing the opportunity for surgical cure, lacking effective treatment options, and resulting in a very poor prognosis. The stomach is a vital digestive organ, and the presence of the primary lesion directly affects the patient's nutritional status and may also lead to various complications such as bleeding, gastrointestinal obstruction, and gastrointestinal perforation.

[0007] Currently, surgical resection remains the primary treatment for gastric cancer and gastroesophageal junction cancer. However, since most patients are diagnosed at middle or late stages, the surgical resection rate is only around 50%, and the efficacy of surgery alone is poor, with a five-year survival rate of only 20%–30%. Therefore, the current treatment principle for advanced gastric and gastroesophageal junction cancer remains a comprehensive approach, primarily based on systemic chemotherapy, including systemic chemotherapy, surgical resection, radiotherapy, targeted therapy, and immunotherapy. Recent data have confirmed that chemotherapy before surgery can effectively reduce tumor size, eliminate distant metastases, and further reduce the risk of tumor metastasis and recurrence.

[0008] Chemotherapy is used preoperatively, intraoperatively, and postoperatively for radical surgery to prolong survival, and there is now substantial evidence-based medicine and rich clinical experience. Treatment of metastatic gastric cancer and gastroesophageal junction cancer is challenging, especially with limited second- and third-line drug options and unsatisfactory efficacy. Traditional chemotherapy drugs for gastric and gastroesophageal junction cancer include fluorouracil, cisplatin, mitomycin C, and doxorubicin, but the efficacy of single-agent or combination regimens is relatively low. With the advent of new drugs such as taxanes, irinotecan, oxaliplatin, capecitabine, and tegafur, patients' progression-free survival and overall survival have been prolonged to varying degrees. Fluorouracil, platinum, and taxanes are the main chemotherapy drugs for advanced gastric cancer, especially taxanes, which have shown sufficient efficacy and safety in clinical research and practice. Currently, all phase III studies on second-line chemotherapy for gastric cancer have used single-agent therapy.

[0009] Docetaxel is a semi-synthetic preparation derived from a non-cytotoxic precursor (10-deacetylated gibberellin III) extracted from the needles of the yew tree. It is a paclitaxel analogue with stronger antitumor activity than paclitaxel. Docetaxel has poor water solubility; currently, the commercially available formulation is its standard injectable solution, originally developed by Sanofi under the brand name TAXOTERE. The usual dosage is once every 3 weeks, administered via intravenous infusion over 1 hour, at a dose of 75 mg / m². 2 However, with Docetaxel injection, for example, is prone to causing severe allergic reactions due to the use of ethanol and Tween 80 in its formulation, requiring dexamethasone pretreatment and resulting in poor patient compliance. In addition, ethanol can affect the central nervous system, necessitating a reduction in the infusion rate to alleviate toxicity symptoms.

[0010] Human serum albumin is an endogenous substance in the human body with excellent biocompatibility. It can serve as a natural carrier for hydrophobic drugs, increasing the solubility of poorly soluble drugs. Furthermore, albumin's unique "gp60-SPARC" channel allows drugs to accumulate in the tumor area, thereby enhancing therapeutic efficacy. Currently, researchers worldwide are exploring the use of human serum albumin to develop albumin-bound drugs.

[0011] WO2022184164A1 discloses a docetaxel albumin composition. Studies show that both the pre-lyophilized suspension and the post-lyophilized reconstituted suspension are stable for at least 24 hours at room temperature and at least 10 days under refrigeration, without suspension turbidity or nanoparticle sedimentation. Compared to commercially available albumin-bound products where the reconstituted suspension is only stable for 8 hours, this product significantly reduces limitations for clinical use. However, the efficacy and safety of the docetaxel albumin composition in treating gastric cancer or gastroesophageal junction cancer have not yet been established. Summary of the Invention

[0012] This application aims to provide the use of a docetaxel albumin composition in the preparation of a medicament for treating gastric cancer or gastroesophageal junction cancer. The docetaxel albumin composition is used in conjunction with commercially available docetaxel injection (…). Compared to TAXOTERE, it does not contain Tween-80 or ethanol, allowing for rapid administration of high concentrations without the need for dexamethasone pretreatment, and offers significant advantages in terms of safety and patient compliance. Clinical studies have shown that docetaxel albumin combination therapy has better efficacy and safety in treating gastric cancer or gastroesophageal junction cancer.

[0013] A first aspect of this application provides the use of a docetaxel albumin composition in the preparation of a medicament for treating gastric cancer or gastroesophageal junction cancer.

[0014] In some embodiments, the gastric cancer or gastroesophageal junction cancer is squamous cell carcinoma or adenocarcinoma, preferably adenocarcinoma.

[0015] In other embodiments, the gastric cancer is selected from gastric cancers occurring in the antrum, greater curvature, lesser curvature, or anterior and posterior walls of the stomach.

[0016] In some other embodiments, the gastroesophageal junction cancer is selected from cancers whose tumor center is located within 5 cm above or below the gastroesophageal junction. In some other embodiments, the gastroesophageal junction cancer is selected from: (1) cancers whose tumor center is within 2 cm below the gastroesophageal junction, but whose tumor has not invaded the gastroesophageal junction upwards; (2) cancers whose tumor center is within 2 cm to 5 cm below the gastroesophageal junction.

[0017] In other embodiments, the gastric cancer is locally advanced or metastatic gastric cancer, preferably locally advanced or metastatic gastric adenocarcinoma.

[0018] In other embodiments, the gastroesophageal junction cancer is locally advanced or metastatic gastroesophageal junction cancer, preferably locally advanced or metastatic gastroesophageal junction adenocarcinoma.

[0019] In some embodiments, the gastric cancer is locally advanced or metastatic gastric adenocarcinoma that has progressed after systemic treatment; and / or the gastroesophageal junction cancer is locally advanced or metastatic gastroesophageal junction adenocarcinoma that has progressed after systemic treatment. In some embodiments, the systemic treatment is selected from one or more of chemotherapy, surgical resection, radiotherapy, targeted therapy, and immunotherapy. In some embodiments, the systemic treatment is selected from one or more of platinum-based chemotherapy and / or fluorouracil-based chemotherapy and immunotherapy. In some embodiments, the platinum-based chemotherapy is selected from one or more of cisplatin, carboplatin, nedaplatin, lobaplatin, and oxaliplatin. In some embodiments, the fluorouracil-based chemotherapy is selected from one or more of 5-fluorouracil, tegafur, tegafur, eufovir, and capecitabine. In some embodiments, the immunotherapy is selected from one or more of pembrolizumab, nivolumab, camrelizumab, tislelizumab, toripalimab, and sintilimab. In other embodiments, the gastric cancer is selected from gastric cancers that are Her-2 negative or positive; and / or the gastroesophageal junction cancer is selected from gastroesophageal junction cancers that are Her-2 negative or positive.

[0020] In some embodiments, this application also provides the use of the docetaxel albumin composition in combination with other drugs in the preparation of a medicament for treating gastric cancer or gastroesophageal junction cancer. In some embodiments, the other drugs are clinically applicable in combination with docetaxel for antitumor therapy.

[0021] In some embodiments, the other drug is selected from granulocyte-stimulating factor (G-CSF), such as pegylated recombinant human granulocyte-stimulating factor injection.

[0022] In some implementations, the gastric cancer or gastroesophageal junction cancer is as described above.

[0023] A second aspect of this application provides a method for treating gastric cancer or gastroesophageal junction cancer, comprising the following steps:

[0024] 1) Administer a therapeutically effective dose of docetaxel albumin composition to patients with gastric cancer or gastroesophageal junction cancer who require treatment.

[0025] In some implementations, step 1) is preceded by the following step: determining the type of Her-2 expression in the patient using genetic testing.

[0026] In some implementations, the gastric cancer or gastroesophageal junction cancer is as described in the first aspect.

[0027] In some embodiments, the administration is by intravenous infusion, and the therapeutically effective dose is 50-125 mg / m². 2Preferably 60-100 mg / m 2 For example, the effective therapeutic dose is 100 mg / m². 2 Or 75mg / m 2 Or 60mg / m 2 In some embodiments, the docetaxel albumin composition is administered once every 3-4 weeks, preferably once every 3 weeks. In some embodiments, each intravenous infusion takes 30-90 minutes, preferably 60 minutes ± 10 minutes. In a preferred embodiment, the therapeutically effective dose is 100 mg / m². 2 Administer once every 3 weeks, with an intravenous infusion time of 60 min ± 10 min.

[0028] In some embodiments, the treatment further includes the following step: 2) administering a clinically acceptable amount of another drug (such as an antitumor drug) to the patient requiring treatment for gastric cancer or gastroesophageal junction cancer concurrently with, before, or after administration of the docetaxel albumin composition. For example, administering the other drug 24-72 hours after administration of the docetaxel albumin composition described in this application.

[0029] In some embodiments, the other drug is selected from granulocyte-stimulating factor (G-CSF), such as pegylated recombinant human granulocyte-stimulating factor injection (trade name: For example, administering PEGylated recombinant human granulocyte colony-stimulating factor injection 24-72 hours after administering the docetaxel albumin composition described in this application.

[0030] In some implementations, the treatment includes the following steps:

[0031] 1) Administer a therapeutically effective dose of docetaxel albumin composition to patients with gastric cancer or gastroesophageal junction cancer who require treatment.

[0032] 2) 48 hours after administration of the docetaxel albumin composition described in this application, administer PEGylated recombinant human granulocyte colony-stimulating factor injection.

[0033] A third aspect of this application provides a medicament for treating gastric cancer or gastroesophageal junction cancer, comprising a docetaxel albumin composition and optionally, a pharmaceutically acceptable carrier.

[0034] In some implementations, the gastric cancer or gastroesophageal junction cancer is as described in the first aspect.

[0035] In some embodiments, the drug also contains other clinically or pharmaceutically acceptable drugs (such as antitumor drugs). The docetaxel albumin composition described in this application, along with other drugs (such as antitumor drugs), can be formulated separately into pharmaceutically acceptable formulations, and further combined and packaged to obtain the final product; or, where pharmaceutically acceptable, different active ingredients can be contained in the same formulation product.

[0036] In some embodiments, the other drug is selected from granulocyte-stimulating factor (G-CSF), such as pegylated recombinant human granulocyte-stimulating factor injection.

[0037] A fourth aspect of this application provides a medicine box for treating gastric cancer or gastroesophageal junction cancer, comprising a docetaxel albumin composition and a drug instruction manual or drug label indicating the dosage and administration of the drug.

[0038] In some embodiments, the dosage and administration include: intravenous infusion, wherein the dosage is 50-125 mg / m². 2 Preferred concentration: 60-100 mg / m³ 2 For example, 100mg / m 2 Or 75mg / m 2 Or 60mg / m 2 The drug is administered once every 3-4 weeks, preferably once every 3 weeks; each intravenous infusion takes 30-90 minutes, preferably 60 minutes ± 10 minutes. More preferably, the dosage and administration method includes intravenous infusion at a dose of 100 mg / m². 2 Administer once every 3 weeks, with an intravenous infusion time of 60 min ± 10 min.

[0039] The fifth aspect of this application provides a docetaxel albumin composition, or a medicament or kit containing a docetaxel albumin composition, for the treatment of gastric cancer or gastroesophageal junction cancer.

[0040] In some implementations, the gastric cancer or gastroesophageal junction cancer is as described in the first aspect.

[0041] The treatments described in the first to fifth aspects above include alleviating or controlling disease progression and / or prolonging progression-free survival and / or overall survival of patients or subjects.

[0042] It should be understood that, within the scope of this application, the above-described technical features and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0043] The docetaxel albumin composition described in this application is prepared using conventional methods in the art for preparing albumin nanoparticle drugs. In some embodiments, the docetaxel albumin composition described in this application is prepared according to the method disclosed in International Application WO2022184164A1.

[0044] In some embodiments, the docetaxel albumin composition described in this application is a docetaxel albumin nanoparticle composition comprising docetaxel and acid-denatured albumin, optionally comprising an osmotic pressure regulator and / or a pH regulator. The acid-denatured albumin is obtained by denaturing human serum albumin by adding acid to adjust it to an appropriate pH value.

[0045] In a preferred embodiment, the acid is selected from acidic amino acids or acidic polypeptides, organic acids, and inorganic acids. The acidic amino acids or acidic polypeptides include, but are not limited to, cysteine ​​hydrochloride and glutathione; the organic acids include, but are not limited to, citric acid and tartaric acid; and the inorganic acids include, but are not limited to, hydrochloric acid and sulfuric acid. The acid is preferably cysteine ​​hydrochloride, glutathione, or hydrochloric acid, and more preferably cysteine ​​hydrochloride. In a preferred embodiment, the appropriate pH value is 3.5–5.5, preferably 3.5–5.0, more preferably 3.8–4.7, and most preferably 4.0–4.5. In a preferred embodiment, the mass ratio of docetaxel to human serum albumin, based on anhydrous docetaxel, is 1:(2.0–10.0), preferably 1:(3.0–7.0), and more preferably 1:(4.0–6.0). In a preferred embodiment, the content of sodium caprylate in the human serum albumin is not higher than 0.08 mmol / g protein, preferably 0.03-0.08 mmol / g protein, more preferably 0.04-0.08 mmol / g protein, and even more preferably 0.04-0.07 mmol / g protein.

[0046] In some embodiments, the docetaxel albumin nanoparticles have a particle size of about 60-200 nm, preferably 90-150 nm, and more preferably 90-135 nm.

[0047] The type of osmotic pressure regulator is not particularly limited, and may be selected from sodium chloride, glucose, phosphate, or citrate, etc., with sodium chloride being preferred. In some embodiments, the osmotic pressure regulator is sodium chloride, and the weight ratio of sodium chloride to docetaxel is (0.75-9):1, preferably (1-7):1, more preferably (1.5-4.5):1, and most preferably 2.25:1.

[0048] The type of pH adjuster is not particularly limited, and it is used to adjust the pH value to an appropriate range. In a preferred embodiment, the pH value range is 3.4-5.8; preferably 3.6-5.6, or 3.8-5.0, more preferably 3.9-4.8.

[0049] The docetaxel albumin composition described in this application has no special requirements regarding whether docetaxel is in hydrate form; it can be selected from any one of anhydrous docetaxel, docetaxel hemihydrate, or docetaxel trihydrate. The docetaxel content described in this application is based on anhydrous docetaxel.

[0050] The medicament described in this application comprises a docetaxel albumin composition. The medicament is in a clinically acceptable dosage form, preferably an injection, more preferably a liquid injection or a lyophilized powder injection. For example, the docetaxel for injection (albumin-bound) used in the specific embodiments is also known as DTX-HSA.

[0051] In some embodiments, the drug is a liquid injection, wherein the pH value of the liquid injection is 3.4-5.8, preferably 3.6-5.6, or 3.8-5.0, more preferably 3.9-4.8. The docetaxel albumin nanoparticles in the liquid injection have a particle size of approximately 60-200 nm, preferably 90-150 nm, more preferably 90-135 nm; the liquid injection contains 0-1.8% (w / v) sodium chloride, preferably 0.45%-1.8% (w / v), more preferably 0.9%-1.8% (w / v), and most preferably 0.9% (w / v). In some embodiments, the liquid injection contains 2-10 mg / ml of docetaxel, preferably 2-8 mg / ml.

[0052] In some embodiments, the drug is a lyophilized powder for injection containing sodium chloride, wherein the weight ratio of sodium chloride to docetaxel is (0.75-9):1, preferably (1-7):1; more preferably (1.5-4.5):1, and most preferably 2.25:1. In some embodiments, the docetaxel albumin nanoparticles have a particle size of about 60-200 nm, preferably 90-150 nm, and more preferably 90-135 nm. In some embodiments, the pH of the suspension used to prepare the lyophilized powder for injection before lyophilization is 3.4-5.8, preferably 3.6-5.6, or 3.8-5.0, and more preferably 3.9-4.8.

[0053] The lyophilized powder for injection is reconstituted into a suspension using a rehydration medium before use. In some embodiments, the rehydration medium is selected from water for injection, sodium chloride solution, or glucose solution, preferably water for injection. In some embodiments, the pH of the resulting reconstituted suspension is 3.4-5.8, preferably 3.6-5.6, or 3.8-5.0, more preferably 3.9-4.8. In some embodiments, the docetaxel albumin nanoparticles in the reconstituted suspension have a particle size of about 60-200 nm, preferably 90-150 nm, more preferably 90-135 nm. In some embodiments, the reconstituted suspension contains 0-1.8% (w / v) sodium chloride, preferably 0.45%-1.8% (w / v), more preferably 0.9%-1.8% (w / v), more preferably 0.9%. In some embodiments, the reconstituted suspension contains 2-10 mg / ml of docetaxel, preferably 2-8 mg / ml.

[0054] The method for preparing the docetaxel albumin composition described in this application includes the following steps:

[0055] (1) Docetaxel is dissolved in an organic solvent to obtain an organic phase solution;

[0056] (2) Take a human blood albumin solution, add acid to adjust the pH value to obtain an acid-denatured albumin aqueous phase solution; take another salt solution;

[0057] (3) Mix the organic phase solution, aqueous phase solution and salt solution to load the drug, and obtain the drug-loaded solution;

[0058] (4) Dialysis to obtain a dialysis suspension.

[0059] Step (2) may optionally include the step of diluting the human serum albumin solution with water for injection to obtain a diluted albumin solution before adding acid to adjust the pH value.

[0060] Step (2) may optionally include an incubation step after adjusting the pH value with acid.

[0061] Step (3) may optionally include a cooling step after mixing and loading the drug.

[0062] Step (4) may optionally include, before dialysis, concentrating the drug-loaded solution obtained in step (3) to obtain a concentrate.

[0063] Step (4) after dialysis may optionally include a concentration or dilution step to adjust the concentration of docetaxel in the postdialysis suspension.

[0064] Optionally, step (5) sterilization filtration is included after step (4).

[0065] Optionally, step (6) freeze-drying is included after step (5).

[0066] In step (1), the docetaxel can be in any form, preferably anhydrous docetaxel, docetaxel hemihydrate, or docetaxel trihydrate. The mass ratio of docetaxel to human serum albumin is 1:(2.0–10.0), preferably 1:(3.0–7.0), and more preferably 1:(4.0–6.0), based on anhydrous docetaxel.

[0067] In step (1), the organic solvent is selected from solvents miscible with water, such as ethanol, methanol, acetone, DMSO, etc., with ethanol being preferred. The organic phase solution contains 45-90 mg / ml of docetaxel, preferably 45-70 mg / ml, based on anhydrous docetaxel.

[0068] In step (2), the content of sodium caprylate in the human serum albumin solution is not higher than 0.12 mmol / g protein, preferably not higher than 0.08 mmol / g protein, and more preferably 0.045-0.08 mmol / g protein.

[0069] In step (2), the albumin diluent contains 6-25 mg / ml of albumin, preferably 10-20 mg / ml, more preferably 12-18 mg / ml, and most preferably 15 mg / ml.

[0070] In step (2), the acid is selected from acidic amino acids or acidic polypeptides, organic acids, and inorganic acids. The acidic amino acids or acidic polypeptides include, but are not limited to, cysteine ​​hydrochloride and glutathione; the organic acids include, but are not limited to, citric acid and tartaric acid; and the inorganic acids include, but are not limited to, hydrochloric acid and sulfuric acid. The acid is preferably cysteine ​​hydrochloride, glutathione, or hydrochloric acid, and more preferably cysteine ​​hydrochloride. The pH value is preferably 3.5–5.5, for example, 3.5–5.0, and more preferably 3.8–4.7, for example, 4.0–4.5.

[0071] In step (2), the incubation refers to raising the temperature to 35℃-42℃, preferably 38℃-42℃, after adjusting the pH value with acid; and incubating for more than 30 minutes, preferably 30 minutes-60 minutes.

[0072] In step (2), the salt solution is selected from aqueous solutions of sodium chloride, potassium chloride, sodium sulfate or magnesium sulfate, preferably an aqueous solution of sodium chloride; the concentration of the salt solution is not less than 2%, preferably 2% to 35%, and more preferably 10% to 20%.

[0073] In step (3), the drug loading conditions are to heat the organic phase solution and the aqueous phase solution to 35℃-42℃, preferably 38℃-42℃, and then mix the three to load the drug.

[0074] In step (3), cooling refers to cooling to below room temperature, preferably 0-20°C, and more preferably 7-15°C.

[0075] The concentrate in step (4) contains about 4-10 mg / ml of docetaxel, preferably 6-10 mg / ml, more preferably 7-9 mg / ml, for example 8 mg / ml.

[0076] In step (4), dialysis is performed to remove excess small molecule compounds. There are no particular restrictions on the type and amount of dialysate or the molecular weight cutoff of the dialysis membrane; those skilled in the art can make selections based on general technical knowledge or experience. For ease of further formulation and clinical use, the dialysate is preferably an aqueous solution of a clinically acceptable osmotic pressure regulator, such as an aqueous solution of sodium chloride, glucose, phosphate, or citrate. In some embodiments, a sodium chloride solution is used as the dialysate in step (4). The molecular weight cutoff of the dialysis membrane is 10-50 kDa, preferably 10-30 kDa, more preferably 10 kDa or 30 kDa. The volume of the dialysate is not less than 3 times that of the drug-loaded solution or concentrate, preferably 3-10 times, more preferably 3-6 times. The concentration of the sodium chloride solution is not higher than 1.8% (w / v), preferably 0.45%-1.8% (w / v), more preferably 0.9%-1.8% (w / v).

[0077] In some implementations, the human serum albumin solution used in step (2) needs to have its sodium caprylate content adjusted beforehand. Those skilled in the art can select appropriate methods to adjust the sodium caprylate content in the human serum albumin solution based on general technical knowledge or experience, including but not limited to dialysis.

[0078] In some embodiments, the method for adjusting the sodium caprylate content in human serum albumin solution is as follows: take commercially available human serum albumin solution, dilute it with water for injection or physiological saline to obtain a diluted albumin solution; use water for injection or physiological saline as a dialysate to dialyze the diluted albumin solution to partially remove sodium caprylate, thereby obtaining a human serum albumin solution with low sodium caprylate content.

[0079] In some embodiments, the human serum albumin solution is diluted at a factor of not less than 4, preferably 4-7. The dialysis membrane has a molecular weight cutoff of 10-50 kDa, preferably 10-30 kDa, more preferably 10 kDa or 30 kDa. The volume of the dialysate can be determined by those skilled in the art through conventional testing based on the required sodium caprylate content. Preferably, the volume of the dialysate is at least 3 times the volume of the diluted albumin solution, more preferably 3-10 times, and more preferably 3-6 times.

[0080] The low sodium caprylate content human serum albumin solution contains less than 0.16 mmol / g of sodium caprylate, preferably less than 0.12 mmol / g of protein, more preferably less than 0.10 mmol / g of protein, and even more preferably less than 0.08 mmol / g of protein. The low sodium caprylate content human serum albumin solution can be used directly to prepare the docetaxel albumin nanoparticle composition described in this application, or it can be mixed with other sodium caprylate content human serum albumin solutions in a certain proportion to obtain the desired content before being used to prepare the docetaxel albumin nanoparticle composition.

[0081] In the preparation method, the dialysis step removes excess small molecule compounds from the drug-loaded solution or concentrate. For example, in some embodiments, step (2) uses acidic amino acids or acidic peptides to adjust the pH to prepare acid-denatured albumin; the dialysis step substantially removes excess acidic amino acids or acidic peptides; the composition contains virtually no free acidic amino acids or acidic peptides. "Remains virtually free of free acidic amino acids or acidic peptides" means that the content of free acidic amino acids or acidic peptides in the composition is less than 0.25% (w / w) of docetaxel. For example, in some embodiments, cysteine ​​hydrochloride or glutathione is used to adjust the pH to prepare acid-denatured albumin, and the content of free cysteine ​​or glutathione in the composition is less than 0.25% (w / w) of docetaxel.

[0082] The docetaxel albumin composition described in this application exhibits stable physical and chemical properties. Accelerated and long-term stability studies show minimal changes in 7-epidocetaxel and protein polymers. Completed accelerated stability tests demonstrate that the lyophilized powder can be stored stably for 18 months at 30°C and 25°C, and based on existing data, it is predicted to be stable for at least 20 months at 30°C and at least 36 months below 25°C. Completed static stability observation tests show that the composition described in this application, whether as a suspension before lyophilization or a reconstituted suspension after lyophilization, is stable for at least 24 hours at room temperature and at least 10 days under refrigeration, without exhibiting suspension turbidity or nanoparticle sedimentation. Compared to commercially available albumin-bound products where the reconstituted suspension is only stable for 8 hours, this product significantly reduces limitations for clinical use.

[0083] The docetaxel albumin composition described in this application can be administered alone or in combination with other clinically or pharmaceutically acceptable drugs (such as antitumor drugs). Accordingly, the treatment methods described in this application can be administered alone or in combination with other treatment methods or therapeutic drugs. In some embodiments, granulocyte-stimulating factor (G-CSF) is administered after administration of the docetaxel albumin composition described in this application, for example, pegylated recombinant human granulocyte-stimulating factor injection (trade name: [trade name missing]) is administered 48 hours after administration of the docetaxel albumin composition described in this application. ).

[0084] The docetaxel albumin composition described in this application can be formulated as a drug on its own or in combination with other drugs (such as antitumor drugs). When the docetaxel albumin composition described in this application is combined with other drugs (such as antitumor drugs) to prepare a drug, they can be formulated separately into pharmaceutically acceptable formulations, which can then be further combined and packaged to obtain the final product; or, where pharmaceutically acceptable, different active ingredients can be contained in the same formulation product.

[0085] In some embodiments, before administering the docetaxel albumin composition described in this application or a drug containing the docetaxel albumin composition to the mammal (e.g., human) requiring treatment, Her-2 expression levels are detected to determine the patient's Her-2 expression status. Many prior art methods exist for detecting Her-2 expression status, including immunohistochemistry, fluorescence in situ hybridization, and bright-field in situ hybridization. Those skilled in the art can select the appropriate method as needed.

[0086] To provide a more concise description, the term "approximately" is not used for some quantitative data herein. It should be understood that, whether the term "approximately" is explicitly used or not, each numerical value given herein includes not only the actual given value (given value), but also approximations of such given value based on reasonable inference by one of ordinary skill in the art, including equivalents and approximations of such given value due to experimental and / or measurement conditions. These approximations are preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the given value. In some embodiments, the given value is obtained by rounding based on the detection or calculation results data.

[0087] Compared with commercially available docetaxel injection In comparison, the docetaxel albumin composition described in this application has significant advantages in clinical application, such as one or more of the following: (1) it does not contain Tween-80 and ethanol, requires no dexamethasone pretreatment, and can be administered at high concentrations rapidly, showing significant advantages in safety and subject compliance; (2) it can be administered at higher doses without allergic reactions, which can further improve efficacy; (3) it has improved compatibility stability and does not require special infusion equipment, improving the convenience of clinical use. Clinical studies have shown that the docetaxel albumin composition described in this application can effectively treat gastric cancer and gastroesophageal junction cancer, with good efficacy and safety.

[0088] Instruction manual illustrations

[0089] Figure 1 shows the subgroup analysis results in Example 5. Detailed Implementation

[0090] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0091] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to one skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the methods of this application. The preferred embodiments and materials described herein are for illustrative purposes only.

[0092] Preparation Example 1

[0093] The docetaxel for injection (albumin-bound) used in this application was manufactured and supplied by CSPC Pharmaceutical Group and prepared according to the method described in Formulation 1-1 of Example 1 of patent application WO2022184164A1. Specifically:

[0094] (1) Weigh 8g of anhydrous docetaxel and dissolve it in 120ml of ethanol to obtain an organic phase solution;

[0095] (2) Take a human serum albumin solution containing 36g of albumin (sodium caprylate content is 0.08mmol / g protein), dilute it with water for injection to a solution containing 15mg / ml of albumin, add an appropriate amount of cysteine ​​hydrochloride to adjust the pH to 4.1, incubate at 42℃ for 30min to obtain an acid-denatured albumin aqueous phase solution; take 18g of sodium chloride and prepare a 20% salt solution with water for injection;

[0096] (3) Heat the organic phase solution and the aqueous phase solution to 42°C, mix the organic phase, aqueous phase and salt solution to load the drug, and place the resulting material in an ice-water bath to cool to 15°C to obtain the drug-loaded solution;

[0097] (4) Concentrate the drug-loaded solution to a concentration of approximately 8 mg / ml of docetaxel to obtain a concentrate; use isotonic sodium chloride solution (0.9%, w / v) as the dialysate to dialyze the concentrate 5 times, with the dialysis membrane having a molecular weight cutoff of 30 kDa, to obtain a post-dialysis suspension; then, add an appropriate amount of dialysate to adjust the suspension concentration to 4 mg / ml of docetaxel;

[0098] (5) The suspension was sterilized by filtration through a 0.45μm+0.2μm membrane to obtain the suspension before lyophilization;

[0099] (6) Take the suspension obtained in step (5) before freeze-drying, freeze-dry it, and obtain freeze-dried powder.

[0100] Example 1: Preclinical Study

[0101] The toxicity test results of a single intravenous administration in NU / NU nude mice showed that intravenous administration of DTX-HSA (docetaxel for injection (albumin-bound)) and TAXOTERE... The maximum tolerated doses (MTDs) were 228.1 mg / kg and 150.0 mg / kg, respectively. This suggests that higher doses of DTX-HSA may be administered, potentially enhancing tumor suppression in clinical practice.

[0102] Beagle dogs were divided into 6 groups of 6 animals each, half male and half female, for a total of 36 animals. They were administered the following medications via single intravenous injection: solvent (0.9% sodium chloride injection), excipient (human serum albumin), DTX-HSA 0.5, 1, and 2 mg / kg, and TAXOTERE 2 mg / kg. The concentration of DTX-HSA and TAXOTERE in both groups was 3.8 mg / mL (calculated as anhydrous docetaxel), and the administration rate was 1 mL / min. All animals in the TAXOTERE group developed severe allergic symptoms, which were relieved after treatment with dexamethasone. In contrast, only one animal in the high-dose DTX-HSA group (2 mg / kg) showed mild allergic symptoms. These results indicate that... In comparison, DTX-HSA causes a significantly lower incidence of allergic reactions in animals and the symptoms are milder, so no dexamethasone pretreatment is required for clinical use.

[0103] In a humanized B-hPD-1 mouse model of MC38 colon cancer transplanted from murine cells, the TAXOTERE and Opdivo combination therapy group simulated clinical dexamethasone (DEX) anti-allergy treatment for 3 days, while the DTX-HSA and Opdivo combination therapy group did not require DEX anti-allergy treatment. In this model, the DTX-HSA / Opdivo group showed significantly better inhibitory effects on MC38 than the equivalent dose TAXOTERE / DEX / Opdivo group. The Opdivo group also showed better inhibitory effects on MC38 than the equivalent dose DEX / Opdivo group, indicating that DEX affects the activity of the PD-1 antibody Opdivo. This is consistent with previous reports and suggests that dexamethasone pretreatment may reduce the efficacy of immunotherapy drugs. The docetaxel albumin composition described in this application does not require dexamethasone pretreatment clinically, providing a possibility for further improving the efficacy of docetaxel in combination with immunotherapy drugs.

[0104] Example 2: Growth inhibition test of docetaxel (albumin-bound) for injection on NCI N87 gastric cancer xenografts in nude mice.

[0105] 1. Test materials

[0106] (1) Cell line

[0107] NCI N87 cells: Purchased from Nanjing Kebai Biotechnology Co., Ltd. Culture conditions: RPMI Medium 1640 medium containing 10% fetal bovine serum (FBS), 37°C, 5% CO2.

[0108] (2) Experimental animals

[0109] SPF-grade NU / NU mice, female, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., animal certificate number: 1100111911006208. Animal production license number: SCXK (Beijing) 2016-0006.

[0110] (3) Experimental drugs

[0111] Docetaxel (albumin-bound) for injection (i.e., DTX-HSA), dosage form: freeze-dried powder for injection; specification: 80 mg / vial; storage conditions: protected from light, stored below 25°C; provided by Shijiazhuang Pharmaceutical Group. Before use, it is reconstituted with sterile water for injection as a stock solution (concentration: 3.8 mg / mL), and then diluted with normal saline to the required concentration.

[0112] The remaining experimental materials were obtained through commercial purchase.

[0113] 2. Experimental methods

[0114] Human gastric cancer NCI N87 cells were inoculated into the subcutaneous tissue of the axilla of the forelimb of NU / NU mice to establish a mouse model with subcutaneous human gastric cancer. When the tumor volume grew to approximately 355 mm 3 (on the 10th day after inoculation), the animals were evenly grouped according to tumor volume (D0), with 7 animals in each group, and were intravenously administered DTX-HSA at 180 mg / kg, 120 mg / kg, 60 mg / kg, 30 mg / kg, 10 mg / kg, and 0.9% sodium chloride injection (0.9% INJ NS, solvent control group). The groups of DTX-HSA at 60 mg / kg, 30 mg / kg, and 10 mg / kg were administered once; however, due to drug concentration limitations, the total drug dose in the groups of DTX-HSA at 180 mg / kg and 120 mg / kg was divided into 3 doses and administered at 4-hour intervals; the single-dose volume was 20 mL / kg, and it was slowly injected.

[0115] The tumor diameter was measured 2 times a week, and the body weight of the mice was weighed, and the data were recorded. By measuring the tumor diameter at different times after administration, the growth changes of the tumor were dynamically observed. After the experiment ended (D18), the tumor was dissected and weighed to investigate the inhibitory effect of different doses of DTX-HSA on the human gastric cancer NCI N87 xenograft tumor.

[0116] Data processing was performed using SPSS 19.0 statistical software. The Repeated Measure procedure was used to analyze changes in tumor volume, relative tumor volume, and body weight over time across multiple measurements. The Multivariate procedure was used to compare differences in tumor volume and relative tumor volume between groups at each measurement. Differences in tumor weight between groups were analyzed using One-way ANOVA.

[0117] Tumor volume (V) = 1 / 2 × a × b 2 Where a and b represent the long and short diameters of the tumor, respectively, and the tumor volume is calculated based on the measurement results.

[0118] Relative tumor volume (RTV) = Vt / V0. V0 is the tumor volume measured when the drug is administered in separate cages (i.e., D0), and Vt is the tumor volume at each measurement.

[0119] Relative tumor volume proliferation rate (T / C, %) = T RTV / C RTV ×100%, where T RTV Treatment group RTV; C RTV Solvent control group RTV.

[0120] Tumor weight inhibition rate % = (1 - tumor weight in the drug treatment group / tumor weight in the solvent control group) × 100%.

[0121] 3. Test Results

[0122] Under the conditions of this experiment, mice in all groups tolerated the treatment well, and no deaths occurred. Compared with the solvent control group, there was no significant change in the weight gain rate of animals in each DTX-HSA dosage group.

[0123] (1) Effect on tumor volume in mice

[0124] The results showed that, compared with the solvent control group, DTX-HSA 30 mg / kg significantly inhibited tumor volume growth from day 7 after administration, while all other treatment groups showed significant inhibition of tumor volume growth from day 4 after administration (see Table 1-1); all treatment groups showed significant inhibition of relative tumor volume growth from day 4 after administration (see Table 1-2). This indicates that DTX-HSA has a rapid onset of action in inhibiting tumor growth. The effect of DTX-HSA in inhibiting tumor volume growth increased with increasing dosage, indicating that the antitumor effect of DTX-HSA is dose-dependent.

[0125] Table 1-1 Changes in tumor volume of human gastric cancer NCI N87 mouse xenografts (mm) 3 , n=7) Note: * P<0.05,** P < 0.01, *** P < 0.001, compared with the solvent control group. D0 represents day 0, D4 represents day 4, and so on.

[0126] Table 1-2 Changes in relative tumor volume of transplanted tumors of human gastric cancer NCI N87 mice n = 7 Note: * P < 0.05, ** P < 0.01, *** P < 0.001, compared with the solvent control group.

[0127] Table 1-3 Effects of DTX-HSA on the relative tumor volume proliferation rate (T / C, %) of transplanted tumors of human gastric cancer NCI N87 mice

[0128] (2) Effects on tumor weight

[0129] Compared with the solvent control group, the tumor weights in the DTX-HSA 180 mg / kg, 120 mg / kg, 60 mg / kg, 30 mg / kg, and 10 mg / kg groups were significantly reduced (P < 0.001), indicating that DTX-HSA can significantly inhibit tumor growth (see Table 1-4).

[0130] Table 1-4 Effects of DTX-HSA on the tumor weight of transplanted tumors of human gastric cancer NCI N87 mice in mice (n = 7) Note: *** P < 0.001, compared with the solvent control group.

[0131] Example 3 Growth inhibition test of docetaxel (albumin-bound) for injection on transplanted tumors of gastric cancer NUGC-4 cells in nude mice

[0132] 1. Test materials

[0133] (1) Cell line

[0134] NUGC-4 cells: Purchased from Nanjing Kebai Biotechnology Co., Ltd. Cell culture conditions: RPMI Medium 1640 medium containing 10% fetal bovine serum (FBS), 37 °C, 5% CO2.

[0135] (2) Test animals [[ID=4​​

[0137] (3) Test drugs

[0138] Docetaxel for Injection (Albumin-Bound) (DTX-HSA), Dosage Form: Lyophilized Powder for Injection; Specification: 80mg / vial; Storage Conditions: Protect from light, store below 25℃; Produced and supplied by CSPC Pharmaceutical Group. Before use, reconstitute with sterile water for injection as a stock solution (concentration 3.8mg / mL), then dilute with physiological saline to the required concentration.

[0139] The remaining experimental materials were commercially available.

[0140] 2. Test Methods

[0141] Human gastric cancer NUGC-4 cells were subcutaneously inoculated into the axillary tissue of NU / NU mice to establish a mouse model of subcutaneous human gastric cancer. The tumor volume was increased to approximately 310 mm². 3 On day 13 post-inoculation, animals were divided into equal groups (D0) based on tumor volume, with 7 animals in each group. Each group received intravenous docetaxel (albumin-bound) (DTX-HSA) at doses of 180 mg / kg, 120 mg / kg, 40 mg / kg, 20 mg / kg, and 10 mg / kg, or 0.9% sodium chloride injection (0.9% INJ NS, solvent control group). The DTX-HSA 40 mg / kg, 20 mg / kg, and 10 mg / kg groups received a single dose; the DTX-HSA 180 mg / kg and 120 mg / kg groups received the total dose divided into three administrations over 24 hours, with a 4-hour interval between administrations. Each single administration was 20 mL / kg, administered slowly as a bolus.

[0142] Tumor diameter was measured twice weekly, and mouse weight was recorded. Tumor growth was dynamically observed by measuring tumor diameter at different time points after drug administration. At the end of the experiment (D21), the tumor was removed and weighed. The inhibitory effects of different doses of DTX-HSA and the control drug TAXOTERE on human gastric cancer NUGC-4 xenografts were investigated, and their antitumor activity was compared with that of the control drug TAXOTERE.

[0143] Data processing was performed using SPSS 19.0 statistical software. The Repeated Measure procedure was used to analyze changes in tumor volume, relative tumor volume, and body weight over time across multiple measurements. The Multivariate procedure was used to compare differences in tumor volume and relative tumor volume between groups at each measurement. Differences in tumor weight between groups were analyzed using One-way ANOVA.

[0144] Tumor volume (V) = 1 / 2 × a × b 2 Where a and b represent the long and short diameters of the tumor, respectively, and the tumor volume is calculated based on the measurement results.

[0145] Relative tumor volume (RTV) = Vt / V0. V0 is the tumor volume measured when the drug is administered in separate cages (i.e., D0), and Vt is the tumor volume at each measurement.

[0146] Relative tumor volume proliferation rate (T / C, %) = T RTV / C RTV ×100%, where T RTV Treatment group RTV; C RTV Solvent control group RTV.

[0147] Tumor weight inhibition rate % = (1 - tumor weight in the drug treatment group / tumor weight in the solvent control group) × 100%.

[0148] 3. Test Results

[0149] Under the conditions of this experiment, all groups of mice tolerated the treatment well, and no deaths occurred. Compared with the solvent control group, there was no significant difference in body weight gain among the DTX-HSA dosage groups.

[0150] (1) Effect on tumor volume in mice

[0151] Table 2-1 shows that, compared with the solvent control group, all drug-treated groups significantly inhibited tumor growth (P<0.001), and this effect was dose-dependent.

[0152] Compared with the solvent control group, each treatment group showed a significant inhibitory effect on tumor volume growth starting from day 3 after administration (see Tables 2-2 and 2-3).

[0153] Table 2-1 Changes in tumor volume of human gastric cancer xenografts in NUGC-4 mice (mm) 3 , n=7) Note: *** P<0.001, compared with the solvent control group. D0 represents day 0, D3 represents day 3, and so on.

[0154] Table 2-2 Changes in relative tumor volume of human gastric cancer xenografts in NUGC-4 mice ( n=7) Note: *** P<0.001, compared with the solvent control group.

[0155] Table 2-3 Effect of DTX-HSA on the relative tumor volume proliferation rate (T / C, %) of human gastric cancer xenografts in NUGC-4 mice

[0156] (2) Effect on tumor weight in mice

[0157] Compared with the solvent control group, the tumor weight of the DTX-HSA groups of 180 mg / kg, 120 mg / kg, 40 mg / kg, 20 mg / kg and 10 mg / kg was significantly reduced (P<0.001), indicating that DTX-HSA can significantly inhibit the growth of human gastric cancer NUGC-4 tumors (see Table 2-4).

[0158] Table 2-4 Effect of DTX-HSA on tumor weight of human gastric cancer xenografts in NUGC-4 mice (n=7) Note: *** P<0.001, compared with the solvent control group.

[0159] Example 4: Preliminary Clinical Study of Docetaxel Injection (Albumin-Bound) for the Treatment of Advanced Solid Tumors

[0160] A Phase I clinical trial is underway to evaluate the safety, tolerability, pharmacokinetic characteristics, and preliminary antitumor activity of docetaxel for injection (albumin-bound) in patients with advanced solid tumors. The study enrolls patients who are histologically or cytologically diagnosed with advanced solid tumors and who have no standard treatment regimen, or who are intolerant or have failed to respond to standard treatment; and who have at least one measurable lesion (defined as measurable based on RECIST version 1.1 criteria). The treatment regimen is as follows: dosing cycles are every 3 weeks, administered intravenously on day 1 of each cycle, with seven provisional dose groups: 60 mg / m². 2 75mg / m 2 100mg / m 2 125mg / m 2 150mg / m 2 175mg / m 2 200mg / m 2 .

[0161] As of September 28, 2022, a total of 203 subjects were enrolled, with 168 subjects completing at least one efficacy evaluation. 38 subjects achieved a partial response (PR), and 73 subjects achieved stable disease (SD). The overall response rate (ORR) was 18.72%, and the disease control rate (DCR) was 54.68%. Compared with equivalent doses... Compared to other treatments, docetaxel (albumin-bound) for injection is more effective in treating advanced solid tumors. The incidence of allergic reactions is 0% without the need for hormone pretreatment. Compared to equivalent doses... Compared to historical data, the incidence of grade ≥3 drug-related adverse events was lower with injectable docetaxel (albumin-bound).

[0162] The study included 31 patients with gastric cancer, 29 of whom underwent at least one efficacy evaluation. Nine patients achieved a partial response (PR), 13 achieved stable disease (SD), and 4 achieved progressive disease (PD). The overall response rate (ORR) was 29.03%, and the disease control rate (DCR) was 70.97%. The trend was higher than that of patients receiving equivalent doses. Historical data.

[0163] Example 5: Comparison of Docetaxel for Injection (Albumin-Bound) A multicenter, randomized, controlled phase II clinical trial for second-line or later treatment of locally advanced or metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

[0164] I. Overall Design

[0165] This trial is an open-label, randomized, positive-controlled, multicenter phase II clinical trial designed to compare docetaxel for injection (albumin-bound) and... The efficacy and safety of second-line and above treatment for locally advanced or metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

[0166] by As a control, the experimental group received docetaxel (albumin-bound) as a single injection. Subjects were randomly assigned to either the experimental or control group in a 1:1 ratio. Randomization factors included prior immunotherapy (yes or no) and ECOG score (0 or 1).

[0167] Subjects received injectable docetaxel (albumin-bound) or Treatment was administered every 3 weeks until disease progression, intolerable toxicity, withdrawal from the trial, or initiation of new anti-tumor therapy or other conditions that met the criteria for discontinuation or withdrawal.

[0168] Efficacy assessment was performed using the RECIST v 1.1 criteria for evaluating efficacy in solid tumors. Imaging assessments (CT or MRI) were conducted every 6 weeks ± 7 days from the start of treatment with the investigational drug, and every 12 weeks ± 7 days thereafter, until disease progression or initiation of new antitumor therapy. Subjects who discontinued treatment for reasons other than disease progression continued to undergo tumor assessments (every 6 weeks ± 7 days, and every 12 weeks ± 7 days thereafter, until disease progression or initiation of new antitumor therapy).

[0169] A treatment termination visit was conducted within 7 days after the last dose; a safety follow-up was conducted 28 days (±3 days) after the last dose.

[0170] Starting with disease progression or the initiation of new anti-tumor therapy, survival follow-up was conducted approximately every 3 months to collect information on subsequent anti-tumor treatment and survival status of the subjects until death, loss to follow-up, or the end of the trial (whichever comes first).

[0171] To assess the pharmacokinetic (PK) characteristics of docetaxel for injection (protein-bound), all subjects treated with docetaxel for injection (protein-bound) were required to have PK blood samples collected during cycle 1, as shown in the PK blood sample collection table. Treatment subjects do not need to undergo PK blood sampling.

[0172] II. Inclusion Criteria for the Study Population

[0173] Participants must meet all of the following criteria to be eligible for selection:

[0174] 1. Age 18 to 75 (inclusive) years old (based on the date of signing the informed consent form).

[0175] 2. Voluntarily sign the informed consent form and be willing and able to follow the protocol for visits, treatments, and laboratory tests.

[0176] 3. Histologically or cytologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

[0177] 4. Locally advanced or metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma that has progressed after receiving at least one first-line systemic therapy (defined as platinum-based / fluorouracil doublet chemotherapy, with or without immunotherapy).

[0178] 5. Patients with a history of negative or positive Her-2 expression can be enrolled. For those with positive Her-2 expression, previous treatment must include anti-Her-2 drug therapy. For those with unknown Her-2 expression, Her-2 status must be determined before enrollment.

[0179] 6. Major organ function met the following criteria within 7 days prior to randomization:

[0180] 7. Individuals with an ECOG score of 0-1 within the previous 7 days.

[0181] 8. The expected survival of the subjects is ≥3 months.

[0182] 9. Female subjects of reproductive age must have a negative serum pregnancy test within 7 days prior to randomization and must agree to use adequate contraception from the time of signing the informed consent form until 6 months after the last dose, during which time the woman must not be breastfeeding; male subjects must agree to contraception and refuse sperm donation.

[0183] 10. According to RECIST V1.1 criteria, there should be at least one evaluable lesion in the area that has not previously received radiotherapy, or there should be evidence that the lesion has clearly progressed after radiotherapy.

[0184] III. Research Intervention

[0185] (I) Investigational Drugs

[0186] Test drug: Docetaxel for injection (albumin-bound); Dosage form: Lyophilized powder for injection; Specification: 80 mg / vial; Storage conditions: Protect from light, store below 25°C. The docetaxel for injection (albumin-bound) used in this experiment was manufactured and supplied by CSPC Pharmaceutical Group. The docetaxel for injection (albumin-bound) was reconstituted with 20 ml of water for injection, and then diluted to 2 mg / ml with sodium chloride solution for injection (9 mg / ml, 0.9%).

[0187] Control drug: Docetaxel injection (trade name: Dosage form: injection; Specification: 0.5ml: 20mg / vial; Storage conditions: Store at 2-25℃ protected from light. The docetaxel injection used in this experiment was manufactured by Sanofi GmbH, Germany.

[0188] Other medications: Pegylated recombinant human granulocyte colony-stimulating factor injection (trade name: Dosage form: Injection; Specification: 3.0mg (1.0ml) / vial; Storage conditions: Store and transport at 2-8℃ protected from light (do not freeze or shake). The polyethylene glycol-modified recombinant human granulocyte colony-stimulating factor injection used in this experiment was produced and supplied by CSPC Pharmaceutical Group.

[0189] (II) Dosing regimen for investigational drug

[0190] Experimental group: Docetaxel for injection (albumin-bound), administered via intravenous infusion, 100 mg / m². 2 Administer once every 3 weeks, with an administration time of 60 minutes.

[0191] Control group: The route of administration is intravenous infusion, 75 mg / m². 2 Administer once every 3 weeks, with an administration time of 60 minutes.

[0192] Dosing period: Until disease progression or intolerance or other reasons lead to discontinuation of the investigational drug treatment.

[0193] Both the experimental and control groups received prophylactic treatment with pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF). In injectable docetaxel (albumin-bound) / Use 48 hours after the infusion is completed. Administer subcutaneously at 100ug / kg, once per chemotherapy cycle (every 3 weeks).

[0194] To reduce the occurrence and severity of allergic reactions, the control group ( In the first group, all subjects were required to take pre-treatment glucocorticoids, for example, starting one day before intravenous administration, with oral dexamethasone 15 mg / day (e.g., twice daily, 10 tablets / time, 0.75 mg / tablet) for 3 consecutive days. Subjects in the experimental group (docetaxel for injection (albumin-bound) group) were not required to take pre-treatment glucocorticoids.

[0195] (III) Dosage Adjustment Principles

[0196] 1. Docetaxel for Injection (Albumin-Bound)

[0197] If toxicity related to the study drug occurs during treatment, the investigator may suspend administration, reduce the dose, or permanently discontinue the drug, depending on the toxicity situation.

[0198] During the study treatment, a maximum of two dose adjustments were permitted for docetaxel (albumin-bound) for injection, with an initial dose of 100 mg / m². 2 The first dose reduction can lower the concentration to 75 mg / m². 2 The second dose reduction can lower the concentration to 60 mg / m². 2 such as 60mg / m 2 If the patient still cannot tolerate the medication, consider discontinuing it.

[0199] 2.

[0200] Dosage adjustments should be made according to clinical practice and the instructions for use, and should be determined by the investigator.

[0201] IV. Efficacy Evaluation

[0202] Efficacy assessment was performed using the RECIST v1.1 criteria for evaluating the efficacy of treatment in solid tumors. During the trial, imaging assessments were conducted every 6 weeks ± 7 days from the start of the investigational drug, and every 12 weeks ± 7 days thereafter. The same imaging modalities (computed tomography / magnetic resonance imaging) used at the screening period were required each time until disease progression or the initiation of new antitumor therapy. Subjects who discontinued treatment for reasons other than disease progression continued to undergo tumor assessments (every 6 weeks ± 7 days, and every 12 weeks ± 7 days thereafter) until disease progression or the initiation of new antitumor therapy.

[0203] The endpoint evaluation indicators for the study include: objective response rate (ORR), overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and duration of response (DoR).

[0204] Progression-free survival (PFS): Defined as the time between the start of investigational therapy and the date of first recorded disease progression (PD) or death. If no disease progression is observed, the cutoff date should be the date of the last tumor measurement.

[0205] Overall response rate (ORR): defined as the proportion of subjects who achieved a complete response (CR) or partial response (PR) (i.e., CR+PR) in the study, as assessed by the investigator according to RECIST v1.1, from the start of treatment with the investigational drug until withdrawal from the study.

[0206] Disease control rate (DCR): defined as the percentage of patients who, according to RECIST v1.1 criteria, achieved a CR, PR, or stable disease (SD) at the optimal time point from the start of treatment with the investigational drug to withdrawal from the study.

[0207] Duration of Response (DoR): The time from the first assessment of CR or PR to the first assessment of PD or death from any cause.

[0208] Overall survival (OS): defined as the time elapsed from the start of use of the investigational drug until death from any cause.

[0209] V. Safety and Pharmacokinetic Assessment

[0210] 1. Security Assessment

[0211] Throughout the study, safety will be assessed by evaluating participants' vital signs, weight, physical examination, electrocardiogram, and laboratory tests. The severity of adverse events will be assessed according to the NCI-CTCAE v5.0 classification.

[0212] 2. Pharmacokinetic assessment

[0213] Venous blood samples should be collected at the specified time points. The date and time of PK sample collection, along with relevant dosing information (including start time, end time, and actual dose), should be recorded in detail in the eCRF. The total plasma concentration and free docetaxel concentration should be determined using a validated method.

[0214] VI. Statistical Considerations

[0215] The statistical analysis in this study was performed using SAS 9.4 or later.

[0216] 1. Primary endpoint analysis: PFS

[0217] The Kaplan-Meier method was used to estimate the median progression-free survival (PFS) time and the corresponding 95% confidence interval. PFS rates and their 95% confidence intervals at months 3, 6, and 9 were also calculated. The difference in PFS between the two groups was assessed using the Log-rank test. The Cox regression model was used to estimate the hazard ratio (HR) and its 95% confidence interval between the treatment groups.

[0218] 2. Secondary endpoint analysis

[0219] OS will be analyzed using the same statistical methods as PFS. The difference in OS between the two groups will be determined using a Log-rank test, and the hazard ratios and their 95% confidence intervals between the treatment groups will be estimated using a Cox model. For subjects who did not die, their last known survival date will be censored.

[0220] Secondary efficacy endpoints also include ORR, DOR, and DCR. The number and percentage of subjects achieving CR or PR in the best overall response to tumor disease are summarized, and the 95% confidence interval for ORR is calculated based on the Clopper-Pearson method. The difference in ORR rates and 95% confidence intervals between the two groups are calculated. The statistical analysis methods for DOR are the same as those for PFS. The statistical analysis methods for DCR are the same as those for ORR.

[0221] VII. Test Results

[0222] Clinical studies have shown that docetaxel for injection (albumin-bound) has low sensitization, requires no dexamethasone pretreatment, and improves subject compliance. Docetaxel for injection (albumin-bound) is free of Tween-80 and ethanol, allowing for rapid administration of high concentrations, and offers significant advantages in safety and subject compliance. Docetaxel for injection (albumin-bound) is effective in treating locally advanced or metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, with superior efficacy compared to equivalent doses of [previous medications]. Based on historical data, and with lower adverse reactions, it has a promising clinical application prospect.

[0223] As of December 31, 2023, 125 patients were enrolled and randomly assigned to either the docetaxel (albumin-bound) injection group (n=63) or the docetaxel (albumin-bound) group. The two groups (n=62) were comparable in baseline characteristics. Overall, the median age was 59.0 years (range 27–75 years), and 98 (78.4%) patients had an ECOGPS of 1. 73 (58.4%), 7 (5.6%), and 6 (4.8%) patients had previously received immunotherapy, anti-angiogenic drugs, and anti-HER2 therapy, respectively.

[0224] 45 patients in the docetaxel (albumin-bound) injection group and Of the 47 patients in the group evaluable for efficacy, the ORR and DCR in the docetaxel (albumin-bound) injection group were 24.4% (11 PR, 95% CI 12.88-39.54) and 57.8% (15 SD, 95% CI 42.15-72.34), respectively. The incidence rates were 14.9% (1 case of CR + 6 cases of PR, 95% CI 6.20-28.31) and 46.8% (15 cases of SD, 95% CI 32.1-61.92) in the docetaxel (albumin-bound) group compared to the albumin-bound group. The disease-free survival (DOR) in the docetaxel (albumin-bound) group was numerically lower than that in the docetaxel (albumin-bound) group. The group had a longer duration of treatment (median DOR: 2.9 months (95% CI 1.41-NA) vs 1.5 months (95% CI 1.451-NA)).

[0225] 87.1% of patients treated with injectable docetaxel (albumin-bound) and 82.3% of patients treated with... Treatment-related adverse events (TRAEs) occurred in all treated patients. Hair loss (38.7% vs 37.1%) and anemia (33.9% vs 35.5%) were the most common TRAEs in both groups. In the docetaxel (albumin-bound) group, 14 patients (22.6%) and... In this group of 15 patients (24.2%), grade ≥3 TRAEs occurred, the most common being anemia, leukopenia, decreased appetite, fatigue, and lymphopenia. There were no treatment-related deaths. In contrast, no new safety signals were observed in the docetaxel (albumin-bound) injection group.

[0226] As of June 25, 2024, a total of 128 patients were randomly assigned to the docetaxel (albumin-bound) injection group (n=65) and the docetaxel (albumin-bound) group. The two groups (n=63) were comparable in baseline characteristics. Overall, the median age was 59.0 years (range 27–75 years), with 106 patients (82.8%) having an ECOGPS score of 1. 76 patients (59.4%) had previously received immunotherapy. 76 patients (59.4%) had ≥2 tumor metastases.

[0227] The median progression-free survival (PFS) in the docetaxel (albumin-bound) group was 4.0 months (95% CI 2.8–4.2), while The duration of treatment in the docetaxel (albumin-bound) group was 2.7 months (95% CI 1.8–3.0), with a hazard ratio (HR) of 0.81 (95% CI 0.53–1.21). The objective response rate and disease control rate in the docetaxel (albumin-bound) group were 21.5% (including 1 CR and 13 PR, 95% CI 12.3–33.5) and 56.9% (20 SD, 95% CI 44.0–69.2), respectively. The median overall survival rates in the docetaxel (albumin-bound) group were 14.3% (including 1 case of complete remission and 8 cases of partial remission, 95% CI 6.8–25.4) and 42.9% (17 cases of stable disease, 95% CI 30.5–56.0), respectively. The median overall survival in the docetaxel (albumin-bound) group was significantly higher than that in the docetaxel (albumin-bound) group. The duration of illness was significantly prolonged in the first group, at 11.3 months and 7.8 months, respectively (HR = 0.59 [95% CI 0.35, 1.01], p = 0.025).

[0228] Subgroup analysis of efficacy (see Figure 1) showed that docetaxel for injection (albumin-bound) was superior in most subgroups. Furthermore, there are significant differences in histological characteristics. The median progression-free survival (PFS) in the gastric adenocarcinoma subgroup and the gastroesophageal junction adenocarcinoma subgroup were 2.73 months and 2.89 months, respectively. After treatment with injectable docetaxel (albumin-bound), the median PFS in the gastric adenocarcinoma subgroup was 2.99 months, but the median PFS in the gastroesophageal junction adenocarcinoma subgroup was 8.11 months, showing a significant prolongation of median PFS. This suggests that injectable docetaxel (albumin-bound) can achieve better efficacy in the treatment of gastroesophageal junction adenocarcinoma.

[0229] The incidence of treatment-related adverse events (TRAE) in the docetaxel (albumin-bound) injection group was 93.8%. The incidence of TRAE in the group was 93.7%. Hair loss (46.2% vs 39.7%), fatigue (43.1% vs 23.8%), and anemia (40% vs 39.7%) were most common in the docetaxel (albumin-bound) group and... The most common type of transaminase-associated encephalopathy (TRAE) was observed in 20 patients (30.8%) in the docetaxel (albumin-bound) injection group. Nineteen patients (30.2%) in the group experienced grade ≥3 TRAE, the most common of which were anemia and fatigue. Three treatment-induced adverse events (TEAEs) resulting in death occurred in the docetaxel (albumin-bound) group, one of which was determined to be treatment-related. However, no fatal TEAEs occurred in the docetaxel (albumin-bound) group. Furthermore, no new safety signals were observed in the docetaxel (albumin-bound) group. These data indicate that, compared to... Docetaxel for injection (albumin-bound) reduced the risk of death by 41% in previously treated patients with advanced gastric / gastroesophageal junction cancer, with manageable safety.

[0230] These results demonstrate that docetaxel for injection (albumin-bound) has a manageable safety profile and good efficacy in patients who have previously received treatment for advanced gastric / gastroesophageal junction cancer. In comparison, injectable docetaxel (albumin-bound) is more effective and no new safety risks have been reported.

Claims

1. Use of the docetaxel albumin composition in the preparation of a medicament for the treatment of gastric cancer or gastroesophageal junction cancer.

2. The use as described in claim 1, wherein the gastric cancer or gastroesophageal junction cancer is selected from squamous cell carcinoma, adenocarcinoma, and preferably adenocarcinoma.

3. The use as described in claim 1, wherein the gastric cancer is selected from gastric cancers occurring in the antrum, greater curvature, lesser curvature, or anterior and posterior walls of the stomach.

4. The use as described in claim 1, wherein the gastroesophageal junction cancer is selected from cancers whose tumor center is located within 5 cm above or below the gastroesophageal junction; preferably, the gastroesophageal junction cancer is selected from: (1) tumors whose tumor center is within 2 cm below the gastroesophageal junction, but the tumor has not invaded the gastroesophageal junction line upwards; or (2) tumors whose tumor center is within 2 cm to 5 cm below the gastroesophageal junction.

5. The use as described in claim 1, wherein the gastric cancer is selected from locally advanced or metastatic gastric cancer, preferably locally advanced or metastatic gastric adenocarcinoma; and / or the gastroesophageal junction cancer is selected from locally advanced or metastatic gastroesophageal junction cancer, preferably locally advanced or metastatic gastroesophageal junction adenocarcinoma.

6. The use as described in claim 1, wherein the gastric cancer is locally advanced or metastatic gastric adenocarcinoma that has progressed after systemic treatment; and / or the gastroesophageal junction cancer is locally advanced or metastatic gastroesophageal junction adenocarcinoma that has progressed after systemic treatment.

7. The use as described in claim 6, wherein the systemic treatment is selected from one or more of chemotherapy, surgical resection, radiotherapy, targeted therapy, and immunotherapy.

8. The use as described in claim 7, wherein the systemic treatment is selected from one or more of platinum-based and / or fluorouracil-based chemotherapy and immunotherapy.

9. The use as described in claim 8, wherein the platinum-based drug is selected from one or more of cisplatin, carboplatin, nedaplatin, lobaplatin, and oxaliplatin.

10. The use as described in claim 8, wherein the fluorouracil drug is selected from one or more of 5-fluorouracil, tegafur, tegafur, eufodine, and capecitabine.

11. The use as described in claim 8, wherein the immunotherapy is selected from one or more of pembrolizumab, nivolumab, camrelizumab, tislelizumab, toripalimab, and sintilimab.

12. The use as claimed in claim 1, wherein the gastric cancer is selected from gastric cancers that are Her-2 negative or positive; and / or the gastroesophageal junction cancer is selected from gastroesophageal junction cancers that are Her-2 negative or positive.

13. Use of docetaxel albumin composition in combination with other drugs in the preparation of a medicament for the treatment of gastric cancer or gastroesophageal junction cancer.

14. A method for treating gastric cancer or gastroesophageal junction cancer, comprising the following steps: 1) Administer a therapeutically effective dose of docetaxel albumin composition to patients with gastric cancer or gastroesophageal junction cancer who require treatment.

15. The method of claim 14, wherein step 1) further comprises the step of determining the type of Her-2 expression in the patient by means of gene detection.

16. The method of claim 14 or 15, wherein the administration is by intravenous infusion, and / or the therapeutically effective dose is 50-125 mg / m². 2 Preferred concentration: 60-100 mg / m³ 2 For example, the effective therapeutic dose is 100 mg / m². 2 Or 75mg / m 2 Or 60mg / m 2 .

17. The method of claim 14 or 15, wherein the docetaxel albumin composition is administered once every 3-4 weeks, preferably once every 3 weeks.

18. The method of claim 16, wherein the duration of each intravenous infusion is 30 min to 90 min, preferably 60 ± 10 min.

19. The method of claim 14 or 15, wherein the therapeutically effective dose is 100 mg / m². 2 Administer once every 3 weeks, with an intravenous infusion time of 60 min ± 10 min.

20. The method of claim 14 or 15, wherein the treatment further comprises the following step: 2) Administer a clinically acceptable amount of another drug that is therapeutically effective to patients with gastric cancer or gastroesophageal junction cancer who require treatment, either concurrently with, before, or after the administration of the docetaxel albumin combination.

21. A medicament for treating gastric cancer or gastroesophageal junction cancer, comprising a docetaxel albumin composition and optionally, a pharmaceutically acceptable carrier.

22. The medicament of claim 21, wherein the medicament further comprises other clinically or pharmaceutically acceptable medicaments.

23. A kit for treating gastric cancer or gastroesophageal junction cancer, wherein the kit contains a docetaxel albumin composition and a drug instruction manual or label indicating the dosage and administration of the drug.

24. The medicine box as claimed in claim 23, wherein the usage and dosage include: The drug is administered via intravenous infusion at a dose of 50-125 mg / m². 2 Preferred concentration: 60-100 mg / m³ 2 For example, 100mg / m 2 Or 75mg / m 2 Or 60mg / m 2 The drug is administered once every 3-4 weeks, preferably once every 3 weeks; each intravenous infusion takes 30-90 minutes, preferably 60 minutes ± 10 minutes; more preferably, the dosage and administration method includes: the drug is administered via intravenous infusion at a dose of 100 mg / m². 2 Administer once every 3 weeks, with an intravenous infusion time of 60 min ± 10 min.

25. Use of docetaxel albumin composition in the preparation of a medicament for use in combination with other drugs to treat gastric cancer or gastroesophageal junction cancer.

26. The use as described in any one of claims 1-13 or 25, the method as described in any one of claims 14-20, the medicament as described in claim 21 or 22, or the kit as described in claim 23 or 24, wherein the docetaxel albumin composition is a docetaxel albumin nanoparticle composition comprising docetaxel and acid-denatured albumin, optionally comprising an osmotic pressure regulator and / or a pH regulator; optionally, the acid-denatured albumin is obtained by denaturing human serum albumin by adding acid to adjust it to an appropriate pH value; Preferably: (1) The acid is selected from acidic amino acids or acidic polypeptides, organic acids, or inorganic acids; the acidic amino acids or acidic polypeptides include cysteine ​​hydrochloride, glutathione, etc., the organic acids include citric acid, tartaric acid, etc., and the inorganic acids include hydrochloric acid, sulfuric acid, etc.; the acid is preferably cysteine ​​hydrochloride, glutathione, or hydrochloric acid, more preferably cysteine ​​hydrochloride; and / or (2) The appropriate pH value is 3.5-5.5, preferably 3.5-5.0, more preferably 3.8-4.7, and most preferably 4.0-4.5; and / or (3) The mass ratio of docetaxel to human serum albumin, based on anhydrous docetaxel, is 1:(2.0-10.0), preferably 1:(3.0-7.0), more preferably 1:(4.0-6.0); and / or (4) The content of sodium caprylate in the human serum albumin is not higher than 0.08 mmol / g protein, preferably 0.03-0.08 mmol / g protein, more preferably 0.04-0.08 mmol / g protein, and most preferably 0.04-0.07 mmol / g protein.

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