WO2024099387A1

WO2024099387A1 - Treatment of cancer by means of administration of ligand-medicament conjugate

Info

Publication number: WO2024099387A1
Application number: PCT/CN2023/130704
Authority: WO
Inventors: 滕燕; 于建刚
Original assignee: 同宜医药（苏州）有限公司
Priority date: 2022-11-09
Filing date: 2023-11-09
Publication date: 2024-05-16

Abstract

Provided is use of a ligand-medicament conjugate in the treatment of cancer, further, use of a ligand-medicament conjugate in the preparation of a medicament for treating platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer.

Description

Treatment of cancer by administration of ligand-drug conjugates

Citation of Related Applications

The present disclosure claims the priority of the invention patent application filed with the Patent Office of China on November 9, 2022, with application number 202211401158.0 and invention name “Treating Cancer by Administering Ligand-Drug Conjugates”, and the invention patent application filed with the Patent Office of China on November 7, 2023, with application number 202311473958.8 and invention name “Treating Cancer by Administering Ligand-Drug Conjugates”, the entire contents of which are incorporated into the present disclosure by reference.

Technical Field

The present invention relates to the field of biomedicine, and in particular to use of a ligand-drug conjugate in preparing a drug for treating platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer.

Background technique

Ovarian cancer is one of the malignant tumors that seriously threaten women's health. Its incidence rate ranks third among malignant tumors of the female reproductive system, and its mortality rate ranks first among gynecological malignancies. In 2020, there were 314,000 new cases of ovarian cancer and 207,000 deaths from ovarian cancer worldwide. In China, it is estimated that there will be 57,090 new cases of ovarian cancer and 39,306 deaths from ovarian cancer in 2022. In the United States, it is estimated that there will be 19,880 new cases of ovarian cancer and 12,810 deaths from ovarian cancer in 2022.

According to histopathological characteristics, ovarian cancer is mainly divided into three categories: epithelial ovarian cancer (EOC), germ cell tumors, and sex cord-stromal tumors. Among them, epithelial tumors are the most common, accounting for about 80% of ovarian malignant tumors. There are five main pathological types of EOC, namely high-grade serous carcinoma, endometrial carcinoma, clear cell carcinoma, mucinous carcinoma, and low-grade serous carcinoma. Each subtype differs in pathogenesis, chemotherapy sensitivity, and prognosis. Among them, the most common subtypes are high-grade serous carcinoma and grade 2/3 endometrial carcinoma. Primary peritoneal cancer and fallopian tube cancer are gynecological tumors with low incidence. Their biological behaviors are similar to those of ovarian epithelial cancer. The diagnosis and treatment principles can refer to the guidelines for the diagnosis and treatment of ovarian epithelial cancer.

Due to the lack of effective screening and early diagnosis measures, 70% of ovarian cancer patients are already in the advanced stage when diagnosed, and the 5-year survival rate is less than 50%. The treatment of ovarian cancer is mainly surgery, supplemented by drug therapy. The initial surgery mainly includes comprehensive staging surgery and tumor cell reduction surgery. The vast majority of patients require comprehensive treatments such as surgery combined with chemotherapy. Very few patients can be cured by surgery alone. The standard treatment for patients with advanced and extraovarian metastasis is tumor cell reduction surgery, and the first-line chemotherapy includes postoperative adjuvant chemotherapy and neoadjuvant chemotherapy. The postoperative adjuvant chemotherapy regimen is a combination of taxanes/platinum or doxorubicin liposomes/carboplatin. For patients with stage II-III with satisfactory tumor reduction, intraperitoneal chemotherapy can be considered, usually cisplatin/paclitaxel. For initially inoperable bulky lesions, neoadjuvant chemotherapy can be given before cytoreductive surgery, with paclitaxel combined with carboplatin as the first choice. There are also studies exploring the use of anti-vascular drugs such as bevacizumab in neoadjuvant therapy, and the efficacy remains to be determined. However, after cytoreductive surgery and first-line chemotherapy after surgery, only a small number of patients can achieve long-term disease-free survival. Even patients who achieve complete remission still have 50%-70% recurrence, with an average recurrence time of 16-18 months. In a meta-analysis by du Bois et al., 76% of patients experienced disease recurrence or progression after surgery and taxane/platinum chemotherapy (N=3126) at a median follow-up time of 53.9 months. The percentages of patients achieving 5-year progression-free survival (PFS) and overall survival (OS) were 22.6% and 39.0%, respectively. The data show that the overall prognosis of recurrent ovarian cancer is poor.

The time interval from the last chemotherapy to recurrence is the main factor affecting the effect of second-line treatment. Based on this, recurrent tumors can be divided into two categories: one is platinum-sensitive recurrence, and the other is platinum-resistant recurrence. The standard treatment for patients with platinum-sensitive recurrent ovarian cancer is platinum-based combination chemotherapy or bevacizumab, followed by maintenance therapy with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors or bevacizumab. Most patients can be relieved after treatment, but they usually relapse, and most patients eventually develop platinum resistance. The prognosis of platinum-resistant recurrence is poor, and there is a lack of effective treatment. Currently, non-platinum monotherapy (liposomal doxorubicin, docetaxel, albumin-bound paclitaxel, oral etoposide, gemcitabine, weekly paclitaxel, topotecan) + bevacizumab are the first choice, but the effect is poor, with an effective rate of only 10%-25%. Platinum-resistant patients have a very low sensitivity to conventional drugs, and the objective response rate (ORR) of second-line monotherapy for platinum-resistant ovarian cancer is mostly between 5% and 20%. For patients who relapse after second-line treatment, the efficacy is further reduced, with an ORR of only 5%-10%. In addition, chemotherapy has considerable toxicity.

At present, the targeted treatments for ovarian cancer mainly include anti-angiogenic drugs and PARP inhibitors. As one of the anti-angiogenic drugs, bevacizumab is valuable in the first-line treatment of ovarian cancer, platinum-sensitive recurrence, and platinum-resistant recurrence. Bevacizumab monotherapy for recurrent platinum-resistant ovarian cancer, ORR is only 15.9%, and PFS is 4.4 months. In the phase III randomized AURELIA study, platinum-resistant patients were randomly divided into chemotherapy groups receiving or not receiving bevacizumab. The results showed that the PFS of the group receiving bevacizumab was significantly improved (6.7 months vs 3.4 months); ORR was 27.3% and 11.9%, respectively. Adverse reactions during the use of bevacizumab include hypertension, proteinuria, etc., which are clinically controllable after symptomatic treatment, but there are serious adverse reactions such as gastrointestinal perforation. PARP inhibitors are mainly used for platinum-sensitive people in ovarian cancer. In platinum-resistant recurrent ovarian cancer, PARP inhibitors are recommended by the National Comprehensive Cancer Network (NCCN) as a second-line treatment option for homologous recombination repair deficiency (HRD)-positive patients, for advanced ovarian cancer patients who have received ≥2 lines of chemotherapy and carry BRCA germline mutations. However, patients with BRCA mutations account for only 10%-15% of epithelial ovarian cancer.

In addition, other treatments for ovarian cancer include immunotherapy, radiotherapy, hormone therapy, and traditional Chinese medicine. Ovarian cancer immunotherapy has a low efficacy in ovarian cancer. Currently, there are several Phase I/II clinical studies on immune checkpoint inhibitors in platinum-resistant recurrent ovarian cancer, showing an ORR of about 10%. Ovarian epithelial cancer is moderately sensitive to radiotherapy, but Treatment is prone to extensive pelvic and abdominal metastasis. Therefore, radiotherapy is basically no longer used in adjuvant treatment after ovarian cancer surgery. For recurrent patients who cannot tolerate chemotherapy or chemotherapy is ineffective, hormone therapy can be considered, with an overall effective rate of about 10%. Traditional Chinese medicine treatment can be combined with Western medicine to supplement and improve the treatment of ovarian cancer based on individual differences of patients, through syndrome differentiation and treatment.

In summary, patients with platinum-resistant recurrent ovarian cancer have a poor prognosis and lack effective treatments. New therapies with durable clinical efficacy and better safety are urgently needed.

Ligand-drug conjugates have the function of mediating cell endocytosis and can be used in the treatment of tumors, immune regulation, and cardiovascular diseases. Their advantages are: ① The combination of targeting and endocytosis structure can realize the use of any ligand-targeted peptide as the guiding part, thereby broadening the targeting range of such drugs; ② The use of dual-targeting ligands to enhance the affinity and targeting of drug conjugates to diseased cells, so that they can carry highly effective toxin drugs such as monomethyl auristatin E (MMAE), enhance drug efficacy and broaden the therapeutic window to avoid drug side effects; ③ The linker cannot release drug molecules outside the cell (intercellular matrix, blood circulation system, etc.), which ensures the stability of the drug when it circulates in the body, reduces drug toxicity, and does not cause toxic effects on normal cells. After entering the targeted cell, the linker cleaves to release drug molecules with therapeutic effects, which can avoid the occurrence of multidrug resistance (MDR).

Summary of the invention

In a first aspect, the present invention provides a use of a ligand-drug conjugate for treating ovarian cancer.

Furthermore, the present invention provides a use of a ligand-drug conjugate in the preparation of a drug for treating platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer.

Furthermore, the present invention provides a use of a ligand-drug conjugate in the preparation of a drug for treating platinum-resistant advanced epithelial ovarian cancer.

Preferably, the ligand-drug conjugate of the present invention is a drug conjugate targeting folate receptor and TRPV6 receptor.

More preferably, the ligand-drug conjugate of the present invention is compound A having the following structure:

Furthermore, the histopathological characteristics of advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer described in the present invention are The type is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (i.e., moderately differentiated and poorly differentiated).

Preferably, the histopathological type of the advanced epithelial ovarian cancer described in the present invention is high-grade serous carcinoma.

Furthermore, the expression level of folate receptor in the advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer described in the present invention is ≥25%.

Furthermore, the histopathological type of the primary peritoneal cancer or fallopian tube cancer described in the present invention is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (i.e., moderately differentiated and poorly differentiated).

In a second aspect, the present invention provides a pharmaceutical composition for treating platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer.

Furthermore, the present invention provides a pharmaceutical composition for treating platinum-resistant advanced epithelial ovarian cancer.

Furthermore, the pharmaceutical composition of the present invention comprises a ligand-drug conjugate as an active ingredient.

Preferably, the ligand-drug conjugate is a drug conjugate targeting folate receptor and TRPV6 receptor.

More preferably, the ligand-drug conjugate has the structure shown in Compound A.

Preferably, the dosage of the ligand-drug conjugate in each administration of the pharmaceutical composition is 0.10-0.20 mg/kg.

More preferably, the dosage of the ligand-drug conjugate of the pharmaceutical composition for each administration is 0.10 mg/kg, 0.11 mg/kg, 0.12 mg/kg, 0.13 mg/kg, 0.14 mg/kg, 0.15 mg/kg, 0.16 mg/kg, 0.17 mg/kg, 0.18 mg/kg, 0.19 mg/kg, or 0.20 mg/kg.

More preferably, in some embodiments of the present invention, the dosage of the ligand-drug conjugate of the pharmaceutical composition for each administration is 0.15 mg/kg or 0.17 mg/kg.

Further preferably, in some embodiments of the present invention, the dosage of the ligand-drug conjugate of the pharmaceutical composition for each administration is 0.15 mg/kg.

Preferably, the pharmaceutical composition is administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

More preferably, in some embodiments of the present invention, the pharmaceutical composition is administered once every 2 weeks.

Preferably, the histopathological type of the advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (ie, moderately differentiated and poorly differentiated).

More preferably, the histopathological type of the advanced epithelial ovarian cancer described in the present invention is high-grade serous carcinoma.

Preferably, the histopathological type of the primary peritoneal cancer or fallopian tube cancer is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (ie, moderately differentiated and poorly differentiated).

In a third aspect, the present invention provides a method for treating platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer.

Furthermore, the present invention provides a method for treating platinum-resistant advanced epithelial ovarian cancer.

Further, the method comprises administering a ligand-drug conjugate to the individual.

Furthermore, the method of the present invention comprises a ligand-drug conjugate as an active ingredient.

Preferably, the dosage of the ligand-drug conjugate administered each time in the method is 0.10-0.20 mg/kg.

More preferably, the method administers the ligand-drug conjugate at a dose of 0.10 mg/kg, 0.11 mg/kg, 0.12 mg/kg, 0.13 mg/kg, 0.14 mg/kg, 0.15 mg/kg, 0.16 mg/kg, 0.17 mg/kg, 0.18 mg/kg, 0.19 mg/kg, or 0.20 mg/kg each time.

More preferably, in some embodiments of the present invention, the dosage of the ligand-drug conjugate administered each time in the method is 0.15 mg/kg or 0.17 mg/kg.

Further preferably, in some embodiments of the present invention, the dosage of the ligand-drug conjugate administered each time in the method is 0.15 mg/kg.

Preferably, the method is administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

More preferably, in some embodiments of the present invention, the administration frequency of the method is once every 2 weeks.

Furthermore, the method comprises administering the ligand-drug conjugate to the individual by intravenous injection.

Preferably, each intravenous injection lasts for 80 min to 100 min.

More preferably, the time of each intravenous injection is 80 min, 82 min, 84 min, 86 min, 88 min, 90 min, 92 min, 94 min, 96 min, 98 min, or 100 min.

More preferably, in some embodiments, the duration of each intravenous injection is 90 minutes.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Maximum reduction in tumor-targeted lesions in evaluable patients.

Detailed ways

The embodiments of the present invention are described below, but the present invention is not limited thereto. The present invention is not limited to the various structures described below, and various changes can be made within the scope of the invention claim, and the embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and embodiments are also included in the technical scope of the present invention. In addition, all the documents recorded in this specification are cited in this specification as references.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In the present invention, the use of the term "comprising" or "including" means including the described elements, integers or steps, but does not exclude any other elements, integers or steps. In this article, when the term "comprising" or "including" is used, unless otherwise specified, the situation consisting of the described elements, integers or steps is also covered.

As used herein, the term "treat" refers to the slowing, prevention or reversal of the progression of cancer in a subject as evidenced by the alleviation or elimination of clinical or diagnostic symptoms of the disease. Treatment may include, for example, reduction in symptom severity, number of symptoms or frequency of recurrence, for example, tumor growth inhibition, tumor growth retardation or regression of an existing tumor.

In the present invention, the term "effective amount" used is generally sufficient to reduce the severity and/or frequency of symptoms, eliminate these symptoms and/or potential causes, prevent symptoms and/or their potential causes from occurring and/or improve or ameliorate damage (e.g., ovarian cancer) caused by or associated with a disease state. In some embodiments, the effective amount is a therapeutically effective amount or a preventive effective amount. A "therapeutically effective amount" is an amount sufficient to treat a disease state or symptom, particularly a state or symptom associated with the disease state, or otherwise prevent, hinder, delay or reverse the disease state or any other undesirable symptom associated with the disease in any way. A "preventive effective amount" is an amount that will have a predetermined preventive effect when administered to a subject, such as preventing or delaying the onset (or recurrence) of the disease state, or reducing the likelihood of the onset (or recurrence) of the disease state or related symptoms. A complete therapeutic or preventive effect may not occur with the administration of one dose, and may only occur after a series of doses are administered. Thus, a therapeutically or preventive effective amount may be administered in one or more administrations.

As used herein, the term "administering" means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

As used herein, the term "dose" is the amount of drug that elicits a therapeutic effect. Unless otherwise indicated, the dose is related to the amount of the drug in free form. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased proportionally compared to the amount of the drug in free form. For example, the dose will be stated on the product packaging or product information sheet.

In the present invention, "cancer" and "tumor" are used synonymously.

The pharmaceutical composition of the present invention can be prepared using a ligand-drug conjugate or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions are prepared by appropriately mixing, diluting or dissolving with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, cosolvents, etc. according to their dosage forms in a manner known in pharmaceutics.

In the present invention, the word "may" includes both performing a certain process and not performing a certain process.

In the present invention, "objective response rate (ORR)" refers to the proportion of patients whose tumors shrink to a certain extent and remain for a certain period of time, including cases of CR and PR. The solid tumor response evaluation criteria (RECIST1.1 standard) are used to assess the objective response of tumors. The subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable (SD), and progressive (PD) according to the RECIST 1.1 standard.

In the present invention, "Disease Control Rate (DCR)" refers to the percentage of confirmed complete remission, partial remission and disease stable (≥8 weeks) cases among patients who can be evaluated for efficacy.

In the present invention, "complete remission (CR)" means that all target lesions disappear, and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10 mm.

In the present invention, "partial response (PR)" means that the sum of the diameters of target lesions is reduced by at least 30% compared with the baseline level.

In the present invention, "disease progression (PD)" refers to a relative increase of at least 20% in the sum of diameters, with the minimum value of the sum of all target lesion diameters measured during the entire experimental study as a reference (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).

In the present invention, "stable disease (SD)" means that the reduction degree of target lesions has not reached the PR level, and the increase degree has not reached the PD level, but is somewhere in between. The minimum value of the sum of diameters can be used as a reference for research.

In the present invention, DCR (Disease control rates) refers to the percentage of cases that achieve remission (PR+CR) and stable lesions (SD) after treatment among the evaluable cases.

In the present invention, "ligand-drug conjugate" is a drug with biological activity connected to a ligand through a chemical link, and the ligand is used as a carrier to transport small molecule drugs into target cells, wherein the ligand can be a polypeptide or a small molecule. Preferably, the ligand-drug conjugate is a dual-ligand drug conjugate, and preferably, the dual-ligand drug conjugate is a drug conjugate targeting folate receptor and TRPV6 receptor. The ligand-drug conjugate of the present invention is recorded in a patent application with application number 201680045855.3 and invention name "Multi-ligand drug conjugate and its use", wherein LDC10B is a dual-ligand conjugate compound, the ligands target TRPV6 receptor and folate receptor respectively, and the drug carrier is MMAE, Its structure is as follows:

The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

Example 1: Efficacy and safety of ligand-drug conjugates in the treatment of platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer

1. Experimental Drugs

Ligand-drug conjugate: Compound A, provided by Tongyi Pharmaceutical (Suzhou) Co., Ltd. Compound A has the following structure:

2. Enrollment of subjects

All of the following inclusion criteria must be met to be eligible for entry into this trial.

(1) Female patients aged ≥18 years when signing the ICF.

(2) Patients must be pathologically confirmed to have platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Histopathological types are limited to high-grade serous carcinoma and endometrioid carcinoma ≥G2 (i.e., moderately differentiated and poorly differentiated). "Platinum resistance" is defined as: a. Patients who have received only one line of platinum-containing drug treatment must receive at least 4 cycles of platinum-containing drug treatment and must achieve disease remission (CR or PR), and PD or relapse within 3 months and 6 months after the last platinum-containing drug treatment; b. Patients who have received 2 or 3 lines of platinum-containing drug treatment must be PD or relapsed within 6 months after the last platinum-containing drug treatment. The interval time should be calculated from the date of the last platinum-containing drug treatment to the date when the imaging examination shows PD. Patients must have imaging evidence of failure of the last anti-tumor treatment or PD before enrollment.

(3) The patient has received ≤3 lines of total treatment since the diagnosis of the disease. “Total lines of treatment ≤3 lines” is defined as: at least 1 line but no more than 3 lines of systemic anti-cancer treatment since the diagnosis: a. Neoadjuvant and/or adjuvant therapy totaling 1 a. Maintenance therapy (including single-agent chemotherapy, targeted therapy, immunotherapy, and hormone therapy in previous combination regimens) is considered as part of the previous treatment (i.e., not counted separately); c. Treatment regimens changed for reasons other than PD are considered as part of the overall treatment regimen (i.e., not counted separately); d. Inadequate treatment (≤2 treatment cycles) without efficacy evaluation is not considered as first-line treatment. Previous treatments can include bevacizumab and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors.

(4) Tumor tissue samples (obtained by biopsy or surgery, fresh tumor biopsy samples that meet the requirements for FRα and TRPV6 receptor expression detection, or 8-10 pre-cut unstained tissue sections that have been fixed with formalin and embedded in paraffin) can be provided to the central laboratory for IHC FRα and TRPV6 detection.

(5) According to the detection standard of the companion diagnostic reagent FOLR1 (BN3.2) antibody reagent (IHC method) of Maijie Translational Medicine Research (Suzhou) Co., Ltd., the FRα expression of tumor tissue samples was positive in the IHC test of the central laboratory.

(6) At baseline, there was at least one measurable lesion that met RECIST V1.1. Lesions that had previously received radiotherapy were considered measurable lesions only if they showed clear progression.

(7) According to NCI CTCAE V5.0, the toxicity of any previous treatment (including surgery, intervention or radiotherapy) must be alleviated to ≤ grade 1 (except for long-term toxicity caused by alopecia, pigmentation or radiotherapy, which is judged by the investigator to be irreversible).

(8) Adequate hematological and end-organ function, as defined by the following relevant examination results: absolute neutrophil count (ANC) ≥ 1.5 × 10 ⁹ /L, and no history of granulocyte colony-stimulating factor (G-CSF) use within 2 weeks before the first dose of this study; platelet (PLT) count ≥ 90 × 10 ⁹ /L, and no history of thrombopoietin (TPO), interleukin (IL)-11 or PLT transfusion within 2 weeks before the first dose of this study; hemoglobin (Hb) ≥ 95g/L, and no history of erythropoietin (EPO) or red blood cell transfusion within 2 weeks before the first dose of this study; total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), TBIL ≤ 2 × ULN in the presence of liver metastasis; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, ALT and AST ≤ 3 × ULN in the presence of liver metastasis; serum creatinine (Cr) ≤ 1.5 × ULN or Serum creatinine clearance (CrCl) calculated by the Cockcroft-Gault formula was ≥60 mL/min (creatinine clearance was calculated only when serum creatinine was >1.5×ULN); activated partial thromboplastin time (APTT) was ≤1.5×ULN, and the APTT of patients receiving unfractionated heparin must be 1.5-2.5×ULN or within the range deemed acceptable by the investigator; international normalized ratio (INR) was ≤1.5, and the INR of patients receiving warfarin must be 2.0-3.0 or within the range deemed acceptable by the investigator; left ventricular ejection fraction (LVEF) was ≥50% or ≥the lower limit of normal value of the participating center.

(9) The patient's ECOG performance status was 0 or 1.

(10) The researchers assess that the expected survival of the patients is at least 12 weeks.

(11) Female patients of childbearing potential (WOCBP) with negative pregnancy test results within 7 days before the first dose of Compound A for injection and who promise to use a medically approved contraceptive method (such as intrauterine contraceptive device [IUD], birth control pills or condoms) during the study drug treatment and within 3 months after the end of the study drug treatment. Note: WOCBP is defined as Non-postmenopausal women who have experienced menarche and have not undergone surgical sterilization (hysterectomy or bilateral salpingo-oophorectomy) or have no other cause of permanent infertility determined by the investigator (such as Müllerian duct agenesis). Postmenopause is defined as amenorrhea for ≥ 12 months in the absence of other biological or physiological causes.

(12) The patient or his/her legally authorized representative must be willing and able to sign the ICF and comply with all study procedures and regulatory requirements in the study protocol.

Exclusion criteria:

a. Patients who are primary platinum-refractory (defined as: no response [CR or PR] or PD < 3 months after the last dose of first-line platinum-containing chemotherapy).

b. Those who meet any of the following conditions: received expanded field radiotherapy within 4 weeks before the first administration of study drug or received palliative radiotherapy within 2 weeks before the first administration of study drug; received Chinese medicine (prepared) medicine with clear anti-tumor effect within 2 weeks before the first administration of study drug; received other anti-tumor treatment, clinical trials or treatments that may interfere with this trial within 4 weeks or 5 half-lives (whichever is shorter) before the first administration of study drug.

c. Patients who have previously received extended-field radiotherapy (RT) with at least 20% of the bone marrow affected.

d. Those with a history of allergic reaction to any component of Compound A for injection.

e. The presence of peripheral neuropathy ≥ grade 2 as specified by NCI CTCAE V5.0.

f. Patients with a history of multiple sclerosis or other demyelinating diseases and/or Lambert-Eaton syndrome (paraneoplastic syndrome).

g. Patients with chronic or active corneal disease, history of corneal transplantation, or active eye disease requiring ongoing treatment/monitoring.

h. Diabetic patients whose blood sugar is still poorly controlled after treatment. Diabetes with poor blood sugar control is defined as glycosylated hemoglobin (HbA1c) ≥ 8% or HbA1c ≥ 7% and < 8% accompanied by diabetes-related symptoms (such as polyuria or thirst) without other explanations.

i. Hepatitis B virus surface antigen (HBsAg) positive and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) copy number ≥500IU/mL (or 2500copies, or the lower limit of the positive detection value of the participating center), HBV infection after treatment HBsAg (-) hepatitis B core antibody (HBcAb) (+) and HBV DNA copy number ≥500IU/mL (or 2500copies, or the lower limit of the positive detection value of the participating center), hepatitis C antibody (HCV-Ab) positive and hepatitis C virus (HCV) ribonucleic acid (RNA) ≥ ULN of the research center; patients with a history of cirrhosis (Child-Pugh B or C), positive human immunodeficiency virus (HIV) antibody, and active syphilis infection.

j. Patients with clinically significant severe cardiovascular disease, including but not limited to: a. Congestive heart failure > grade II as defined by the New York Heart Association (NYHA) criteria; b. Unstable angina within 6 months prior to the first administration of study drug c. severe arrhythmia within 6 months before the first administration of study drug; d. poorly controlled hypertension (those whose blood pressure is controlled to ≤ grade 2 hypertension [NCI CTCAE V5.0 standard] by medication are eligible for inclusion); e. the average resting QTc interval obtained from 3 12-ECGs (3 consecutive 12-ECGs with an interval of at least 5-10 minutes) is ≥470msec (corrected according to Fridericia formula).

k. Clinically severe thromboembolic disease (including acute peripheral arteriovenous thrombosis, acute pulmonary embolism, acute coronary syndrome, acute cerebrovascular disease and disseminated intravascular coagulation, etc.) occurred within 6 months before the first administration of the study drug.

l. Patients who have undergone major surgery within 4 weeks before the first administration of the study drug (the definition of major surgical surgery refers to the Level 3 and Level 4 surgeries specified in the "Regulations on the Management of Clinical Application of Medical Technology" implemented on May 1, 2009) or are in the recovery period of surgery (the researcher judges that there are still risks in joining the clinical trial).

m. Subjects with active bleeding (such as hemoptysis, hematemesis, bloody stools or melena) within 1 month before the first administration of study drug and requiring clinical treatment or who have not received clinical treatment but are expected to need clinical treatment in the future; subjects with a history of treated peptic ulcer or perforation within 6 months and no endoscopic evidence of recovery; subjects with a history of intestinal obstruction within 6 months (if incomplete intestinal obstruction persists, the researcher needs to judge the risk after enrollment and selective enrollment).

n. Unexplained fever > 38.5°C (if the researcher determines that it is tumor-related fever, the risk of enrollment in this trial needs to be assessed before deciding whether to enroll).

o. Active infection requiring systemic treatment (oral or intravenous), excluding local treatment, within 2 weeks prior to the first use of study drug.

p. Have a history of non-infectious interstitial lung disease (ILD), such as idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia, pneumoconiosis, and drug-related interstitial pneumonia, or have severely impaired lung function.

q. Suffering from other malignant tumors within the previous 5 years (except for early malignant tumors [carcinoma in situ or stage I tumors] that are judged to be clinically cured, such as basal cell or squamous cell skin cancer and superficial bladder cancer, etc.).

r. Patients with untreated active brain metastases or meningeal metastases (if the brain metastases are stable after treatment, and imaging examinations at least 4 weeks before medication show stable lesions with no new lesions, corticosteroid treatment is discontinued 3 days before the first dose of study drug, and neurological symptoms have recovered to NCI CTCAE V5.0≤1, then they are allowed to enter the group).

s. Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage (drainage performed once a month or more frequently/drainage performed within 2 weeks prior to the first dose of Compound A for injection).

t. History of drug abuse or alcoholism within 6 months before the first administration of study drug (alcoholism is defined as drinking more than 14 units per week, 1 unit = 285 mL beer = 25 mL liquor = 80 mL wine).

u. Subjects who have received or are expected to receive a live virus vaccine within 4 weeks before the first dose of study drug during the treatment period of this study.

v. Pregnant or lactating female subjects.

w. History of autoimmune disease, immunodeficiency disease or organ transplantation.

x. Patients who have previously received other FRα or TRPV6 targeted drug treatments.

y. Foods or drugs known to be strong or moderate CYP3A inhibitors or strong CYP3A inducers that have been used or are expected to be used within 2 weeks before the first dose of study drug.

z. Suffering from known mental illness disorders that may affect trial compliance or poor compliance.

z2. In the investigator's judgment, there is any history or current evidence of any disease, treatment, or laboratory abnormality that may confound the trial results, interfere with the subject's participation in the full trial, or is not in the best interest of the subject's participation in the trial.

3. Method of administration

Dosage and Administration: Compound A for injection is administered by intravenous injection (iv) at a dose of 0.15 mg/kg and 0.17 mg/kg.

Dosage schedule: Compound A for injection will be administered via iv, with each infusion time of 90 min (±10 min), Q2W, ie, once on D1 and D15 of each cycle, and each cycle is 28 days.

4. Experimental results

In terms of safety, the experimental statistics were started from January 2019 to June 25, 2023, and a total of 206 subjects were included. The most common adverse events (TRAEs) related to the study drug (incidence ≥ 20%) included: decreased neutrophil count (80.6%), decreased white blood cell count (75.2%), fever (70.4%), increased aspartate aminotransferase (70.4%), increased alanine aminotransferase (54.4%), nausea (53.4%), vomiting (48.1%), anemia (39.8%), loss of appetite (39.8%), decreased hemoglobin (33.5%), fatigue (32.5%), diarrhea (31.6%), hair loss (28.2%), increased blood glucose (28.2%), and urine protein detection (23.3%). Common TRAEs of grade 3 or above included: decreased neutrophil count (49.5%), decreased white blood cell count (27.2%), increased aspartate aminotransferase (5.3%), and increased alanine aminotransferase (5.3%). A total of 30 subjects experienced 40 serious adverse events (SAEs) related to the study drug. Four dose-limiting toxicity (DLT) events were observed in three subjects, including neutropenia (n=2), hypophosphatemia (n=1), and increased ALT (n=1). The data showed that the overall safety of compound A was good and controllable.

In terms of efficacy, among the subjects with platinum-resistant advanced ovarian cancer (histopathology type is high-grade serous carcinoma) who were given a dose of ≥0.15 mg/kg, a total of 83 cases with evaluable efficacy data were obtained, including 21 cases of PR, ORR of 25% (21/83), and DCR of 66% (55/83). Among the subjects with platinum-resistant advanced ovarian cancer (histopathology type is high-grade serous carcinoma) who were given a dose of =0.15 mg/kg, a total of 56 cases with evaluable efficacy data were obtained, including 14 cases of PR, ORR of 25% (14/56), and DCR of 66% (37/56). In addition, in this cohort, there were 25 cases with previous systemic anti-cancer. Data analysis showed that there were 9 PRs in subjects with platinum-resistant advanced ovarian cancer who had received ≤3 lines of tumor treatment. The ORR was 36% (9/25) and the DCR was 84% (21/25). Preliminary data showed that Compound A for injection showed a certain efficacy in subjects with platinum-resistant advanced ovarian cancer, and showed better efficacy in the enriched population who had received ≤3 lines of previous systemic anti-tumor treatment.

Example 2: FRα expression level predicts drug efficacy in subjects

Immunohistochemical staining was performed on tumor tissue samples of subjects with platinum-resistant advanced ovarian cancer (histopathological type was high-grade serous carcinoma) who were given a dose of 0.15 mg/kg in Example 1, and the protein expression level of FRα in each tumor sample was obtained by quantitative analysis of the tumor cell positive percentage score (TPS). A total of 20 evaluable efficacy data were obtained.

The results showed that among subjects with platinum-resistant advanced ovarian cancer (histopathological type was high-grade serous carcinoma) who were FRα-positive (expression ≥ 25%) and had ≤ 3 lines of previous systemic anti-tumor treatment, the ORR was 40%, significantly higher than that of the subjects in the whole population (ORR was 25%) (see Figure 1). Preliminary data showed that a better efficacy was shown in the enriched population with positive FRα expression and ≤ 3 lines of previous systemic anti-tumor treatment.

Claims

A use of a ligand-drug conjugate in the preparation of a drug for treating platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, wherein the ligand-drug conjugate is a drug conjugate targeting a folate receptor and a TRPV6 receptor;

Preferably, the use is the use of the ligand-drug conjugate in the preparation of a drug for treating platinum-resistant advanced epithelial ovarian cancer;

Preferably, the ligand-drug conjugate is compound A having the following structure:
The use according to claim 1, characterized in that the histopathological type of the advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (i.e., moderately differentiated and poorly differentiated);

Preferably, the histopathological type of the advanced epithelial ovarian cancer is high-grade serous carcinoma.
The use according to claim 1 or 2, characterized in that the folate receptor expression level of the advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer is ≥ 25%.
The use according to claim 1 is characterized in that the histopathological type of the primary peritoneal cancer or fallopian tube is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (i.e., moderately differentiated and poorly differentiated).
A pharmaceutical composition for treating platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, characterized in that a ligand-drug conjugate is used as an active ingredient, the dosage of the ligand-drug conjugate is 0.10-0.20 mg/kg each time, and the administration frequency is once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; wherein the ligand-drug conjugate is a drug conjugate targeting folate receptors and TRPV6 receptors;

Preferably, the pharmaceutical composition is used to treat platinum-resistant advanced epithelial ovarian cancer;

Preferably, the ligand-drug conjugate is compound A having the following structure:
The pharmaceutical composition according to claim 5, characterized in that the ligand-drug conjugate is used as an active ingredient, and the dosage of the ligand-drug conjugate administered each time is 0.10 mg/kg, 0.11 mg/kg, 0.13 mg/kg, 0.15 mg/kg, 0.16 mg/kg, 0.17 mg/kg, 0.18 mg/kg, 0.19 mg/kg or 0.20 mg/kg;

Preferably, the dose of the ligand-drug conjugate administered each time is 0.15 mg/kg or 0.17 mg/kg;

More preferably, the dosage of the ligand-drug conjugate administered each time is 0.15 mg/kg.
The pharmaceutical composition according to claim 5, characterized in that the ligand-drug conjugate is used as an active ingredient and the administration frequency is once every 2 weeks.
The pharmaceutical composition according to any one of claims 5 to 7, characterized in that the histopathological type of the advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (i.e., moderately differentiated and poorly differentiated);

Preferably, the histopathological type of the advanced epithelial ovarian cancer is high-grade serous carcinoma.
The pharmaceutical composition according to any one of claims 5 to 8, characterized in that the folate receptor expression level of the advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer is ≥ 25%.
The pharmaceutical composition according to any one of claims 5 to 7, characterized in that the histopathological type of the primary peritoneal cancer or fallopian tube cancer is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (i.e., moderately differentiated and poorly differentiated).
A method for treating platinum-resistant advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer, comprising administering a ligand-drug conjugate to an individual, wherein the ligand-drug conjugate is a drug conjugate targeting a folate receptor and a TRPV6 receptor;

Preferably, the method is used to treat platinum-resistant advanced epithelial ovarian cancer;

Preferably, the ligand-drug conjugate is compound A having the following structure:
The method according to claim 11, characterized in that the histopathological type of the advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (i.e., moderately differentiated and poorly differentiated);

Preferably, the histopathological type of the advanced epithelial ovarian cancer is high-grade serous carcinoma.
The method according to claim 11 or 12, characterized in that the folate receptor expression level of the advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer is ≥ 25%.
The method according to claim 11 is characterized in that the histopathological type of the primary peritoneal cancer or fallopian tube cancer is high-grade serous carcinoma or endometrioid carcinoma of grade ≥G2 (i.e., moderately differentiated and poorly differentiated).
The method according to any one of claims 11 to 14, characterized in that the ligand-drug conjugate is used as an active ingredient, and the dosage of the ligand-drug conjugate administered each time is 0.10-0.20 mg/kg, preferably, the dosage of the ligand-drug conjugate administered each time is 0.10 mg/kg, 0.11 mg/kg, 0.13 mg/kg, 0.15 mg/kg, 0.17 mg/kg, 0.19 mg/kg, 0.20 mg/kg; more preferably, the dosage of the ligand-drug conjugate administered each time is 0.15 mg/kg or 0.17 mg/kg; further preferably, the dosage of the ligand-drug conjugate administered each time is 0.15 mg/kg;

The administration frequency is once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; preferably, the administration frequency is once every 2 weeks.
The method according to any one of claims 11 to 14, characterized in that the ligand-drug conjugate is administered to the individual by intravenous injection.
The method according to claim 16, characterized in that each intravenous injection lasts for 80 min to 100 min;

Preferably, each intravenous injection lasts for 90 minutes.