WO2023207931A1 - 米托蒽醌脂质体联合抗血管生成靶向药治疗卵巢癌的用途 - Google Patents
米托蒽醌脂质体联合抗血管生成靶向药治疗卵巢癌的用途 Download PDFInfo
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- WO2023207931A1 WO2023207931A1 PCT/CN2023/090462 CN2023090462W WO2023207931A1 WO 2023207931 A1 WO2023207931 A1 WO 2023207931A1 CN 2023090462 W CN2023090462 W CN 2023090462W WO 2023207931 A1 WO2023207931 A1 WO 2023207931A1
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- mitoxantrone
- ovarian cancer
- liposome
- sorafenib
- bevacizumab
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Definitions
- the invention belongs to the field of anti-tumor, and specifically relates to the use of mitoxantrone liposomes combined with anti-angiogenic targeted drugs, especially bevacizumab or sorafenib, in the treatment of ovarian cancer, especially platinum-resistant recurrent ovarian cancer. the use of.
- Ovarian cancer is one of the common malignant tumors in women. Due to the lack of typical symptoms and signs, once it is discovered, it is mostly in the middle and late stages, and the survival time is very short. In 2020, there were 55,342 new cases of ovarian cancer and 37,519 new deaths in my country. The incidence rate ranked third among malignant tumors of the female reproductive system and the mortality rate ranked second. There are many pathological types of ovarian cancer, among which epithelial ovarian cancer is the most common, accounting for 95%, followed by malignant germ cell tumors and sex cord stromal tumors.
- Platinum-containing combination chemotherapy is the main recommended regimen for postoperative chemotherapy for advanced ovarian cancer. About 10% to 15% of ovarian cancer patients are intrinsically resistant to standard first-line platinum drug combination therapy, and their overall survival time is less than 9 months. Even if advanced patients achieve complete remission after platinum-containing treatment, 70%-80% will still relapse (Xie Xing, Martin, Shen Keng et al., Chinese expert consensus on pegylated liposomal doxorubicin for the treatment of ovarian cancer (2018 Year), Progress in Modern Obstetrics and Gynecology, 2018, 27(09): 641-644).
- the preferred treatment options include single-agent chemotherapy.
- Single-agent chemotherapy includes liposomal doxorubicin, paclitaxel, topotecan, gemcitabine, docetaxel, etoposide, etc.
- the ORR of docetaxel or etoposide can be higher than 20%, but the median OS is 12.7 months and 10.8 months respectively, which does not improve survival compared with the above four chemotherapy drugs (Rose P G, Blessing J A, Ball H G, et al., A Phase II Study of Docetaxel in Paclitaxel-Resistant Ovarian and Peritoneal Carcinoma: A Gynecologic Oncology Group Study, Gynecol Oncol, 2003, 88(2): 130-5). Therefore, there is no one chemotherapy drug that is better than another Drugs are more prominent in terms of effectiveness.
- Single-agent chemotherapy has a low ORR rate, a short sustained response time, and an overall survival time of about 1 year.
- Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (Vascular endothelial growth factor, VEGF).
- VEGF vascular endothelial growth factor
- bevacizumab combined with chemotherapy improved the ORR of platinum-resistant ovarian cancer to 27.3%; in terms of safety, the bevacizumab group was generally safe and tolerated, with grade ⁇ 2 hypertension ( 20%), proteinuria (2%), gastrointestinal perforation (2%), and fistula/abscess (2%) more common (Eric Pujade-Lauraine, Felix Hilpert et al., Bevacizumab Combined with Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial, Journal of Clinical Oncology, 2014, 32(13), 1302-1311).
- Sorafenib is a classic multi-target kinase inhibitor. In vitro experiments show that it not only inhibits the signaling pathways of tumor angiogenesis such as VEGF receptor and platelet-derived growth factor receptor (PDGFR). In addition, it can also inhibit tumor cell proliferation targets such as RAF, c-Kit, and FLT-3. Sorafenib has been approved by the FDA for unresectable hepatocellular carcinoma, advanced renal cell carcinoma, and recurrent metastatic thyroid cancer. A phase II single-arm study showed that sorafenib monotherapy in platinum-resistant ovarian cancer had an ORR of 3.4% and a median OS of 16.33 months.
- platinum-resistant recurrent ovarian cancer has a poor prognosis and a short survival period, and the efficacy of existing drug treatments (including chemotherapy and targeted therapy) is not satisfactory. Therefore, there is a need for new drugs or therapies for the treatment of platinum-resistant recurrent ovarian cancer that can improve disease response rates, prolong survival, and are safely tolerated.
- Mitoxantrone is a drug currently widely used clinically, and the FDA-approved indications are multiple Sexual sclerosis, prostate cancer and acute myeloid leukemia, clinically used for malignant lymphoma, breast cancer, lung cancer, melanoma, soft tissue sarcoma, multiple myeloma, liver cancer, colorectal cancer, renal cancer, endometrial cancer, testicular tumors , ovarian cancer and head and neck cancer also have certain effects.
- liposome preparations Compared with ordinary preparations of mitoxantrone, liposome preparations have lower toxicity (especially cardiotoxicity), and have the characteristics of passively targeting tumor tissues, improving anti-tumor activity.
- the inventors of the present application tried to combine mitoxantrone liposomes with anti-angiogenesis targeted drugs, especially bevacizumab and sorafenib, for the treatment of platinum-resistant recurrent ovarian cancer, and the results achieved improved results. Disease response rate and safe tolerability, thus providing a new option for the treatment of platinum-resistant recurrent ovarian cancer.
- the present invention relates to the use of mitoxantrone liposomes combined with anti-angiogenesis targeting drugs in the treatment of ovarian cancer.
- a first aspect of the present invention relates to the use of mitoxantrone liposomes and anti-angiogenesis targeting drugs in the preparation of drugs for the treatment of ovarian cancer, wherein the anti-angiogenesis targeting drugs are selected from the group consisting of bevacizumab and serotonin. Rafenib.
- a second aspect of the present invention relates to the use of mitoxantrone liposomes in the preparation of a drug for improving the efficacy of an anti-angiogenesis targeting drug in the treatment of ovarian cancer, wherein the anti-angiogenesis targeting drug is selected from the group consisting of bevacizumab and sorafenib.
- a third aspect of the invention relates to a method of treating ovarian cancer, the method comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and an anti-angiogenic targeting agent, wherein the anti-angiogenic targeting agent
- the drugs are selected from bevacizumab and sorafenib.
- the fourth aspect of the present invention relates to a method for improving the efficacy of anti-angiogenesis targeting drugs in the treatment of ovarian cancer.
- the method includes, on the basis of administering anti-angiogenesis targeting drugs to ovarian cancer patients, further combined with the administration of a therapeutically effective amount.
- Mitoxantrone liposome, wherein the anti-angiogenesis targeting drug is selected from the group consisting of bevacizumab and sorafenib.
- a fifth aspect of the present invention relates to a medicament for treating ovarian cancer, the medicament comprising mitoxantrone liposomes and an anti-angiogenesis targeting drug, wherein the anti-angiogenesis targeting drug is selected from bevacizumab monoclonal antibodies and sorafenib.
- a sixth aspect of the present invention relates to a composition for treating ovarian cancer, the composition comprising mitoxantrone liposomes and an anti-angiogenesis targeting drug, wherein the anti-angiogenesis targeting drug is selected from the group consisting of Valclizumab and sorafenib.
- a seventh aspect of the present invention relates to a drug for improving the efficacy of an anti-angiogenesis targeting drug in the treatment of ovarian cancer, the drug comprising mitoxantrone liposomes, wherein the anti-angiogenesis targeting drug is selected from the group consisting of: Valclizumab and sorafenib.
- An eighth aspect of the present invention relates to a kit for treating ovarian cancer, the kit comprising mitoxantrone liposomes and an anti-angiogenesis targeting drug, wherein the anti-angiogenesis targeting drug is selected from the group consisting of Valclizumab and sorafenib.
- the ovarian cancer is recurrent ovarian cancer.
- the ovarian cancer is platinum-resistant recurrent ovarian cancer.
- the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- the mitoxantrone liposome is an injectable formulation.
- bevacizumab is an injectable form.
- sorafenib is a tablet.
- composition means a combination of two or more active ingredients, wherein the active ingredients may be present in the same formulation for administration together, or the active ingredients may be present in different formulations, in the same or different formulations.
- Mode of administration Simultaneous or sequential administration. In this sense, “composition” and “combination” are used interchangeably.
- the term "therapeutically effective amount” or “effective amount” refers to a dose that exhibits the desired benefit in a subject treated.
- the “therapeutically effective amount” or “effective amount” will depend on the species of the subject being treated, the severity of the disease, the frequency of administration, the metabolic characteristics of the drug and other factors, and may be judged by the prescribing physician based on routine practice. It should be noted that all numerical ranges mentioned in this application include both endpoints of the range, all values within the range, and the subrange formed by any two values therein.
- treatment means controlling, alleviating or ameliorating the pathological progression of a disease. development and prolonging the survival of diseased subjects.
- the terms “subject”, “subject” and “patient” include individual animals to which the medicaments or compositions of the present application are intended to be administered, including but not limited to humans and other mammals, such as mice and rats. , cats, monkeys, dogs, horses, pigs, etc. Preferably, the subject is a human being. Unless otherwise indicated, the terms “subject,” “subject,” and “patient” are used interchangeably.
- platinum-resistant recurrent ovarian cancer refers to ovarian cancer that recurs within 1 to 6 months after at least 4 cycles of platinum-containing regimens.
- a first aspect of the present invention relates to the use of mitoxantrone liposomes and anti-angiogenesis targeting drugs in the preparation of drugs for the treatment of ovarian cancer, wherein the anti-angiogenesis targeting drugs are selected from the group consisting of bevacizumab and serotonin. Rafenib.
- the anti-angiogenesis targeted agent is bevacizumab. In some embodiments, the anti-angiogenesis targeted agent is sorafenib.
- the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
- the mitoxantrone liposome is a liquid injection
- the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
- bevacizumab is an injection, including liquid injection, powder for injection, tablet for injection, etc.
- bevacizumab is a liquid injection, it contains the active ingredient bevacizumab 25mg/ml.
- sorafenib is a tablet containing 200 mg of active ingredient per tablet.
- the use of mitoxantrone liposomes and bevacizumab in the preparation of a medicament for the treatment of ovarian cancer is provided.
- the use of mitoxantrone liposomes and bevacizumab in the preparation of a medicament for the treatment of platinum-resistant recurrent ovarian cancer is provided.
- the use of mitoxantrone liposomes and bevacizumab in the preparation of a medicament for the treatment of platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is provided.
- mitoxantrone liposome is an injection, containing 0.5-5 mg/ml of active ingredient based on mitoxantrone; bevacizumab is an injection, containing 25 mg/ml of active ingredient.
- mitoxantrone liposomes and sorafenib in the preparation of a medicament for treating ovarian cancer is provided. In some embodiments, the use of mitoxantrone liposomes and sorafenib in the preparation of a medicament for the treatment of platinum-resistant recurrent ovarian cancer is provided. In some embodiments, the use of mitoxantrone liposomes and sorafenib in the preparation of a medicament for the treatment of platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is provided. In these embodiments, mitoxantrone liposome is an injection, containing 0.5-5 mg/ml of active ingredient based on mitoxantrone; sorafenib is a tablet, containing 200 mg of active ingredient per tablet.
- a second aspect of the present invention relates to the use of mitoxantrone liposomes in the preparation of a drug for improving the efficacy of an anti-angiogenesis targeting drug in the treatment of ovarian cancer, wherein the anti-angiogenesis targeting drug is selected from the group consisting of bevacizumab and sorafenib.
- the anti-angiogenesis targeted agent is bevacizumab. In some embodiments, the anti-angiogenesis targeted agent is sorafenib.
- the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
- the mitoxantrone liposome is a liquid injection
- the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
- bevacizumab is an injection, including liquid injection, powder for injection, tablet for injection, etc.
- bevacizumab is a liquid injection, it contains the active ingredient bevacizumab 25mg/ml.
- sorafenib is a tablet containing 200 mg of active ingredient per tablet.
- the use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of bevacizumab in the treatment of ovarian cancer is provided.
- the use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of bevacizumab in the treatment of platinum-resistant recurrent ovarian cancer is provided.
- the use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of bevacizumab in the treatment of platinum-resistant relapsed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is provided.
- mitoxantrone liposome is an injection, containing 0.5-5 mg/ml of active ingredient based on mitoxantrone; bevacizumab is an injection, containing 25 mg/ml of active ingredient.
- mitoxantrone is provided Use of liposomes in the preparation of drugs that improve the efficacy of sorafenib in the treatment of platinum-resistant recurrent ovarian cancer.
- the use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of sorafenib in the treatment of platinum-resistant relapsed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is provided.
- mitoxantrone liposome is an injection, containing 0.5-5 mg/ml of active ingredient based on mitoxantrone; sorafenib is a tablet, containing 200 mg of active ingredient per tablet.
- a third aspect of the invention relates to a method of treating ovarian cancer, the method comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and an anti-angiogenic targeting agent, wherein the anti-angiogenic targeting agent
- the drugs are selected from bevacizumab and sorafenib.
- the anti-angiogenesis targeted agent is bevacizumab. In some embodiments, the anti-angiogenesis targeted agent is sorafenib.
- the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- mitoxantrone is administered liposomally by injection.
- mitoxantrone liposomes are administered intravenously in a therapeutically effective amount of 8-30 mg/ m2 , preferably 20 mg/ m2 .
- mitoxantrone liposomes are administered every 3 weeks.
- mitoxantrone liposomes are administered intravenously every 3 weeks at a therapeutically effective amount of 20 mg/m.
- bevacizumab is administered by injection. In some embodiments, bevacizumab is administered by injection at a dose of 15 mg/kg.
- sorafenib is administered orally. In some embodiments, sorafenib is administered orally at a dose of 400 mg/dose. In some embodiments, sorafenib is administered twice daily. In some embodiments, sorafenib is administered orally twice daily at a dose of 400 mg/dose.
- methods of treating ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and bevacizumab.
- a method of treating ovarian cancer is provided, the method comprising administering a therapeutically effective amount of mitoxantrone liposomes to a patient with ovarian cancer, and administering betaine at any time after the administration of the mitoxantrone liposomes.
- Valclizumab is provided, comprising administering a therapeutically effective amount of mitoxantrone liposomes to a patient with ovarian cancer, and administering betaine at any time after the administration of the mitoxantrone liposomes.
- a method of treating ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and a therapeutically effective amount of mitoxantrone liposomes at 15 mg/kg.
- Valclizumab after 1-8 cycles Bevacizumab maintenance therapy was administered at 15 mg/kg every 3 weeks.
- a method of treating ovarian cancer is provided, the method comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and a therapeutically effective amount of mitoxantrone liposomes at 15 mg/kg.
- a method of treating ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and a therapeutically effective amount of mitoxantrone liposomes at 15 mg/kg.
- bevacizumab maintenance therapy was given at 15 mg/kg every 3 weeks.
- the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
- methods of treating ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and sorafenib.
- a method of treating ovarian cancer is provided, the method comprising administering a therapeutically effective amount of mitoxantrone liposomes to a patient with ovarian cancer, and before, during and after the administration of mitoxantrone liposomes Administer sorafenib at any time.
- a method of treating ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and 400 mg/dose twice daily For sorafenib, administer sorafenib maintenance therapy at 400 mg/dose twice daily after 1 to 8 cycles.
- a method of treating ovarian cancer is provided, the method comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and 400 mg/dose twice daily For sorafenib, administer sorafenib maintenance therapy at 400 mg/dose twice daily after 5 to 7 cycles.
- a method of treating ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and 400 mg/dose twice daily After 8 cycles of sorafenib, sorafenib maintenance therapy was administered at 400 mg/dose twice daily.
- the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
- the fourth aspect of the present invention relates to a method for improving the efficacy of anti-angiogenesis targeting drugs in the treatment of ovarian cancer.
- the method includes, on the basis of administering anti-angiogenesis targeting drugs to ovarian cancer patients, further combined with the administration of a therapeutically effective amount.
- Mitoxantrone liposome, wherein the anti-angiogenesis targeting drug is selected from the group consisting of bevacizumab and sorafenib.
- the anti-angiogenesis targeted agent is bevacizumab. In a In some embodiments, the anti-angiogenesis targeted drug is sorafenib.
- the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- mitoxantrone is administered liposomally by injection.
- mitoxantrone liposomes are administered intravenously in a therapeutically effective amount of 8-30 mg/ m2 , preferably 20 mg/ m2 .
- mitoxantrone liposomes are administered every 3 weeks.
- mitoxantrone liposomes are administered intravenously every 3 weeks at a therapeutically effective amount of 20 mg/m.
- bevacizumab is administered by injection. In some embodiments, bevacizumab is administered by injection at a dose of 15 mg/kg.
- sorafenib is administered orally. In some embodiments, sorafenib is administered orally at a dose of 400 mg/dose. In some embodiments, sorafenib is administered twice daily. In some embodiments, sorafenib is administered orally twice daily at a dose of 400 mg/dose.
- a method for improving the efficacy of bevacizumab in the treatment of ovarian cancer comprising, on the basis of administering bevacizumab to ovarian cancer patients, further combined with the administration of a therapeutically effective amount of mitoxantron Quinone liposomes.
- a method of improving the efficacy of bevacizumab in the treatment of ovarian cancer comprising administering methotrexate at a dose of 20 mg/m every 3 weeks at any time before administration of bevacizumab. Anthraquinone liposomes.
- a method of improving the efficacy of bevacizumab in the treatment of ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and A therapeutically effective dose of bevacizumab at 15 mg/kg was administered for 1-8 cycles, followed by bevacizumab maintenance therapy at 15 mg/kg every 3 weeks.
- a method of improving the efficacy of bevacizumab in the treatment of ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and A therapeutically effective dose of bevacizumab at 15 mg/kg was administered for 5-7 cycles, followed by bevacizumab maintenance therapy at 15 mg/kg every 3 weeks.
- a method of improving the efficacy of bevacizumab in the treatment of ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and A therapeutically effective dose of bevacizumab at 15 mg/kg was administered for 8 cycles, followed by bevacizumab maintenance therapy at 15 mg/kg every 3 weeks.
- the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant relapsed ovarian cancer.
- Ovarian cancer is more preferably platinum-resistant and recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
- a method for improving the efficacy of sorafenib in treating ovarian cancer comprising, on the basis of administering sorafenib to ovarian cancer patients, further combined with administering a therapeutically effective amount of mitoxantrone lipid plastid.
- a method of improving the efficacy of sorafenib in the treatment of ovarian cancer comprising administering at a dose of 20 mg/m every 3 weeks at any time before, during, or after the administration of sorafenib. Mitoxantrone liposomes.
- a method for improving the efficacy of sorafenib in the treatment of ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and every Sorafenib is administered at 400 mg/dose twice daily, followed by maintenance therapy at 400 mg/dose twice daily after 1-8 cycles.
- a method for improving the efficacy of sorafenib in the treatment of ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and every Sorafenib is administered at 400 mg/dose twice daily, followed by maintenance therapy at 400 mg/dose twice daily after 5-7 cycles.
- a method for improving the efficacy of sorafenib in the treatment of ovarian cancer comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and every Sorafenib was administered at 400 mg/dose twice daily, followed by maintenance therapy at 400 mg/dose twice daily after 8 cycles.
- the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
- a fifth aspect of the present invention relates to a medicament for treating ovarian cancer, the medicament comprising mitoxantrone liposomes and an anti-angiogenesis targeting drug, wherein the anti-angiogenesis targeting drug is selected from bevacizumab monoclonal antibodies and sorafenib.
- the drug comprises mitoxantrone liposomes and bevacizumab. In some embodiments, the drug comprises mitoxantrone liposomes and sorafenib. In some embodiments, the drug optionally includes other first-line and second-line drugs known in the art for the treatment of ovarian cancer.
- the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
- mitoxantrone liposome is a liquid injection
- Mitoxantrone contains an active ingredient of 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml.
- bevacizumab is an injection, including liquid injection, powder for injection, tablet for injection, etc.
- bevacizumab is a liquid injection, it contains the active ingredient bevacizumab 25mg/ml.
- sorafenib is a tablet containing 200 mg of active ingredient per tablet.
- a sixth aspect of the present invention relates to a composition for treating ovarian cancer, the composition comprising mitoxantrone liposomes and an anti-angiogenesis targeting drug, wherein the anti-angiogenesis targeting drug is selected from the group consisting of Valclizumab and sorafenib.
- the composition comprises mitoxantrone liposomes and bevacizumab. In some embodiments, the composition comprises mitoxantrone liposomes and sorafenib.
- the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- mitoxantrone is administered liposomally by injection.
- mitoxantrone liposomes are administered intravenously in a therapeutically effective amount of 8-30 mg/ m2 , preferably 20 mg/ m2 .
- mitoxantrone liposomes are administered every 3 weeks.
- mitoxantrone liposomes are administered intravenously every 3 weeks at a therapeutically effective amount of 20 mg/m.
- bevacizumab is administered by injection. In some embodiments, bevacizumab is administered by injection at a dose of 15 mg/kg.
- sorafenib is administered orally. In some embodiments, sorafenib is administered orally at a dose of 400 mg/dose. In some embodiments, sorafenib is administered twice daily. In some embodiments, sorafenib is administered orally twice daily at a dose of 400 mg/dose.
- the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and bevacizumab. In some embodiments, the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and administering bevacizumab at any time after administration of mitoxantrone liposomes.
- the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m and a therapeutically effective amount of bevacizumab at 15 mg/kg every 3 weeks for 1 -Bevacizumab maintenance therapy at 15 mg/kg every 3 weeks after 8 cycles.
- the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantron at 20 mg/m every 3 weeks Quinone liposomes and a therapeutically effective dose of bevacizumab at 15 mg/kg, followed by bevacizumab maintenance therapy at 15 mg/kg every 3 weeks after 5-7 cycles.
- the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m and a therapeutically effective amount of bevacizumab at 15 mg/kg every 3 weeks for 8 After each cycle, bevacizumab maintenance therapy was given at 15 mg/kg every 3 weeks.
- the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
- the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and sorafenib. In some embodiments, the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and administering sorafen at any time before, during, or after the administration of mitoxantrone liposomes Ni.
- the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and 400 mg/dose of sorafenib twice daily, administered Sorafenib maintenance therapy was administered at 400 mg/dose twice daily after cycles 1-8.
- the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and 400 mg/dose of sorafenib twice daily, administered Sorafenib maintenance therapy was administered at 400 mg/dose twice daily after 5-7 cycles.
- the treatment includes administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks and 400 mg/dose of sorafenib twice daily, administered After 8 cycles, sorafenib maintenance therapy was administered at 400 mg/dose twice daily.
- the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
- a seventh aspect of the present invention relates to a drug for improving the efficacy of an anti-angiogenesis targeting drug in the treatment of ovarian cancer, the drug comprising mitoxantrone liposomes, wherein the anti-angiogenesis targeting drug is selected from the group consisting of: Valclizumab and sorafenib.
- the anti-angiogenesis targeted agent is bevacizumab. In some embodiments, the anti-angiogenesis targeted agent is sorafenib.
- the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- mitoxantrone is administered liposomally by injection.
- mitoxantrone liposomes are administered intravenously in a therapeutically effective amount of 8-30 mg/m 2 , preferably 20 mg/m 2 medicine.
- mitoxantrone liposomes are administered every 3 weeks.
- mitoxantrone liposomes are administered intravenously every 3 weeks at a therapeutically effective amount of 20 mg/m.
- bevacizumab is administered by injection. In some embodiments, bevacizumab is administered by injection at a dose of 15 mg/kg.
- sorafenib is administered orally. In some embodiments, sorafenib is administered orally at a dose of 400 mg/dose. In some embodiments, sorafenib is administered twice daily. In some embodiments, sorafenib is administered orally twice daily at a dose of 400 mg/dose.
- a medicament for improving the efficacy of bevacizumab in the treatment of ovarian cancer is provided, and the improvement includes further combined administration of a therapeutically effective amount of mAb on the basis of administering bevacizumab to ovarian cancer patients.
- Toxantrone liposomes is provided.
- a medicament is provided for improving the efficacy of bevacizumab in the treatment of ovarian cancer, said improvement comprising administering at a dose of 20 mg/m every 3 weeks at any time before the administration of bevacizumab Mitoxantrone liposomes.
- a medicament for improving the efficacy of bevacizumab in the treatment of ovarian cancer, the improvement comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone lipid at 20 mg/m every 3 weeks.
- a therapeutically effective dose of bevacizumab is administered to the body and 15 mg/kg, and bevacizumab maintenance therapy is given at 15 mg/kg every 3 weeks after 1-8 cycles.
- a medicament is provided for improving the efficacy of bevacizumab in the treatment of ovarian cancer, the improvement comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone lipid at 20 mg/m every 3 weeks.
- a therapeutically effective dose of bevacizumab is administered to the body and 15 mg/kg, and maintenance therapy with bevacizumab is given at 15 mg/kg every 3 weeks after 5-7 cycles.
- a medicament is provided for improving the efficacy of bevacizumab in the treatment of ovarian cancer, the improvement comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone lipid at 20 mg/m every 3 weeks.
- the therapeutically effective dose of bevacizumab was administered to the body and 15 mg/kg, and after 8 cycles, bevacizumab maintenance therapy was given at 15 mg/kg every 3 weeks.
- the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
- a medicament for improving the efficacy of sorafenib in treating ovarian cancer comprising further combined administration of a therapeutically effective amount of mitoxantron on the basis of sorafenib to patients with ovarian cancer.
- Quinone liposomes are provided.
- medicaments are provided for improving the efficacy of sorafenib in treating ovarian cancer, the improvement comprising: Mitoxantrone liposomes were administered every 3 weeks at a dose of 20 mg/ m2 at any time before, during, and after administration.
- a medicament for improving the efficacy of sorafenib in the treatment of ovarian cancer, the improvement comprising administering to an ovarian cancer patient a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks. and sorafenib at 400 mg/dose twice daily, followed by maintenance therapy at 400 mg/dose twice daily after 1 to 8 cycles.
- a medicament is provided for improving the efficacy of sorafenib in the treatment of ovarian cancer, the improvement comprising administering to an ovarian cancer patient a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks.
- a medicament for improving the efficacy of sorafenib in the treatment of ovarian cancer, the improvement comprising administering to an ovarian cancer patient a therapeutically effective amount of mitoxantrone liposomes at 20 mg/m every 3 weeks. and sorafenib at 400 mg/dose twice daily, followed by maintenance therapy at 400 mg/dose twice daily after 8 cycles.
- the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
- An eighth aspect of the present invention relates to a kit for treating ovarian cancer, the kit comprising mitoxantrone liposomes and an anti-angiogenesis targeting drug, wherein the anti-angiogenesis targeting drug is selected from the group consisting of Valclizumab and sorafenib.
- the anti-angiogenesis targeted agent is bevacizumab. In some embodiments, the anti-angiogenesis targeted agent is sorafenib.
- the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
- the mitoxantrone liposome and the anti-angiogenic targeted agent are each separate formulations.
- mitoxantrone liposomes are in the form of injections, including liquid injections, powders for injection, tablets for injection, and the like.
- the mitoxantrone liposome is a liquid injection
- the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, and more preferably 1 mg/ml based on mitoxantrone.
- bevacizumab is an injection, including liquid injection, powder for injection, tablet for injection, etc.
- bevacizumab is a liquid injection, it contains the active ingredient bevacizumab 25mg/ml.
- sorafenib is a tablet containing 200 mg of active ingredient per tablet.
- the kit includes mitoxantrone liposomes and bevacizumab.
- the mitoxantrone liposome is an injection and contains 0.5-5 mg/ml of active ingredient based on mitoxantrone; the bevacizumab is an injection and contains 25 mg/ml of active ingredient.
- the kit includes mitoxantrone liposomes and sorafenib.
- mitoxantrone liposome is an injection, containing 0.5-5 mg/ml of active ingredient based on mitoxantrone; sorafenib is a tablet, containing 200 mg of active ingredient per tablet.
- bevacizumab may be provided in the form of a pharmaceutical preparation, such as an injection.
- a pharmaceutical preparation such as an injection.
- Such pharmaceutical preparations are commercially available.
- sorafenib is preferably sorafenib tosylate.
- Sorafenib may be provided in the form of pharmaceutical preparations, such as tablets. Such pharmaceutical preparations are commercially available.
- mitoxantrone liposomes are not particularly limited. Without being bound by any particular theory, the inventors of the present application have discovered that one or more of the following properties are advantageous for liposomal formulations of mitoxantrone:
- the mitoxantrone liposome is mitoxantrone hydrochloride liposome
- the particle size of mitoxantrone liposomes is about 30-80nm, such as about 35-75nm, about 40-70nm, about 40-60nm or about 60nm; for example, about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80nm.
- NanoZS NanoZS
- Mitoxantrone forms an insoluble precipitate with multivalent counterions (such as sulfate, citrate or phosphate) in the liposome;
- the phospholipid bilayer in mitoxantrone liposomes contains phospholipids with a phase transition temperature (Tm) higher than body temperature, so the phase transition temperature of the liposomes is higher than body temperature.
- the phospholipids include, but are not limited to, hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dispalmitate lecithin, distearate lecithin or any combination of the above;
- the phospholipid bilayer in mitoxantrone liposomes contains hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine (DSPE-PEG2000);
- the phospholipid bilayer in the mitoxantrone liposome contains hydrogenated soy lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1, hydrochloric acid Mitoxantrone forms an insoluble precipitate with the polyvalent acid ions in the liposomes, and the particle size of the mitoxantrone hydrochloride liposomes is about 60 nm;
- Mitoxantrone liposomes are mitoxantrone liposomes with national drug approval number H20220001.
- the mitoxantrone liposome meets one or more of the following:
- the mitoxantrone liposome is mitoxantrone hydrochloride liposome
- the phospholipid bilayer in the mitoxantrone liposome contains a phospholipid with a phase transition temperature (Tm) higher than body temperature, which is selected from the group consisting of hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, and double soft fat. acid lecithin, distearyl lecithin, or any combination of the above.
- Tm phase transition temperature
- the mitoxantrone liposome is mitoxantrone hydrochloride liposome.
- the therapeutically effective amount or dose of the mitoxantrone liposome or mitoxantrone hydrochloride liposome is calculated in terms of mitoxantrone.
- the mitoxantrone liposomes can be prepared by conventional methods in the art, or by any method disclosed in the prior art, for example, by the method disclosed in WO2008/080367 A1, the contents of which are disclosed in this patent. The entire text is incorporated by reference.
- the mitoxantrone hydrochloride liposome preparation of the present application can be prepared according to the following method, where the "lipid-to-drug ratio" refers to the components of the phospholipid bilayer in the liposome (including HSPC, DSPE- Mass ratio of PEG2000 and Chol) to mitoxantrone:
- Hydrogenated soy lecithin (HSPC), cholesterol (Chol) and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine (DSPE-PEG2000) were weighed according to the mass ratio of 3:1:1, and dissolved in 95% ethanol , a clear solution (i.e., ethanol solution of phospholipids) was obtained.
- a clear solution i.e., ethanol solution of phospholipids
- a microfluidic device was then used to reduce the particle size of the liposomes.
- the encapsulation efficiency was demonstrated to be approximately 100% using gel exclusion chromatography.
- the resulting product was named PLM60.
- the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in PLM60 is 9.58:3.19:3.19:1, and the osmotic pressure of the sucrose glycine solution is close to the physiological value.
- amino acid species that can be replaced by glycine in the external phase to form a transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, and alanine.
- the mass ratio of HSPC, Chol and DSPE-PEG2000 can be appropriately adjusted.
- lipid-to-drug ratio parameters in preparing specific liposome drug preparations those skilled in the art can design, test, and ultimately obtain a suitable lipid-to-drug ratio to maximize the drug loading capacity while reducing drug leakage.
- a wide range of lipid-to-drug ratio can be used, such as as low as 2:1 or as high as 30:1, 40:1 or 50:1, and more
- a suitable lipid-to-drug ratio may be about (15-20):1, such as about 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1. Therefore, several advantageous properties of the mitoxantrone hydrochloride liposome formulation described above are more important, and the methodologies for achieving these properties are diverse.
- mitoxantrone liposomes and anti-angiogenesis targeting drugs such as bevacizumab or sorafenib
- the efficacy of platinum-resistant recurrent ovarian cancer can be improved and the disease remission rate can be improved. And it can control the progression of the disease and prolong survival.
- the mitoxantrone hydrochloride liposome injection used in the following examples was provided by CSPC Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd. (National Drug Approval Number H20220001).
- Example 1 Mitoxantrone hydrochloride liposome combined with anti-angiogenesis targeted drugs in the treatment of ovarian cancer clinical research
- This study is a single-arm, multi-center, open phase Ib clinical study. Patients with platinum-resistant recurrent ovarian cancer were treated with mitoxantrone hydrochloride liposome injection alone or in combination with anti-angiogenic targeted drugs. To explore the safety and efficacy of mitoxantrone hydrochloride liposome monotherapy and combination therapy. The research is divided into single drug exploration phase and combined exploration phase.
- the screening period is 28 days, and qualified subjects will enter the treatment period.
- mitoxantrone hydrochloride liposome injection 20 mg/m 2 was given every 3 weeks. It was administered once (q3w) for a total of 8 cycles.
- the researcher and the sponsor will discuss whether the treatment can be continued.
- Safety evaluation will be conducted as planned during the treatment period, and efficacy evaluation will be conducted every two cycles.
- the treatment will end and enter the follow-up period, with safety and efficacy evaluations conducted 28 days after the last dose; subsequent efficacy evaluations will be conducted every 6 weeks until disease progression or new anti-tumor treatment is started; and survival follow-up will be conducted every 6 weeks thereafter.
- the research entered the joint exploration phase.
- the screening period is 28 days, and qualified subjects will enter the treatment period and be assigned to combined cohort A or combined cohort B according to the order of enrollment. It is planned that after 30 subjects are enrolled in the joint team A, 26 subjects will be enrolled in the joint team B.
- Combined Cohort A Treated with mitoxantrone hydrochloride liposome (20 mg/m 2 ) combined with bevacizumab injection (15 mg/kg), once every 3 weeks (q3w), combined with mitoxantrone hydrochloride liposome (20 mg/m 2 ) and bevacizumab injection (15 mg/kg) Toxantrone liposome enters the maintenance phase after up to 8 cycles, and maintenance therapy with bevacizumab (15 mg/kg, q3w) is given until disease progression, death, intolerable toxicity, or the investigator determines that there is no benefit. .
- Combined cohort B treated with mitoxantrone hydrochloride liposome (20 mg/m 2 ) combined with sorafenib tosylate tablets [400 mg/dose, calculated as sorafenib, twice a day (bid)].
- Mitoxantrone hydrochloride liposomes are administered once every 3 weeks (q3w), and sorafenib tosylate tablets are administered orally daily.
- the combined administration of mitoxantrone hydrochloride liposomes lasts up to 8 cycles. Entering the maintenance phase, sorafenib tosylate (400 mg/dose, bid) will be given as maintenance treatment until disease progression, death, intolerable toxicity, or the investigator's judgment that there is no benefit.
- Safety evaluation will be conducted as planned during the treatment period, and efficacy evaluation will be conducted every two cycles.
- the treatment will end and enter the follow-up period, with safety and efficacy evaluations conducted 28 days after the last dose; subsequent efficacy evaluations will be conducted every 6 weeks until disease progression or new anti-tumor treatment is started; and survival follow-up will be conducted every 6 weeks thereafter.
- Epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer confirmed by histopathology (Except mucinous carcinoma and low-grade serous carcinoma);
- Single drug exploration phase platinum-resistant relapsed subjects who have failed at least standard platinum-containing regimens; combined exploration phase: platinum-resistant relapsed subjects who have failed at least standard platinum-containing regimens, and who have become platinum-resistant Only allowed to receive no more than 1 line of systemic treatment regimen;
- ANC Absolute neutrophil count
- Hemoglobin (Hb) ⁇ 90g/L (no red blood cell transfusion treatment within 1 week before laboratory examination);
- Platelets ⁇ 100x10 9 /L (no platelet transfusion, thrombopoietin, interleukin-11 or other platelet-elevating drug treatment was received within 1 week before the laboratory test);
- AST Alanine aminotransferase
- ALT aspartate aminotransferase
- ⁇ Coagulation function prothrombin time (PT), international normalized ratio (INR) ⁇ 1.5x ULN (or when the patient is treated with a stable therapeutic dose of warfarin, the INR is usually between 2-3), and partial thromboplastin time (PTT) ⁇ 1.2 ⁇ ULN; if the patient has received a stable dose of anticoagulants for at least 2 weeks before the start of the first study treatment, and the INR or activated partial thromboplastin time (APTT) is within the therapeutic range (based on study center criteria) , then the use of full doses of oral or injectable anticoagulants is allowed;
- PT prothrombin time
- INR international normalized ratio
- PTT partial thromboplastin time
- Female subjects have negative urine or blood HCG (except for menopause and hysterectomy).
- Female subjects of childbearing age and their partners should take effective contraceptive measures (such as combined hormones) during the trial and within 6 months after the last dose. (containing estrogen and progesterone) combined to inhibit ovulation, progestin contraceptive combined to inhibit ovulation, intrauterine device, intrauterine hormone releasing system, bilateral infusion Tubal ligation, vasectomy, avoidance of sexual intercourse, etc.);
- brain metastases with stable symptoms after treatment are defined as subjects whose brain symptoms are relieved after systemic treatment or local radiotherapy, and who are asymptomatic and have no progression 2-4 weeks after stopping treatment) );
- Any clinically identifiable thrombotic, embolic, venous or arterial event within 6 months before the first dose such as deep vein thrombosis, pulmonary embolism, cerebrovascular accident, short-term Transient ischemic attack, subarachnoid hemorrhage, etc. (except asymptomatic catheter-related venous thrombosis);
- a pulmonary bleeding event with CTCAE ⁇ grade 2 or any other bleeding event with CTCAE ⁇ grade 3 occurred within 3 months before the first dose;
- Abnormal cardiac function including:
- ⁇ Cardiac ejection fraction is lower than 50% or lower than the lower limit of the laboratory test value range of the research center;
- CR complete response, defined as the disappearance of all evidence of disease.
- PR local response, defined as measurable reduction of lesions and no new lesions.
- PD Disease progression, defined as the appearance of any new lesions or an increase of ⁇ 50% from the nadir of the original lesions.
- SD Stable disease, defined as not falling into any one condition.
- Overall response rate (ORR) (CR + PR) / total number of evaluable cases * 100%
- DCR (CR+PR+SD)/total number of evaluable cases*100%.
- the most common hematological toxicity was still common hematological toxicity during chemotherapy, such as reduced white blood cell count, reduced neutrophil count, and reduced platelet count.
- the adverse reactions mentioned above can all be recovered or improved after symptomatic treatment, and no unbearable serious adverse reactions were found.
- No. 1 After surgery for bilateral high-grade serous ovarian cancer, paclitaxel liposome + nedaplatin chemotherapy was given for 8 cycles. Two years and 10 months after finishing chemotherapy, he went to the hospital again because of "abdominal pain for 6 months". After it was confirmed that the tumor had recurred, he underwent a second cytoreductive surgery. After the operation, he was given a course of albumin-paclitaxel + carboplatin chemotherapy, and albumin-paclitaxel + loboplatin chemotherapy. 3 journeys. After reexamination of disease progression, 2 courses of albumin-paclitaxel + carboplatin were given. Patients were enrolled in this trial after progression. After enrollment in this trial, patients were treated with mitoxantrone hydrochloride liposome (20 mg/m 2 ) combined with bevacizumab injection (15 mg/kg), once every 3 weeks (q3w), and combined for 5 cycle.
- mitoxantrone hydrochloride liposome (20 mg
- No. 2 After being diagnosed with high-grade serous carcinoma of both ovaries, ovarian cancer reduction surgery + mesenteric mass resection was performed. Postoperatively, patients were given 8 courses of albumin-paclitaxel + carboplatin regimen chemotherapy, and were enrolled in this trial after the progression was assessed more than 5 months after the last dose. After enrollment in this trial, patients were treated with mitoxantrone hydrochloride liposome (20 mg/m 2 ) combined with bevacizumab injection (15 mg/kg), once every 3 weeks (q3w), and combined for 7 After the cycle, the patient entered the maintenance phase, and maintenance therapy with bevacizumab (15 mg/kg, q3w) was given for 4 cycles.
Abstract
米托蒽醌脂质体联合抗血管生成靶向药,特别是贝伐珠单抗和索拉非尼在治疗卵巢癌,尤其是铂耐药复发卵巢癌中的用途。所述米托蒽醌脂质体和抗血管生成靶向药的联合进一步提高了对卵巢癌的疗效,提高了疾病缓解率,且能够控制疾病的进展,从而为卵巢癌的治疗提供了新的选择。
Description
本发明属于抗肿瘤领域,具体涉及米托蒽醌脂质体联合抗血管生成靶向药,特别是贝伐珠单抗或索拉非尼在治疗卵巢癌,尤其是铂耐药复发卵巢癌中的用途。
卵巢癌作为女性常见恶性肿瘤之一,由于缺乏典型的症状及体征,一旦发现,大多处于中晚期,生存时间很短。2020年我国新增卵巢癌病例55342例,新增死亡37519例,发病率位居女性生殖系统恶性肿瘤第三位,死亡率位居第二位。卵巢癌有多种病理类型,其中最常见的上皮性卵巢癌占95%,其次是恶性生殖细胞肿瘤和性索间质肿瘤。
含铂的联合化疗方案是晚期卵巢癌术后化疗的主要推荐方案。约有10%~15%的卵巢癌患者对标准一线铂类药物联合治疗具有内在抵抗力,总生存时间小于9个月。晚期患者即使经过含铂方案治疗获得完全缓解,仍有70%-80%出现复发(谢幸,马丁,沈铿等,聚乙二醇化脂质体阿霉素治疗卵巢癌的中国专家共识(2018年),现代妇产科进展,2018,27(09):641-644)。
在铂耐药卵巢癌中,首选治疗方案包括单药化疗。单药化疗包括多柔比星脂质体、紫杉醇、拓扑替康、吉西他滨、多西他赛、依托泊苷等。多个III期随机对照研究显示,多柔比星脂质体、紫杉醇、拓扑替康、吉西他滨治疗铂耐药卵巢癌,两两相比疗效相当,客观缓解率(ORR)仅为5%-15%,中位无进展生存期(PFS)约2-4个月,中位总生存期(OS)约8-14个月(Ten Bokkel Huinink W,Gore M,Carmichael J,et al.,Topotecan versus Paclitaxel for The Treatment of Recurrent Epithelial Ovarian Cancer,J Clin Oncol,1997,15(6):2183-93)。II期单臂研究中多西他赛或依托泊苷的ORR可高于20%,然而中位OS分别为12.7个月、10.8个月,较上述四种化疗药物未改善生存(Rose P G,Blessing J A,Ball H G,et al.,A Phase II Study of Docetaxel in Paclitaxel-Resistant Ovarian and Peritoneal Carcinoma:A Gynecologic Oncology Group Study,Gynecol Oncol,2003,88(2):130-5)。因此,并没有一种化疗药比其他
药物在有效性方面更突出,单药化疗的ORR率低,持续响应时间短,总生存时间约1年。
近年来,抗血管生成靶向药应用于上皮性卵巢癌取得显著进展,有望提高卵巢癌生存率。贝伐珠单抗是靶向血管内皮生长因子(Vascular endothelial growth factor,VEGF)的单克隆抗体。作为第一个抗血管生成靶向药,现已被批准用于非小细胞肺癌、乳腺癌、肾癌、宫颈癌、卵巢癌等多个实体瘤。在一项III期AURELIA研究中,贝伐珠单抗联合化疗使得铂耐药卵巢癌的ORR提高至27.3%;安全性方面,贝伐珠单抗组整体安全耐受,≥2级高血压(20%)、蛋白尿(2%)、胃肠道穿孔(2%)和瘘管/脓肿(2%)更常见(Eric Pujade-Lauraine,Felix Hilpert et al.,Bevacizumab Combined with Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer:The AURELIA Open-Label Randomized Phase III Trial,Journal of Clinical Oncology,2014,32(13),1302-1311)。索拉非尼是一种经典的多靶点激酶抑制剂,体外试验显示它除了抑制VEGF受体、血小板源性生长因子受体(Platelet-derived growth factor receptor,PDGFR)等肿瘤血管生成的信号通路外,还可抑制RAF、c-Kit、FLT-3等肿瘤细胞增殖靶点。索拉非尼已被FDA批准用于不可切除的肝细胞癌、晚期肾细胞癌和复发转移甲状腺癌。一项II期单臂研究显示,索拉非尼单药治疗铂耐药卵巢癌的ORR为3.4%,中位OS为16.33个月,71名受试者中,显著的3或4级毒性包括:皮疹(n=7),手足综合征(n=9),代谢毒性(n=10),胃肠道反应(n=3)等(Matei D,Sill M W,Lankes H A,et al.,Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis:A Gynecologic Oncology Group Trial,J Clin Oncol,2011,29(1):69-75)。
综上所述,铂耐药复发卵巢癌的预后差,生存期短,现有药物治疗(包括化疗和靶向治疗等)的疗效尚不令人满意。因此,需要治疗铂耐药复发卵巢癌的新的药物或疗法,其能够提高疾病缓解率,延长生存期,并且安全耐受。
米托蒽醌是目前临床应用广泛的药物,FDA批准的适应症为多发
性硬化症、前列腺癌和急性髓性白血病,临床上对恶性淋巴瘤、乳腺癌、肺癌、黑色素瘤、软组织肉瘤、多发性骨髓瘤、肝癌、大肠癌、肾癌、子宫内膜癌、睾丸肿瘤、卵巢癌和头颈部癌也有一定疗效。相对于米托蒽醌普通制剂,脂质体制剂的毒性(特别是心脏毒性)更低,并具备了被动靶向肿瘤组织的特性,提高了抗肿瘤活性。
本申请的发明人尝试将米托蒽醌脂质体与抗血管生成靶向药,特别是贝伐珠单抗和索拉非尼联合用于治疗铂耐药复发卵巢癌,结果实现了提高的疾病缓解率并且安全耐受,从而为铂耐药复发卵巢癌的治疗提供了新的选择。
发明内容
本发明涉及米托蒽醌脂质体联合抗血管生成靶向药在治疗卵巢癌中的用途。
本发明的第一方面涉及米托蒽醌脂质体和抗血管生成靶向药在制备治疗卵巢癌的药物中的用途,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
本发明的第二方面涉及米托蒽醌脂质体在制备改善抗血管生成靶向药治疗卵巢癌的疗效的药物中的用途,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
本发明的第三方面涉及一种治疗卵巢癌的方法,所述方法包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
本发明的第四方面涉及一种改善抗血管生成靶向药治疗卵巢癌的疗效的方法,所述方法包括在对卵巢癌患者施用抗血管生成靶向药的基础上,进一步联合施用治疗有效量的米托蒽醌脂质体,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
本发明的第五方面涉及一种用于治疗卵巢癌的药物,所述药物包含米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
本发明的第六方面涉及一种用于治疗卵巢癌的组合物,所述组合物包含米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
本发明的第七方面涉及一种用于改善抗血管生成靶向药治疗卵巢癌的疗效的药物,所述药物包含米托蒽醌脂质体,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
本发明的第八方面涉及一种用于治疗卵巢癌的试剂盒,所述试剂盒包含米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在上述各方面的一些实施方案中,所述卵巢癌为复发卵巢癌。
在上述各方面的一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。
在上述各方面的一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在上述各方面的一些实施方案中,米托蒽醌脂质体为注射剂。
在上述各方面的一些实施方案中,贝伐珠单抗为注射剂。
在上述各方面的一些实施方案中,索拉菲尼为片剂。
定义
在下文的详细描述中,除非另有定义,否则本文使用的所有科技术语具有本领域普通技术人员所理解的相同含义。
本文使用的术语“包含(或其等同术语例如“包括”、“含有”等)”包括“由......组成”的情况,除非另外说明。
本文使用的术语“组合物”表示两种或更多种活性成分的组合,其中各活性成分可存在于同一制剂中一起施用,或者各活性成分可以存在于不同的制剂中,以相同或不同的施用方式同时或相继施用。在此意义上,“组合物”和“组合”可互换使用。
本文使用的术语“治疗有效量”或“有效量”是指在治疗的对象中显示期望益处的剂量。“治疗有效量”或“有效量”将取决于接受治疗的对象的种属、疾病的严重程度、施用频率、药物的代谢特征等因素,并可由处方医师根据常规实践来判断。需要注意的是,本申请中提及的所有数值范围均包括该范围的两个端点、该范围之内的所有数值以及由其中任意两个数值形成的子范围。
本文使用的术语“治疗”是指控制、减轻或缓解疾病的病理学进
展和延长患病对象的存活期。
本文使用的术语“对象”、“受试者”、“患者”包括预期要对其施用本申请的药物或组合物的动物个体,包括但不限于人类和其它哺乳动物,例如小鼠、大鼠、猫、猴子、狗、马、猪等。优选地,所述对象是人类。除非标明,否则术语“对象”、“受试者”、“患者”可以互换使用。
本文使用的术语“铂耐药复发卵巢癌”是指经至少4个周期含铂方案治疗后1至6个月内复发的卵巢癌。
本发明实施方案详述
本发明的第一方面涉及米托蒽醌脂质体和抗血管生成靶向药在制备治疗卵巢癌的药物中的用途,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在一些实施方案中,所述抗血管生成靶向药为贝伐珠单抗。在一些实施方案中,所述抗血管生成靶向药为索拉非尼。
在一些实施方案中,所述卵巢癌为复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,米托蒽醌脂质体为注射剂,包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时,以米托蒽醌计,含活性成分0.5-5mg/ml,优选1-2mg/ml,更优选1mg/ml。
在一些实施方案中,贝伐珠单抗为注射剂,包括液体注射剂、注射用粉剂、注射用片剂等。当贝伐珠单抗为液体注射剂时,含活性成分贝伐珠单抗25mg/ml。
在一些实施方案中,索拉菲尼为片剂,含活性成分200mg/片。
在一些实施方案中,提供米托蒽醌脂质体和贝伐珠单抗在制备治疗卵巢癌的药物中的用途。在一些实施方案中,提供米托蒽醌脂质体和贝伐珠单抗在制备治疗铂耐药复发卵巢癌的药物中的用途。在一些实施方案中,提供米托蒽醌脂质体和贝伐珠单抗在制备治疗铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌的药物中的用途。在这些实施方案中,米托蒽醌脂质体为注射剂,以米托蒽醌计,含活性成分0.5-5mg/ml;贝伐珠单抗为注射剂,含活性成分25mg/ml。
在一些实施方案中,提供米托蒽醌脂质体和索拉非尼在制备治疗卵巢癌的药物中的用途。在一些实施方案中,提供米托蒽醌脂质体和索拉非尼在制备治疗铂耐药复发卵巢癌的药物中的用途。在一些实施方案中,提供米托蒽醌脂质体和索拉非尼在制备治疗铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌的药物中的用途。在这些实施方案中,米托蒽醌脂质体为注射剂,以米托蒽醌计,含活性成分0.5-5mg/ml;索拉非尼为片剂,含活性成分200mg/片。
本发明的第二方面涉及米托蒽醌脂质体在制备改善抗血管生成靶向药治疗卵巢癌的疗效的药物中的用途,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在一些实施方案中,所述抗血管生成靶向药为贝伐珠单抗。在一些实施方案中,所述抗血管生成靶向药为索拉非尼。
在一些实施方案中,所述卵巢癌为复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,米托蒽醌脂质体为注射剂,包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时,以米托蒽醌计,含活性成分0.5-5mg/ml,优选1-2mg/ml,更优选1mg/ml。
在一些实施方案中,贝伐珠单抗为注射剂,包括液体注射剂、注射用粉剂、注射用片剂等。当贝伐珠单抗为液体注射剂时,含活性成分贝伐珠单抗25mg/ml。
在一些实施方案中,索拉菲尼为片剂,含活性成分200mg/片。
在一些实施方案中,提供米托蒽醌脂质体在制备改善贝伐珠单抗治疗卵巢癌的疗效的药物中的用途。在一些实施方案中,提供米托蒽醌脂质体在制备改善贝伐珠单抗治疗铂耐药复发卵巢癌的疗效的药物中的用途。在一些实施方案中,提供米托蒽醌脂质体在制备改善贝伐珠单抗治疗铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌的疗效的药物中的用途。在这些实施方案中,米托蒽醌脂质体为注射剂,以米托蒽醌计,含活性成分0.5-5mg/ml;贝伐珠单抗为注射剂,含活性成分25mg/ml。
在一些实施方案中,提供米托蒽醌脂质体在制备改善索拉非尼治疗卵巢癌的疗效的药物中的用途。在一些实施方案中,提供米托蒽醌
脂质体在制备改善索拉非尼治疗铂耐药复发卵巢癌的疗效的药物中的用途。在一些实施方案中,提供米托蒽醌脂质体在制备改善索拉非尼治疗铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌的疗效的药物中的用途。在这些实施方案中,米托蒽醌脂质体为注射剂,以米托蒽醌计,含活性成分0.5-5mg/ml;索拉非尼为片剂,含活性成分200mg/片。
本发明的第三方面涉及一种治疗卵巢癌的方法,所述方法包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在一些实施方案中,所述抗血管生成靶向药为贝伐珠单抗。在一些实施方案中,所述抗血管生成靶向药为索拉非尼。
在一些实施方案中,所述卵巢癌为复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,米托蒽醌脂质体注射给药。在一些实施方案中,米托蒽醌脂质体以8-30mg/m2,优选20mg/m2的治疗有效量静脉给药。在一些实施方案中,米托蒽醌脂质体每3周给药一次。在一些实施方案中,米托蒽醌脂质体以20mg/m2的治疗有效量每3周一次静脉给药。
在一些实施方案中,贝伐珠单抗注射给药。在一些实施方案中,贝伐珠单抗以15mg/kg的剂量注射给药。
在一些实施方案中,索拉非尼口服给药。在一些实施方案中,索拉非尼以400mg/剂的剂量口服给药。在一些实施方案中,索拉非尼每日给药两次。在一些实施方案中,索拉非尼以400mg/剂的剂量每日两次口服给药。
在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体和贝伐珠单抗。在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体,并在米托蒽醌脂质体施用后的任意时间施用贝伐珠单抗。在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用1-8个周期后以
15mg/kg每3周一次给予贝伐珠单抗维持治疗。在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用5-7个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用8个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在上述实施方案中,所述卵巢癌为复发卵巢癌,优选为铂耐药复发卵巢癌,更优选为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体和索拉非尼。在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体,并在米托蒽醌脂质体给药前、中、后的任意时间施用索拉非尼。在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用1-8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用5-7个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在一些实施方案中,提供治疗卵巢癌的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在上述实施方案中,所述卵巢癌为复发卵巢癌,优选为铂耐药复发卵巢癌,更优选为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
本发明的第四方面涉及一种改善抗血管生成靶向药治疗卵巢癌的疗效的方法,所述方法包括在对卵巢癌患者施用抗血管生成靶向药的基础上,进一步联合施用治疗有效量的米托蒽醌脂质体,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在一些实施方案中,所述抗血管生成靶向药为贝伐珠单抗。在一
些实施方案中,所述抗血管生成靶向药为索拉非尼。
在一些实施方案中,所述卵巢癌为复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,米托蒽醌脂质体注射给药。在一些实施方案中,米托蒽醌脂质体以8-30mg/m2,优选20mg/m2的治疗有效量静脉给药。在一些实施方案中,米托蒽醌脂质体每3周给药一次。在一些实施方案中,米托蒽醌脂质体以20mg/m2的治疗有效量每3周一次静脉给药。
在一些实施方案中,贝伐珠单抗注射给药。在一些实施方案中,贝伐珠单抗以15mg/kg的剂量注射给药。
在一些实施方案中,索拉非尼口服给药。在一些实施方案中,索拉非尼以400mg/剂的剂量口服给药。在一些实施方案中,索拉非尼每日给药两次。在一些实施方案中,索拉非尼以400mg/剂的剂量每日两次口服给药。
在一些实施方案中,提供改善贝伐珠单抗治疗卵巢癌的疗效的方法,所述方法包括在对卵巢癌患者施用贝伐珠单抗的基础上,进一步联合施用治疗有效量的米托蒽醌脂质体。在一些实施方案中,提供改善贝伐珠单抗治疗卵巢癌的疗效的方法,所述方法包括在贝伐珠单抗施用前的任意时间以20mg/m2的剂量每3周一次施用米托蒽醌脂质体。在一些实施方案中,提供改善贝伐珠单抗治疗卵巢癌的疗效的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用1-8个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在一些实施方案中,提供改善贝伐珠单抗治疗卵巢癌的疗效的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用5-7个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在一些实施方案中,提供改善贝伐珠单抗治疗卵巢癌的疗效的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用8个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在上述实施方案中,所述卵巢癌为复发卵巢癌,优选为铂耐药复
发卵巢癌,更优选为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,提供改善索拉非尼治疗卵巢癌的疗效的方法,所述方法包括在对卵巢癌患者施用索拉非尼的基础上,进一步联合施用治疗有效量的米托蒽醌脂质体。在一些实施方案中,提供改善索拉非尼治疗卵巢癌的疗效的方法,所述方法包括在索拉非尼施用前、中、后的任意时间以20mg/m2的剂量每3周一次施用米托蒽醌脂质体。在一些实施方案中,提供改善索拉非尼治疗卵巢癌的疗效的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用1-8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在一些实施方案中,提供改善索拉非尼治疗卵巢癌的疗效的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用5-7个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在一些实施方案中,提供改善索拉非尼治疗卵巢癌的疗效的方法,所述方法包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在上述实施方案中,所述卵巢癌为复发卵巢癌,优选为铂耐药复发卵巢癌,更优选为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
本发明的第五方面涉及一种用于治疗卵巢癌的药物,所述药物包含米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在一些实施方案中,所述药物包含米托蒽醌脂质体和贝伐珠单抗。在一些实施方案中,所述药物包含米托蒽醌脂质体和索拉非尼。在一些实施方案中,所述药物任选地包含本领域已知的其他治疗卵巢癌的一线、二线药物。
在一些实施方案中,所述卵巢癌为复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,米托蒽醌脂质体为注射剂,包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时,以
米托蒽醌计,含活性成分0.5-5mg/ml,优选1-2mg/ml,更优选1mg/ml。
在一些实施方案中,贝伐珠单抗为注射剂,包括液体注射剂、注射用粉剂、注射用片剂等。当贝伐珠单抗为液体注射剂时,含活性成分贝伐珠单抗25mg/ml。
在一些实施方案中,索拉菲尼为片剂,含活性成分200mg/片。
本发明的第六方面涉及一种用于治疗卵巢癌的组合物,所述组合物包含米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在一些实施方案中,所述组合物包含米托蒽醌脂质体和贝伐珠单抗。在一些实施方案中,所述组合物包含米托蒽醌脂质体和索拉非尼。
在一些实施方案中,所述卵巢癌为复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,米托蒽醌脂质体注射给药。在一些实施方案中,米托蒽醌脂质体以8-30mg/m2,优选20mg/m2的治疗有效量静脉给药。在一些实施方案中,米托蒽醌脂质体每3周给药一次。在一些实施方案中,米托蒽醌脂质体以20mg/m2的治疗有效量每3周一次静脉给药。
在一些实施方案中,贝伐珠单抗注射给药。在一些实施方案中,贝伐珠单抗以15mg/kg的剂量注射给药。
在一些实施方案中,索拉非尼口服给药。在一些实施方案中,索拉非尼以400mg/剂的剂量口服给药。在一些实施方案中,索拉非尼每日给药两次。在一些实施方案中,索拉非尼以400mg/剂的剂量每日两次口服给药。
在一些实施方案中,所述治疗包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体和贝伐珠单抗。在一些实施方案中,所述治疗包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体,并在米托蒽醌脂质体施用后的任意时间施用贝伐珠单抗。在一些实施方案中,所述治疗包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用1-8个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在一些实施方案中,所述治疗包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽
醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用5-7个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在一些实施方案中,所述治疗包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用8个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在上述实施方案中,所述卵巢癌为复发卵巢癌,优选为铂耐药复发卵巢癌,更优选为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,所述治疗包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体和索拉非尼。在一些实施方案中,所述治疗包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体,并在米托蒽醌脂质体给药前、中、后的任意时间施用索拉非尼。在一些实施方案中,所述治疗包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用1-8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在一些实施方案中,所述治疗包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用5-7个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在一些实施方案中,所述治疗包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在上述实施方案中,所述卵巢癌为复发卵巢癌,优选为铂耐药复发卵巢癌,更优选为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
本发明的第七方面涉及一种用于改善抗血管生成靶向药治疗卵巢癌的疗效的药物,所述药物包含米托蒽醌脂质体,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在一些实施方案中,所述抗血管生成靶向药为贝伐珠单抗。在一些实施方案中,所述抗血管生成靶向药为索拉非尼。
在一些实施方案中,所述卵巢癌为复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,米托蒽醌脂质体注射给药。在一些实施方案中,米托蒽醌脂质体以8-30mg/m2,优选20mg/m2的治疗有效量静脉给
药。在一些实施方案中,米托蒽醌脂质体每3周给药一次。在一些实施方案中,米托蒽醌脂质体以20mg/m2的治疗有效量每3周一次静脉给药。
在一些实施方案中,贝伐珠单抗注射给药。在一些实施方案中,贝伐珠单抗以15mg/kg的剂量注射给药。
在一些实施方案中,索拉非尼口服给药。在一些实施方案中,索拉非尼以400mg/剂的剂量口服给药。在一些实施方案中,索拉非尼每日给药两次。在一些实施方案中,索拉非尼以400mg/剂的剂量每日两次口服给药。
在一些实施方案中,提供用于改善贝伐珠单抗治疗卵巢癌的疗效的药物,所述改善包括在对卵巢癌患者施用贝伐珠单抗的基础上,进一步联合施用治疗有效量的米托蒽醌脂质体。在一些实施方案中,提供用于改善贝伐珠单抗治疗卵巢癌的疗效的药物,所述改善包括在贝伐珠单抗施用前的任意时间以20mg/m2的剂量每3周一次施用米托蒽醌脂质体。在一些实施方案中,提供用于改善贝伐珠单抗治疗卵巢癌的疗效的药物,所述改善包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用1-8个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在一些实施方案中,提供用于改善贝伐珠单抗治疗卵巢癌的疗效的药物,所述改善包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用5-7个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在一些实施方案中,提供用于改善贝伐珠单抗治疗卵巢癌的疗效的药物,所述改善包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用8个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗。在上述实施方案中,所述卵巢癌为复发卵巢癌,优选为铂耐药复发卵巢癌,更优选为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,提供用于改善索拉非尼治疗卵巢癌的疗效的药物,所述改善包括在对卵巢癌患者施用索拉非尼的基础上,进一步联合施用治疗有效量的米托蒽醌脂质体。在一些实施方案中,提供用于改善索拉非尼治疗卵巢癌的疗效的药物,所述改善包括在索拉非尼
施用前、中、后的任意时间以20mg/m2的剂量每3周一次施用米托蒽醌脂质体。在一些实施方案中,提供用于改善索拉非尼治疗卵巢癌的疗效的药物,所述改善包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用1-8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在一些实施方案中,提供用于改善索拉非尼治疗卵巢癌的疗效的药物,所述改善包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用5-7个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在一些实施方案中,提供用于改善索拉非尼治疗卵巢癌的疗效的药物,所述改善包括对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。在上述实施方案中,所述卵巢癌为复发卵巢癌,优选为铂耐药复发卵巢癌,更优选为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
本发明的第八方面涉及一种用于治疗卵巢癌的试剂盒,所述试剂盒包含米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
在一些实施方案中,所述抗血管生成靶向药为贝伐珠单抗。在一些实施方案中,所述抗血管生成靶向药为索拉非尼。
在一些实施方案中,所述卵巢癌为复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发卵巢癌。在一些实施方案中,所述卵巢癌为铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
在一些实施方案中,米托蒽醌脂质体和抗血管生成靶向药各自为独立制剂。
在一些实施方案中,米托蒽醌脂质体为注射剂,包括液体注射剂、注射用粉剂、注射用片剂等。当米托蒽醌脂质体为液体注射剂时,以米托蒽醌计,含活性成分0.5-5mg/ml,优选1-2mg/ml,更优选1mg/ml。
在一些实施方案中,贝伐珠单抗为注射剂,包括液体注射剂、注射用粉剂、注射用片剂等。当贝伐珠单抗为液体注射剂时,含活性成分贝伐珠单抗25mg/ml。
在一些实施方案中,索拉菲尼为片剂,含活性成分200mg/片。
在一些实施方案中,所述试剂盒包含米托蒽醌脂质体和贝伐珠单抗。在一些实施方案中,米托蒽醌脂质体为注射剂,以米托蒽醌计,含活性成分0.5-5mg/ml;贝伐珠单抗为注射剂,含活性成分25mg/ml。
在一些实施方案中,所述试剂盒包含米托蒽醌脂质体和索拉非尼。在一些实施方案中,米托蒽醌脂质体为注射剂,以米托蒽醌计,含活性成分0.5-5mg/ml;索拉非尼为片剂,含活性成分200mg/片。
在上述各方面中,贝伐珠单抗可以以药物制剂,例如注射剂的形式提供。这样的药物制剂是市售可得的。
在上述各方面中,索拉非尼优选为甲苯磺酸索拉非尼。索拉非尼可以以药物制剂,例如片剂的形式提供。这样的药物制剂是市售可得的。
在上述各方面中,对米托蒽醌脂质体无特别限制。不被任何特定理论所束缚,本申请的发明人发现以下一项或多项性质对于米托蒽醌脂质体制剂是有利的:
(i)所述米托蒽醌脂质体为盐酸米托蒽醌脂质体;
(ii)米托蒽醌脂质体的粒径为约30-80nm,例如约35-75nm、约40-70nm、约40-60nm或约60nm;例如约30、35、40、45、50、55、60、65、70、75或80nm。粒径测定的方式有多种,包括但不限于NanoZS;
(iii)米托蒽醌与脂质体内的多价反离子(例如硫酸根、柠檬酸根或磷酸根)形成难以溶解的沉淀;
(iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂,从而脂质体的相转变温度高于体温。所述磷脂包括但不限于氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合;
(v)米托蒽醌脂质体中的磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000);
(vi)米托蒽醌脂质体中的磷脂双分子层含有质量比为约3∶1∶1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺,盐酸米托蒽醌与脂质体内的多价酸根离子形成难以溶解的沉淀,并且所述盐酸米托蒽醌脂质体的粒径为约60nm;
(vii)采用中国专利申请200610102339.8号或PCT申请WO2008/080367A1公开的方法制备的米托蒽醌脂质体制剂;和
(viii)米托蒽醌脂质体为国药准字H20220001的米托蒽醌脂质体。
优选的,所述米托蒽醌脂质体满足以下一项或多项:
(i)所述米托蒽醌脂质体为盐酸米托蒽醌脂质体;
(ii)米托蒽醌脂质体的粒径为30-80nm;
(iii)米托蒽醌与脂质体内的多价反离子形成难以溶解的沉淀;和
(iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂,其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合。
优选的,所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。所述米托蒽醌脂质体或盐酸米托蒽醌脂质体的治疗有效量或剂量均以米托蒽醌计。
所述米托蒽醌脂质体可以采用本领域常规方法制备,也可以采用现有技术公开的任意一种方法制备,例如采用WO2008/080367 A1公开的方法制备,该专利公开的内容在此被全文引入作为参考。作为非限制性的实例,本申请的盐酸米托蒽醌脂质体制剂可以按照以下方法制备,其中“脂药比”是指脂质体中磷脂双分子层的组成成分(包含HSPC、DSPE-PEG2000和Chol)与米托蒽醌的质量比:
将氢化大豆卵磷脂(HSPC)、胆固醇(Chol)和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000)按照3∶1∶1的质量比称重,溶解于95%乙醇中,得到澄明溶液(即磷脂的乙醇溶液)。将磷脂的乙醇溶液与300mM的硫酸铵溶液混合,在60-65℃震荡水化lh,得到不均匀的多室脂质体。之后使用微射流设备降低脂质体的粒度。将所获得的样品用浓度0.9%的NaCl溶液稀释200倍后,用NanoZS进行检测,粒子的平均粒度约为60nm,主峰集中在40-60nm之间。之后使用超滤装置移去空白脂质体外相的硫酸铵,将外相置换成290mM蔗糖及10mM甘氨酸,以便形成跨膜硫酸铵梯度。按照脂药比16∶1的比例,在空白脂质体中加入盐酸米托蒽醌溶液(以米托蒽醌计,10mg/mL),在60-65℃进行载药。孵育约lh后,使用凝胶排阻色谱可证明包封效率约为100%。由此得到的产品被命名为PLM60。PLM60中HSPC∶Chol∶DSPE-PEG2000∶米托蒽醌的重量比为9.58∶3.19∶3.19∶1,蔗糖甘氨酸溶液的渗透压与生理值接近。
应当理解的是,上述示例性制备方法中的多个技术细节和参数可
以由本领域技术人员在合理的范围内进行调试和确定。例如,用于形成跨膜硫酸铵梯度的外相中的甘氨酸可替换的氨基酸种类包括但不限于组氨酸、天冬酰胺、谷氨酸、亮氨酸、脯氨酸、丙氨酸。再例如,HSPC、Chol和DSPE-PEG2000的质量比可以进行适当的调整。还例如,对于制备具体脂质体药物制剂中的脂药比参数,本领域技术人员可以设计、测试并最终得出合适的脂药比,以尽量提高载药量同时减少药物漏出量。对于本申请的盐酸米托蒽醌脂质体制剂而言,可以使用的脂药比是宽范围的,例如低至2∶1或高至30∶1、40∶1或50∶1,更为适合的脂药比可以为约(15-20)∶1,例如约15∶1、16∶1、17∶1、18∶1、19∶1或20∶1。因此,上文描述的盐酸米托蒽醌脂质体制剂的数点有利性质是更为重要的,实现这些性质的方法学是多样的。
通过向卵巢癌患者联合施用米托蒽醌脂质体和抗血管生成靶向药如贝伐珠单抗或索拉非尼,能够提高对铂耐药复发卵巢癌的疗效,提高疾病缓解率,并且能够控制疾病的进展,延长生存期。
实施例
以下实施例旨在对本发明进行具体说明,而不应解释为对本发明的范围构成限制。
以下实施例中使用的盐酸米托蒽醌脂质体注射液由石药集团中诺药业(石家庄)有限公司提供(国药准字H20220001)。
实施例1盐酸米托蒽醌脂质体联合抗血管生成靶向药治疗卵巢癌
的临床研究
本研究是一项单臂、多中心、开放的Ib期临床研究,纳入铂耐药复发性卵巢癌患者,给予盐酸米托蒽醌脂质体注射液单药或联合抗血管生成靶向药,旨在探索盐酸米托蒽醌脂质体单药和联合治疗的安全性和疗效。研究分为单药探索阶段和联合探索阶段。
一、研究设计
单药探索阶段
此阶段入组不少于30例受试者。筛选期为28天,筛选合格受试者进入治疗期。治疗期给予盐酸米托蒽醌脂质体注射液20mg/m2,每3周
给药一次(q3w),共给药8个周期。对于已完成8个治疗周期给药的受试者,如仍治疗获益且可耐受,由研究者与申办方共同商讨后确定是否可继续治疗。治疗期按计划进行安全性评价,每两个周期进行一次疗效评价。治疗结束进入随访期,在末次给药后28天进行安全性评价和疗效评价;随后每6周进行一次疗效评价,直至疾病进展或开始新的抗肿瘤治疗;随后每6周进行一次生存随访。
联合探索阶段
单药探索阶段初步获得盐酸米托蒽醌脂质体单药的安全性和疗效后,研究进入联合探索阶段。筛选期为28天,筛选合格受试者进入治疗期,按入组顺序分配至联合A队列或联合B队列。拟在联合A队列入组30例受试者后,继续入组26例受试者至联合B队列。
联合A队列:给予盐酸米托蒽醌脂质体(20mg/m2)联合贝伐珠单抗注射液(15mg/kg)治疗,每3周给药一次(q3w),联合给药至盐酸米托蒽醌脂质体最多达8个周期后进入维持期,给予贝伐珠单抗(15mg/kg,q3w)维持治疗,直至疾病进展、死亡、不可耐受的毒性或研究者判断无法获益。
联合B队列:给予盐酸米托蒽醌脂质体(20mg/m2)联合甲苯磺酸索拉非尼片[400mg/剂,以索拉非尼计,每日两次(bid)]治疗,盐酸米托蒽醌脂质体每3周给药一次(q3w),甲苯磺酸索拉非尼片每日口服给药,联合给药至盐酸米托蒽醌脂质体最多达8个周期后进入维持期,给予甲苯磺酸索拉非尼(400mg/剂,bid)维持治疗,直至疾病进展、死亡、不可耐受的毒性或研究者判断无法获益。
治疗期按计划进行安全性评价,每两个周期进行一次疗效评价。治疗结束进入随访期,在末次给药后28天进行安全性评价和疗效评价;随后每6周进行一次疗效评价,直至疾病进展或开始新的抗肿瘤治疗;随后每6周进行一次生存随访。
二、试验人群
(一)入选标准
符合下列全部标准的受试者方可入选本研究:
1)受试者自愿参加研究,并签署知情同意书;
2)年龄≥18周岁女性受试者;
3)经病理组织学确诊的上皮性卵巢癌、输卵管癌或原发性腹膜癌
(粘液性癌和低级别浆液性除外);
4)单药探索阶段:至少经标准含铂方案治疗失败的铂耐药复发受试者;联合探索阶段:至少经标准含铂方案治疗失败的铂耐药复发受试者,且铂耐药后仅允许接受不超过1线系统治疗方案;
5)基线至少存在一处符合RECIST 1.1定义的可测量病灶;
6)单药探索阶段:ECOG评分0~2;联合探索阶段:ECOG评分0~1;
7)既往抗肿瘤治疗毒性恢复至≤CTCAE 1级(脱发、色素沉着或研究中认为对受试者无安全性风险的其他毒性除外);
8)受试者实验室检查数值符合以下要求:
●中性粒细胞绝对值(ANC)≥1.5x109/L(实验室检查前1周内,未接受G-CSF升自治疗);
●血红蛋白(Hb)≥90g/L(实验室检查前1周内,未接受输注红细胞治疗);
●血小板≥100x109/L(实验室检查前1周内,未接受输注血小板、促血小板生成素、白介素-11或其他升高血小板的药物治疗);
●肌酐≤1.5x ULN,尿蛋白<2+(基线尿蛋白≥2+时,7天内进行24小时尿蛋白定量检测,当尿蛋白<1g时方可入选);
●总胆红素≤1.5x ULN;
●丙氨酸氨基转移酶(AST)/天冬氨酸氨基转移酶(ALT)≤2.5x ULN;
●白蛋白≥3.0g/dL;
●凝血功能:凝血酶原时间(PT)、国际标准化比值(INR)≤1.5x ULN(或在患者采用华法林稳定治疗剂量治疗时,INR通常介于2-3),且部分凝血激酶时间(PTT)≤1.2×ULN;如患者在首次研究治疗开始前接受至少2周稳定剂量的抗凝血药,且INR或活化部分凝血激酶时间(APTT)在治疗性范围内(基于研究中心标准),则允许使用完整剂量口服或注射抗凝血药;
9)女性受试者尿或血HCG阴性(绝经和子宫切除除外),育龄期女性受试者及其伴侣在试验期间和末次用药结束后6个月内采取有效的避孕措施(例如:联合激素(含雌激素和孕激素)结合抑制排卵、孕激素避孕结合抑制排卵、宫内节育器、宫内激素释放系统、双侧输
卵管结扎术、输精管切除术、避免性行为等);
10)受试者能够和研究者进行良好的沟通,并且理解和自愿遵守本项研究的各项要求者。
(二)排除标准
符合下列任一标准的受试者,不可入选本研究
1)已知对研究药物或其任何辅料过敏或对其他单克隆抗体发生过严重过敏反应者;
2)中枢神经系统转移,治疗后症状稳定的脑转移除外(症状稳定的脑转移定义为:经全身治疗或局部放疗后脑症状缓解,停止治疗后2-4周,无症状无进展的受试者);
3)经CT或彩超显示存在大量胸腔积液、大量盆/腹腔积液、中/大量心包积液者;
4)既往异体器官移植或异体骨髓移植;
5)活动性乙型肝炎(HbsAg或HBcAb阳性且HBV DNA高于正常值上限)、活动性丙型肝炎(HCV抗体阳性且HCV RNA高于研究中心检测值下限)、HIV抗体阳性的患者;
6)研究药物给药前1周内患有需要系统治疗的活动性细菌感染、真菌感染、病毒感染或间质性肺炎;
7)既往接受过腹部或盆腔任何部位放疗;
8)既往接受过索拉非尼相似的酪氨酸激酶抑制剂类药物;
9)首次给药前10天内使用阿司匹林(>325mg/日)、氯吡格雷(>75mg/日)或使用双嘧达莫、噻氯匹定或西洛他唑进行治疗;
10)在首次给药前4周内接受过任何抗肿瘤治疗者(中药或中成药除外),在首次给药前2周内接受过有抗肿瘤适应症的中药或中成药;
11)在首次给药前4周内接受过其它临床研究药物治疗;
12)在首次给药前3个月内接受过重大手术(手术分级:3~4级手术,静脉输液港植入术除外),或在首次给药前7天内进行空心针穿刺活检或其他小手术(不包括放置血管通路设备),或者计划在研究期间进行重大手术者;
13)在首次给药前6个月内存在任何临床可识别的血栓形成、栓塞、静脉或动脉事件,如深静脉血栓形成、肺栓塞、脑血管意外、短
暂性脑缺血发作、蛛网膜下腔出血等(除外无症状的导管相关静脉血栓);
14)合并CTCAE≥2级的外周血管病;
15)在首次给药前3个月内发生CTCAE≥2级肺出血事件或CTCAE≥3级的任何其他出血事件;
16)具有活动性出血或出血倾向(例如已知的出血性疾病、凝血障碍或累及大血管的肿瘤);
17)严重未愈合伤口、溃疡或骨折;
18)具有胃肠阻塞临床症状且需要肠外营养补充者;
19)在首次给药前6个月内存在肠梗阻、腹瘘、胃肠穿孔或腹内脓肿病史;
20)需要药物治疗的癫痫症受试者;
21)在首次给药前4周内使用强效CYP3A4诱导剂的患者(例如,苯妥英、卡马西平、苯巴比妥、地塞米松(日剂量超过16mg)、利福平或利福喷汀);
22)在首次给药前3年内患有其他恶性活动性肿瘤,已治愈的局部可治性癌症除外,例如基底或鳞状细胞皮肤癌、浅表膀胱癌或原位前列腺、宫颈或乳腺癌;
23)具有高血压危象或高血压脑病病史;
24)心脏功能异常,包括:
●长QTc综合征或QTc间期>480ms;
●完全性左束支传导阻滞,II度或III度房室传导阻滞;
●需要药物治疗的严重、未控制的心律失常;
●NYHA≥2级;
●心脏射血分数低于50%或低于研究中心实验室检查值范围下限;
●CTCAE>2级的心脏瓣膜病;
●不可控的高血压(定义为在药物控制情况下,多次测量收缩压>150mmHg或舒张压>90mmHg);
●在首次给药前6个月内出现心肌梗死、不稳定心绞痛、严重的心包疾病病史、有急性缺血性或活动性传导系异常的心电图证据。
25)曾接受过阿霉素或其他蒽环类治疗,且阿霉素累积剂量超过
350mg/m2(蒽环类等效剂量计算:1mg阿霉素=2mg表柔比星=2mg吡柔比星=2mg柔红霉素=0.5mg去甲氧柔红霉素=0.45mg米托蒽醌;阿霉素脂质体除外);
26)预期生存时间<3个月;
27)怀孕或哺乳期妇女;
28)患有任何严重的和/或不可控制的疾病,经研究者判定,可能影响患者参加本研究的其他疾病(包括但不限于,未得到有效控制的糖尿病、需要透析的肾脏疾病、严重的肝脏疾病、危及生命的自身免疫系统疾病和出血性疾病、药物滥用、神经系统疾病等);
其他研究者判定不适宜参加的情况。
(三)退出/终止标准
受试者在研究期间发生以下任意一种情况,受试者退出研究。
(1)失访;
(2)受试者撤回知情同意或受试者或家属要求退出试验;
(3)研究终止;
(4)其它。
三、研究结果
1.疗效评价
根据RECIST 1.1标准对受试者用药前基线水平及治疗期间疗效进行评估。
截至2022年12月26日,共入组5例铂耐药上皮性卵巢癌受试者,接受米托蒽醌脂质体+贝伐珠单抗治疗。
共5例进行至少一次疗效评价,最佳疗效:PR 2例,SD 1例,PD 2例。经计算,ORR为40.0%,DCR为60.0%。结果如下表所示:
注:上述各缩写含义如下:
CR:完全缓解,定义为所有疾病证据消失。
PR:局部缓解,定义为可测量病灶缩小,且无新发病灶。
PD:疾病进展,定义为出现任何新发病灶,或原有病灶较最低点
增大≥50%。
SD:疾病稳定,定义为不属于任何一种情况。
总缓解率(ORR)=(CR+PR)/总的可评价病例数*100%
疾病控制率(DCR)=(CR+PR+SD)/总的可评价病例数*100%。
CR:完全缓解,定义为所有疾病证据消失。
PR:局部缓解,定义为可测量病灶缩小,且无新发病灶。
PD:疾病进展,定义为出现任何新发病灶,或原有病灶较最低点
增大≥50%。
SD:疾病稳定,定义为不属于任何一种情况。
总缓解率(ORR)=(CR+PR)/总的可评价病例数*100%
疾病控制率(DCR)=(CR+PR+SD)/总的可评价病例数*100%。
2.安全性评价
受试者所发生的TEAE中,最常见的仍为化疗中常见的血液学毒性,例如白细胞计数降低、中性粒细胞计数降低、血小板计数降低等。所述不良反应经对症治疗后均可恢复或好转,未见不可承受的严重不良反应。
3.典型病例:
1号:双侧卵巢高级别浆液性癌术后,给予紫杉醇脂质体+奈达铂化疗8程。结束化疗后2年10个月因“腹痛6月”再次就诊,明确肿瘤复发后行二次肿瘤细胞减灭术,术后给予白蛋白紫杉醇+卡铂化疗1程、白蛋白紫杉醇+洛铂化疗3程。复查疾病进展后给予白蛋白紫杉醇+卡铂2程。进展后入组本试验。入组本试验后给予盐酸米托蒽醌脂质体(20mg/m2)联合贝伐珠单抗注射液(15mg/kg)治疗,每3周给药一次(q3w),联合给药5个周期。
2号:确诊双侧卵巢高级别浆液性癌后,行卵巢癌减灭术+肠系膜肿物切除术。术后给予白蛋白紫杉醇+卡铂方案化疗8程,末次用药后5月余评估进展后入组本试验。入组本试验后给予盐酸米托蒽醌脂质体(20mg/m2)联合贝伐珠单抗注射液(15mg/kg)治疗,每3周给药一次(q3w),联合给药7个周期后进入维持期,给予贝伐珠单抗(15mg/kg,q3w)维持治疗4个周期。
以上所述仅为本发明的具体实施方式,但本发明的保护范围不限于此。任何熟悉本技术领域的技术人员在本发明披露的技术范围内,可轻易想到各种变化或替换,这些变化和替换都应涵盖在本发明的保护范围之内。本发明的保护范围应以所述权利要求的保护范围为准。
Claims (23)
- 米托蒽醌脂质体和抗血管生成靶向药在制备治疗卵巢癌的药物中的用途,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
- 如权利要求1所述的用途,其中所述卵巢癌为复发卵巢癌,优选铂耐药复发卵巢癌,更优选铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
- 如权利要求1或2所述的用途,其中所述米托蒽醌脂质体满足以下一项或多项:(i)所述米托蒽醌脂质体为盐酸米托蒽醌脂质体;(ii)米托蒽醌脂质体的粒径为30-80nm;(iii)米托蒽醌与脂质体内的多价反离子形成难以溶解的沉淀;和(iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂,其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合。
- 如权利要求1或2所述的用途,其中所述米托蒽醌脂质体为注射剂。
- 如权利要求1或2所述的用途,其中贝伐珠单抗为注射剂,或索拉非尼为片剂。
- 一种治疗卵巢癌的方法,包括对卵巢癌患者施用治疗有效量的米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
- 如权利要求6所述的方法,其中所述卵巢癌为复发卵巢癌,优选铂耐药复发卵巢癌,更优选铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
- 如权利要求6或7所述的方法,其中所述米托蒽醌脂质体满足以下一项或多项:(i)所述米托蒽醌脂质体为盐酸米托蒽醌脂质体;(ii)米托蒽醌脂质体的粒径为30-80nm;(iii)米托蒽醌与脂质体内的多价反离子形成难以溶解的沉淀;和(iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂,其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷 脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合。
- 如权利要求6或7所述的方法,其中所述米托蒽醌脂质体以8-30mg/m2的治疗有效量每3周一次静脉给药。
- 如权利要求6或7所述的方法,其中贝伐珠单抗注射给药,或索拉非尼口服给药。
- 如权利要求6或7所述的方法,其包括:对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用1-8个周期后以15mg/kg每3周一次给予贝伐珠单抗维持治疗,或者对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用1-8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。
- 一种用于治疗卵巢癌的组合物,包含米托蒽醌脂质体和抗血管生成靶向药,其中所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
- 如权利要求12所述的组合物,其中所述卵巢癌为复发卵巢癌,优选铂耐药复发卵巢癌,更优选铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
- 如权利要求12或13所述的组合物,其中所述米托蒽醌脂质体满足以下一项或多项:(i)所述米托蒽醌脂质体为盐酸米托蒽醌脂质体;(ii)米托蒽醌脂质体的粒径为30-80nm;(iii)米托蒽醌与脂质体内的多价反离子形成难以溶解的沉淀;和(iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂,其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合。
- 如权利要求12或13所述的组合物,其中所述米托蒽醌脂质体以8-30mg/m2的治疗有效量每3周一次静脉给药。
- 如权利要求12或13所述的组合物,其中贝伐珠单抗注射给药,或索拉非尼口服给药。
- 如权利要求12或13所述的组合物,其中所述治疗包括:对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和15mg/kg治疗有效量的贝伐珠单抗,施用1-8个周期后以15mg/kg每3周一 次给予贝伐珠单抗维持治疗,或者对卵巢癌患者每3周一次施用20mg/m2治疗有效量的米托蒽醌脂质体和每日两次施用400mg/剂的索拉非尼,施用1-8个周期后以400mg/剂每日两次施用索拉非尼维持治疗。
- 一种用于治疗卵巢癌的试剂盒,其含有米托蒽醌脂质体和抗血管生成靶向药,所述抗血管生成靶向药选自贝伐珠单抗和索拉非尼。
- 如权利要求18所述的试剂盒,其中所述卵巢癌为复发卵巢癌,优选铂耐药复发卵巢癌,更优选铂耐药复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌。
- 如权利要求18或19所述的试剂盒,其中所述米托蒽醌脂质体满足以下一项或多项:(i)所述米托蒽醌脂质体为盐酸米托蒽醌脂质体;(ii)米托蒽醌脂质体的粒径为30-80nm;(iii)米托蒽醌与脂质体内的多价反离子形成难以溶解的沉淀;和(iv)米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂,其选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合。
- 如权利要求18或19所述的试剂盒,其中米托蒽醌脂质体和抗血管生成靶向药各自以独立制剂存在。
- 如权利要求18或19所述的试剂盒,其中所述米托蒽醌脂质体为注射剂。
- 如权利要求18或19所述的试剂盒,其中贝伐珠单抗为注射剂,或索拉非尼为片剂。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101209243A (zh) * | 2006-12-29 | 2008-07-02 | 石药集团中奇制药技术(石家庄)有限公司 | 一种脂质体药物及其制备方法 |
US20100178328A1 (en) * | 2007-06-27 | 2010-07-15 | Poniard Pharmaceuticals, Inc. | Combination therapy for ovarian cancer |
CN104334577A (zh) * | 2012-03-13 | 2015-02-04 | 霍夫曼-拉罗奇有限公司 | 治疗卵巢癌的联合疗法 |
CN105287383A (zh) * | 2015-11-19 | 2016-02-03 | 吉林大学 | 新型米托蒽醌脂质体联合化疗药物在抗肿瘤治疗中的应用 |
CN107049951A (zh) * | 2017-04-19 | 2017-08-18 | 中国药科大学 | 一种共载中空金纳米粒和肿瘤治疗剂的热敏脂质体制备及三联一体化应用 |
CN110711178A (zh) * | 2018-07-11 | 2020-01-21 | 石药集团中奇制药技术(石家庄)有限公司 | 盐酸米托蒽醌脂质体治疗非霍奇金淋巴瘤的用途 |
-
2023
- 2023-04-25 WO PCT/CN2023/090462 patent/WO2023207931A1/zh unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101209243A (zh) * | 2006-12-29 | 2008-07-02 | 石药集团中奇制药技术(石家庄)有限公司 | 一种脂质体药物及其制备方法 |
US20100178328A1 (en) * | 2007-06-27 | 2010-07-15 | Poniard Pharmaceuticals, Inc. | Combination therapy for ovarian cancer |
CN104334577A (zh) * | 2012-03-13 | 2015-02-04 | 霍夫曼-拉罗奇有限公司 | 治疗卵巢癌的联合疗法 |
CN105287383A (zh) * | 2015-11-19 | 2016-02-03 | 吉林大学 | 新型米托蒽醌脂质体联合化疗药物在抗肿瘤治疗中的应用 |
CN107049951A (zh) * | 2017-04-19 | 2017-08-18 | 中国药科大学 | 一种共载中空金纳米粒和肿瘤治疗剂的热敏脂质体制备及三联一体化应用 |
CN110711178A (zh) * | 2018-07-11 | 2020-01-21 | 石药集团中奇制药技术(石家庄)有限公司 | 盐酸米托蒽醌脂质体治疗非霍奇金淋巴瘤的用途 |
Non-Patent Citations (1)
Title |
---|
LIANG, YONGQIN ET AL.: "Application Progress of Antiangiogenic Drugs in Platinum - Resistant Ovarian Cancer", JOURNAL OF PRACTICAL ONCOLOGY, vol. 34, no. 01, 31 December 2020 (2020-12-31), pages 60 - 63, XP009550066, ISSN: 1002-3070 * |
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