WO2023169384A1 - 西奥罗尼联合抗代谢化疗药物治疗乳腺癌的用途 - Google Patents

西奥罗尼联合抗代谢化疗药物治疗乳腺癌的用途 Download PDF

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WO2023169384A1
WO2023169384A1 PCT/CN2023/079947 CN2023079947W WO2023169384A1 WO 2023169384 A1 WO2023169384 A1 WO 2023169384A1 CN 2023079947 W CN2023079947 W CN 2023079947W WO 2023169384 A1 WO2023169384 A1 WO 2023169384A1
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breast cancer
drug
treatment
use according
pharmaceutical composition
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French (fr)
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周游
鲁先平
宁志强
潘德思
王雨蝶
李丹丹
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深圳微芯生物科技股份有限公司
成都微芯药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of biomedicine, and specifically relates to the use of Ciorani combined with anti-metabolite chemotherapy drugs in the treatment of breast cancer.
  • Breast cancer is the most common female malignant tumor in the world and in my country, accounting for 30% of all female malignant tumor incidences, and ranks second in the mortality rate among female malignant tumors. According to statistics from the World Health Organization, there were 2.1 million new cases of breast cancer in 2018, accounting for 1/4 of all cancers in women. According to statistics from the American Cancer Society, there were 317,000 new cases in 2019, and 42,000 women will die from the disease. According to hormone receptor (HR) and human epidermal growth factor receptor (HER2) classification, HR+/HER2- breast cancer has the highest incidence, accounting for about 66%, and triple-negative breast cancer, which has the highest incidence, accounts for about 10%. The survival rate of breast cancer varies greatly depending on the stage of diagnosis.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor
  • breast cancer can usually be divided into non-invasive cancer, early invasive cancer, invasive cancer, etc.
  • Non-invasive cancers are early stage, including the common ductal carcinoma in situ, and usually have a good prognosis. On the contrary, the overall prognosis of invasive cancers is worse. To achieve good results, more comprehensive treatment is usually required.
  • Invasive cancer is the most common, accounting for more than 80%. It can be further subdivided into invasive ductal carcinoma, invasive lobular carcinoma, etc.
  • Molecular typing refers to the genetic and protein level detection of breast cancer, and grouping according to the characteristics of gene mutations and protein expression.
  • Immunotherapy is an emerging field in breast cancer treatment, especially for triple-negative breast cancer where there are no specific targeted therapies. Studies have shown that the combined use of the PD-L1 checkpoint inhibitor atezolizumab and nano-nab-paclitaxel in the first line can prolong patient survival. Targeted therapy includes the application of anti-angiogenic drugs, PARP inhibitors, etc., but it is still in the clinical exploration stage, and there is an urgent need to find new methods for the treatment of this type of breast cancer after chemotherapy failure.
  • HR-positive/HER2-negative breast cancer is by far the most common subtype across racial/ethnic groups.
  • the American Society of Clinical Oncology (ASCO) clinical practice guidelines for chemotherapy and targeted therapy for HER2-negative breast cancer recommend that for women with hormone receptor-positive advanced breast cancer, unless they have immediately life-threatening lesions (such as symptomatic visceral metastasis) or endocrine If resistance develops, endocrine therapy should be used as the first-line standard treatment. However, endocrine therapy is prone to primary or secondary drug resistance, which limits its application.
  • the US NCCN guidelines state that systemic chemotherapy needs to be considered if there is no benefit from three consecutive endocrine therapy regimens or if symptomatic visceral metastasis occurs.
  • Scioronib is a new molecule independently developed by Shenzhen Microchip Biotechnology Co., Ltd. with global patent protection. It has no indications approved for marketing at home and abroad. It is a small molecule anti-tumor targeting multiple protein kinases. Targeted drugs, through highly selective inhibitory activity on VEGFR/PDGFR/c-Kit, Aurora B, and CSF-1R targets, have three-channel anti-tumor effects, including anti-tumor angiogenesis, inhibiting tumor cell mitosis, and regulating the tumor inflammatory microenvironment. The synergistic mechanism exerts a comprehensive anti-tumor effect; at the same time, its high target selectivity also reduces the risk of side effects caused by off-target effects.
  • CN200910223861.5 discloses Sioroni compounds, which specifically discloses a naphthylamide derivative, its preparation method and application. This type of compound has both protein kinase inhibitory activity and histone deacetylase inhibitory activity, and can be used to treat diseases related to abnormal protein kinase activity or abnormal histone deacetylase activity, including inflammation, autoimmune diseases, and cancer. , neurological and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergies, asthma and hormone-related diseases.
  • CN201610856945.2 discloses the unsolvated crystals A, B, and C of Sioronib and their preparation methods. It also relates to pharmaceutical compositions containing the crystals, and the preparation of the crystals for the treatment of abnormal protein kinase activity. Or application in drugs for diseases related to abnormal histone deacetylase activity.
  • Anti-metabolite chemotherapy drugs refer to drugs that affect nucleic acid biosynthesis. Their chemical structures are similar to essential substances for nucleic acid metabolism. They can prevent cell division and proliferation by specifically interfering with nucleic acid metabolism. Common antimetabolite chemotherapy drugs include methotrexate, mercaptopurine, fluorouracil, tegafur, Tigeol, cytarabine, pemetrexed, raltitrexed, capecitabine, gemcitabine, and fludala Bin and hydroxyuria.
  • Capecitabine chemical name is 5-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytosine nucleoside, which is a new oral fluorouracil carbamate drug. It does not have anti-tumor activity in vitro. It must be converted into 5'-deoxy-5-fluorocytidine (5'-DFCR) by intrahepatic carboxyl esterase in the body before it can act on tumor cells and then pass through the liver and tumors.
  • 5'-DFCR 5'-deoxy-5-fluorocytidine
  • 5-FU 5'-deoxy-5-fluorouracil
  • 5-FU 5-FU is the active ingredient to exert anti-tumor effect. Therefore, in the anti-tumor activity test or mechanism study of capecitabine (CAP) which lacks liver cell metabolism in vitro, 5'-deoxy-5-fluorocytidine (5'-DFCR) or 5-fluorouracil ( 5-FU) acts on tumor cells instead of CAP.
  • CAP capecitabine
  • 5-FU 5-fluorouracil
  • the first-line treatment for patients with advanced breast cancer has clear systemic endocrine therapy or chemotherapy regimens that can benefit based on the expression of HR receptors and HER2 tumor markers.
  • the patient's benefit rate gradually decreases, toxic reactions increase, and tolerance decreases.
  • Treatment options are limited, and palliative treatment is often chosen to improve the patient's quality of life. Therefore, there is an unmet clinical need in the treatment of advanced breast cancer.
  • there is a huge demand for clinical drugs for triple-negative breast cancer patients whose incidence is increasing year by year, endocrine and targeted therapies are ineffective, and the prognosis is extremely poor.
  • the object of the present invention is to provide a drug combination composition that can effectively prevent and/or treat advanced breast cancer after first-line, especially multi-line treatment.
  • the present invention proposes the use of a pharmaceutical composition comprising cealani or a derivative thereof and an antimetabolite chemotherapeutic drug in the preparation of a medicament for the treatment and/or prevention of breast cancer, wherein the breast cancer is Advanced breast cancer.
  • the breast cancer includes advanced triple-negative breast cancer, and further, the breast cancer has been treated with anthracyclines.
  • Advanced triple-negative breast cancer that has failed treatment with taxanes or taxanes.
  • the cioronib derivatives include pharmaceutically acceptable salts thereof and unsolvated crystals A, B and C
  • the anti-metabolite chemotherapy drugs include methotrexate, mercaptopurine, fluorouracil, tegafur, and tegrin Austria, cytarabine, pemetrexed, raltitrexed, capecitabine, gemcitabine, fludarabine and hydroxyurea, preferably capecitabine.
  • the unit dosage of the ceopronil or its derivative is 1-100 mg, preferably 5-50 mg, further preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg , 60mg, 65mg, 70mg, 75mg, 80mg, 90mg, 100mg;
  • the unit dose of the antimetabolite chemotherapy drug is 100-2500mg, preferably 200-2000mg, further preferably 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2 000mg, 2100
  • the drug is a first-line, second-line, third-line, fourth-line, fifth-line or sixth-line drug.
  • the pharmaceutical composition of the present invention includes compound preparations or pharmaceutical kits.
  • a pill box refers to a set of packages containing therapeutic drugs.
  • medicine boxes provide the correct proportions of various medicines and are packaged in the best and most economical form for those expensive and hard-to-obtain medicines, where each medicine has a precise dosage and can be used as a set in the treatment of diseases.
  • the compound preparation includes solid preparation and liquid preparation.
  • the solid preparations include tablets, capsules, granules, pills, powders and suppositories, and the liquid preparations include oral liquids and injections.
  • the kit is a unit preparation of ceopronil or its derivatives and an anti-metabolite chemotherapy drug having the same or different specifications, respectively, wherein the unit preparations are placed in separate containers or in the same container.
  • the present invention provides a pharmaceutical composition, which contains ceopronib or a derivative thereof and an antimetabolite chemotherapy drug.
  • the antimetabolite chemotherapy drug includes methotrexate, mercaptopurine, fluorouracil, and tegafur. , Tigeol, cytarabine, pemetrexed, raltitrexed, capecitabine, gemcitabine, fludarabine and hydroxyurea.
  • Said sironil derivatives include pharmaceutically acceptable salts and unsolvated crystals A, B and C thereof.
  • the antimetabolite chemotherapy drug is preferably capecitabine.
  • the unit dosage of the ceopronil or its derivative is 1-100 mg, preferably 5-50 mg, further preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg , 60mg, 65mg, 70mg, 75mg, 80mg, 90mg, 100mg;
  • the unit dose of the antimetabolite chemotherapy drug is 100-2500mg, preferably 200-2000mg, further preferably 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, 1800mg, 1900mg, 2000mg, 2100m
  • the present invention also provides a method for treating and/or preventing advanced breast cancer, which includes the step of administering the above-mentioned pharmaceutical composition containing cealani or its derivatives and an antimetabolite chemotherapy drug.
  • the breast cancer includes advanced triple-negative breast cancer, and further, the breast cancer is advanced triple-negative breast cancer that has failed previous treatment with anthracyclines and taxanes.
  • the present invention proves through in vitro tumor cell survival rate testing experiments that: 5'-deoxy-5-fluorocytidine (5'-DFCR), the anti-tumor active component of cealani combined with the tumor-targeting prodrug capecitabine (CAP) Or 5-fluorouracil (5-FU) can synergistically inhibit the cell survival of human triple-negative breast cancer cell HCC1395.
  • 5'-DFCR 5'-deoxy-5-fluorocytidine
  • CAP tumor-targeting prodrug capecitabine
  • 5-fluorouracil 5-fluorouracil
  • Ciorani combined with antimetabolite chemotherapy drugs (such as capecitabine) has excellent efficacy and controllable safety in patients with advanced triple-negative breast cancer who have failed previous anthracycline or taxane treatment. .
  • Figure 1 The results of the cell viability inhibition test of Sioronil alone on the human triple-negative breast cancer cell line HCC1395.
  • Figure 3 The results of the cell viability inhibition test of the human triple-negative breast cancer cell line HCC1395 when combined with cealani and 5’-deoxy-5-fluorocytidine (5’-DFCR).
  • Figure 4 The results of the cell viability inhibition test of the human triple-negative breast cancer cell line HCC1395 when combined with cioronib and 5-fluorouracil (5-FU).
  • Example 1 Testing the effects of drugs or drug combinations on cell viability
  • the human triple-negative breast cancer cell line HCC1395 was purchased from the American type culture collection (ATCC; CRL-2324TM) and cultured with 1% double antibody (penicillin-streptomycin, Hyclone) and 10% fetal calf serum ( Gibco) RPMI-1640 culture medium (Hyclone) culture.
  • the human triple-negative breast cancer cell line HCC1395 cells in the logarithmic growth phase were digested and collected, and 10,000 cells per well were inoculated into a 96-well cell culture plate (the inoculation volume was 190 ⁇ L when testing a single drug, and the inoculation volume was 180 ⁇ L when testing drug combinations) , and leave the BLANK wells without seeding cells, only add the same volume of culture medium; culture under the conditions of 5% CO2 and 37°C. Cultivate overnight and administer the drug after the cells adhere.
  • the final concentration of ceopronil per well is 0, 4, 8 ⁇ M and the final concentration of 5'-DFCR per well is 0, 1, 3, 10 ⁇ M or the final concentration of 5-FU per well is 0 , 0.1, 0.3, and 1 ⁇ M, respectively, by adding 10 ⁇ L of corresponding DMSO dilutions to form different dose combinations of Cioroni and 5'-DFCR or 5-FU in the cell culture plate.
  • ceopronib alone has a certain inhibitory effect on the cell viability of human triple-negative breast cancer cell HCC1395.
  • the inhibitory rates of 4 ⁇ M and 8 ⁇ M doses of ceopronib on HCC1395 cell viability are close to 25% and 25%, respectively. 35%.
  • 5'-DFCR alone has a certain inhibitory effect on the cell viability of human triple-negative breast cancer cell HCC1395.
  • a dose of 5'-DFCR above 3 ⁇ M may have a clear impact on the cell viability of HCC1395.
  • 3 ⁇ M of 5' -DFCR can inhibit HCC1395 cell viability by nearly 15%.
  • 5-FU alone also has a certain inhibitory effect on the cell viability of human triple-negative breast cancer cells HCC1395.
  • a dose of 5-FU above 0.1 ⁇ M can have a clear effect on the cell viability of HCC1395.
  • 0.1 ⁇ M 5-FU can inhibit the cell viability of HCC1395 cells. Vitality produces nearly 20% inhibition.
  • the inhibition rate of a single drug is about 22.7%; when 8 ⁇ M dose of cealonil is combined with 3 ⁇ M or 10 ⁇ M dose of 5'-DFCR on HCC1395, the average inhibition rate is 70.9% and 79.0% respectively.
  • the inhibition rate of 8 ⁇ M dose of ceopronib alone is approximately 38.6%.
  • the inhibitory rates of 3 ⁇ M and 10 ⁇ M doses of 5'-DFCR alone were approximately 18.7% and 32.5% respectively.
  • the inhibitory effects of 4 ⁇ M or 8 ⁇ M doses of cealanib combined with 5'-DFCR on HCC1395 were obvious. Stronger than the combined effects of the two drugs alone.
  • the inhibitory rates of 0.1 ⁇ M and 0.3 ⁇ M doses of 5-FU alone were approximately 21.3% and 43.6% respectively.
  • the 4 ⁇ M or 8 ⁇ M doses of cealani combined with 5-FU had strong inhibitory effects on HCC1395. The sum of the effects of the two drugs alone.
  • the experimental results show that compared with ceoronib alone or 5'-deoxy-5-fluorocytidine (5'-DFCR) alone, ceoronib combined with 5'-deoxy-5-fluorocytidine (5'-DFCR) has a synergistic inhibitory effect on the viability of human triple-negative breast cancer cell HCC1395; compared with ceopronib alone or 5-fluorouracil (5-FU) alone, ceopronib combined with 5-fluorouracil (5-FU) 5-FU) has a synergistic inhibitory effect on the viability of human triple-negative breast cancer cells HCC1395.
  • Example 2 A multi-center phase II clinical trial of Sioroni capsules combined with capecitabine in patients with advanced triple-negative breast cancer who failed anthracycline and taxane treatment.
  • Age ⁇ 18 years old when signing the informed consent form.
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 human epidermal growth factor receptor 2
  • Hb hemoglobin
  • ANC absolute neutrophil count
  • PHT platelet count
  • Coagulation function international normalized ratio (PT-INR) ⁇ 1.5.
  • taxane (anthracycline) treatment failure refers to disease progression during taxane (anthracycline) rescue treatment (at least two cycles of treatment completed), or relapse within 12 months after the end of adjuvant treatment transfer.
  • Dose exploration phase 3 to 6 patients in each group, and approximately 7 more subjects will be enrolled in the phase II recommended dose group, totaling 16 to 25 patients.
  • Randomized control phase Each group is expected to have 43 cases, with a total of 86 cases in both groups.
  • This trial is divided into two phases, namely the dose exploration phase and the randomized control phase.
  • a concomitant pharmacokinetic study is carried out during the dose exploration phase, and the first cycle of the dose exploration phase is the DLT observation period.
  • Capecitabine is fixed at 1000 mg/m 2 , and cioronib is divided into 3 dose levels (25 mg, 35 mg and 50 mg) according to the "3+3" dose escalation method. Only the previous dose level is judged to be safe. Ciorani will be enrolled at the next dose level, with no more than 6 subjects at each dose level. After preliminary safety assessment and efficacy analysis of different doses of ceopronib and fixed doses of capecitabine, approximately 7 subjects were continued to be enrolled in the initially determined phase II recommended dose group, and then entered the follow-up phase. machine controlled trial stage. All subjects were treated until tumor progression, death, intolerable toxic reactions, withdrawal of informed consent, loss to follow-up or the end of the trial (whichever occurred first).
  • Subjects in the same dosage group are allowed to be enrolled at the same time.
  • the trial consists of a screening period, a treatment period and a follow-up period.
  • the enrolled subjects were randomly assigned at a ratio of 1:1 to the cealani combined with capecitabine group (experimental group) and placebo combined with capecitabine group (control group), and were treated until tumor progression, death, or intolerance. toxic reactions, withdrawal of informed consent, loss to follow-up or end of the trial (whichever occurs first). Efficacy evaluation will be conducted every 6 weeks starting from the first dose. Safety assessments are conducted every 3 weeks.
  • Safety follow-up The subjects will conduct a safety follow-up 28 days ( ⁇ 7 days) after the last use of the trial drug.
  • survival follow-up Subjects who terminate trial drug treatment due to disease progression will directly enter survival follow-up; subjects who terminate trial drug treatment early due to reasons other than disease progression will enter survival follow-up after the efficacy follow-up. Calculated from the earliest imaging examination date of the last efficacy evaluation, it will be conducted every 12 weeks ( ⁇ 7 days), with outpatient follow-up or telephone follow-up until death, loss to follow-up, withdrawal of notification, or the end of the trial. During the survival follow-up period, the subsequent anti-tumor treatment regimens received by the subjects need to be recorded.
  • Capecitabine tablets 1000 mg/m 2 , taken orally within 30 minutes after meals, once in the morning and once in the evening. Every 21 days is a treatment cycle. Take the medicine on the 1st to 14th day of each cycle, and stop on the 15th to 21st day. medicine.
  • Sioroni capsule test group
  • Sioloni simulation capsule control group: 25mg or 35mg or 50mg (according to Each group takes the corresponding dose), take it orally on an empty stomach every morning, once a day, and take it continuously.
  • PFS Progression-free survival
  • Objective response rate According to the RECIST1.1 standard, the proportion of the sum of the subjects with the best response reaching complete response (CR) and partial response (PR) to the total number of people in the analysis set.
  • CBR Clinical benefit rate
  • Duration of response The length of time from the first occurrence of remission (CR or PR, whichever occurs first) to the first occurrence of disease recurrence or progression.
  • OS Overall survival: the time from randomization (the first dose of the drug in the dose-finding phase) to death from any cause. OS data will be collected until the end of the trial specified in this protocol.
  • Safety indicators frequency and severity of adverse events, changes in vital signs and laboratory indicators. The severity of adverse events was judged according to CTCAE 5.0 standards.
  • Imaging examinations completed within 28 days before the first dose of medication are acceptable for baseline tumor assessment.
  • Tumor assessments will be performed every 6 weeks starting from the date of first dose until disease progression, death, withdrawal of consent, loss to follow-up, receipt of new anti-tumor therapy, or end of trial (whichever occurs first), regardless of whether the trial drug is terminated prematurely treat. count If disease progression is suspected at any time during the scheduled interval between two efficacy assessments, the investigators may decide to add additional imaging studies.
  • Tumor imaging examinations include CT or MRI of the neck, chest, whole abdomen, and pelvis, and examinations of other parts are performed when necessary based on clinical indications. The same technique and method should be used to measure the same lesion in the same subject at baseline and follow-up assessments. 8. Data statistical analysis
  • Intention to treat population includes all randomized subjects.
  • Response evaluable population includes all subjects who are randomized and have at least one post-baseline response assessment.
  • Safety data set Subjects who have taken the trial drug at least once after enrollment and have safety indicator records.
  • Adverse event statistics will be mainly descriptive statistics, and the occurrence of adverse events, serious adverse events, adverse reactions, hematological toxic reactions, important adverse events, etc. will be described based on CTCAE 5.0 standards.
  • Scioronib combined with capecitabine has excellent efficacy and controllable safety in patients with advanced triple-negative breast cancer who have failed previous anthracycline and taxane treatments.

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Abstract

本发明涉及生物医药领域，具体涉及西奥罗尼联合抗代谢化疗药物治疗乳腺癌的用途。本发明提供了包含西奥罗尼或其衍生物与抗代谢化疗药物的药物组合物在制备用于治疗和/或预防乳腺癌的药物中的用途。本发明通过体外肿瘤细胞存活率测试实验证明：西奥罗尼联合卡培他滨(CAP)的抗肿瘤活性成分5'-脱氧-5-氟胞苷(5'-DFCR)或5-氟尿嘧啶(5-FU)可协同抑制人三阴性乳腺癌细胞HCC1395存活。本发明通过临床试验证明，西奥罗尼联合抗代谢化疗药物在经蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌患者中疗效优异，安全性可控。

Description

西奥罗尼联合抗代谢化疗药物治疗乳腺癌的用途 技术领域
本发明涉及生物医药领域，具体涉及西奥罗尼联合抗代谢化疗药物治疗乳腺癌的用途。
背景技术
乳腺癌是全球及我国发病率最高的女性恶性肿瘤，占全部女性恶性肿瘤发病人数30％，在女性恶性肿瘤死亡率第二。世界卫生组织统计2018年乳腺癌新增210万，占女性所有癌症的1/4。据美国癌症协会统计，2019年新增病例31.7万，4.2万女性将死于该疾病。根据激素受体(HR)和人表皮生长因子受体(HER2)分型，发病率最高的为HR+/HER2-乳腺癌约占66％，侵袭性最高的三阴性乳腺癌约占10％。乳腺癌的存活率因诊断阶段不同而有很大差异，临床分期越高5年生存率越低，I期98％、II期92％、III期75％、IV期27％。2018年我国最新乳腺癌数据报告，女性乳腺癌发病例数和死亡例数分别占全球发病和死亡的11.2％和9.2％，在世界范围位居前列，位居我国女性恶性肿瘤发病率和死亡率第1位和第5位。全国肿瘤登记2015年年报数据显示，乳腺癌新发病例数达26.9万，占女性全部新发恶性肿瘤的15％，6.95万女性因乳腺癌死亡，并且呈现年轻化趋势。乳腺癌已经成为威胁中国女性健康的重要因素。
乳腺癌的分型有两大类方法，一类是病理分型，二类是分子分型。
乳腺癌病理分型，是通过在显微镜下观察肿瘤细胞特征，从而判断它的性质。按照这个系统，通常可以把乳腺癌分为非浸润性癌，早期浸润性癌，浸润性癌等。非浸润性癌属于早期，包括常见的原位导管癌，通常预后很好，相反，浸润性癌整体预后就要差一些，要想达到好的效果，通常需要比较综合的治疗。浸润性癌最常见，占了80％以上，它又可以再细分为浸润性导管癌，浸润性小叶癌等。
分子分型，是指对乳腺癌进行基因和蛋白水平检测，根据基因突变和蛋白表达的特性来进行分组。乳腺癌的分子分型不止一种系统，最经典的是通过癌细胞是否表达ER(雌激素受体)，PR(孕酮受体)和HER2三种蛋白来分类。根据它们的阳性和阴性，形成了不同的组合，也带来了不同的乳腺癌亚型。比如：如果一个乳腺癌是ER阳性或PR阳性，HER2阴性(ER+PR+HER2-)，那么我们称它为激素受体阳性乳腺癌。如果一个乳腺癌是ER阴性，PR阴性，但HER2阳性(ER-PR-HER2+)，那么我们称它为HER2阳性乳腺癌。如果一个乳腺癌是ER阴性，PR阴性，HER2阴性(ER-PR-HER2-)，那么我们称它为三阴性乳腺癌。
5-10％的乳腺癌患者确诊时已发生远处转移，而接受治疗的早期患者中，仍有20-50％会 出现复发转移。研究显示，晚期转移性乳腺癌患者中位生存期为2-3年，五年生存率仅25％，尤其是HER2阴性的晚期乳腺癌，因缺乏有效的靶向治疗药物，其科学的治疗方案确立显得更加重要。
HR阴性/HER2阴性乳腺癌的治疗进展落后于其它分子亚型，迄今仅限于非转移性疾病的化疗，但该病理类型呈现高侵袭性，易发生远处转移。复发转移晚期乳腺癌一线、二线、后线化疗尚未确定最优方案，包括蒽环类药物、紫杉烷、和卡培他滨等，治疗采用单药化疗或联合化疗的方式。大量证据表明紫衫类和蒽环类药物优选作为一线治疗。后线治疗方案的选择应综合考量之前的治疗、药物毒性、共存疾病、病人意愿等。经多线化疗，患者疗效获益呈现逐渐递减趋势，如连续3个化疗方案无效或ECOG评分≥3，不再考虑使用细胞毒药物，改用姑息治疗。免疫治疗是乳腺癌治疗的一个新兴领域，特别是针对没有特效靶向治疗的三阴性乳腺癌。研究表明PD-L1检查点抑制剂atezolizumab与纳米白蛋白结合型紫杉醇在一线联合使用可以延长患者的生存期。靶向治疗包括抗血管生成药，PARP抑制剂等的应用，但仍处于临床探索阶段，亟待寻求新的方法用于化疗失败后该类乳腺癌的治疗。
HR阳性/HER2阴性乳腺癌是目前各个种族/民族组中最常见的亚型。美国临床肿瘤学会(ASCO)关于HER2阴性乳腺癌化疗和靶向治疗临床实践指南推荐，对于激素受体阳性晚期乳腺癌女性，除了有立即危及生命的病变(如有症状的内脏转移)或者对内分泌治疗产生耐药，应将内分泌疗法作为一线标准治疗方案。但内分泌治疗容易出现原发或继发耐药，导致其应用受限。美国NCCN指南指出，连续3个内分泌治疗方案无获益或出现有症状的内脏转移，则需考虑系统化疗。但大多数抗肿瘤药物同时又会诱发不良反应，影响病人生活质量，内分泌治疗耐药的分子机制和相关靶向药物研究是当前亟待解决的问题。现阶段，内分泌联合用药方案在内分泌耐药受试者中的研究包括联合CDK4/6抑制剂、联合PI3Kα抑制剂、联合AKT抑制剂、联合HDAC抑制剂均能有效延长无进展生存期，在过去30年间提高了转移性疾病的生存率，对于激素受体阳性内分泌治疗耐药的受试者是一个新的契机。其它联合用药方案是否对内分泌耐药患者有效，是否可以为该部分人群提供一种新的治疗选择，这是领域内一个值得研究的课题。
西奥罗尼是深圳微芯生物科技股份有限公司自主研发的具全球专利保护的全新分子体，在国内外尚无适应症获批上市，是一个以多蛋白激酶为靶点的小分子抗肿瘤靶向药物，通过对VEGFR/PDGFR/c-Kit、Aurora B、CSF-1R靶点的高选择抑制活性，具有抗肿瘤血管生成、抑制肿瘤细胞有丝分裂、调控肿瘤炎性微环境等三通路抗肿瘤协同作用机制，发挥综合抗肿瘤作用；同时其高的靶标选择性也降低了因脱靶效应带来的副作用风险。
CN200910223861.5公开了西奥罗尼化合物，其具体公开了一种萘酰胺的衍生物、其制备方法及应用。该类化合物同时具有蛋白激酶抑制活性和组蛋白去乙酰化酶抑制活性，可以用于治疗与蛋白激酶活性异常或组蛋白去乙酰化酶活性异常相关的疾病，包括炎症、自身免疫性疾病、癌症、神经系统疾病和神经退化性疾病、心血管疾病、代谢病、过敏、哮喘以及与激素相关的疾病。CN201610856945.2公开了西奥罗尼的的非溶剂化晶体A、B、C及其制备方法，还涉及含有所述晶体的药物组合物，以及所述晶体在制备用于治疗与蛋白激酶活性异常或组蛋白去乙酰化酶活性异常相关的疾病的药物中的应用。
抗代谢化疗药物是指影响核酸生物合成的药物，它们的化学结构和核酸代谢的必需物质类似，可以通过特异性干扰核酸的代谢阻止细胞的分裂和增殖。常见的抗代谢化疗药物包括甲氨蝶玲，巯嘌呤，氟尿嘧啶，替加氟，替吉奥，阿糖胞苷，培美曲赛，雷替曲赛，卡培他滨，吉西他滨，氟达拉滨和羟基尿。其中，卡培他滨(Capecitabine,CAP)：化学名为5-脱氧-5-氟-N-[(戊氧基)羰基]-胞嘧啶核苷，其作为新型口服氟尿嘧啶氨甲酸酯类药物，自身在体外不具备抗肿瘤活性，须在体内经肝内羧基酯酶转变为转变成5’-脱氧-5-氟胞苷(5’-DFCR)，才能作用于肿瘤细胞，而后经肝脏和肿瘤组织内高活性的胞苷脱氨基酶转化为5’-脱氧-5-氟尿嘧啶核苷(5’-DFUR，去氧氟尿苷)，最后激活肿瘤组织中高表达的胸腺嘧啶磷酸化酶转化为5-氟尿嘧啶(5-Fluorouracil,5-FU)，5-FU作为活性成分才能发挥抗肿瘤功效。因此，在体外缺少肝细胞代谢环节的卡培他滨(CAP)的抗肿瘤活性测试或机制研究中，可采用5’-脱氧-5-氟胞苷(5’-DFCR)或5-氟尿嘧啶(5-FU)替代CAP作用于肿瘤细胞。目前，卡培他滨已获批单药或联合方案治疗结肠癌、乳腺癌、胃癌。
晚期乳腺癌患者一线治疗根据HR受体和HER2肿瘤标志物表达情况，有较明确的能够获益的系统内分泌治疗或化疗方案。但经过一线特别是多线治疗后，患者的受益率逐渐下降，毒性反应增加、耐受性降低，可选择治疗方案有限，常选择姑息治疗，以提高患者生存质量。因此，晚期乳腺癌治疗存在未能满足的临床需求。尤其是，针对发病率逐年上升、内分泌及靶向治疗无效、预后极差的三阴性乳腺癌患者对临床用药存在巨大需求。
发明内容
本发明的目的是提供一种在一线特别是多线治疗后能够有效预防和/或治疗晚期乳腺癌的药物联用组合物。
为实现该目的，本发明提出了包含西奥罗尼或其衍生物与抗代谢化疗药物的药物组合物在制备用于治疗和/或预防乳腺癌的药物中的用途，其中所述乳腺癌为晚期乳腺癌。
优选的，其中所述乳腺癌包括晚期三阴性乳腺癌，进一步的，所述乳腺癌为既往经蒽环 类或紫杉类治疗失败的晚期三阴性乳腺癌。
其中，所述西奥罗尼衍生物包括其可药用盐以及非溶剂化晶体A、B和C，所述抗代谢化疗药物包括甲氨蝶玲，巯嘌呤，氟尿嘧啶，替加氟，替吉奥，阿糖胞苷，培美曲赛，雷替曲赛，卡培他滨，吉西他滨，氟达拉滨和羟基尿，优选为卡培他滨。
所述西奥罗尼或其衍生物的单位剂量为1-100mg，优选为5-50mg，进一步优选为1mg，5mg，10mg，15mg，20mg，25mg，30mg，35mg，40mg，45mg，50mg，55mg，60mg，65mg，70mg，75mg，80mg，90mg，100mg；所述抗代谢化疗药物的单位剂量为100-2500mg，优选为200-2000mg，进一步优选为100mg，150mg，200mg，250mg，300mg，350mg，400mg，450mg，500mg，550mg，600mg，650mg，700mg，750mg，800mg，850mg，900mg，950mg，1000mg，1100mg，1200mg，1300mg，1400mg，1500mg，1600mg，1700mg，1800mg，1900mg，2000mg，2100mg，2200mg，2300mg，2400mg，2500mg。
其中所述药物为一线、二线、三线、四线、五线或六线用药物。
本发明所述的药物组合物包括复方制剂或者药盒。
药盒是指包括有治疗用药物的成套包装。通常药盒中提供各种药物的正确比例，并以能使那些昂贵的和难以获得的药物以最好和节省的形式包装，其中个药物具有精确的剂量，在治疗疾病时可成套使用。
其中，所述复方制剂包括固体制剂和液体制剂。所述固体制剂包括片剂、胶囊、颗粒剂、丸剂、散剂和栓剂，所述液体制剂包括口服液和注射剂。所述药盒为分别具有相同或不同规格的西奥罗尼或其衍生物和抗代谢化疗药物单位制剂，其中所述单位制剂分别置于单独容器中或者置于同一容器中。
本发明在第二方面提供了一种药物组合物，其包含西奥罗尼或其衍生物与抗代谢化疗药物，所述抗代谢化疗药物包括甲氨蝶玲，巯嘌呤，氟尿嘧啶，替加氟，替吉奥，阿糖胞苷，培美曲赛，雷替曲赛，卡培他滨，吉西他滨，氟达拉滨和羟基尿。
所述西奥罗尼衍生物包括其可药用盐以及非溶剂化晶体A、B和C。所述抗代谢化疗药物优选卡培他滨。
所述西奥罗尼或其衍生物的单位剂量为1-100mg，优选为5-50mg，进一步优选为1mg，5mg，10mg，15mg，20mg，25mg，30mg，35mg，40mg，45mg，50mg，55mg，60mg，65mg，70mg，75mg，80mg，90mg，100mg；所述抗代谢化疗药物的单位剂量为100-2500mg，优选为200-2000mg，进一步优选为100mg，150mg，200mg，250mg，300mg，350mg，400mg，450mg，500mg，550mg，600mg，650mg，700mg，750mg，800mg，850mg，900mg， 950mg，1000mg，1100mg，1200mg，1300mg，1400mg，1500mg，1600mg，1700mg，1800mg，1900mg，2000mg，2100mg，2200mg，2300mg，2400mg，2500mg。
本发明同时还提供了治疗和/或预防晚期乳腺癌的方法，其中包括施用上述包含西奥罗尼或其衍生物与抗代谢化疗药物的药物组合物的步骤。
优选的，其中所述乳腺癌包括晚期三阴性乳腺癌，进一步的，所述乳腺癌为既往经蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌。
本发明的有益效果：
本发明通过体外肿瘤细胞存活率测试实验证明：西奥罗尼联合肿瘤靶向前药卡培他滨(CAP)的抗肿瘤活性成分5’-脱氧-5-氟胞苷(5’-DFCR)或5-氟尿嘧啶(5-FU)可协同抑制人三阴性乳腺癌细胞HCC1395的细胞存活。实验结果表明，相比西奥罗尼或卡培他滨单药，西奥罗尼与卡培他滨(或其活性代谢产物)的药物组合物能够很好地协同治疗三阴性乳腺癌，为三阴性乳腺癌的治疗提供了一种更好的选择。
本发明通过临床试验证明，西奥罗尼联合抗代谢化疗药物(如卡培他滨)在既往经蒽环类或紫杉类治疗失败的晚期三阴性乳腺癌患者中疗效优异，安全性可控。
附图说明
图1.西奥罗尼单独作用对人三阴性乳腺癌细胞系HCC1395的细胞活力抑制试验结果。
图2.5’-脱氧-5-氟胞苷(5’-DFCR)或5-氟尿嘧啶(5-FU)单独作用对人三阴性乳腺癌细胞系HCC1395的细胞活力抑制试验结果。
图3.西奥罗尼和5’-脱氧-5-氟胞苷联合用药(5’-DFCR)对人三阴性乳腺癌细胞系HCC1395的细胞活力抑制试验结果。
图4.西奥罗尼和5-氟尿嘧啶(5-FU)联合用药对人三阴性乳腺癌细胞系HCC1395的细胞活力抑制试验结果。
具体实施方式
以下进一步通过非限制性实例来说明本发明，其不旨在限制本发明所涵盖的范围。
除非另有定义，否则本文中使用的所有技术和科学术语均具有与本领域一般技术人员通常所理解的含义相同的含义。
实施例一：测试药物或药物组合对细胞活力的影响
一、试验材料
人三阴性乳腺癌细胞系HCC1395购自美国模式培养物保藏中心(American type culture collection,ATCC；CRL-2324TM)，用含1％双抗(青链霉素，Hyclone)及10％胎牛血清(Gibco)的RPMI-1640培养液(Hyclone)培养。
西奥罗尼(Chiauranib)来源于深圳微芯生物科技股份有限公司，5’-脱氧-5-氟胞苷(5’-DFCR)购自大连美仑生物技术有限公司(货号：MB7554)；5-氟尿嘧啶(5-FU)购自MCE(MedChemExpress)公司(货号：HY-90006)。将上述化合物分别溶于二甲基亚砜(Dimethyl sulfoxide,DMSO；购自生工生物工程(上海)股份有限公司(下简称“上海生工”)，货号：DN3039A)中，配置成30mM的贮备液，置于-20℃的冰箱中备用，使用时根据各项实验需要配置相应终浓度的工作液。
二、主要实验试剂及仪器设备
alamarBlueTM Cell Viability Reagent(Invitrogen,DAL1100)
超净工作台(苏净安泰)
CO2细胞培养箱(RS Biotech,Galaxy S)
倒置显微镜(广州市明美科技有限公司)
Denovix CellDropTMFL细胞计数仪
Tecan SparkTM多功能酶标仪
三、实验方法：
将对数生长期的人三阴性乳腺癌细胞系HCC1395细胞消化收集，按每孔10000个接种到96孔细胞培养板中(测试单药时接种体积为190μL，测试药物组合时接种体积为180μL)，并留出BLANK孔不接种细胞，只加入相同体积的培养液；在5％CO2、37℃的条件下培养。培养过夜，待细胞贴壁后给药。
给药前，首先用DMSO将西奥罗尼、5’-DFCR或5-FU稀释成每孔终浓度的1000倍，再将西奥罗尼、5’-DFCR或5-FU的DMSO稀释液按1:50稀释到培养液中。
测试西奥罗尼单药对细胞活力的影响时，按每孔终浓度0、1、2、4、8、16μM加入10μL相应西奥罗尼的DMSO稀释液；测试5’-DFCR或5-FU单药时，按每孔终浓度0、0.01、0.03、0.1、0.3、1、3、10、30μM加入10μL相应5’-DFCR或5-FU的DMSO稀释液。测试药物组合时，根据单药测试结果，按每孔西奥罗尼终浓度0、4、8μM及每孔5’-DFCR终浓度0、1、3、10μM或每孔5-FU终浓度0、0.1、0.3、1μM分别加入相应的DMSO稀释液各10μL，使西奥罗尼分别与5’-DFCR或5-FU在细胞培养板中形成不同剂量的组合。
四、数据处理和分析
药物作用120小时后检测，将96孔培养板中的培养液吸出，每孔加入100μL检测液(含90μLPBS和10μL alamarBlueTM Cell Viability Reagent)。37℃孵育1～2小时，通过Tecan SparkTM多功能酶标仪读取每孔吸光度值(Ex544/Em590)。
上述各剂量药物或药物组合均重复3次，根据BLANK孔的读数求平均值ODBLK(背景值)，各孔读数减去ODBLK后获得扣除背景值的各给药孔的ODT及阴性对照孔(孔内加细胞和营养液，不给药)的ODT0。求得阴性对照孔ODT0的平均值ODT0-A，各给药孔相对细胞存活率根据公式进行计算：相对细胞存活率(％)＝(ODT÷ODT0-A)×100％。
五、实验结果与分析：
如图1所示，西奥罗尼单药对人三阴性乳腺癌细胞HCC1395的细胞活力有一定抑制作用，其中4μM和8μM剂量的西奥罗尼对HCC1395细胞活力的抑制率分别接近25％和35％。
如图2所示，5’-DFCR单药对人三阴性乳腺癌细胞HCC1395的细胞活力有一定抑制作用，3μM以上剂量的5’-DFCR可能对HCC1395的细胞活力产生明确影响，3μM的5’-DFCR可对HCC1395细胞活力产生接近15％的抑制作用。而5-FU单独作用对人三阴性乳腺癌细胞HCC1395的细胞活力也有一定抑制作用，0.1μM以上剂量的5-FU能对HCC1395的细胞活力产生明确影响，0.1μM的5-FU可对HCC1395细胞活力产生接近20％的抑制作用。
如图3所示，4μM或8μM剂量的西奥罗尼分别与1μM、3μM和10μM剂量的5’-DFCR联合用药作用于人三阴性乳腺癌细胞HCC1395，测得的细胞相对活力数据表明，各剂量两药组合对HCC1395细胞活力的抑制率均高于相应剂量单药的抑制率。尤其地，当4μM剂量的西奥罗尼分别与3μM或10μM剂量的5’-DFCR联合作用于HCC1395时，平均抑制率分别为47.9％和64.6％，而本次实验中4μM剂量西奥罗尼单药的抑制率约为22.7％；8μM剂量的西奥罗尼分别与3μM或10μM剂量的5’-DFCR联合作用于HCC1395时，平均抑制率分别为70.9％和79.0％，而本次实验中8μM剂量西奥罗尼单药的抑制率约为38.6％。综合本次实验中3μM和10μM剂量5’-DFCR单药的抑制率分别约为18.7％和32.5％进行分析，4μM或8μM剂量西奥罗尼联合5’-DFCR用药对HCC1395的抑制作用均明显强于两药单独作用之和。
如图4所示，4μM或8μM剂量的西奥罗尼分别与0.03μM、0.1μM和0.3μM剂量的5-FU联合用药作用于人三阴性乳腺癌细胞HCC1395，测得的细胞相对活力数据表明，各剂量两药组合对HCC1395细胞活力的抑制率均高于相应剂量单药的抑制率。尤其地，当4μM剂量的西奥罗尼分别与0.1μM或0.3μM剂量的5-FU联合作用于HCC1395时，平均抑制率分别为56.6％和80.0％，而本次实验中4μM剂量西奥罗尼单药的抑制率约为29.4％；8μM剂量 的西奥罗尼分别与0.1μM或0.3μM剂量的5-FU联合作用于HCC1395时，平均抑制率分别为76.8％和82.6％，而本次实验中8μM剂量西奥罗尼单药的抑制率约为37.0％。综合本次实验中0.1μM和0.3μM剂量5-FU单药的抑制率分别约为21.3％和43.6％进行分析，4μM或8μM剂量西奥罗尼联合5-FU用药对HCC1395的抑制作用均强于两药单独作用之和。
综上，实验结果表明：相比西奥罗尼单药或5’-脱氧-5-氟胞苷(5’-DFCR)单药，西奥罗尼联合5’-脱氧-5-氟胞苷(5’-DFCR)对人三阴性乳腺癌细胞HCC1395的活力具有协同抑制作用；相比西奥罗尼单药或5-氟尿嘧啶(5-FU)单药，西奥罗尼联合5-氟尿嘧啶(5-FU)对人三阴性乳腺癌细胞HCC1395的活力具有协同抑制作用。
实施例二：西奥罗尼胶囊联合卡培他滨在蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌患者中的多中心II期临床试验
一、试验目的
1.主要目的：
探索西奥罗尼联合卡培他滨在蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌患者中的初步疗效。
2.次要目的：
观察西奥罗尼联合卡培他滨在蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌患者中的安全性。
分析西奥罗尼联合卡培他滨用药后的伴随药代动力学(PK)特征。
3.探索性目的：
探索潜在生物标志物与初步疗效的关系。
二、入选标准
必须符合以下所有条件方可入选：
1.理解并自愿签署书面知情同意书。
2.年龄：签署知情同意书时≥18周岁。
3.性别：女性。
4.组织学或细胞学确诊的三阴性乳腺癌患者。(定义为雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(HER2)均为阴性)。
5.入组前疾病状态为不可切除的局部晚期或转移性疾病，且经蒽环类和紫杉类治疗失败的患者*。
6.根据RECIST1.1标准，至少有一个可测量的靶病灶，放疗或局部区域治疗的病灶必须有疾病进展的影像学证据方可视为靶病灶。
7.ECOG体力状态评分：0或1分。
8.筛选时，实验室检查符合下列标准：
血常规检查：血红蛋白(Hb)≥90g/L、中性粒细胞绝对值(ANC)≥1.5×109/L、血小板计数(PLT)≥100×109/L；(评估前2周内未进行下述参数的纠正和支持治疗)
生化检查：血清肌酐(Cr)≤1.5×正常值上限(ULN)；总胆红素(TBIL)≤1.5×ULN；谷丙转氨酶(ALT)、谷草转氨酶(AST)≤2.5×ULN(肝脏转移病例：≤5ULN)；
凝血功能：国际标准化比率(PT-INR)<1.5。
9.研究者判断，预期寿命至少有3个月。
*注：
紫杉类(蒽环类)治疗失败的定义：指紫杉类(蒽环类)药物解救治疗过程中发生疾病进展(至少完成两个周期治疗)，或辅助治疗结束后12个月内发生复发转移。
对紫杉类存在禁忌症或不耐受的患者，如果接受紫杉类治疗至少1个周期且在该周期期间或结束时表现出禁忌症或不耐受，其它条件均符合的情况下，则允许参加研究。
(其他条件均符合，但不能再使用蒽环类药物治疗，例如已经接受了累积剂量400mg/m2阿霉素或阿霉素同类物也允许入组。)
三、样本量
剂量探索阶段：每组3～6例，并在II期推荐剂量组继续入组约7例受试者，总计16～25例。
随机对照阶段：每组预计43例，两组合计86例。
整个试验总计入组102～111例。
四、试验总体设计
本试验分为两个阶段，即剂量探索阶段和随机对照阶段。在剂量探索阶段开展伴随药代动力学研究，剂量探索阶段的第一个周期为DLT观察期。
剂量探索阶段：
固定卡培他滨1000mg/m2，西奥罗尼分3个剂量水平(25mg、35mg和50mg)，按照“3+3”剂量递增方式进行，只有前一个剂量水平被判定为安全后才进行西奥罗尼下一个剂量入组，每个剂量水平不超过6例受试者。在对不同西奥罗尼剂量与卡培他滨固定剂量进行安全性评估和有效性初步分析后，在初步确定的II期推荐剂量组继续入组约7例受试者，然后进入随 机对照试验阶段。所有受试者均治疗至肿瘤进展、死亡、出现不可耐受的毒性反应、撤销知情同意、失访或试验结束(以先发生者为准)。
注：
1)每个受试者只能参加一个剂量组的研究。
2)同一剂量组的受试者允许同时入组。
3)每个剂量组所有入组受试者第一治疗周期观察结束并评估为安全后，才可开始入组下一剂量组。
随机对照阶段：
在前一阶段的基础上，采用西奥罗尼推荐剂量(预期为50mg)与卡培他滨1000mg/m2联合进行多中心、双盲、随机对照研究。
试验包括筛选期、治疗期和随访期。
入组受试者按1:1随机分配至西奥罗尼联合卡培他滨组(试验组)和安慰剂联合卡培他滨组(对照组)治疗至肿瘤进展、死亡、出现不可耐受的毒性反应、撤销知情同意、失访或试验结束(以先发生者为准)。从首次用药开始计算，每6周进行一次疗效评估。安全性评估每3周进行一次。
受试者在结束试验药物治疗后进入随访期。
安全性随访：受试者在末次使用试验药物后28天(±7天)进行一次安全性随访。
疗效随访：针对非疾病进展原因提前结束试验药物治疗的受试者，继续按原计划进行肿瘤评估，直到疾病进展、死亡、撤回知情、失访、接受新的抗肿瘤治疗或试验结束(以先发生者为准)。
生存随访：因疾病进展结束试验药物治疗的受试者直接进入生存随访；非疾病进展原因提前结束试验药物治疗的受试者在疗效随访结束后进入生存随访。从末次疗效评估的最早的影像学检查日开始计算，每12周(±7天)进行一次，可门诊随访或电话随访，至死亡、失访、撤销知情或试验结束。生存随访期间需要记录受试者接受的后续抗肿瘤治疗方案。
五、试验治疗及给药方案
试验药物：西奥罗尼胶囊，规格：5mg，25mg；西奥罗尼模拟胶囊；卡培他滨片，规格：0.15g，0.5g，以上试验药物由深圳微芯生物科技股份有限公司统一提供。
卡培他滨片：1000mg/m2，餐后30分钟内口服，早、晚各1次，每21天为1个治疗周期，每个周期第1～14天用药，第15～21天停药。
西奥罗尼胶囊(试验组)或西奥罗尼模拟胶囊(对照组)：25mg或35mg或50mg(根据 各自组别服用相应剂量)，每日早上空腹口服，每日1次，连续用药。
所有药物均治疗至肿瘤进展、死亡、出现不可耐受的毒性反应、撤销知情同意、失访或试验结束(以先发生者为准)。经研究者判断其中一种药物永久停药，单独使用另一种药物仍能临床获益时，允许另一种药物单独继续试验治疗。
六、试验终点指标
1.主要终点指标
无进展生存期(PFS)：从随机开始(剂量探索阶段人群从首次服药开始)，至出现疾病进展或复发(依据RECIST1.1标准)或任何原因引起死亡的时间长度(以先发生者为准)。PFS数据收集至本方案规定的试验结束时间为止。
2.次要终点指标
客观缓解率(ORR)：依据RECIST1.1标准，最佳反应达到完全缓解(CR)和部分缓解(PR)的受试者之和占分析集总人数的比例。
临床获益率(CBR)：依据RECIST1.1标准，最佳反应达到完全缓解(CR)、部分缓解(PR)和疾病稳定时间(SD)≥24周的受试者之和占分析集总人数的比例。
缓解持续时间(DOR)：第一次出现缓解(CR或PR，以先发生者为准)到第一次出现疾病复发或进展的时间长度。
总生存期(OS)：从随机开始(剂量探索阶段人群从首次服药开始)，至因任何原因引起死亡的时间。OS数据收集至本方案规定的试验结束时间为止。
安全性指标：不良事件的频率及严重程度、各项生命体征和实验室指标的变化。不良事件的严重程度按照CTCAE 5.0标准判断。
药代动力学参数。
3.探索性指标
潜在生物标志物与ORR、PFS等的关系。
七、疗效指标及评估
疗效评估标准：
由研究者依据RECIST1.1标准进行疗效评估。
疗效评估频率和手段：
基线期肿瘤评估可接受首次用药前28天内完成的影像学检查。
从首次用药日开始，每6周进行一次肿瘤评估，直到疾病进展、死亡、撤回知情、失访、接受新的抗肿瘤治疗或试验结束(以先发生者为准)，无论是否提前结束试验药物治疗。计 划的两次疗效评估间隔期内，任何时间怀疑疾病进展，研究者可决定增加额外的影像学检查。
肿瘤影像学检查包括颈部、胸部、全腹、盆腔CT或MRI，其他部位检查根据临床指征，有需要时进行。同一受试者的同一病灶在基线和后续评估测量应采用同样的技术和方法。八、数据统计分析
分析集：
意向性治疗人群(ITT，Intent To Treat population)：包括所有随机化受试者。
疗效可评价人群(RES)：包括所有随机且至少有一次基线后疗效评估的受试者。
安全数据集(SS，Safety Set)：入组后至少服用过一次试验药物，且有安全性指标记录的受试者。
疗效分析：
计算ORR、CBR及其95％可信区间。采用Kaplan-Meier法估计PFS、DOR、OS的中位值及其95％可信区间，并估计12个月、18个月和24个月的生存率及其95％可信区间。
安全性分析：
安全性分析将在SS展开。不良事件统计将以描述性统计为主，将基于CTCAE 5.0标准对不良事件、严重不良事件、不良反应、血液学毒性反应、重要不良事件等的发生情况进行描述。
肿瘤生物标志物分析：
以ORR和PFS作为疗效指标，分析其与肿瘤标志物检测指标的关联性。
八、试验结果
西奥罗尼联合卡培他滨在既往经蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌患者中的疗效优异，安全性可控。
以上对本发明进行了详细的介绍，本文中应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想，包括最佳方式，并且也使得本领域的任何技术人员都能够实践本发明，包括制造和使用任何装置或系统，和实施任何结合的方法。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。本发明专利保护的范围通过权利要求来限定，并可包括本领域技术人员能够想到的其他实施例。如果这些其他实施例具有不是不同于权利要求文字表述的结构要素，或者如果它们包括与权利要求的文字表述无实质差异的等同结构要素，那么这些其他实施例也 应包含在权利要求的范围内。

Claims (18)

  1. 包含西奥罗尼或其衍生物与抗代谢化疗药物的药物组合物在制备用于治疗和/或预防乳腺癌的药物中的用途，其中所述乳腺癌为晚期乳腺癌。
  2. 根据权利要求1所述的用途，其中所述乳腺癌包括晚期三阴性乳腺癌。
  3. 根据权利要求1所述的用途，其中所述乳腺癌为既往经蒽环类或紫杉类治疗失败的晚期三阴性乳腺癌。
  4. 根据权利要求1所述的用途，所述西奥罗尼衍生物包括其可药用盐以及非溶剂化晶体A、B和C。
  5. 根据权利要求1所述的用途，其中所述抗代谢化疗药物包括甲氨蝶玲，巯嘌呤，氟尿嘧啶，替加氟，替吉奥，阿糖胞苷，培美曲赛，雷替曲赛，卡培他滨，吉西他滨，氟达拉滨和羟基尿，优选为卡培他滨。
  6. 根据权利要求1所述的用途，其中所述西奥罗尼或其衍生物的单位剂量为1-100mg，优选为5-50mg，所述抗代谢化疗药物的单位剂量为100-2500mg，优选为200-2000mg。
  7. 根据权利要求1所述的用途，其中所述药物为一线、二线、三线、四线、五线或六线用药物。
  8. 根据权利要求1所述的用途，其中所述药物组合物包括复方制剂或者药盒。
  9. 根据权利要求8所述的用途，其中所述复方制剂包括固体制剂和液体制剂。
  10. 根据权利要求9所述的用途，其中所述固体制剂包括片剂、胶囊、颗粒剂、丸剂、散剂和栓剂，所述液体制剂包括口服液和注射剂。
  11. 根据权利要求8所述的用途，其中所述药盒为分别具有相同或不同规格的西奥罗尼或其衍生物和抗代谢化疗药物单位制剂。
  12. 根据权利要求11所述的用途，其中所述单位制剂分别置于单独容器中或者置于同一容器中。
  13. 一种药物组合物，其包含西奥罗尼或其衍生物与抗代谢化疗药物，所述抗代谢化疗药物包括甲氨蝶玲，巯嘌呤，氟尿嘧啶，替加氟，替吉奥，阿糖胞苷，培美曲赛，雷替曲赛，卡培他滨，吉西他滨，氟达拉滨和羟基尿。
  14. 根据权利要求13所述的药物组合物，所述西奥罗尼衍生物包括其可药用盐以及非溶剂化晶体A、B和C。
  15. 根据权利要求13所述的药物组合物，所述抗代谢化疗药物优选卡培他滨。
  16. 根据权利要求13-15任一项所述的药物组合物，其中所述西奥罗尼或其衍生物的单 位剂量为1-100mg，优选为5-50mg，所述抗代谢化疗药物的单位剂量为100-2500mg，优选为200-2000mg。
  17. 一种治疗和/或预防晚期乳腺癌的方法，其包括施用权利要求13-16任一项所述的药物组合物。
  18. 根据权利要求17所述的方法，所述乳腺癌包括晚期三阴性乳腺癌；优选的，所述乳腺癌为既往经蒽环类或紫杉类治疗失败的晚期三阴性乳腺癌。
PCT/CN2023/079947 2022-03-09 2023-03-07 西奥罗尼联合抗代谢化疗药物治疗乳腺癌的用途 WO2023169384A1 (zh)

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Citations (2)

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US20060178387A1 (en) * 2005-02-04 2006-08-10 Kaori Fujimoto-Ouchi Combined treatment with capecitabine and an epidermal growth factor receptor kinase inhibitor
CN109908143A (zh) * 2018-12-18 2019-06-21 厦门大学附属第一医院 西奥罗尼在制备治疗急性髓系白血病药物的新用途

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CN109908143A (zh) * 2018-12-18 2019-06-21 厦门大学附属第一医院 西奥罗尼在制备治疗急性髓系白血病药物的新用途

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