CN116726182A - Use of Siro-Ronii in combination with antimetabolite chemotherapeutic agents for the treatment of breast cancer - Google Patents
Use of Siro-Ronii in combination with antimetabolite chemotherapeutic agents for the treatment of breast cancer Download PDFInfo
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- CN116726182A CN116726182A CN202310245768.4A CN202310245768A CN116726182A CN 116726182 A CN116726182 A CN 116726182A CN 202310245768 A CN202310245768 A CN 202310245768A CN 116726182 A CN116726182 A CN 116726182A
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- 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
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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
- A61K31/70—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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to the field of biological medicine, in particular to an application of Siro-Raney combined with an antimetabolite chemotherapeutic drug in treating breast cancer. The invention provides the use of a pharmaceutical composition comprising Siro-lonib or a derivative thereof and an antimetabolite chemotherapeutic agent in the manufacture of a medicament for the treatment and/or prophylaxis of breast cancer. The invention is proved by in vitro tumor cell survival rate test experiments: the antitumor active ingredient 5 '-deoxy-5-fluorocytidine (5' -DFCR) or 5-fluorouracil (5-FU) of the combination of sirolimus and Capecitabine (CAP) can synergistically inhibit the survival of human triple negative breast cancer cells HCC 1395. Clinical experiments prove that the Siro-Ni combined antimetabolite chemotherapeutic medicament has excellent curative effect and controllable safety in patients with advanced triple negative breast cancer which fail to be treated by anthracyclines and taxanes.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to an application of Siro-Raney combined with an antimetabolite chemotherapeutic drug in treating breast cancer.
Background
There are two main types of methods for typing breast cancer, one is pathological typing and the second is molecular typing.
Breast cancer is pathologically typed by observing the characteristics of tumor cells under a microscope, thereby judging the properties of the breast cancer. According to this system, breast cancer can be generally classified into non-invasive cancer, early invasive cancer, and the like. Non-invasive cancers are early stages, including common ductal carcinoma in situ, and generally have a good prognosis, whereas invasive cancers generally have a poor prognosis, and more comprehensive treatment is often required to achieve good results. Invasive carcinoma is the most common, accounting for more than 80%, and it can be subdivided into invasive catheter carcinoma, invasive lobular carcinoma, etc.
Molecular typing refers to the detection of gene and protein levels for breast cancer, grouping according to the characteristics of gene mutation and protein expression. Molecular typing of breast cancer is more than one system, most classically classified by whether cancer cells express three proteins, ER (estrogen receptor), PR (progesterone receptor) and HER 2. Depending on their positivity and negativity, different combinations are formed, also bringing about different breast cancer subtypes. Such as: if a breast cancer is ER-positive or PR-positive, HER 2-negative (ER+PR+HER2-), we call it hormone receptor positive breast cancer. If one breast cancer is ER-negative, PR-negative, but HER 2-positive (ER-PR-HER2+), we call it HER 2-positive breast cancer. If one breast cancer is ER-negative, PR-negative, HER 2-negative (ER-PR-HER 2-), we call it a triple negative breast cancer.
Distant metastasis has occurred in 5-10% of breast cancer patients at diagnosis, while recurrent metastasis still occurs in 20-50% of early-stage patients receiving treatment. Studies show that the median survival time of patients with advanced metastatic breast cancer is 2-3 years, the five-year survival rate is only 25%, and especially HER2 negative advanced breast cancer is more important due to the lack of effective targeted therapeutic drugs, and the establishment of a scientific therapeutic scheme is more important.
The progress of treatment for HR negative/HER 2 negative breast cancers lags behind other molecular subtypes, limited to chemotherapy for non-metastatic disease to date, but this pathological type presents high aggressiveness, with susceptibility to distant metastasis. The first-line, second-line and later-line chemotherapy of recurrent metastatic advanced breast cancer has not yet determined the optimal scheme, including anthracyclines, taxanes, capecitabine and the like, and the treatment adopts a single-drug chemotherapy or combined chemotherapy mode. There is a great deal of evidence that the jersey and anthracyclines are preferred as first line therapies. The choice of the post-line treatment regimen should integrate prior treatments, drug toxicity, co-existence of the disease, patient willingness, etc. Through multi-line chemotherapy, the curative effect benefit of patients shows a gradually decreasing trend, for example, continuous 3 chemotherapy schemes are invalid or ECOG score is more than or equal to 3, and cytotoxic drugs are not considered any more, and palliative treatment is adopted instead. Immunotherapy is an emerging area of breast cancer treatment, particularly for triple negative breast cancers without specific targeted therapies. Studies have shown that the use of the PD-L1 checkpoint inhibitor atezolizumab in combination with nanoalbumin-conjugated paclitaxel in-line can extend patient survival. Targeted therapies include the use of anti-angiogenic drugs, PARP inhibitors, etc., but are still in the clinical exploration phase, there is a need to find new methods for the treatment of such breast cancers after chemotherapy failure.
HR positive/HER 2 negative breast cancer is currently the most common subtype. Clinical oncology society of America (ASCO) recommends clinical practice guidelines for HER2 negative breast cancer chemotherapy and targeted therapy that endocrine therapy be the first-line standard regimen for hormone receptor positive advanced breast cancer females, in addition to immediate life-threatening lesions (such as symptomatic visceral metastasis) or resistance to endocrine therapy. Endocrine therapy is susceptible to primary or secondary resistance, resulting in limited use. The NCCN guidelines in the united states indicate that no benefit or symptomatic visceral metastasis occurs in 3 consecutive endocrine treatment regimens, and that systemic chemotherapy is a consideration. However, most of antitumor drugs can induce adverse reactions at the same time, so that the life quality of patients is affected, and the research on molecular mechanisms and related targeted drugs of endocrine treatment drug resistance is a current urgent problem to be solved. At present, the study of endocrine combination dosing schemes in endocrine resistant subjects comprises that CDK4/6 inhibitor, PI3K alpha inhibitor, AKT inhibitor and HDAC inhibitor can effectively prolong the progression-free survival period, improve the survival rate of metastatic diseases in the past 30 years, and is a new opportunity for hormone receptor positive endocrine treatment resistant subjects. Whether other combination regimens are effective in endocrine resistant patients or whether a new therapeutic option can be provided for that part of the population is a subject of considerable research in the field.
The Siro is a brand new molecular body with global patent protection, which is independently developed by Shenzhen micro-core biotechnology, inc., has no indication and is marketed in batches at home and abroad, is a small-molecule antitumor targeting drug taking polyprotein kinase as a target point, and has three-way antitumor synergistic action mechanisms of antitumor angiogenesis, tumor cell mitosis inhibition, tumor inflammatory microenvironment regulation and the like through high selective inhibition activity on VEGFR/PDGFR/c-Kit, aurora B and CSF-1R targets; and simultaneously, the high target selectivity of the method also reduces the side effect risk caused by off-target effect.
CN200910223861.5 discloses a sierozen compound, which specifically discloses a derivative of naphthalene amide, a preparation method and application thereof. The compounds have protein kinase inhibitory activity and histone deacetylase inhibitory activity at the same time, and can be used for treating diseases related to abnormal protein kinase activity or abnormal histone deacetylase activity, including inflammation, autoimmune diseases, cancers, nervous system diseases and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergy, asthma and diseases related to hormone. CN201610856945.2 discloses a non-solvated crystal A, B, C of sirolimus and a preparation method thereof, and also relates to a pharmaceutical composition containing the crystal, and application of the crystal in preparing a medicament for treating diseases related to abnormal protein kinase activity or abnormal histone deacetylase activity.
Antimetabolite chemotherapeutic agents refer to agents that affect nucleic acid biosynthesis, whose chemical structure is similar to that of essential substances for nucleic acid metabolism, and which can prevent cell division and proliferation by specifically interfering with nucleic acid metabolism. Common antimetabolite chemotherapeutic agents include methotrexate, mercaptopurine, fluorouracil, tegafur, cytarabine, pemetrexed, raltitrexed, capecitabine, gemcitabine, fludarabine, and hydroxyurea. Wherein Capecitabine (CAP): the chemical name is 5-deoxy-5-fluoro-N- [ (pentyloxy) carbonyl ] -cytidine, which is taken as a novel oral Fluorouracil carbamate drug, has no anti-tumor activity in vitro, and can act on tumor cells only by being converted into 5 '-deoxy-5-fluorocytidine (5' -DFCR) through intrahepatic carboxylesterase, then being converted into 5 '-deoxy-5-Fluorouracil nucleoside (5' -DFUR, deoxyfluorouridine) through high-activity cytidine deaminase in liver and tumor tissues, and finally activating thymine phosphorylase which is highly expressed in the tumor tissues to be converted into 5-Fluorouracil (5-FU), and the 5-FU can play an anti-tumor role as an active ingredient. Thus, in the in vitro test or mechanism of Capecitabine (CAP) lacking a metabolic link in hepatocytes, 5 '-deoxy-5-fluorocytidine (5' -DFCR) or 5-fluorouracil (5-FU) may be used to replace CAP for tumor cells. At present, capecitabine has been used as a lot of single drugs or in combination with a regimen for the treatment of colon cancer, breast cancer and stomach cancer.
Advanced breast cancer patients first line treatment have a well-defined systemic endocrine treatment or chemotherapy regimen that would benefit based on HR receptor and HER2 tumor marker expression. However, after first-line, particularly multi-line, treatment, the patient's rate of benefit gradually decreases, toxic response increases, tolerability decreases, alternative treatment regimens are limited, and palliative treatment is often selected to improve patient quality of life. Thus, there is an unmet clinical need for advanced breast cancer treatment. Especially, for patients with triple negative breast cancer, the incidence rate of which rises year by year, endocrine targeted therapy is ineffective, and prognosis is extremely poor, great demands are made on clinical medication.
Disclosure of Invention
The invention aims to provide a drug combination composition capable of effectively preventing and/or treating advanced breast cancer after first-line treatment, particularly multi-line treatment.
To achieve this object, the present invention proposes the use of a pharmaceutical composition comprising seoronib or a derivative thereof and an antimetabolite chemotherapeutic agent in the manufacture of a medicament for the treatment and/or prevention of breast cancer, wherein the breast cancer is advanced breast cancer.
Preferably, the breast cancer comprises advanced triple negative breast cancer, further, the breast cancer is advanced triple negative breast cancer which has failed past anthracycline or taxane treatment.
Wherein the Siro-lonil derivative comprises pharmaceutically acceptable salts thereof and non-solvated crystals A, B and C, and the antimetabolite chemotherapeutic agent comprises methotrexate, mercaptopurine, fluorouracil, tegafur, cytarabine, pemetrexed, raltitrexed, capecitabine, gemcitabine, fludarabine and hydroxyurea, preferably capecitabine.
The unit dose of the Siro-lonib or the Siro-lonib derivative is 1-100mg, preferably 5-50mg, further preferably 1mg,5mg,10mg,15mg,20mg,25mg,30mg,35mg,40mg,45mg,50mg,55mg,60mg,65mg,70mg,75mg,80mg,90mg,100mg; the unit dose of the antimetabolite chemotherapeutic agent is 100-2500mg, preferably 200-2000mg, further preferable are 100mg,150mg,200mg,250mg,300mg,350mg,400mg,450mg,500mg,550mg,600mg,650mg,700mg,750mg,800mg,850mg,900mg, 650mg, 1000mg,1100mg,1200mg, 1500mg, 190 mg,2000mg, 1100mg, 230 mg,2400mg,250 mg.
Wherein the medicine is one-line, two-line, three-line, four-line, five-line or six-line medicine.
The pharmaceutical composition provided by the invention comprises a compound preparation or a medicine box.
The kit refers to a kit comprising a therapeutic agent. The correct proportions of the various drugs are typically provided in a kit and are packaged in a form that enables those drugs, which are expensive and difficult to obtain, to be used in a kit for the treatment of disease, with the individual drugs being in precise doses.
Wherein the compound preparation comprises a solid preparation and a liquid preparation. The solid preparation comprises tablets, capsules, granules, pills, powder and suppositories, and the liquid preparation comprises oral liquid and injection. The kit is a unit preparation of the Siro-lonib or the derivative thereof and the antimetabolite chemotherapeutic agent, which have the same or different specifications, respectively, wherein the unit preparations are placed in separate containers or in the same container, respectively.
In a second aspect, the invention provides a pharmaceutical composition comprising sirolimus or a derivative thereof and an antimetabolite chemotherapeutic agent comprising methoprene, mercaptopurine, fluorouracil, tegafur, cytarabine, pemetrexed, raltitrexed, capecitabine, gemcitabine, fludarabine, and hydroxyurea.
The Siro-lonil derivative comprises pharmaceutically acceptable salts thereof and unsolvated crystals A, B and C. The antimetabolite chemotherapeutic agent is preferably capecitabine.
The unit dose of the Siro-lonib or the Siro-lonib derivative is 1-100mg, preferably 5-50mg, further preferably 1mg,5mg,10mg,15mg,20mg,25mg,30mg,35mg,40mg,45mg,50mg,55mg,60mg,65mg,70mg,75mg,80mg,90mg,100mg; the unit dose of the antimetabolite chemotherapeutic agent is 100-2500mg, preferably 200-2000mg, further preferable are 100mg,150mg,200mg,250mg,300mg,350mg,400mg,450mg,500mg,550mg,600mg,650mg,700mg,750mg,800mg,850mg,900mg, 650mg, 1000mg,1100mg,1200mg, 1500mg, 190 mg,2000mg, 1100mg, 230 mg,2400mg,250 mg.
The invention also provides a method for treating and/or preventing advanced breast cancer, which comprises the step of applying the pharmaceutical composition containing the Siro-lonib or the derivatives thereof and an antimetabolite chemotherapeutic medicament.
Preferably, the breast cancer comprises advanced triple negative breast cancer, further, the breast cancer is advanced triple negative breast cancer which has failed past anthracycline and taxus treatments.
The invention has the beneficial effects that:
the invention is proved by in vitro tumor cell survival rate test experiments: the antitumor active ingredient 5 '-deoxy-5-fluorocytidine (5' -DFCR) or 5-fluorouracil (5-FU) of the combination tumor targeting prodrug Capecitabine (CAP) can synergistically inhibit the cell survival of human triple negative breast cancer cells HCC 1395. Experimental results show that compared with the single drug of the clobetadine of the Luo Nihuo, the pharmaceutical composition of the clobetadine of the Luo Niyu (or the active metabolite thereof) can be used for treating the triple negative breast cancer in a good synergistic way, and a better choice is provided for treating the triple negative breast cancer.
Clinical experiments prove that the Siro-Ni combined antimetabolite chemotherapeutic medicament (such as capecitabine) has excellent curative effect and controllable safety in the patients with advanced triple negative breast cancer which fail to be treated by anthracyclines or taxanes in the past.
Drawings
FIG. 1 shows the results of a cell viability inhibition assay of Siro-lonib alone on human triple negative breast cancer cell line HCC 1395.
FIG. 2.5 '-deoxy-5-fluorocytidine (5' -DFCR) or 5-fluorouracil (5-FU) alone on human triple negative breast cancer cell line HCC 1395.
FIG. 3 shows the results of a cell viability inhibition assay of the human triple negative breast cancer cell line HCC1395 with the combination of Siro-tinib and 5 '-deoxy-5-fluorocytidine (5' -DFCR).
FIG. 4 shows the results of a cell viability inhibition assay of human triple negative breast cancer cell line HCC1395 using a combination of Siro-Ni and 5-fluorouracil (5-FU).
Detailed Description
The invention is further illustrated by the following non-limiting examples, which are not intended to limit the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Embodiment one: testing the effect of a drug or drug combination on cell viability
1. Test materials
Human triple negative breast cancer cell line HCC1395 was purchased from American type culture Collection (American type culture collection, ATCC; CRL-2324. TM.) and cultured with RPMI-1640 medium (Hyclone) containing 1% of diabody (Green chain mycin, hyclone) and 10% of fetal bovine serum (Gibco).
Siro (Chiauranib) was derived from Shenzhen micro-core Biotechnology Co., ltd, and 5 '-deoxy-5-fluorocytidine (5' -DFCR) was purchased from Dalian Mei Lun Biotechnology Co., ltd (cat# MB 7554); 5-fluorouracil (5-FU) is available from MCE (MedChemExpress) company (cat# HY-90006). The above-mentioned compounds are respectively dissolved in dimethyl sulfoxide (Dimethyl sulfoxide, DMSO; purchased from Shanghai Biotechnology Co., ltd., product number: DN 3039A) to prepare 30mM stock solution, and placed in a refrigerator at-20deg.C for use, and working solution with corresponding final concentration is prepared according to the requirements of each experiment.
2. Main experiment reagent and instrument
alamarBlueTM Cell Viability Reagent(Invitrogen,DAL1100)
Ultra-clean bench (Sujing an tai)
CO2 cell incubator (RS Biotech Galaxy S)
Inverted microscope (Guangzhou city Mingmei technology Co., ltd.)
Denovix CellDrop TM FL cell counter
Tecan Spark TM Multifunctional enzyme labeling instrument
3. The experimental method comprises the following steps:
human triple negative breast cancer cell line HCC1395 cells in logarithmic growth phase are digested and collected, 10000 cells per well are inoculated into a 96-well cell culture plate (the inoculation volume is 190 mu L when single drugs are tested, and 180 mu L when the drugs are combined), BLANK holes are reserved for not inoculating cells, and only culture solution with the same volume is added; culturing under 5% CO2 at 37deg.C. Culturing overnight, and administering after cell adhesion.
Before administration, the final concentration of Siro-nylon, 5'-DFCR or 5-FU per well was 1000 times as high as that of DMSO, and the DMSO dilution of Siro-nylon, 5' -DFCR or 5-FU was diluted 1:50 into the culture medium.
When testing the effect of the sierozem Luo Nishan drug on cell viability, 10 μl of DMSO dilutions of the corresponding sierozem were added at final concentrations of 0, 1, 2, 4, 8, 16 μΜ per well; when testing 5'-DFCR or 5-FU single drug, 10. Mu.L of DMSO dilution of the corresponding 5' -DFCR or 5-FU was added at a final concentration of 0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30. Mu.M per well. When the drugs are tested for combination, according to the test results of single drugs, 10 mu L of corresponding DMSO dilutions are respectively added according to 0, 4 and 8 mu M of the Siro Luo Nizhong concentration per well and 0, 1, 3 and 10 mu M of the 5'-DFCR final concentration per well or 0, 0.1, 0.3 and 1 mu M of the 5-FU final concentration per well, so that Siro is respectively combined with the 5' -DFCR or the 5-FU in different doses in the cell culture plate.
4. Data processing and analysis
After 120 hours of drug action, the culture medium in the 96-well plate was aspirated, and 100. Mu.L of the test medium (containing 90. Mu.LPBS and 10. Mu. L alamarBlueTM Cell Viability Reagent) was added to each well. Incubation at 37℃for 1-2 hours by means of a Tecan Spark TM The absorbance value per well (Ex 544/Em 590) was read by a multifunctional microplate reader.
The above doses or drug combinations were repeated 3 times and ODBLK (background value) was averaged based on the BLANK well readings, and ODT0 was obtained for each dosing well and negative control well (cells and nutrient solution were added to the well, not dosed) with background value subtracted from each well reading. Average value ODT0-a of negative control wells ODT0 was calculated for each dosing well relative cell viability according to the formula: relative cell viability (%) = (ODT/(ODT 0-a) ×100%).
5. Experimental results and analysis:
as shown in fig. 1, the sierozem Luo Nishan drug has a certain inhibition effect on the cell viability of human triple negative breast cancer cells HCC1395, wherein the inhibition rates of the sierozem doses of 4 μm and 8 μm on the cell viability of HCC1395 are close to 25% and 35%, respectively.
As shown in FIG. 2, the 5' -DFCR single drug has a certain inhibition effect on the cell viability of the human triple negative breast cancer cell HCC1395, and the 5' -DFCR with the dosage of more than 3 mu M can have a clear effect on the cell viability of the HCC1395, and the 5' -DFCR with the dosage of 3 mu M can have an inhibition effect on the cell viability of the HCC1395 by nearly 15%. The independent action of the 5-FU has a certain inhibition effect on the cell viability of the HCC1395 of the human triple negative breast cancer cell, the cell viability of the HCC1395 can be clearly influenced by the 5-FU with the dosage of more than 0.1 mu M, and the inhibition effect of the 5-FU with the dosage of 0.1 mu M on the cell viability of the HCC1395 is approximately 20%.
As shown in fig. 3, the relative cell viability data measured for the human triple negative breast cancer cells HCC1395 with the combination of the 4 μm or 8 μm doses of the sierozen with the 1 μm, 3 μm and 10 μm doses of the 5' -DFCR, respectively, indicated that the inhibition rate of each dose of the two-drug combination on the cell viability of HCC1395 was higher than that of the corresponding dose of the single drug. In particular, when a 4. Mu.M dose of Siro-lonil was combined with a 3. Mu.M or 10. Mu.M dose of 5' -DFCR to act on HCC1395, the average inhibition rates were 47.9% and 64.6%, respectively, whereas the inhibition rate of 4. Mu.M dose of Siro-Luo Nishan drug in this experiment was about 22.7%; the average inhibition rates were 70.9% and 79.0% for the 8. Mu.M dose of Siro-lonib in combination with the 3. Mu.M or 10. Mu.M dose of 5' -DFCR, respectively, on HCC1395, whereas the inhibition rate for the 8. Mu.M dose of Siro-Luo Nishan drug in this experiment was approximately 38.6%. Comprehensive analysis shows that the inhibition rates of the 5'-DFCR single drugs at the doses of 3 mu M and 10 mu M in the experiment are about 18.7% and 32.5%, respectively, and the inhibition effect of the 5' -DFCR combined drug of the Siro-Raney at the doses of 4 mu M or 8 mu M on HCC1395 is obviously stronger than the sum of the independent effects of the two drugs.
As shown in fig. 4, the combination of the 4 μm or 8 μm dose of the seolony and the 0.03 μm, 0.1 μm and 0.3 μm dose of 5-FU was used to treat human triple negative breast cancer cells HCC1395, and the measured cell relative viability data indicated that the inhibition rate of each dose of the two-drug combination was higher than that of the corresponding dose of the single drug. In particular, when a 4. Mu.M dose of Siro-lonil was combined with a 0.1. Mu.M or 0.3. Mu.M dose of 5-FU to HCC1395, the average inhibition rates were 56.6% and 80.0%, respectively, whereas the inhibition rate of 4. Mu.M dose of Siro-Luo Nishan drug in this experiment was about 29.4%; the average inhibition rates were 76.8% and 82.6% for the combination of 8. Mu.M dose of Siro-lonib with 0.1. Mu.M or 0.3. Mu.M dose of 5-FU, respectively, in HCC1395, whereas the inhibition rate was about 37.0% for the 8. Mu.M dose of Siro-Luo Nishan in this experiment. Comprehensive analysis shows that the inhibition rates of the single drugs of 5-FU at the doses of 0.1 mu M and 0.3 mu M in the experiment are about 21.3% and 43.6%, respectively, and the inhibition effect of the single drug of 5-FU at the doses of 4 mu M or 8 mu M in combination with the drug of 5-FU on HCC1395 is stronger than the sum of the independent effects of the two drugs.
In summary, the experimental results show that: compared with the Siro Luo Nishan drug or the 5 '-deoxy-5-fluorocytidine (5' -DFCR) single drug, the Siro-lonib combined with the 5 '-deoxy-5-fluorocytidine (5' -DFCR) has synergistic inhibition effect on the activity of human triple negative breast cancer cells HCC 1395; the combination of Siro and 5-fluorouracil (5-FU) has synergistic inhibition effect on human triple negative breast cancer cell HCC1395 activity compared with Siro Luo Nishan or 5-fluorouracil (5-FU) single drug.
Embodiment two: multi-center phase II clinical trial of Siro-Raney capsules in combination with capecitabine in patients with advanced triple negative breast cancer with anthracycline and Taxus therapy failure
1. Purpose of test
1. The main purpose is as follows:
the initial efficacy of the combination of cioroniside and capecitabine in patients with advanced triple negative breast cancer who failed anthracycline and taxus therapy was explored.
2. The secondary purpose is as follows:
the safety of the combination of cioroniside and capecitabine in advanced triple negative breast cancer patients with failure of anthracycline and taxus therapy was observed.
Concomitant Pharmacokinetic (PK) profiles following the administration of the combination capecitabine with rio were analyzed.
3. Exploratory purposes:
exploring the relationship between the potential biomarker and the primary curative effect.
2. Criteria for inclusion
All the following conditions must be met for opt-in:
1. understand and voluntarily sign written informed consent.
2. Age: the informed consent was signed at 18 years old or more.
3. Gender: female.
4. Histologically or cytologically confirmed patients with triple negative breast cancer. (defined as Estrogen Receptor (ER), progestin Receptor (PR), human epidermal growth factor receptor 2 (HER 2) are all negative).
5. The pre-group disease state is unresectable locally advanced or metastatic disease and is a patient who fails to be treated with anthracyclines and taxanes.
6. According to RECIST1.1 criteria, at least one measurable target lesion, a lesion for which radiotherapy or local area treatment must have imaging evidence of disease progression, may be considered a target lesion.
Ecog physical status score: 0 or 1 minute.
8. At the time of screening, laboratory checks met the following criteria:
blood routine examination: hemoglobin (Hb) of not less than 90g/L and neutrophil absolute value (ANC) of not less than 1.5X10 9 The platelet count (PLT) is more than or equal to 100×10 9 L; (correction and support therapy of the following parameters were not performed within the first 2 weeks of evaluation)
Biochemical examination: serum creatinine (Cr) is less than or equal to 1.5 times the upper limit of normal value (ULN); total Bilirubin (TBIL) is less than or equal to 1.5 XULN; glutamic-pyruvic transaminase (ALT) and glutamic-oxalacetic transaminase (AST) are less than or equal to 2.5 XULN (liver metastasis case is less than or equal to 5 ULN);
coagulation function: international normalized ratio (PT-INR) <1.5.
9. Researchers judged that the life expectancy was at least 3 months.
* And (3) injection:
definition of treatment failure of taxanes (anthracyclines): refers to the occurrence of disease progression (at least two cycles of treatment) during rescue treatment of taxanes (anthracyclines), or recurrent metastasis within 12 months after the end of adjuvant therapy.
Patients with contraindications or intolerance to the taxanes are allowed to participate in the study if they are treated for at least 1 cycle and exhibit contraindications or intolerance during or at the end of the cycle, with other conditions being met.
(other conditions are met but anthracycline treatment is no longer available, e.g. a cumulative dose of 400mg/m has been accepted) 2 Doxorubicin or doxorubicin analogs are also allowed to enter the group. )
3. Sample size
Dose exploration phase: 3-6 subjects per group and the recommended dose group continued to group about 7 subjects in phase II for a total of 16-25 subjects.
Random control phase: 43 cases are expected for each group, and 86 cases are calculated for two groups.
The whole test totals 102 to 111 cases.
4. Test population design
The trial was divided into two phases, namely a dose discovery phase and a randomized control phase. Concomitant pharmacokinetic studies were conducted during the dose discovery phase, with the first cycle of the dose discovery phase being the DLT observation phase.
Dose exploration phase:
fixed capecitabine 1000mg/m 2 The 3 dose levels (25 mg,35mg and 50 mg) of Siro-lonil were performed in a "3+3" dose escalation manner, with the next dose of Siro-lonil into the group only if the previous dose level was judged safe, and no more than 6 subjects per dose level. After safety assessment and preliminary analysis of efficacy for different dosages of cioronib and fixed doses of capecitabine, the group of approximately 7 subjects continued to be enrolled in the group at the initially determined group II recommended dose, and then entered the randomized controlled trial phase. By a means ofAll subjects were treated to tumor progression, death, appearance of intolerable toxic responses, withdrawal of informed consent, loss of visit, or end of trial (based on the prior occurrence).
Note that:
1) Each subject can only participate in one dose group study.
2) Subjects in the same dose group were allowed to enter the group at the same time.
3) After the first treatment cycle observation of all the subjects in each dose group was completed and evaluated as safe, the next dose group in the group could be started.
Random control phase:
based on the previous stage, the recommended dose of Siro-Raney (expected to be 50 mg) and capecitabine 1000mg/m are used 2 Multi-center, double-blind, random control studies were performed in combination.
The trial included a screening period, a treatment period, and a follow-up period.
Group-in subjects were randomly assigned to the cioronib combined capecitabine group (test group) and placebo combined capecitabine group (control group) at 1:1 for treatment to tumor progression, death, intolerance to toxic response, withdrawal of informed consent, loss of visit, or end of trial (based on the prior occurrence). Efficacy assessment was performed every 6 weeks, calculated from the first dose. Safety assessments were performed every 3 weeks.
The subjects entered a follow-up period after the end of trial drug treatment.
Security follow-up: subjects were subjected to a safety follow-up 28 days (+ -7 days) after the last use of the test drug.
Follow-up treatment: subjects who had previously ended trial drug treatment for reasons other than disease progression continue tumor assessment as originally planned until disease progression, death, withdrawal of knowledge, loss of visit, receiving new anti-tumor treatment, or trial ends (based on the prior occurrence).
Survival follow-up: subjects who ended the trial drug treatment for disease progression entered directly into survival follow-up; subjects who had advanced end of trial drug treatment for reasons other than disease progression entered survival follow-up after the end of efficacy follow-up. The calculation is started from the earliest imaging examination day of the last curative effect evaluation, and the calculation is carried out every 12 weeks (+ -7 days), and the clinic follow-up or telephone follow-up can be carried out until death, lost visit, withdrawal of knowledge or test is finished. Follow-up survival requires recording of subsequent anti-tumor treatment regimens received by the subject.
5. Trial treatment and dosing regimen
Test drug: siro-Nib capsule, specification: 5mg,25mg; a sironi simulation capsule; capecitabine tablet, specification: 0.15g,0.5g of the above test drugs were uniformly supplied by Shenzhen micro-core Biotech Co., ltd.
Capecitabine tablet: 1000mg/m 2 The medicine is orally taken within 30 minutes after meal, 1 treatment period is adopted every 21 days in the morning and evening, the medicine is taken every 1 to 14 days in each period, and the medicine is stopped every 15 to 21 days.
Siro-nylon capsules (test group) or Siro-nylon simulated capsules (control group): 25mg or 35mg or 50mg (corresponding to the respective dose administered according to the respective group) is orally administered on an empty stomach in the morning, 1 time a day, continuously.
All medications were treated to tumor progression, death, appearance of intolerable toxic responses, withdrawal of informed consent, loss of visit, or end of trial (based on the prior occurrence). The investigator judged that one of the drugs was permanently stopped and the other drug alone was still clinically beneficial, allowing the other drug alone to continue trial treatment.
6. End point index of test
1. Main end point index
Progression Free Survival (PFS): from random onset (the dose exploration phase of the population from the first dose) to the time period of disease progression or recurrence (according to RECIST1.1 criteria) or death from any cause (based on the first occurrence). The PFS data was collected until the end of the trial specified in the protocol.
2. Secondary endpoint indicator
Objective Remission Rate (ORR): according to RECIST1.1 criteria, the optimal response achieved a ratio of the sum of subjects with Complete Remission (CR) and Partial Remission (PR) to the total number of people analyzed.
Clinical Benefit Rate (CBR): the sum of subjects who achieved Complete Remission (CR), partial Remission (PR) and disease stabilization time (SD) for 24 weeks was the proportion of the total number of people analyzed according to RECIST1.1 criteria.
Duration of remission (DOR): the length of time between first onset of remission (CR or PR, whichever occurs first) to first onset of disease recurrence or progression.
Total lifetime (OS): from random onset (the dose exploration phase group started from the first dose) to the time of death for any reason. The OS data is collected until the test end time specified in the present embodiment.
Safety index: the frequency and severity of adverse events, and the variation of individual vital signs and laboratory indicators. The severity of adverse events was judged according to CTCAE 5.0 criteria.
Pharmacokinetic parameters.
3. Exploratory index
Relationship of potential biomarkers to ORR, PFS, etc.
7. Efficacy index and assessment
Efficacy evaluation criteria:
efficacy assessment was performed by researchers according to RECIST1.1 criteria.
Efficacy evaluation frequency and means:
the baseline tumor assessment may accept imaging examinations completed within 28 days prior to the first dose.
Tumor assessment is performed every 6 weeks, starting on the first day of administration, until disease progression, death, withdrawal of knowledge, loss of visit, new anti-tumor therapy received or trial completed (based on the first occurrence), whether trial medication was completed in advance or not. During the planned interval between two efficacy assessments, at any time during which disease progression is suspected, the researcher may decide to add additional imaging exams.
Tumor imaging examinations include cervical, thoracic, full-abdominal, pelvic CT or MRI, with other site examinations being performed as needed according to clinical indications. The same lesion of the same subject should be measured at baseline and subsequent assessments using the same techniques and methods. 8. Statistical analysis of data
Analysis set:
intentional treatment population (ITT, intent To Treat population): including all randomized subjects.
Efficacy evaluable population (RES): all subjects randomized and at least one post-baseline efficacy assessment were included.
Secure data Set (SS), security Set): and (3) taking the test medicine at least once after the group is put into the group, and recording the safety index of the subjects.
Curative effect analysis:
the ORR, CBR and 95% confidence intervals were calculated. The median value of PFS, DOR, OS and its 95% confidence interval were estimated by Kaplan-Meier method, and the survival rates of 12 months, 18 months and 24 months and their 95% confidence intervals were estimated.
Safety analysis:
the security analysis will be deployed at the SS. Adverse event statistics will be mainly descriptive statistics, and occurrence of adverse events, serious adverse events, adverse reactions, hematological toxic reactions, important adverse events, and the like will be described based on CTCAE 5.0 standards.
Tumor biomarker analysis:
and (3) using ORR and PFS as curative effect indexes, and analyzing the relevance between the ORR and PFS and tumor marker detection indexes.
8. Test results
The Siro-Ni combined capecitabine has excellent curative effect and controllable safety in the advanced triple negative breast cancer patients who fail to be treated by anthracyclines and taxanes.
While the invention has been described in detail and with specific examples, the principles and embodiments of the invention are described herein, the above examples are provided solely to aid in the understanding of the method of the invention and its core concept, including the best mode, and to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims. The scope of the patent protection is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.
Claims (18)
1. Use of a pharmaceutical composition comprising sirolimus or a derivative thereof and an antimetabolite chemotherapeutic agent in the manufacture of a medicament for the treatment and/or prevention of breast cancer, wherein the breast cancer is advanced breast cancer.
2. The use of claim 1, wherein the breast cancer comprises advanced triple negative breast cancer.
3. The use of claim 1, wherein the breast cancer is advanced triple negative breast cancer that failed prior anthracycline or taxus therapy.
4. The use according to claim 1, said seoronic derivative comprising a pharmaceutically acceptable salt thereof and non-solvated crystals A, B and C.
5. The use according to claim 1, wherein the antimetabolite chemotherapeutic agent comprises methoprene, mercaptopurine, fluorouracil, tegafur, cytarabine, pemetrexed, raltitrexed, capecitabine, gemcitabine, fludarabine and hydroxyurea, preferably capecitabine.
6. The use according to claim 1, wherein the unit dose of the seology or derivative thereof is 1-100mg, preferably 5-50mg, and the unit dose of the antimetabolite chemotherapeutic agent is 100-2500mg, preferably 200-2000mg.
7. The use of claim 1, wherein the medicament is a one-wire, two-wire, three-wire, four-wire, five-wire or six-wire medicament.
8. The use of claim 1, wherein the pharmaceutical composition comprises a compound formulation or a kit.
9. The use of claim 8, wherein the compound formulation comprises a solid formulation and a liquid formulation.
10. The use according to claim 9, wherein the solid formulation comprises tablets, capsules, granules, pills, powders and suppositories, and the liquid formulation comprises oral liquids and injections.
11. The use according to claim 8, wherein the kit is a unit preparation of seology or a derivative thereof and an antimetabolite chemotherapeutic agent, each having the same or different specifications.
12. The use according to claim 11, wherein the unit formulations are placed in separate containers or in the same container, respectively.
13. A pharmaceutical composition comprising sirolimus or a derivative thereof and an antimetabolite chemotherapeutic agent comprising methoprene, mercaptopurine, fluorouracil, tegafur, cytarabine, pemetrexed, raltitrexed, capecitabine, gemcitabine, fludarabine, and hydroxyurea.
14. The pharmaceutical composition of claim 13, wherein the seolinib derivative comprises a pharmaceutically acceptable salt thereof and non-solvated crystals A, B and C.
15. The pharmaceutical composition according to claim 13, the antimetabolite chemotherapeutic agent preferably capecitabine.
16. The pharmaceutical composition according to any one of claims 13-15, wherein the unit dose of the seology or derivative thereof is 1-100mg, preferably 5-50mg, and the unit dose of the antimetabolite chemotherapeutic agent is 100-2500mg, preferably 200-2000mg.
17. A method of treating and/or preventing advanced breast cancer comprising administering the pharmaceutical composition of any one of claims 13-16.
18. The method of claim 17, wherein the breast cancer comprises advanced triple negative breast cancer; preferably, the breast cancer is advanced triple negative breast cancer which has failed past anthracycline or taxane treatment.
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