Use of utidelone in treatment of solid tumors

Abstract

Disclosed in the present application is the use of a compound of formula I in the preparation of a drug for treating the following tumors, which are selected from gastric cancer, esophageal cancer, cholangiocarcinoma, nasopharyngeal cancer, soft tissue sarcoma, prostate cancer, liver cancer, non-small cell lung cancer, breast cancer, glioma, leukemia, ovarian cancer, cervical cancer, endometrial carcinoma, primary brain tumors, brain metastatic tumors, pancreatic cancer and angiosarcoma. Further disclosed is the use of the compound in combination with other anti-tumor drugs in the treatment of the above-mentioned cancers.

Description

Use of ortataxel in treatment of solid tumors TECHNICAL FIELD

[0001] The present application relates to the use of ortataxel, an epothilone derivative, and its pharmaceutical formulations in the treatment of cancer, in particular to the use of the formulations alone or in combination with other anti-tumor drugs in the treatment of cancer, especially in the treatment of solid tumors. BACKGROUND

[0002] Cancer is the leading cause of death worldwide, with the global cancer incidence increasing from 18.1 million cases in 2018 to 20.2 million cases in 2022. Due to population aging, the cancer incidence is expected to reach 24.5 million cases in 2030. In terms of mortality, cancer is the second leading cause of death in China. The cancer incidence in China has been steadily increasing over the past five years, from 4.3 million cases in 2018 to 4.8 million cases in 2022, and is expected to reach 5.8 million cases in 2030. Natural epothilones are a class of 16-membered macrocyclic lactone compounds, among which epothilones A and B were first isolated and identified from the secretions of the South African cellulose pile mucous bacteria (Soorangium cellulosum) by German natural product chemist Hofle and microbiologist Reichenbach. In 1995, Bollag et al. first reported the potential anti-tumor effect of epothilones, which has a mechanism similar to that of taxanes. Epothilones bind to the β-subunit of α, β-tubulin heterodimer, promoting the polymerization of tubulin to form microtubules and stabilizing microtubules, inhibiting their depolymerization, leading to the abnormal arrangement of microtubule bundles, forming star bodies, and then inhibiting the formation of normal mitotic spindles in cells, causing cell mitosis to be arrested at the G2 / M transition, thereby inhibiting the growth of tumor cells and causing cytotoxicity leading to cell death.

[0003] Ortataxel, as a new generation of epothilone derivative, has a mechanism similar to that of taxanes (microtubule stabilizers), which have been widely used in cancer treatment for more than three decades. Based on the past success of taxanes, we believe that ortataxel has the potential to become the next widely used chemotherapy drug. Ortataxel differs from taxanes in that it has a different tubulin binding site and chemical structure, and has other characteristics such as P-glycoprotein insensitivity, inhibition of ERK1 / 2 and AKT phosphorylation, and down-regulation of Bcl-2 levels. SUMMARY

[0004] Ortataxel has several advantages, including better efficacy, superior safety, broader anti-cancer spectrum, effectiveness against multi-drug resistant tumors without easy drug resistance, and the ability to penetrate the blood-brain barrier, thus having the potential to prevent and treat brain metastases.

[0005] Preclinical in vitro cytotoxicity studies show that orteronel has high anti-tumor activity on more than ten human tumor cell lines, including endogenous and acquired drug-resistant cell lines. Preclinical in vivo pharmacodynamic studies also show that, compared with paclitaxel, orteronel has stronger anti-tumor activity on nude mouse human tumor xenograft models, including lung cancer, liver cancer, colon cancer, breast cancer, and prostate cancer. The results of multiple clinical studies also show that orteronel, as a single agent or in combination, has excellent efficacy in treating solid tumors such as gastric cancer, esophageal cancer, ovarian cancer, and brain tumors. Orteronel has great potential for expanding new indications and extensive combination therapy.

[0006] Although orteronel has significant broad-spectrum anti-tumor properties, in actual clinical applications, it is difficult for the skilled person to determine the optimal treatment regimen for different tumors, including the use of single-agent therapy or combination therapy, and the choice of anticancer drugs. The present application is dedicated to improving the efficacy of orteronel in the treatment of solid tumors through appropriate single-agent or combination therapy, as well as appropriate dosages and administration methods, so as to achieve the most ideal clinical drug regimen and maximize the benefits for tumor patients.

[0007] The present application provides the use of orteronel or a combination of orteronel and other anticancer drugs in the preparation of a medicament for treating some solid tumors, such as gastric cancer, esophageal cancer, cholangiocarcinoma, nasopharyngeal carcinoma, soft tissue sarcoma, prostate cancer, liver cancer, non-small cell lung cancer, breast cancer, glioma, leukemia, ovarian cancer, cervical cancer, endometrial cancer, primary brain tumor, brain metastasis, pancreatic cancer, and angiosarcoma.

[0008] The structural formula of orteronel is shown in Formula I:

[0009] wherein R2 = CH3.

[0010] According to some embodiments, orteronel is administered in the form of intravenous administration or oral administration.

[0011] According to some embodiments, the medicament is used to treat cancer that has not been treated before or has been treated.

[0012] According to some embodiments, orteronel can be used in combination with at least one other anticancer drug.

[0013] According to some embodiments, the other anticancer drugs include, but are not limited to, chemotherapeutic drugs, targeted drugs, endocrine drugs, tumor immunotherapy drugs, and ADC drugs.

[0014] According to some embodiments, the other anticancer drugs are selected from one or more chemotherapy drugs, including: 1) metabolites: fluorouracil, capecitabine, tegafur, leucovorin, methotrexate, pemetrexed; 2) platinum drugs: oxaliplatin, cisplatin, lobaplatin, carboplatin, nedaplatin; 3) microtubule inhibitors: docetaxel, paclitaxel, albumin-bound paclitaxel, vinorelbine; 4) anthracycline antibiotics: doxorubicin, epirubicin; 5) alkylating agents: cyclophosphamide, ifosfamide, hexamethylmelamine, cetepidine, temozolomide, dacarbazine; 6) topoisomerase inhibitors: topotecan, topotecan, etoposide, irinotecan; 7) DNA polymerase inhibitors: cytarabine, gemcitabine; or one or more endocrine drugs, including anastrozole, exemestane, letrozole, leuprorelin, goserelin, triptorelin, megestrol acetate, tamoxifen, fulvestrant; or one or more targeted drugs, including 1) HER2-targeted drugs: trastuzumab, ramoximumab, pyrotinib, or HER2-targeted ADC drugs: detrastuzumab, vidictetumab, trastuzumab emtansine; 2) Target mutation-targeted drugs: dabrafenib, entrectinib, larotrectinib, trametinib, serpatinib, bimetinib, sotorasiib, adagraxib; 3) Targeted anti- Angiogenesis drugs: apatinib, anlotinib, sorafenib; bevacizumab, fruquintinib; 4) PARP inhibitors: olaparib, niraparib, fluzoparib, pamiparib; abiraterone, bicalutamide, enzalutamide; 5) Cycle-dependent kinase inhibitors: reboxil, palbociclib, abeciclib, triasidib, dalcirib; 6) Epidermal growth factor receptor inhibitors: such as gefitinib, erlotinib, icotinib, afatinib, osimertinib, ametinib, vormetinib, crizotinib, ceritinib, alectinib, ensartinib, lorlatinib, brigatinib, imatinib; or select one or more of the following tumor immunotherapy drugs, including 1) PD-1 monoclonal antibodies: pembrolizumab, nivolumab, sintilimab, tislelizumab, camrelizumab, toripalimab, penaprilimab, cepalimumab, dotalimumab, slulilimumab; 2) PD-L1 monoclonal antibodies: durvalumab, atezolizumab, durvalumab, envorimab; 3) CTLA-4 monoclonal antibodies: ipilimumab, trimemumab; 4) Bispecific antibodies with PD-1 / PD-L1 and CTLA-4 as one of the antigens: cantulimumab; or selected from one or more other targeted ADC drugs, including velpostuzumab, brentuximab, ozogazolizumab, gosatuzumab.

[0015] According to some embodiments of the present application, the pharmaceutical preparation is administered in the form of intravenous infusion and / or pump infusion and / or oral administration. For example, administration is performed on day 1 to day 5, once a day, for 5 consecutive days, every 3 weeks as a treatment cycle; or administration is performed on day 1 to day 7, once a day, for 7 consecutive days, every 3 weeks as a treatment cycle; or, administration is performed on day 1 and day 8, once a day, every 3 weeks as a treatment cycle; or, administration is performed on day 1, day 8 and day 15, once a day, every 3 weeks as a treatment cycle; or, administration is performed on day 1, day 8 and day 15, once a day, every 4 weeks as a treatment cycle; or, administration is performed on day 1 to day 5, intravenous pump infusion, for 5 consecutive days, every 3 weeks as a treatment cycle; or, administration is performed on day 1 to day 2, once a day, intravenous pump infusion from day 3 to day 5, for 5 consecutive days, every 3 weeks as a treatment cycle; or, administration is performed on day 1, once, intravenous pump infusion from day 2 to day 5, for 5 consecutive days, every 3 weeks as a treatment cycle. The dose of the pharmaceutical preparation is 15 mg / m 2 2 / day to 150 mg / m 2 2 / day.

[0016] DETAILED DESCRIPTION

[0017] Optideride can be formulated into intravenous pharmaceutical formulations. The final dilution at the time of clinical use can be accomplished with an appropriate diluent, such as 5% dextrose injection, sterile water for injection, or sterile normal saline and lactated Ringer's injection, to make an injectable solution of volume from about 50 ml to 300 ml, preferably from about 100 ml to 250 ml. The diluted solution can be stored at room temperature for not less than about 24 hours before administration, so that the final administration concentration of the compound of Formula I preferably comprises from about 0.05 mg / ml to 0.5 mg / ml of the compound of Formula I. The administration dose and frequency for a particular patient can vary depending on many factors, such as the metabolism of the drug, the general condition of the patient, and the severity of the cancer disease and the different adverse reactions to the drug. For example, intravenous administration from day 1 to day 5, once a day, for 5 consecutive days, every 3 weeks for a treatment cycle; or intravenous administration on day 1 and day 8, once a day, every 3 weeks for a treatment cycle; or intravenous administration on day 1, day 8 and day 15, once a day, every 3 weeks for a treatment cycle; or intravenous administration on day 1, day 8 and day 15, once a day, every 4 weeks for a treatment cycle; or intravenous infusion administration from day 1 to day 5, for 5 consecutive days, every 3 weeks for a treatment cycle; or intravenous administration from day 1 to day 2, once a day, and intravenous infusion administration from day 3 to day 5. For 5 consecutive days, every 3 weeks for a treatment cycle; or intravenous administration once on day 1, and intravenous infusion administration from day 2 to day 5. For 5 consecutive days, every 3 weeks for a treatment cycle; the administration dose of the compound of Formula I per cycle ranges from 50 to 300 mg, such as from 15 mg / m 2 / day to 150 mg / m 2 / day, and more preferably from 20 mg / m 2 / day to 40 mg / m 2 / day.

[0018] Optideride can also be administered orally, and the administration dose and frequency for a particular patient can vary depending on many factors, such as the metabolism of the drug, the general condition of the patient, and the severity of the cancer disease and the different adverse reactions to the drug. For example, oral administration from day 1 to day 5, once a day or twice a day; or oral administration from day 1 to day 7, once a day, twice a day, every 3 weeks for a treatment cycle or every 4 weeks for a treatment cycle. The administration dose of the compound of Formula I per cycle ranges from 150 to 1200 mg, such as the administration dose is from about 15 mg / m 2 / day to 100 mg / m 2 / day, and more preferably from 30 mg / m 2 / day to 80 mg / m 2 / day.

[0019] The pharmaceutical preparation of Ortataxel of the present application can be used alone or in combination with other anticancer drugs or therapies. For example, the other anticancer drugs or therapies that can be used in combination with Ortataxel are selected from one or more of the following: 1) metabolic drugs: fluorouracil, capecitabine, tegafur, leucovorin, methotrexate, pemetrexed; 2) platinum drugs: oxaliplatin, cisplatin, lobaplatin, carboplatin, nedaplatin; 3) microtubule inhibitors: docetaxel, paclitaxel, albumin-bound paclitaxel, vinorelbine; 4) antibiotic anthracycline antitumor drugs: doxorubicin, epirubicin; 5) alkylating agents: cyclophosphamide, ifosfamide, hexamethylmelamine, triaziquone, temozolomide, dacarbazine; 6) topoisomerase inhibitors: topotecan, irinotecan, etoposide, irinotecan; 7) DNA polymerase inhibitors: cytarabine, gemcitabine; or selected from one or more of the following: 1) endocrine drugs: anastrozole, exemestane, letrozole, leuprolide, goserelin, triptorelin, megestrol, tamoxifen, fulvestrant; or selected from one or more of the following: 1) HER2 targeted drugs: trastuzumab, ramucirumab, pyrotinib, or HER2 targeted ADC drugs: drotuximab, vedisimab, emtansine; 2) target mutation targeting drugs: dabrafenib, entrectinib, larotrectinib, trametinib, seriplimab, binimetinib, sotorasib, adagrasib; 3) targeted anti-angiogenic drugs: apatinib, anlotinib, sorafenib, bevacizumab, fumitecan; 4) PARP inhibitors: olaparib, niraparib, talazoparib, pamiparib; abiraterone, bicalutamide, enzalutamide; 5) cell cycle-dependent kinase inhibitors: ribociclib, pebiclib, abemaciclib, trilaciclib, daraciclib; 6) epidermal growth factor receptor inhibitors: such as gefitinib, erlotinib, icotinib, afatinib, osimertinib, amatinib, fostamatinib, crizotinib, seribantinib, alectinib, ensartinib, larotrectinib, brigatinib, imatinib; or selected from one or more of the following: 1) PD-1 mAb: pembrolizumab, nivolumab, cediranisb, tislembra, camrelizumab, tislembra, patritumab, spartalizumab, domvanalimab, sasanlimab; 2) PD-L1 mAb: durvalumab, atezolizumab, durvalumab, envafolimab; 3) CTLA-4 mAb: ipilimumab, tremelimumab; 4) bispecific antibodies with PD-1 / PD-L1 and CTLA-4 as one of the antigens: camidanisb; or selected from one or more of the following: 1) other targeted ADC drugs: inotuzumab, vibostolimab, ocaratuzumab, gosartumab. The combination therapy can be administered sequentially, i.e., the pharmaceutical preparation of the present application and the other chemotherapy drugs are administered separately, or simultaneously.

[0020] According to some embodiments, the combination of oltipraz with other anticancer drugs includes the following combinations: oltipraz and oxaliplatin; oltipraz, oxaliplatin and PD-1 antibody (such as sintilimab); oltipraz, capecitabine and PD-1 antibody (such as toripalimab); oltipraz, etoposide and bevacizumab; oltipraz and bevacizumab; oltipraz and methotrexate; oltipraz, doxorubicin and cyclophosphamide; oltipraz and gemcitabine; oltipraz, bevacizumab and gemcitabine; oltipraz and PD-1 or PD-L1 monoclonal antibody (such as camrelizumab, spartalizumab, toripalimab, sintilimab, envafolimab); oltipraz and platinum anticancer drugs (such as nedaplatin, lobaplatin, carboplatin); oltipraz and anlotinib; oltipraz combined with pyrotinib; oltipraz combined with pyrotinib and inotuzumab; oltipraz, PD-1 antibody and bevacizumab.

[0021] The tumors treated by oltipraz or its combination with other anticancer drugs include gastric cancer, esophageal cancer, cholangiocarcinoma, nasopharyngeal carcinoma, soft tissue sarcoma, prostate cancer, liver cancer, non-small cell lung cancer, breast cancer, glioma, leukemia, ovarian cancer, cervical cancer, endometrial cancer, brain primary tumor, brain metastasis, angiosarcoma and pancreatic cancer. These solid tumors can be metastatic tumors or primary tumors. For example, the brain tumors mentioned herein can be brain primary tumors such as brain glioma, or brain metastasis such as breast cancer brain metastasis, lung cancer brain metastasis, etc. The tumors of the present application can be tumors that have not been previously treated or tumors that have been previously treated. The tumors of the present application can be tumors that have previously received radiotherapy and chemotherapy alone or simultaneously, or tumors that are naturally insensitive or later become insensitive to taxanes. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 shows the distribution of oltipraz in tissues;

[0023] Figure 2 shows the concentration of oltipraz in plasma and brain tumor cyst fluid. DETAILED DESCRIPTION

[0024] The following examples are for illustrative purposes only and should not be construed as limiting the present application.

[0025] Example 1. Preparation of injection preparation

[0026] 1. Take 100 grams of Captisol and dissolve in 200 ml of water (WFI) to prepare a 50% Captisol concentrated solution;

[0027] 2. Take 400 mg of compound of formula 1, add 10 ml of ethanol to dissolve, to prepare a 40 mg / ml ethanol sample solution.

[0028] 3. The sample solution containing Captisol was configured according to the following table:

[0029] 4. After preparation of Formulation A, 1 ml sample was taken after 0h and 24h at room temperature, respectively, and centrifuged at 12000 rpm for 10 minutes. The supernatant was taken, diluted with acetonitrile solvent, and analyzed by HPLC. The recovery rate was >98%.

[0030] 5. After 24 hours at room temperature, the compound of Formula I was completely dissolved in the solution of Formulation A, and no precipitation occurred within 24 hours, indicating that the drug has good solubility and stability, which is beneficial for storage. After dilution of Formulation A, the Captisol was 2.5% or 1.25%, and no precipitation occurred within 24 hours.

[0031] 6. Formulation A was prepared as a concentrated solution with a volume of 5 ml for storage. When used clinically, it can be diluted with a diluent such as sterile water for injection or sterile normal saline, or phosphate buffer to prepare a solution containing 0.5 mg / ml-1.0 mg / ml of the compound of Formula 1. The diluent did not change significantly within 12 hours at room temperature.

[0032] Example 2. Preparation of capsule formulation

[0033] Oral solid formulation of oltipazidone

[0034] *: Solvent used in the process and finally removed.

[0035] The prescribed amount of oltipazidone and polyoxyethylene (40) hydrogenated castor oil was placed in a beaker and dissolved with the prescribed amount of anhydrous ethanol. The prescribed amount of hydroxypropyl methyl cellulose E50 and K100 was added to the prescribed amount of purified water and stirred until dissolved. The hydroxypropyl methyl cellulose solution was slowly added to the anhydrous ethanol solution, and stirring was continued for about 1 hour to ensure uniform mixing. The prescribed amount of core was added to a multifunctional granulation and coating machine, and the coating was completed after drying. The resulting pellets were filled into capsules to obtain oltipazidone capsules.

[0036] Example 3. In vitro pharmacodynamic experiment

[0037] We tested the cytotoxic activity of Ortataxel against twelve human tumor cell lines, including MCF-7 (breast carcinoma), NCI / ADR-Res (breast carcinoma, multidrug resistant, MDR), LS1034 (colon carcinoma, MDR), HCT-15 (colon carcinoma, MDR), PC-3 (prostate carcinoma), HepG2 (liver carcinoma), NCI-H460 (non-small cell lung carcinoma), SF-268 (glioma), HL-60 (promyelocytic leukemia), HL60 / MX2 (MDR subline of HL-60), CCRF-CEM (T cell leukemia) and CEM / C2 (MDR subline of CCRF-CEM).

[0038] The cytotoxic activity of the test compounds was determined using the Sulforhodamine B (SRB) assay against the adherent tumor cell lines MCF-7, NCI / ADR-Res, NCI-H460, SF268 and LS1034. One hundred μl of tumor cell suspension (5-7.5 x 103 cells) were added to each well of a 96-well plate and incubated for 24 hours. Then, 100 μl of drug solution at different concentrations (0.001 nM to 1000 nM) were added to each well, with three replicates for each concentration. Negative and positive controls were also included in the assay. After 3 days of incubation with the drug solution, the cells were fixed with 100 μl of 10% trichloroacetic acid for 1 hour at 4°C, and then stained with 0.2% SRB / 1% acetic acid for 20 minutes at room temperature. Unbound SRB stain was washed with 1% acetic acid, and the bound SRB was solubilized with 200 μl of 10 mM Tris. The OD515nm absorbance of each well was then determined using a microplate reader. The data obtained were analyzed using the KaleidaGraph program and IC50values (concentration of compound that inhibits cell growth by 50%) were calculated.

[0039] The modified MTT assay, Celltiter 96 Cell Proliferation Assay Kit (Promega), was used to analyze the cytotoxic activity of Ortataxel against the suspension tumor cell lines HL-60, HL60 / MX2, CCRD-CEM, CEM / C2. Approximately 5-7.5 x 103 cells / well were seeded in a 96-well plate in a total volume of 50 μl / well. After 24 hours of incubation, 50 μl of drug at concentrations ranging from 0.001 nM to 1000 nM were added to each well, and incubated for 72 hours. Then, 15 μl of MTT stain solution was added to each well, and incubated for another 4 hours. The precipitate formed was then solubilized with 100 μl of solubilization / stop solution. After 1 hour, the contents of each well were mixed on a shaker, and the OD570nm absorbance of each well was determined using a microplate reader. The data obtained were analyzed using the same method as described above.

[0040] Optidepron showed comparable or slightly better growth inhibition activity than paclitaxel against non-drug resistant tumor cell lines, including glioma and prostate cancer, with IC50 values of less than 10 nM (see Table 1). Optidepron also showed strong activity against MDR cell lines, including NCI-ADR-Res, HL60 / MX2, CEM / C2, HCT-15 and LS1034, while paclitaxel showed no activity against these cell lines with IC50 values of greater than 1000 nM. These results indicate that optidepron is a potent cytotoxic agent that shows good growth inhibition against a wide variety of tumor cell lines, including MDR cell lines, and is superior to paclitaxel, which has a similar mechanism of action.

[0041] Table 1. Growth inhibition activity of optidepron against human tumor cell lines

[0042] Example 4. In vivo pharmacodynamic experiments

[0043] The pharmaceutical formulations of the present application (Example 1) were tested in vivo against human tumor xenograft models using intravenous bolus administration.

[0044] We examined the therapeutic effect of optidepron against five of the most common human tumor xenograft models in nude mice. These five human tumors were lung cancer A549, liver cancer HepG2, colon cancer HCT-15, breast cancer Bcap-37 and prostate cancer PC-3. Optidepron was administered at 2.5, 1.0 and 0.4 mg / kg / d, iv x 10 bid. The results showed that optidepron showed strong anti-tumor effects against all five of the most common human cancer models, with high dose tumor inhibition rates of 75-89%, medium dose tumor inhibition rates of 63-79% and low dose tumor inhibition rates of 42-58%. For the colon, breast and prostate cancer models, we also added a very low dose group of 0.16 mg / kg / d. The results showed that the very low dose group also achieved tumor inhibition rates of greater than 40% against these three tumors. Paclitaxel, which was tested in parallel, showed an optimal tumor inhibition rate of only about 50% against non-drug resistant models. All of the tests were reproducible. (See Table 2) Tumor inhibition rate (%) = [(average tumor weight of negative control group - average tumor weight of drug administration group) / average tumor weight of negative control group] x 100%

[0045] These results fully demonstrate that the compound of Formula I is effective in treating human tumors and can be used to prepare pharmaceutical compositions for treating these five solid tumors, which are superior to the control drug paclitaxel.

[0046] Table 2. Anti-tumor effects of optidepron against various human tumor xenograft models

[0047] Example 5. Clinical trials of optidepron for treating gastric cancer, esophageal cancer, etc.

[0048] Oltipraz injection monotherapy for gastric cancer, esophageal cancer, cholangiocarcinoma, cervical cancer and other 6 kinds of tumor solid tumor patients. Among them, 15 cases of gastric cancer patients were enrolled in the gastric cancer treatment cohort, and received oltipraz injection 35mg / m 2 / d, continuous administration for 5 days, every 21 days for a treatment cycle, a total of 15 patients were enrolled, of which 3 cases were PR (partial remission of disease), 5 cases were SD (stable disease), and the disease control rate was 53%; Among them, a total of 10 cases of esophageal cancer patients were enrolled in the esophageal cancer treatment cohort, of which 1 case was CR (complete remission of disease), 3 cases were PR, and 3 cases were SD, and the disease control rate was 70%; Among them, a total of 4 cases of cholangiocarcinoma patients were enrolled in the cholangiocarcinoma treatment cohort, and the best efficacy of 4 patients was stable disease; Among them, a total of 5 cases of cervical cancer patients were enrolled in the cervical cancer treatment cohort, of which 3 cases were stable disease. In summary, after each solid tumor patient received oltipraz monotherapy, the patients generally benefited.

[0049] Oltipraz injection combined with oxaliplatin and programmed death receptor 1 (PD-1) antibody drug sintilimab for the treatment of gastric cancer, oltipraz injection 30mg / m 2 / d, continuous administration for 5 days, sintilimab 200mg, intravenous administration once every 3 weeks, oxaliplatin 130mg / m 2 / d, intravenous administration once every 3 weeks, all for a 21-day treatment cycle. Among the 23 patients who could evaluate the efficacy, the best efficacy evaluation was 15 cases of PR, 8 cases of SD, and the disease control rate was 100%, which was higher than that of oltipraz monotherapy. The experimental results show that the synergistic effect of drug combination.

[0050] Oltipraz injection combined with capecitabine (a prodrug of 5Fu) and PD-1 antibody drug tislelizumab for the treatment of esophageal cancer, oltipraz injection 30mg / m 2 / d, continuous administration for 5 days, tislelizumab 200mg, intravenous administration once every 3 weeks, capecitabine 2000mg / m 2 / d, continuous administration for 14 days, all for a 21-day treatment cycle. Among the 18 patients who could evaluate the efficacy, the best efficacy evaluation was 1 case of CR, 5 cases of PR, and 12 cases of SD, and the disease control rate was 100%, which was higher than that of oltipraz monotherapy. The experimental results show that the synergistic effect of drug combination.

[0051] Oltipraz 60mg / m 2 / day, iv, qd, for 3 weeks, in combination with PD-1 for the treatment of esophageal cancer in real-world clinical cases, the combined PD-1 antibodies include pembrolizumab, spartalizumab, camrelizumab, and toripalimab. A total of 4 patients were evaluated for efficacy, all of which were SD, and the disease control rate was 100%, higher than that of oltidronate monotherapy. The experimental results show the synergistic effect of drug combination.

[0052] Oltidronate 50 mg / m 2 / day, iv, qd, for 3 weeks, in combination with PD-1 for the treatment of esophageal cancer in real-world clinical cases, the combined PD-1 antibodies include pembrolizumab, spartalizumab, camrelizumab, and toripalimab. A total of 4 patients were evaluated for efficacy, all of which were SD, and the disease control rate was 100%, higher than that of oltidronate monotherapy. The experimental results show the synergistic effect of drug combination.

[0053] To further prove the synergistic effect of oltidronate combined with oxaliplatin or 5-Fu, we carried out the efficacy experiment of oltidronate combined with oxaliplatin or 5-Fu on human tumor xenograft subcutaneous solid tumor model in the axillary. Oltidronate was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, oltidronate at this dose regimen combined with oxaliplatin ED50 dose of 1 mg / kg / d, iv x 7, qd, or oxaliplatin alone 1 mg / kg / d, iv x 7, qd, respectively, the tumor inhibition rates of human tumor gastric cancer MKN-45 xenograft subcutaneous solid tumor model in the axillary were 52.82%, 85.78%, and 43.12%, respectively.

[0054] The tumor inhibition rates of oltipraz at a dose of 0.4 mg / kg / d, iv x 10 bid, oltipraz at this dose regimen combined with 5Fu ED50 dose 15 mg / kg / d, iv x 7 qd, or 5Fu 15 mg / kg / d, iv x 7 qd alone, respectively, were 49.37%, 80.54%, and 35.22% in the human esophageal cancer KYSE-150 xenograft subcutaneous tumor model. According to the literature (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50), the dose-effect relationship can be analyzed by in vivo and in vitro pharmacodynamic experiments with a small sample size, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; when CI = 1, it indicates additive effect; and when CI > 1, it indicates antagonistic effect. We used the combination index analysis software CompuSyn V1.0 to analyze a series of data from the above experiments, and the combination index of oltipraz combined with oxaliplatin in the pharmacodynamic model of gastric cancer and 5Fu in esophageal cancer was 0.39 and 0.52, respectively, indicating that the two combination therapies have synergistic effects.

[0055] Example 6. Clinical trials of oltipraz for the treatment of ovarian cancer, prostate cancer, and pancreatic cancer

[0056] In a cohort of oltipraz injection monotherapy for the treatment of advanced ovarian cancer, 10 patients with ovarian cancer were enrolled, and received oltipraz injection 35 mg / m 2 / d, for 5 consecutive days, with a treatment cycle of every 21 days. A total of 10 patients with ovarian cancer were enrolled, of which 1 patient had PR and 3 patients had SD in the best efficacy evaluation.

[0057] In a tolerability clinical trial of oltipraz oral capsules in patients with solid tumors, the enrolled tumor patients included ovarian cancer, testicular cancer, prostate cancer, pancreatic cancer, intestinal cancer, non-small cell lung cancer, and soft tissue sarcoma, and received oltipraz oral capsules monotherapy at a dose of 25 mg / m 2 / d-100 mg m 2The total dose of 2 cases of ovarian cancer was included, one of which was continuously reduced, and the best response evaluation was CR. The best response evaluation of the other case of ovarian cancer was PR, and the ORR was 100%. Patients also generally benefited from other tumors treated with olaparib monotherapy, including 1 case of prostate cancer, 2 cases of pancreatic cancer, 1 case of testicular cancer, 2 cases of non-small cell lung cancer, 1 case of soft tissue sarcoma, and 1 case of intestinal cancer, all of which had stable disease after 4 cycles of treatment.

[0058] A clinical study of olaparib injection monotherapy for prostate cancer (mCRPC) patients was conducted at a dose of 150 mg / m 2 , and the treatment was given for 5 consecutive days, with a treatment cycle of 21 days, until disease progression or the occurrence of intolerable adverse events. The results showed that the PSA response rate was 16%, and the median rPFS and OS were 4.9 months and 7.1 months, respectively. One patient had a sustained remission for 19.2 months and was still taking the drug. Among the 10 patients who could be evaluated for efficacy, 1 patient had PR, and 4 patients had SD. The ORR and DCR were 10% and 50%, respectively.

[0059] In a clinical study of olaparib injection combined with gemcitabine for the treatment of patients with advanced pancreatic cancer, olaparib injection 30 mg / m 2 / d was given for 5 consecutive days, and gemcitabine 1000 mg / m 2 / d was given on the 1st and 8th days, with a treatment cycle of 21 days. Among the 11 patients who could be evaluated for efficacy, 3 had the best efficacy of PR, and 5 had the best efficacy of SD. The DCR was 72.73%. The 12-month survival rate was 63.64%, which was higher than that of olaparib monotherapy. The experimental results showed the synergistic effect of drug combination.

[0060] Olaparib injection 40 mg / m 2 / d was given intravenously on the 1st, 8th and 15th days, once a day, with a treatment cycle of every 4 weeks. In a real-world clinical case of olaparib injection combined with bevacizumab and gemcitabine for the treatment of pancreatic cancer, 6 patients could be evaluated for efficacy, and all 6 patients had SD.

[0061] To further demonstrate the synergistic effect of oltipraz combined with gemcitabine, we carried out the efficacy experiment of oltipraz combined with gemcitabine on the human pancreatic cancer xenograft model. Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with gemcitabine ED50 dose 50 mg / kg / d, iv x 3, q3d, or gemcitabine 50 mg / kg / d, iv x 3, q3d alone, respectively. The tumor inhibition rates of human tumor pancreatic cancer CFPAC-1 xenografts in the subcutaneous solid tumor model of the axillary were 55.84%, 78.36%, and 39.21%, respectively. According to the literature (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50), the dose-effect relationship can be analyzed by small sample size in vivo and in vitro pharmacodynamic experiments, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; CI = 1 indicates additive effect; CI > 1 indicates antagonistic effect. We used the combination index analysis Combination Index (CI) software CompuSyn V1.0 to analyze a series of data from the above experiments, and the combination index of oltipraz combined with gemcitabine in the pharmacodynamic model of pancreatic cancer was 0.55, which proved that the two combination therapies had synergistic effect.

[0062] Example 7. Clinical trial of oltipraz for treating brain tumors

[0063] Clinical study of oltipraz combined with etoposide and bevacizumab for breast cancer patients with brain metastasis. Patients received oltipraz (30 mg / m 2 , intravenous injection, days 1-5) and etoposide (100 mg / m 2 , intravenous injection, days 1-3) combined with bevacizumab (10 mg / kg, intravenous injection, day 1) every 21 days as a treatment cycle. After 6 cycles, oltipraz and bevacizumab were maintained until disease progression or unacceptable toxicity occurred. Among the 34 subjects who could be evaluated for efficacy, the CNS-ORR rate was 67.6%, and the CNS-CBR was 88.2%. The median CNS-PFS was 15 months (95% CI, 4.265-7.735), and the median overall PFS was 6 months (95% CI, 6.760-23.240). The experimental results showed the synergistic effect of drug combination.

[0064] Clinical study of olpadronate combined with bevacizumab for Her2- breast cancer patients with brain metastasis, patients received olpadronate (30mg / m 2 / day, continuous intravenous infusion, 1-5 days) combined with bevacizumab (15mg / kg, intravenous injection, 1 day), 21 days for a treatment cycle, 6 cycles of olpadronate and bevacizumab maintenance treatment until disease progression or unacceptable toxicity. CNS-ORR was 43.5% (20 / 46), CNS-CBR was 91% (43 / 46). The median PFS was 7.7 months. The experimental results show the synergistic effect of drug combination.

[0065] Clinical study of olpadronate combined with bevacizumab for non-small cell lung cancer patients with brain metastasis, patients received olpadronate treatment 30mg / m 2 / day, intravenous injection, continuous 5 days combined with bevacizumab 15mg / kg, intravenous injection, 1 day, 21 days for a treatment cycle. Among the 2 patients with evaluable efficacy, 1 case of intracranial lesions was SD, and the whole body lesions were PR, 1 case of intracranial lesions and whole body lesions were SD. The experimental results show the synergistic effect of drug combination.

[0066] To further demonstrate the synergistic effect of oltipraz combined with bevacizumab, we carried out the efficacy experiment of oltipraz combined with bevacizumab on breast cancer brain metastasis human tumor xenograft model. Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with bevacizumab ED50 dose of 0.5 mg / kg, biw, or bevacizumab alone 0.5 mg / kg, biw, respectively, and the tumor inhibition rates of breast cancer brain metastasis human tumor xenograft model were 63.33%, 70.24%, and 31.54%, respectively. Literature reports (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50) that the dose-effect relationship can be analyzed by small sample size in vivo and in vitro pharmacodynamic experiments, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; when CI = 1, it indicates additive effect; and when CI > 1, it indicates antagonistic effect. We used the combination index analysis software CompuSyn V1.0 to analyze a series of data from the above experiments, and the combination index of oltipraz combined with bevacizumab in the breast cancer brain metastasis pharmacodynamic model was 0.68, which proved that the two combination therapies had synergistic effect.

[0067] Example 8. Experiment of oltipraz penetrating the blood-brain barrier

[0068] The concentration of oltipraz in various tissues at different time points (5, 30 min, 2, 8, 24, 90 h and 1 week after administration) after sublingual intravenous injection of oltipraz (2.0 mg / kg) in male SD rats is shown in the following figure. As can be seen from Figure 1, oltipraz is widely distributed in all tissues tested, including: spleen, kidney, small intestine, stomach, brain, liver, etc. The drug concentration in most tissues is higher than that in plasma, and there is still a small amount of drug in the brain and bone marrow 7 days after administration, indicating that oltipraz can be used to treat brain tumors.

[0069] In addition, we conducted a test to determine the concentration of oltipraz in the plasma and brain tumor cyst fluid of a breast cancer brain metastasis patient, and the test showed that oltipraz can penetrate the blood-brain barrier into the brain. The following Figure 2 shows the concentration of oltipraz in plasma and brain tumor cyst fluid:

[0070] Example 9. Clinical trial of oltipraz for treating soft tissue sarcoma

[0071] The clinical trial of olpadronate monotherapy for soft tissue sarcoma, patients received olpadronate (30 mg / m2, intravenous injection, 1-5 days), a total of 27 cases of soft tissue sarcoma patients, the best efficacy evaluation for 1 case of PR and 20 cases of SD, disease control rate (DCR) reached 77.8%, the median PFS was 4.3 months.

[0072] Example 10. Clinical trial of olpadronate combined with platinum and / or targeted drugs and / or PD-1 for treating gynecological tumors

[0073] Olpadronate capsules 60 mg / m 2 / d, oral administration, continuous administration for 5 days, combined with fuitinib 4 mg oral administration for the treatment of patients with ovarian cancer, continuous administration for 14 days, 21 days for a treatment cycle. Among the 6 subjects with evaluable efficacy, 4 achieved the best efficacy PR, and the experimental results showed the synergistic effect of drug combination.

[0074] Olpadronate was administered at a dose of 150 mg / m 2 for 120 hours by continuous intravenous infusion, combined with bevacizumab for the treatment of patients with evaluable efficacy of gynecological tumors, including 1 case of cervical cancer and 1 case of vulvar cancer, 1 case of ovarian cancer PR; combined with anlotinib for the treatment of patients with evaluable efficacy of gynecological tumors, including 1 case of cervical cancer, 1 case of ovarian cancer, and 6 cases of PR, the experimental results showed the synergistic effect of drug combination.

[0075] Olpadronate 30-50 mg / m 2 was administered intravenously on days 1 and 2, and was administered by intravenous infusion from day 3 to day 5. Continuous administration for 5 days, every 3 weeks for a treatment cycle, combined with PD-1 for the treatment of cervical cancer, the combined PD-1 includes cari- zebumab, slulimab, and tirilumab. Currently, there are a total of 10 patients with evaluable efficacy, all of whom are SD. The experimental results showed the synergistic effect of drug combination.

[0076] Olpadronate 30-50 mg / m 2 was administered intravenously on day 1, and was administered by intravenous infusion from day 2 to day 5. Continuous administration for 5 days, every 3 weeks for a treatment cycle, combined with PD-1 sindilumab or PD-L1 en- vokilumab for the treatment of ovarian cancer, currently a total of 3 patients with evaluable efficacy, including 1 case of CR and 2 cases of SD. The experimental results showed the synergistic effect of drug combination.

[0077] Olpadronate 50 mg / m 2 was administered intravenously (days 1-3) combined with platinum for the treatment of endometrial cancer, olpadronate was combined with nedaplatin, lobaplatin, and carboplatin, respectively. Currently, there are a total of 10 patients with evaluable efficacy, including 9 cases of PR and 1 case of SD. The experimental results showed the synergistic effect of drug combination.

[0078] To further demonstrate the synergistic effect of oltipraz combined with anlotinib in ovarian cancer, we carried out the efficacy experiment of oltipraz combined with anlotinib on the human tumor xenograft subcutaneous tumor model in the axillary. Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with anlotinib ED50 dose of 3 mg / kg, qd, or anlotinib alone 3 mg / kg, qd, respectively, and the tumor inhibition rates of human tumor ovarian cancer Skov3 xenograft subcutaneous tumor model in the axillary were 50.13%, 68.45%, and 27.91%, respectively. Literature reports (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50) that the quantitative relationship between in vivo and in vitro pharmacodynamics experiments can be analyzed by small sample size, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; when CI = 1, it indicates additive effect; when CI > 1, it indicates antagonistic effect. We used the combination index analysis Combination Index (CI) software CompuSyn V1.0 to analyze a series of data from the above experiments, and the combination index of oltipraz combined with anlotinib in the pharmacodynamic model of ovarian cancer was 0.36, which proved that the two combined therapies had synergistic effect.

[0079] To further prove the synergistic effect of oltipraz combined with bevacizumab, we carried out the efficacy experiment of oltipraz combined with bevacizumab on the human ovarian cancer xenotransplantation model. Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with bevacizumab ED50 dose 0.5 mg / kg, biw, or bevacizumab alone 0.5 mg / kg, biw, respectively. The tumor inhibition rates of human tumor ovarian cancer Skov3 xenotransplanted subcutaneous tumor model were 50.13%, 73.73%, and 33.77%, respectively. Literature reports (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50) that the dose-effect relationship can be analyzed by small sample size in vivo and in vitro pharmacological experiments, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; CI = 1 indicates additive effect; CI > 1 indicates antagonistic effect. We used the combination index analysis Combination Index (CI) software CompuSyn V1.0 to analyze a series of data from the above experiments, and the combination index of oltipraz combined with bevacizumab in the ovarian cancer pharmacological model was 0.32, which proved that the two combined therapies had synergistic effect.

[0080] Example 11. Clinical trial of oltipraz combined with other drugs for the treatment of nasopharyngeal carcinoma

[0081] Oltipraz 35 mg / m 2 2 days, once a day, from the 3rd to the 5th day, continuous administration for 5 days, every 3 weeks as a treatment cycle, combined with platinum and oltipraz combined with methotrexate for the treatment of nasopharyngeal carcinoma. At present, a total of 7 patients with evaluable efficacy were included, of which 1 case was CR, 2 cases were PR, and 3 cases were SD. The experimental results showed that the synergistic effect of drug combination.

[0082] To further prove the synergistic effect of oltipraz combined with platinum or methotrexate, we carried out the efficacy experiment of oltipraz combined with oxaliplatin or methotrexate on nasopharyngeal carcinoma human tumor xenograft model. Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with oxaliplatin ED50 dose of 1 mg / kg / d, iv x 7, qd, or oxaliplatin alone 1 mg / kg / d, iv x 7, qd, respectively. The tumor inhibition rates of nasopharyngeal carcinoma human tumor xenograft model were 59.67%, 78.37%, and 40.21%, respectively.

[0083] Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with methotrexate ED50 dose of 2 mg / kg / d, ip x 7, qd, or methotrexate alone 2 mg / kg / d, ip x 7, qd, respectively. The tumor inhibition rates of nasopharyngeal carcinoma human tumor xenograft model were 42.98%, 69.22%, and 21.54%, respectively. According to the literature (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50), the dose-effect relationship can be analyzed by in vivo and in vitro pharmacodynamic experiments with small sample size, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; when CI = 1, it indicates additive effect; when CI > 1, it indicates antagonistic effect. We used the combination index analysis software CompuSyn V1.0 to analyze a series of data from the above experiments. The combination index of oltipraz combined with oxaliplatin and oltipraz combined with methotrexate in the nasopharyngeal carcinoma pharmacodynamic model was 0.54 and 0.66, respectively, indicating that both combination therapies had synergistic effects.

[0084] Oltipraz 50 mg / m 2 / day, administered intravenously on days 1, 8, and 15, once a day, every 3 weeks as a treatment cycle, combined with PD-1 for the treatment of nasopharyngeal carcinoma. The combined PD-1 includes tiragolumab, spartalizumab, tislelizumab, and camrelizumab. Currently, a total of 10 patients can be evaluated for efficacy, including 2 cases of CR, 7 cases of PR, and 1 case of SD. The experimental results show the synergistic effect of drug combination.

[0085] Example 12. Oltipraz combined with targeted drugs for the treatment of esophageal cancer clinical trial

[0086] Oltipraz combined with Anlotinib in the first-line standard treatment of advanced recurrent metastatic esophageal cancer. Oltipraz, 20 mg / m 2 2 Oltipraz, 20 mg / m 2 , Anlotinib, 8 mg / d, oral administration once a day from the 1st to the 14th day. A treatment cycle is 21 days, and the treatment is continued until disease progression or the occurrence of intolerable toxicity. A total of 5 patients are currently evaluable for efficacy, 2 of which are PR, and 1 is SD. The experimental results show the synergistic effect of drug combination.

[0087] To further prove the synergistic effect of oltipraz combined with anlotinib, we carried out an experiment on the efficacy of oltipraz combined with anlotinib on human tumor xenograft subcutaneous solid tumor models in the axillary. Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with anlotinib ED50 dose of 3 mg / kg, qd, or anlotinib alone at a dose of 3 mg / kg, qd, and the tumor inhibition rates of human esophageal cancer KYSE-150 xenograft subcutaneous solid tumor models were 47.66%, 76.05%, and 30.19%, respectively. According to the literature (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50), the dose-effect relationship can be analyzed by in vivo and in vitro pharmacodynamic experiments with small sample sizes, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; when CI = 1, it indicates additive effect; and when CI > 1, it indicates antagonistic effect. We used the combination index analysis software CompuSyn V1.0 to analyze a series of data from the above experiments, and the combination index of oltipraz combined with anlotinib in the pharmacodynamic model of esophageal cancer was 0.44, which proved that the two combination therapies had synergistic effects.

[0088] Example 13. Clinical trial of oltipraz combined with chemotherapy for neoadjuvant therapy of breast cancer

[0089] Trial (a): Oltipraz injection 30 mg / m 2 , intravenous administration once a day for 1-5 days of each cycle, doxorubicin 50 mg / m 2 , cyclophosphamide 500 mg / m 2, once a day on the first day of each cycle; 21 days for a treatment cycle. A total of 6 cycles. After completing neoadjuvant therapy, all patients suitable for surgery should receive surgical treatment. Postoperative evaluation of patients for pathological remission. So far, 175 cases have completed 6 cycles of treatment and surgery, of which 8 cases are CR, 141 cases are PR, 32 cases are SD, the ORR is 80.98%, and 20 cases are PCR (pathological complete remission), the PCR rate is 11.43%. In the triple-negative breast cancer subgroup, the ORR is 86.96%, and the PCR rate is 36.36%. The experimental results show that the synergistic effect of the combination of drugs.

[0090] To further prove the synergistic effect of oltipraz combined with doxorubicin and cyclophosphamide, we carried out an experiment on the efficacy of oltipraz combined with doxorubicin and cyclophosphamide on human tumor xenograft subcutaneous solid tumor models in the axillary. Oltipraz at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with doxorubicin at an ED50 dose of 4 mg / kg / d, iv x 3 qd, and cyclophosphamide at an ED50 dose of 20 mg / kg / d, or doxorubicin at 4 mg / kg / d, iv x 3 qd, and cyclophosphamide at 20 mg / kg / d, the tumor inhibition rates of human tumor breast cancer xenograft subcutaneous solid tumor models were 54.23%, 78.15%, and 43.33%, respectively. Literature reports (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50) that the dose-effect relationship can be analyzed by in vivo and in vitro pharmacodynamic experiments with small sample sizes, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; when CI = 1, it indicates additive effect; when CI > 1, it indicates antagonistic effect. We used the combination index analysis Combination Index (CI) software CompuSyn V1.0 to analyze a series of data from the above experiments, and the combination index of oltipraz combined with doxorubicin and cyclophosphamide in the breast cancer pharmacodynamic model was 0.78, proving that the two combination therapies have synergistic effects.

[0091] Test (b): In the study of single-week oltipraz combined with cisplatin neoadjuvant therapy for early high-risk, locally advanced, and inflammatory breast cancer patients, oltipraz 50 mg / m 2 , intravenous infusion, days 1, 8, 15, and 22; 28 days for a cycle, a total of 4 cycles; cisplatin 25 mg / m 2, intravenous drip, 1st, 8th, 15th day; 28 days 1 cycle, a total of 4 cycles, combined or not combined with trastuzumab or trastuzumab or Herceptin injection subcutaneous injection of compound preparation for the treatment of HER2 positive or HER2 negative patients. A total of 14 cases were completed after postoperative evaluation, 4 cases reached tpCR, and 5 cases reached bpCR (breast pathological complete remission). Among them, 5 cases were HER2 positive patients, 3 cases reached tpCR (4 cases of patients reached bpCR). 9 cases of HER2 negative patients, 1 case reached tpCR, and the experimental results showed the synergistic effect of drug combination.

[0092] To further prove the synergistic effect of olpadronate combined with cisplatin, we carried out the efficacy experiment of olpadronate combined with cisplatin on human tumor xenograft subcutaneous solid tumor model in the axillary. Olpadronate at a dose of 0.4 mg / kg / d, iv x 10 bid, olpadronate at this dose regimen combined with cisplatin ED50 dose of 1 mg / kg / d, iv x 7, qd, or cisplatin alone 1 mg / kg / d, iv x 7, qd, were administered respectively, and the tumor inhibition rates of human tumor breast cancer xenograft subcutaneous solid tumor model were 48.88%, 82.61%, and 39.54%, respectively. Literature reports (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50) that the dose-effect relationship can be analyzed by in vivo and in vitro pharmacodynamic experiments with small sample size, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; CI = 1 indicates additive effect; CI > 1 indicates antagonistic effect. We used the combination index analysis Combination Index (CI) software CompuSyn V1.0 to analyze a series of data from the above experiments, and the combination index of olpadronate combined with cisplatin in the breast cancer pharmacodynamic model was 0.73, which proved that the two combined therapies had synergistic effect.

[0093] In a study of a new adjuvant therapy based on olpadronate for early high-risk or locally advanced breast cancer, olpadronate 30 mg / m 2 / d, intravenous injection, continuous administration for 5 days, combined with carboplatin AUC 6, intravenous injection, once every 3 weeks, 21 days a cycle for triple-negative breast cancer population. The results showed that 10 patients received surgery, and 5 patients were evaluated as pCR; olpadronate 30 mg / m 2iv, 5 days in a row, combined with carboplatin AUC 6, iv, once every 3 weeks and trastuzumab first dose 8 mg / kg, then 6 mg / kg and pertuzumab 840 mg, then 420 mg, iv, once every 3 weeks, 21 days a cycle for HER2 positive breast cancer population. The results show that 8 patients received surgery, 5 of which were rated as pCR. The experimental results show the synergistic effect of drug combination.

[0094] To further prove the synergistic effect of oltipraz combined with carboplatin, we carried out an experiment on the efficacy of oltipraz combined with carboplatin on human tumor xenograft subcutaneous solid tumor model in the axillary. Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, oltipraz at this dose regimen combined with carboplatin ED50 dose 1.5 mg / kg / d, iv x 7, qd, or carboplatin alone 1.5 mg / kg / d, iv x 7, qd, respectively. The tumor inhibition rates of human tumor breast cancer xenograft subcutaneous solid tumor model were 47.21%, 69.98%, and 35.22%, respectively. Literature reports (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50) that the dose-effect relationship can be analyzed by in vivo and in vitro pharmacodynamic experiments with small sample size, and the Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is <1, it indicates synergistic effect; CI = 1 indicates additive effect; CI > 1 indicates antagonistic effect. We used the combination index analysis Combination Index (CI) software CompuSyn V1.0 to analyze a series of data from the above experiments. The combination index of oltipraz combined with carboplatin in the breast cancer pharmacodynamic model was 0.77, which proved that the two combination therapies had synergistic effect.

[0095] Example 14 Clinical trial of oltipraz combined with anti-HER2 targeted drugs for the treatment of breast cancer

[0096] HER2-positive advanced breast cancer patients received inotuzumab (first cycle 8 mg / kg, subsequent treatment cycle 6 mg / kg, intravenous administration once on day 1 of each cycle), pyrotinib (400 mg / d, once a day) and oltipraz injection (30 mg / m 2, 1-5 days per cycle, once a day intravenous administration). Up to now, 29 patients can be evaluated, among which 23 patients are PR, and 4 patients are SD. The ORR is 79.3%, and the DCR is 93.1%. The results show the synergistic effect of the combination of drugs.

[0097] To further prove the synergistic effect of oltipraz combined with anti-HER2 targeted drugs, we carried out an experiment on the efficacy of oltipraz combined with pyrotinib on human tumor xenograft subcutaneous solid tumor model in the axillary. Oltipraz was administered at a dose of 0.4 mg / kg / d, iv x 10 bid, or oltipraz at this dose regimen combined with pyrotinib ED50 dose 30 mg / kg, qd, or pyrotinib 30 mg / kg, qd alone. The tumor inhibition rates of human breast cancer xenograft subcutaneous solid tumor model were 50.32%, 67.56%, and 33.28%, respectively. According to the literature (Ting-Chao Chou. The combination index (CI<1) as the definition of synergism and of synergy claims. Synergy. 2018; 7: 49-50), the dose-effect relationship can be analyzed by in vivo and in vitro pharmacodynamic experiments with small sample size. The Combination Index Equation (CIE) can be automatically simulated using CompuSyn software. When the combination index (CI) is less than 1, it indicates synergistic effect; when CI = 1, it indicates additive effect; when CI > 1, it indicates antagonistic effect. We used the combination index analysis software CompuSyn V1.0 to analyze a series of data from the above experiments. The combination index of oltipraz combined with pyrotinib in the breast cancer pharmacodynamic model was 0.48, which proved that the two combination therapies had synergistic effect.

[0098] Example 15 Clinical trial of oltipraz combined with PD-1 and bevacizumab for the treatment of lung cancer

[0099] Oltipraz 15 mg / m 2 2, intravenous pump administration on days 1-5, continuous administration for 5 days, every 3 weeks as a treatment cycle, combined with PD-1 for the treatment of lung cancer, said PD-1 including tiragolumab, sintyrozumab, patitumumab, sulumab, sepranolimab, camrelizumab, and pembrolizumab. Currently, a total of 42 patients can be evaluated, among which 6 patients are PR, and 36 patients are SD. The results show the synergistic effect of the combination of drugs.

[0100] Oltipraz 65 mg / m 2Example 1. Oltipraz combined with bevacizumab for the treatment of lung cancer

[0101] Example 16. Oltipraz combined with targeted drugs for the treatment of angiosarcoma

[0102] In a clinical study of oltipraz combined with anlotinib for the first-line treatment of advanced, metastatic or unresectable angiosarcoma, oltipraz 30 mg / m 2 2 dose was administered once a day for 1-5 days, and 21 days constituted a treatment cycle. Anlotinib 12 mg was administered orally, once a day for 1-14 days, and 21 days constituted a treatment cycle. Treatment was continued until disease progression or the occurrence of intolerable toxicity. Four cases were reported, all of which showed efficacy. In case 1, local bleeding stopped after 3 days of treatment, and the disease was stable after 4 cycles of treatment. In case 2, the tumor on the top of the head was well controlled after 3 cycles of treatment. In case 3, local tumor shrinkage was observed after the first cycle of treatment. In case 4, after 4 cycles of treatment, the lung and lower abdominal lesions were basically eliminated, and the left thigh subcutaneous soft tissue mass was smaller than before. The experimental results showed a synergistic effect of the combination of drugs.

[0103] Example 17. Oltipraz combined with chemotherapy for the adjuvant treatment of breast cancer after surgery

[0104] A study of oltipraz capsules combined with capecitabine for the postoperative adjuvant treatment of patients with triple-negative early breast cancer who did not achieve pathological complete remission after neoadjuvant therapy. Oltipraz capsules 50 mg / m 2 2 dose was administered once a day for 1-5 days, and 21 days constituted a treatment cycle. Capecitabine 1000 mg / m dose was administered twice a day for 1-14 days, and 21 days constituted a treatment cycle, for a total of 8 cycles. The patients were evaluated for postoperative recurrence and metastasis. As of now, the 4 subjects enrolled have all achieved stable efficacy, and no postoperative recurrence or metastasis has occurred.

Claims

1. Use of a compound of formula I ###0001### in the manufacture of a medicament for the treatment of a tumor selected from the group consisting of gastric cancer, esophageal cancer, cholangiocarcinoma, nasopharyngeal carcinoma, soft tissue sarcoma, prostate cancer, liver cancer, non-small cell lung cancer, breast cancer, glioma, leukemia, ovarian cancer, cervical cancer, endometrial cancer, brain primary tumor, brain metastasis, pancreatic cancer and angiosarcoma. R2= CH3in formula I.

2. Use according to claim 1, wherein the compound can be used in combination with at least one other anticancer drug.

3. Use according to any one of claims 1 to 2, wherein the other anticancer drug is selected from the group consisting of chemotherapeutic drugs, targeted drugs, endocrine drugs, tumor immunotherapeutic drugs and ADC drugs.

4. Use according to claim 3, wherein the chemotherapeutic drug is selected from the group consisting of metabolic drugs, platinum drugs, microtubule inhibitors, antibiotic anthracycline antitumor drugs, alkylating agent drugs, topoisomerase inhibitors and DNA polymerase inhibitors.

5. Use according to claim 3, wherein the targeted drug is selected from the group consisting of HER2 targeted drugs, target mutation targeted drugs, targeted antiangiogenic drugs, PARP inhibitors, cell cycle-dependent kinase inhibitors and epidermal growth factor receptor inhibitors.

6. Use according to claim 3, wherein the tumor immunotherapeutic drug is selected from the group consisting of PD-1 mAbs, PD-L1 mAbs, CTLA-4, and bispecific antibodies to one of PD-1 / PD-L1 and CTLA-4 as antigens.

7. The use according to any one of claims 1 to 6, wherein, The compound of formula I is olaparib and the combination is selected from the group consisting of: olaparib and a platinum drug; olaparib, a platinum drug and a PD-1 antibody; olaparib, a metabolic chemotherapeutic drug and a PD-1 antibody; olaparib and a PD-1 antibody; olaparib and a targeted antiangiogenic drug (such as bevacizumab, vofatinib or anlotinib); olaparib, a PD-1 antibody and a targeted antiangiogenic drug; olaparib, a targeted antiangiogenic drug and another chemotherapeutic drug; olaparib and a metabolic chemotherapeutic drug; olaparib, a double chemotherapeutic drug (such as an antibiotic anthracycline antitumor drug and an alkylating agent drug) ± a HER2 targeted drug.

8. Use according to any one of claims 1 to 7, wherein olaparib is administered by a non-gastrointestinal route (intramuscular, subcutaneous injection, intravenous administration) or orally.

9. Use according to any one of claims 1 to 8, wherein the medicament is for use in a cancer that has not been previously treated or has been previously treated.

10. The use according to any one of claims 1 to 9, wherein the Oltipraz is administered in the form of intravenous infusion and / or pump infusion and / or oral administration, administered once a day for 5 consecutive days on day 1 to day 5, every 3 weeks as a treatment cycle; or administered once a day for 7 consecutive days on day 1 to day 7, every 3 weeks as a treatment cycle; or administered once a day on day 1 and day 8, every 3 weeks as a treatment cycle; or administered once a day on day 1, day 8 and day 15, every 3 weeks as a treatment cycle; or administered once a day on day 1, day 8 and day 15, every 4 weeks as a treatment cycle; or administered by intravenous pump infusion on day 1 to day 5, for 5 consecutive days, every 3 weeks as a treatment cycle; or administered by intravenous infusion once a day on day 1 to day 2, and by intravenous pump infusion from day 3 to day 5, for 5 consecutive days, every 3 weeks as a treatment cycle; or administered by intravenous infusion once a day on day 1, and by intravenous pump infusion from day 2 to day 5, for 5 consecutive days, every 3 weeks as a treatment cycle.

11. The use according to any one of claims 1 to 10, wherein the dose of administration of oxertifenol is from 15 mg / m 2 to 150 mg / m 2 per day.

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