HK1238631B - Quinoline derivative against non-small cell lung cancer - Google Patents

Description

Quinoline derivatives for non-small cell lung cancer

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of Chinese Patent Application No. 201410749394.0, filed on December 9, 2014, with the State Intellectual Property Office of China, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

This application belongs to the field of medical technology and relates to the use of quinoline derivatives for anti-tumor purposes. Specifically, this application relates to the use of quinoline derivatives in the treatment of non-small cell lung cancer (e.g., lung adenocarcinoma).

Background Art

Cancer is a major public health problem in many parts of the world. Lung cancer, due to its high morbidity and mortality, has become one of the leading causes of cancer death worldwide. Although platinum-based combination chemotherapy can improve patient survival, the prognosis for advanced non-small cell lung cancer (NSCLC) remains extremely poor, with a 5-year survival rate of less than 10%. Further research into the mechanisms of tumorigenesis and chemoresistance in lung cancer has been reported to improve survival rates (Jemal A et al., Cancer Statistics, CA Cancer. J. Clin., 56, 106-130, 2006). Based on cell morphology, adenocarcinoma is the most common histological classification of NSCLC (Travis et al., Lung Cancer Principles and Practice, Lippincott-Raven, New York, 361-395, 1996). First-line chemotherapy regimens for NSCLC typically include a platinum-based doublet, which involves adding a second chemotherapy drug (paclitaxel, pemetrexed, gemcitabine, vinorelbine, etc.) to a platinum-based drug (cisplatin or carboplatin) (D'Addario et al., 2010; National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Non-Small Cell Lung Cancer, V.2.2010). For advanced non-small cell lung cancer, especially lung adenocarcinoma, although targeted therapy for driver genes has achieved certain clinical efficacy, drug resistance eventually develops, leading to disease progression. Furthermore, the treatment of lung adenocarcinoma without driver genes is still primarily based on platinum-based combination chemotherapy. Therefore, more drugs are still needed to be developed for non-small cell lung cancer and its histological type lung adenocarcinoma in order to achieve better therapeutic effects, improve survival rates, and bring substantial benefits to patients.

SUMMARY OF THE INVENTION

In one aspect, the present application provides a method for treating non-small cell lung cancer, comprising administering to a patient in need of treatment a therapeutically effective amount of Compound I having the following structural formula or a pharmaceutically acceptable salt thereof.

On the other hand, the present application provides use of Compound I having the above structural formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer.

In another aspect, the present application provides a compound I or a pharmaceutical composition having the above structural formula for treating non-small cell lung cancer, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

Detailed Description of the Invention

In one aspect, the present application provides a method for treating non-small cell lung cancer, comprising administering to a patient in need of treatment a therapeutically effective amount of Compound I having the following structural formula or a pharmaceutically acceptable salt thereof.

In some embodiments of the present application, a method for treating advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer is provided, comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

In some embodiments of the present application, a method for treating EGFR mutation-negative non-small cell lung cancer is provided, comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

In some embodiments of the present application, a method for treating lung adenocarcinoma is provided, comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

In some embodiments of the present application, a method for treating advanced lung adenocarcinoma and/or metastatic lung adenocarcinoma is provided, comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

In some embodiments of the present application, a method for treating EGFR mutation-negative lung adenocarcinoma is provided, comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

Compound I can be administered in the form of its free base, or in the form of its salts, hydrates, and prodrugs, which are converted in vivo to the free base form of Compound I. For example, pharmaceutically acceptable salts of Compound I are within the scope of this application, and such salts can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, the compound 1 is administered as the hydrochloride salt. In some embodiments, the compound 1 is administered as the monohydrochloride salt. In some embodiments, the compound 1 is administered as the dihydrochloride salt. In some embodiments, the compound 1 is administered as a crystalline hydrochloride salt. In a specific embodiment, the compound 1 is administered as a crystalline dihydrochloride salt.

The chemical name of compound I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine, which has the following structural formula:

Compound 1 or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal, and intrathecal. In a specific embodiment, administration is by oral administration.

The amount of Compound 1 or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. In some embodiments, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 3 mg to 30 mg. In some embodiments, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg. In some embodiments, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In a specific embodiment, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 8 mg. In a specific embodiment, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 10 mg. In a specific embodiment, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 12 mg.

Compound 1 or a pharmaceutically acceptable salt thereof can be administered once or more daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the oral solid dosage form is administered once daily.

In the above-mentioned treatment methods, the method of administration can be comprehensively determined based on the activity, toxicity and tolerance of the drug. Preferably, Compound I or a pharmaceutically acceptable salt thereof is administered in an intermittent manner. The intermittent administration includes an administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof can be administered once or multiple times a day during the administration period. For example, Compound I or a pharmaceutically acceptable salt thereof is administered every day during the administration period, and then the administration is stopped for a period of time during the withdrawal period, followed by the administration period and then the withdrawal period, and this can be repeated multiple times. Among them, the ratio of the administration period to the withdrawal period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, and more preferably 2:0.5-1.

In some embodiments, the drug is administered for 2 consecutive weeks followed by 2 weeks of rest. In some embodiments, the drug is administered once a day for 14 consecutive days, followed by 14 days of rest; then the drug is administered once a day for 14 consecutive days, followed by 14 days of rest. This 2-week on-dose and 2-week off dosing regimen can be repeated multiple times.

In some embodiments, the drug is administered for 2 consecutive weeks followed by 1 week of rest. In some embodiments, the drug is administered once a day for 14 consecutive days, followed by 7 days of rest; then administered once a day for 14 consecutive days, followed by 7 days of rest. This 2-week on-dose and 1-week off dosing regimen can be repeated multiple times.

In some embodiments, the drug is administered for 5 consecutive days and then rested for 2 days. In some embodiments, the drug is administered once a day for 5 consecutive days, followed by a 2-day rest; then the drug is administered once a day for 5 consecutive days, followed by a 2-day rest. This 5-day dosing and 2-day rest interval administration pattern can be repeated multiple times.

In certain specific embodiments, the drug is administered orally at a dose of 12 mg once daily for 2 consecutive weeks and then 1 week off.

On the other hand, the present application also provides the use of Compound I having the following structural formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer.

In some embodiments of the present application, provided is the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer.

In some embodiments of the present application, there is also provided use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating EGFR mutation-negative non-small cell lung cancer.

In some embodiments of the present application, provided is the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating lung adenocarcinoma.

In some embodiments of the present application, provided is the use of Compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating EGFR mutation-negative lung adenocarcinoma.

In some embodiments of the present application, there is also provided use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating advanced lung adenocarcinoma and/or metastatic lung adenocarcinoma.

Compound I may be in the form of its free base, or in the form of its salts, hydrates, and prodrugs, which are converted in vivo to the free base form of Compound I. For example, pharmaceutically acceptable salts of Compound I are within the scope of this application, and such salts can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in the form of a hydrochloride salt of Compound 1. In some embodiments, it is in the form of a monohydrochloride salt of Compound 1. In some embodiments, it is in the form of a dihydrochloride salt of Compound 1. In some embodiments, it is in the form of a crystalline form of a hydrochloride salt of Compound 1. In a specific embodiment, it is in the form of a crystalline form of a dihydrochloride salt of Compound 1.

The amount of Compound 1 or a pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. In some embodiments, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 3 mg to 30 mg. In some embodiments, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg. In some embodiments, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg.

On the other hand, the present application also provides a compound I or a pharmaceutical composition having the following structural formula for treating non-small cell lung cancer, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present application, a compound I or a pharmaceutical composition for treating advanced non-small cell lung cancer and/or metastatic non-small cell lung cancer is provided, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present application, a compound I or a pharmaceutical composition for treating EGFR mutation-negative non-small cell lung cancer is provided, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present application, a compound I or a pharmaceutical composition for treating lung adenocarcinoma is provided, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present application, a compound I or a pharmaceutical composition for treating advanced lung adenocarcinoma and/or metastatic lung adenocarcinoma is provided, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present application, a compound I or a pharmaceutical composition for treating EGFR mutation-negative lung adenocarcinoma is provided, wherein the pharmaceutical composition comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Compound I may be in the form of its free base, or in the form of its salts, hydrates, and prodrugs, which are converted in vivo to the free base form of Compound I. For example, pharmaceutically acceptable salts of Compound I are within the scope of this application, and such salts can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in the form of a hydrochloride salt of Compound 1. In some embodiments, it is in the form of a monohydrochloride salt of Compound 1. In some embodiments, it is in the form of a dihydrochloride salt of Compound 1. In some embodiments, it is in the form of a crystalline form of a hydrochloride salt of Compound 1. In a specific embodiment, it is in the form of a crystalline form of a dihydrochloride salt of Compound 1.

The amount of Compound 1 or a pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. In some embodiments, the pharmaceutical composition contains 3 mg to 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof on a unit dose basis. In some embodiments, the pharmaceutical composition contains 5 mg to 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof on a unit dose basis. In some embodiments, the pharmaceutical composition contains 8 mg to 16 mg of Compound 1 or a pharmaceutically acceptable salt thereof on a unit dose basis. In some embodiments, the pharmaceutical composition contains 10 mg to 14 mg of Compound 1 or a pharmaceutically acceptable salt thereof on a unit dose basis. In the present application, for example, for tablets or capsules, "containing 12 mg of Compound 1 on a unit dose basis" means that each tablet or capsule finally produced contains 12 mg of Compound 1.

In some specific embodiments, the pharmaceutical composition contains 8, 10 or 12 mg of Compound 1 or a pharmaceutically acceptable salt thereof on a unit dose basis.

In some embodiments, Compound I can be formulated into a preparation suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal, and intrathecal administration; preferably, preparations suitable for oral administration include tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules. Tablets can be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets, or enteric-coated tablets, and capsules can be ordinary capsules, sustained-release capsules, controlled-release capsules, or enteric-coated capsules. The oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. Fillers include starch, lactose, mannitol, and microcrystalline cellulose; absorbents include calcium sulfate, calcium hydrogen phosphate, and calcium carbonate; wetting agents include water and ethanol; binders include hypromellose, povidone, and microcrystalline cellulose; disintegrants include croscarmellose sodium, crospovidone, surfactants, and low-substituted hydroxypropyl cellulose; and lubricants include magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, micropowdered silica gel, and talc. Pharmaceutical excipients also include colorants and sweeteners.

The pharmaceutical composition can be a preparation suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal, and intrathecal administration; preferably, preparations suitable for oral administration include tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., with tablets and capsules being preferred. Tablets can be conventional tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets, or enteric-coated tablets; capsules can be conventional capsules, sustained-release capsules, controlled-release capsules, or enteric-coated capsules. The oral preparation can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. Fillers include starch, lactose, mannitol, and microcrystalline cellulose; absorbents include calcium sulfate, calcium hydrogen phosphate, and calcium carbonate; wetting agents include water and ethanol; binders include hypromellose, povidone, and microcrystalline cellulose; disintegrants include croscarmellose sodium, crospovidone, surfactants, and low-substituted hydroxypropyl cellulose; and lubricants include magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, micropowdered silica gel, and talc. Pharmaceutical excipients also include colorants and sweeteners.

Preferably, Compound I or the pharmaceutical composition is administered in an intermittent manner. The intermittent administration includes a dosing period and a rest period, during which Compound I or the pharmaceutical composition can be administered once or more daily. For example, Compound I or the pharmaceutical composition is administered daily during the dosing period, followed by a period of cessation of administration during the rest period, followed by a dosing period, followed by a rest period, and this can be repeated multiple times. The ratio of the dosing period to the rest period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, and even more preferably 2:0.5-1.

In some embodiments, the drug is administered for 2 consecutive weeks followed by 2 weeks of rest. In some embodiments, the drug is administered once a day for 14 consecutive days, followed by 14 days of rest; then the drug is administered once a day for 14 consecutive days, followed by 14 days of rest. This 2-week on-dose and 2-week off dosing regimen can be repeated multiple times.

In some embodiments, the drug is administered for 2 consecutive weeks followed by 1 week of rest. In some embodiments, the drug is administered once a day for 14 consecutive days, followed by 7 days of rest; then administered once a day for 14 consecutive days, followed by 7 days of rest. This 2-week on-dose and 1-week off dosing regimen can be repeated multiple times.

In some embodiments, the drug is administered for 5 consecutive days and then rested for 2 days. In some embodiments, the drug is administered once a day for 5 consecutive days, followed by a 2-day rest; then the drug is administered once a day for 5 consecutive days, followed by a 2-day rest. This 5-day dosing and 2-day rest interval administration pattern can be repeated multiple times.

In some embodiments, Compound 1 or the pharmaceutical compositions described above can be administered once or more daily. In some embodiments, Compound 1 or the pharmaceutical compositions described above are administered once daily. In one embodiment, the oral solid dosage form is administered once daily.

In certain specific embodiments, the drug is administered orally at a dose of 12 mg once daily for 2 consecutive weeks and then 1 week off.

As used herein, "advanced stage" refers to the staging of non-small cell lung cancer based on the extent of the lesion and concurrent diseases, for example, it may be stage III-IV non-small cell lung cancer according to the TNM classification of the AJCC cancer staging manual lung cancer staging system. In some embodiments, advanced non-small cell lung cancer is stage IIIB-IV non-small cell lung cancer.

As used herein, "EGFR" refers to epidermal growth factor receptor.

For those skilled in the art, "EGFR mutation-negative" generally refers to the absence of EGFR gene mutations using commonly used genetic testing methods for clinical diagnosis. EGFR mutation status can be assessed using a variety of methods, with DNA mutation testing being the preferred method. Various DNA mutation assays can be used to assess EGFR mutation status in tumor cells. For patients with non-small cell lung cancer, the most common EGFR mutations are exon 19 deletions and exon 21 mutations. Direct DNA sequencing of exons 18-21 (or just exons 19 and 21) is a reasonable option.

Herein, unless otherwise indicated, the dosage amounts and ranges provided herein are calculated based on the molecular weight of the free base form of Compound I.

Herein, the amount of Compound I administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the patient's age and health status. The administration cycle can be determined comprehensively based on the drug's activity, toxicity, and the patient's tolerance.

For the purposes of this application, unless otherwise stated, the following terms used in the specification and claims shall have the following meanings.

"Patient" refers to a mammal, preferably a human.

"Pharmaceutically acceptable" means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that which is acceptable for human pharmaceutical use.

"Pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like.

"Therapeutically effective amount" means the amount of a compound that, when administered to a human for treating a disease, is sufficient to achieve control of the disease.

"Treatment" means any administration of a therapeutically effective amount of a compound, and includes:

(1) inhibiting the disease in a human being who is experiencing or exhibiting the pathology or symptomology of the disease (i.e., preventing further development of the pathology and/or symptomology), or

(2) Ameliorating a disease in a human who is experiencing or exhibiting the pathology or symptomology of the disease (i.e., reversing the pathology and/or symptomology).

In this article, progression-free survival P25 refers to the time when 75% of the patients participating in the statistics have no disease progression; progression-free survival P50 refers to the time when 50% of the patients participating in the statistics have no disease progression; progression-free survival P75 refers to the time when 25% of the patients participating in the statistics have no disease progression; and mean progression-free survival refers to the average value of the progression-free survival of the patients participating in the results statistics.

Specific embodiments

The technical solution of the present application is described below with reference to specific embodiments, but the protection scope of the present application is not limited to the scope of the embodiments described.

Example 1 1-[[[4-(4-Fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine dihydrochloride

1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine was prepared by referring to the method of Example 24 in WO2008112407, and then the title compound was prepared by referring to the preparation method of the salt form example in the specification.

Example 2 Capsules containing 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine dihydrochloride (dihydrochloride of Compound I)

The dihydrochloride of Compound I was crushed and passed through an 80-mesh sieve; then mixed evenly with mannitol and hydroxypropyl cellulose; then the prescribed amount of microcrystalline cellulose was added, mixed evenly, and passed through a 0.8 mm sieve; finally, the prescribed amount of magnesium stearate was added, mixed evenly, and filled into capsules.

Example 3

A randomized, double-blind, placebo-controlled clinical trial was conducted in patients with pathologically confirmed non-small cell lung cancer with measurable lesions, who had received second-line or higher treatment or were intolerant to treatment and who had received other cytotoxic drugs, radiotherapy or surgery for more than four weeks. In this study, the effectiveness of Compound I dihydrochloride capsules in treating patients with non-small cell lung cancer was preliminarily evaluated compared with placebo. The main indicator of evaluation was progression-free survival (PFS). In this study, 117 patients with non-small cell lung cancer were enrolled, of whom 57 were randomly enrolled in the placebo group and 60 were randomly enrolled in the Compound I dihydrochloride group. The ages of these patients were between 18 and 70 years old.

Eligible patients with non-small cell lung cancer (NSCLC) will receive Compound I dihydrochloride/placebo in a clinical trial. A 12mg/0mg dose is administered once daily for two consecutive weeks followed by one week off, for a three-week (21-day) cycle. Treatment will continue until the investigator deems the patient unsuitable for continued treatment or when the efficacy assessment indicates progressive disease (PD).

Research results: A total of 117 patients with non-small cell lung cancer were recruited, of whom 57 were randomly assigned to the placebo group and 60 were randomly assigned to the compound I dihydrochloride group. Currently, 43 patients in the placebo group and 32 patients in the compound I dihydrochloride group are being statistically analyzed. The remaining cases were not included in the data statistics because the subjects dropped out or were eliminated during the trial or the subjects have not yet left the group and are still being visited. The statistical results are shown in the following table:

The above results show that Compound I dihydrochloride can significantly prolong the progression-free survival of patients with non-small cell lung cancer.

Example 4

A randomized, double-blind, placebo-controlled clinical trial was conducted in patients with pathologically confirmed lung adenocarcinoma with measurable lesions, who had received second-line or higher treatment or were intolerant to treatment, and who had received other cytotoxic drugs, radiotherapy, or surgery for more than four weeks. In this study, the effectiveness of Compound I dihydrochloride capsules in treating patients with lung adenocarcinoma was preliminarily evaluated compared with placebo. The primary indicator of evaluation was progression-free survival (PFS). In this study, 104 patients with lung adenocarcinoma were enrolled, of whom 50 were randomly assigned to the placebo group and 54 were randomly assigned to the Compound I dihydrochloride group. The ages of these patients were between 18 and 70 years old.

Eligible patients with lung adenocarcinoma will receive Compound I dihydrochloride/placebo in a clinical trial. The regimen is administered at a dose of 12 mg/0 mg once daily for two consecutive weeks followed by one week off, for a three-week (21-day) cycle. Treatment will continue until the investigator deems the patient unsuitable for continued treatment or when the efficacy assessment indicates progressive disease (PD).

Research results: A total of 104 patients with lung adenocarcinoma were recruited, of whom 50 were randomly assigned to the placebo group and 54 were randomly assigned to the compound I dihydrochloride group. Currently, 37 patients in the placebo group and 30 patients in the compound I dihydrochloride group are being analyzed. The remaining patients were not included in the data statistics because they dropped out or were excluded during the trial or were not yet out of the group and were still being visited. The statistical results are shown in the following table:

According to the above results, compound I dihydrochloride can significantly prolong the progression-free survival of patients with lung adenocarcinoma.

Example 5

A) Medical history

A 45-year-old female patient, born on January 11, 1968, was a nonsmoker with a history of hyperlipidemia. On January 6, 2011, a bronchial brushing examination revealed non-small cell carcinoma, with a high likelihood of adenocarcinoma. Combined with imaging findings, the clinical diagnosis was right lower lung adenocarcinoma with metastases to the right pleura, both lungs, mediastinal lymph nodes, and brain (T4N2M1b, stage IV). From January 20, 2011, to April 1, 2011, the patient received four cycles of pemetrexed + cisplatin chemotherapy, with the best response evaluation being SD (stable disease); from May 5, 2011, to May 30, 2012, the patient received erlotinib treatment, with the best response evaluation being PR (partial response); from June 4, 2012, to August 18, 2012, the patient received four cycles of docetaxel + nedaplatin treatment, with the best response evaluation being SD (stable disease); from December 3, 2012, to August 3, 2013, the patient received erlotinib treatment, with the best response evaluation being SD (stable disease); from May 13, 2013, to August 10, 2013, the patient received five cycles of gemcitabine + carboplatin treatment, with the best response evaluation being PR (partial response).

On September 3, 2013, the patient began to receive treatment with Compound I dihydrochloride capsules at a dose of 12 mg orally once daily (one treatment cycle consisting of 2 consecutive weeks on and 1 week off).

B) Toxicity and response assessment of treatment

Treatment toxicity was assessed at 3-week follow-up visits, and blood cell counts and blood chemistries were analyzed at 1-2 week intervals, and therapeutic response was assessed using CT scans.

C) CT results

After 6 weeks of treatment with Compound I dihydrochloride, the sum of the 2 evaluable lesions was reduced from 45.7 mm to 31.43 mm (a decrease of 31.22%). After 10 cycles of continuous medication (210 days), the lesions were reduced to 26 mm (a decrease of 43.1%). The best efficacy evaluation was PR (partial remission).

D) Tolerance

In general, treatment with Compound I dihydrochloride was well tolerated, and there were no significant changes in routine tests such as blood cell counts.

Example 6

A) Medical history

A 67-year-old retired woman smoked 20 cigarettes daily for 30 years and had undergone thyroid adenoma resection 10 years prior. Previous bronchial brushings revealed non-small cell carcinoma, with a high likelihood of adenocarcinoma. Combined with imaging findings, the clinical diagnosis was left upper lobe adenocarcinoma with bilateral lung metastases, mediastinal lymph node metastases, and bilateral supraclavicular lymph node metastases (T4N3M1a, stage IV). She also had multiple lacunar infarcts, pericardial effusions, and intrabiliary bile duct stones. She received one cycle of TP (paclitaxel and cisplatin) chemotherapy from August 1, 2013, to September 1, 2013, with poor response. The chemotherapy regimen was subsequently changed to GP (gemcitabine and cisplatin) for one cycle from December 26, 2013, to January 15, 2014, with continued poor response. On January 20, 2014, a trial of icotinib hydrochloride tablets 125 mg orally three times a day was initiated, with unknown efficacy. On February 27, 2014, a CT scan revealed a 37 mm long diameter lesion in the anterior segment of the left upper lobe and a 21 mm short-necked lesion in the mediastinal lymph node. Multiple lesions were also present in both lungs, the left hilar lymph nodes, and the bilateral supraclavicular lymph nodes. The tumor marker CEA test result was abnormal, reaching 107.41 ng/mL.

On February 28, 2014, the patient was started to receive treatment with Compound I dihydrochloride capsules at a dose of 12 mg orally once daily (one treatment cycle is 2 weeks of continuous use and 1 week of rest).

B) CT results

After treatment with Compound I dihydrochloride, the sum of the long diameters of the patient's tumor target lesions was significantly reduced. Before taking Compound I dihydrochloride, the sum of the diameters of the two measurable target lesions was 58 mm (37 mm for the lesion in the anterior segment of the left upper lobe and 21 mm for the mediastinal lymph node lesion). Three weeks after the start of treatment with Compound I dihydrochloride, the sum of the target lesion diameters decreased to 36 mm, a decrease of 37.9% (18 mm for the anterior segment of the left upper lobe lesions and 18 mm for the mediastinal lymph node lesions); six weeks later, the sum of the target lesion diameters decreased to 29 mm, a decrease of 50% (14 mm for the anterior segment of the left upper lobe lesions and 15 mm for the mediastinal lymph node lesions); nine weeks later, the sum of the target lesion diameters decreased to 26 mm, a decrease of 55.2% (10 mm for the anterior segment of the left upper lobe lesions and 16 mm for the mediastinal lymph node lesions); twelve weeks later, the sum of the target lesion diameters still decreased to 26 mm, a decrease of 55.2% (10 mm for the anterior segment of the left upper lobe lesions and 16 mm for the mediastinal lymph node lesions); and fifteen weeks later, the sum of the target lesion diameters decreased to 25 mm, a decrease of 56.9% (10 mm for the anterior segment of the left upper lobe lesions and 15 mm for the mediastinal lymph node lesions). No non-target lesions progressed, and no new lesions appeared. As of December 4, 2014, the patient had been treated with Compound I dihydrochloride for 279 days. During the 14th treatment cycle, the patient continued to take Compound I dihydrochloride, and the tumor continued to respond and the clinical performance remained good.

C) Tolerance

Treatment with Compound I dihydrochloride was generally well tolerated. There were no significant changes in blood test results, and no drug-related cardiotoxicity was observed during treatment.

Example 7

A 62-year-old woman underwent CT on June 2, 2014, to develop left lung cancer with bilateral lung metastases, as well as metastases to bilateral hilar and mediastinal lymph nodes and the right supraclavicular lymph node. ECT revealed bone metastases, and cranial MRI showed metastases to the left frontal lobe. A CT-guided lung puncture confirmed non-small cell lung cancer adenocarcinoma. Genetic testing was negative for EML4-ALK fusion gene mutations and EGFR gene mutations.

From June 9, 2014, to September 25, 2014, the patient received six cycles of cisplatin and pemetrexed chemotherapy, achieving a response (PR) with grade II gastrointestinal reactions but no myelosuppression. From October 17, 2014, to November 1, 2014, before discharge, the patient took oral S-100 capsules for two weeks, with relief of cough and mild chest tightness. On January 27, 2015, disease progression was detected. From January 31, 2015, to June 21, 2015, the patient received six cycles of icotinib combined with docetaxel chemotherapy, achieving a response (SD) with a best response. On July 8, 2015, the patient entered a clinical study of Compound I dihydrochloride capsules and began treatment that same day with 12 mg of Compound I dihydrochloride capsules taken orally once daily (two weeks on, one week off).

On July 29, 2015, the patient received one cycle of treatment. Enhanced CT scan showed left upper lobe cancer with obstructive inflammation, bilateral lung metastasis, thickening of the interlobular septa in the bilateral lower lobes, left hilar and mediastinal lymph node metastasis, and right supraclavicular lymph node enlargement. Bilateral interlobar pleural metastasis was considered, with some metastases improving and others showing no significant changes. The best therapeutic effect was PR as evaluated by RECIST 1.1.

On August 20, 2015, the patient's head enhanced CT scan showed that the left temporal lobe nodule was slightly smaller than the baseline.

On November 12, 2015, enhanced CT scans indicated continued control of the disease, and the patient's response rate was confirmed to be PR. As of the filing date, the patient's adverse reactions were generally tolerable and he continued to receive treatment.

Example 8

A 62-year-old man was diagnosed with squamous cell carcinoma of the non-small cell lung cancer (NSCLC) by CT-guided lung puncture in March 2013. Cranial MRI showed left frontal lobe metastasis. Genetic testing showed no mutations in the EML4-ALK fusion gene or the EGFR gene.

From March 26, 2013, to June 5, 2013, the patient received four cycles of chemotherapy with cisplatin and gemcitabine, achieving a best response of SD. Following completion of these cycles, the patient underwent one cycle of localized lung radiotherapy, with mild adverse reactions. From September 9, 2013, to October 6, 2013, the patient received two cycles of chemotherapy with cisplatin and gemcitabine. A follow-up CT scan in December 2013 showed progressive disease. On March 24, 2014, the patient received one cycle of docetaxel. Following this, the patient developed bone marrow suppression, oral infection, and pneumonia, which resolved with symptomatic treatment. A follow-up CT scan on December 10, 2014, revealed the following: 1. Soft tissue shadows in the right upper hilum, which were larger than previously observed; 2. Multiple bullae in both lungs, which were minimally altered; 3. Bilateral pneumonia, which had decreased in size; and 4. Multiple lymph nodes in the left supraclavicular region, mediastinum, and right hilum, which were slightly larger than previously observed. From January 7 to January 29, 2015, gemcitabine and nedaplatin (NDP) were administered. Grade III myelosuppression developed after chemotherapy, but recovered after leukocyte suppression. A follow-up CT scan on March 4, 2015, revealed an enlarged right lung mass. Oral T-1a was initiated on March 6, 2015. A follow-up CT scan on May 27, 2015, revealed progression. A pathological diagnosis on June 2, 2015, revealed poorly differentiated squamous cell carcinoma of the right lung, following chemoradiotherapy.

On June 4, 2015, the patient began taking 12 mg of Compound I dihydrochloride capsules orally once daily (one treatment cycle consisting of two weeks of continuous use followed by one week off). On June 25, 2015, after one cycle of treatment, enhanced CT revealed a soft tissue mass in the right hilum, which was slightly smaller than before; multiple lymph nodes in the left supraclavicular region, mediastinum, and right hilum; bilateral pneumonia, which was not significantly different in extent; and multiple bullae in both lungs, which were also not significantly different from before. RECIST 1.1 evaluation was SD (small), with the total target lesion size being 66 mm, a 10 mm decrease from baseline.

On July 15, 2015, the patient underwent enhanced CT scan, which revealed a right hilar soft tissue mass that had slightly shrunk compared to the previous scan. The total target lesion size was 63 mm. On September 8, 2015, an enhanced CT scan showed further reduction in the mass, with the total target lesion size reaching 57 mm. On October 16, 2015, an enhanced CT scan showed a similar reduction in the mass, with the total target lesion size reaching 56 mm. As of the application date, the patient's adverse reactions were generally tolerable and he continued to receive treatment.

Claims (17)

1. Use of the dihydrochloride salt of compound I having the following structural formula in the preparation of a medicament for the treatment of lung adenocarcinoma in patients in need, wherein the patient is a human. 2. The use as described in claim 1, wherein the lung adenocarcinoma is advanced lung adenocarcinoma and/or metastatic lung adenocarcinoma. 3. The use as described in claim 1, wherein the lung adenocarcinoma is EGFR mutation-negative lung adenocarcinoma. 4. The use as described in any one of claims 1-3, wherein the patient is a patient who has previously received second-line or higher treatment or is unable to tolerate treatment and has received other cytotoxic drugs, radiation therapy or surgery for more than four weeks. 5. The use as described in claim 4, wherein the patient is a patient who has previously received second-line treatment. 6. The use as described in claim 4, wherein the patient is a patient who has previously received cytotoxic drug treatment. 7. The use as described in any one of claims 1-3, wherein the dihydrochloride salt of compound I is formulated into a formulation suitable for oral administration. 8. The use as described in claim 7, wherein the oral formulation is a tablet or capsule. 9. The use as described in any one of claims 1-3, wherein the dihydrochloride of compound I is administered in a regimen of continuous administration for 2 weeks followed by a 1-week off-season. 10. The use as described in any one of claims 1-3, wherein the daily dose of the dihydrochloride of compound I is 3 mg to 30 mg. 11. The use as described in claim 10, wherein the daily dose administered is 5 mg to 20 mg. 12. The use as described in claim 10, wherein the daily dose administered is 8 mg to 16 mg. 13. The use as described in claim 10, wherein the daily dose administered is 8 mg to 12 mg. 14. The use as described in claim 10, wherein the daily dose administered is 8 mg, 10 mg, or 12 mg. 15. The use as described in claim 10, wherein the dihydrochloride salt of said compound I is administered once daily. 16. The use according to any one of claims 1-3, wherein the dihydrochloride of said compound I is administered orally. 17. The use as claimed in claim 16, wherein the dihydrochloride of said compound I is administered orally at a daily dose of 12 mg.