CN117982508A

CN117982508A - Bei Futi Nib for postoperative adjuvant treatment of non-small cell lung cancer

Info

Publication number: CN117982508A
Application number: CN202311454622.7A
Authority: CN
Inventors: 程红科; 金向宇; 袁晓玢; 姚林; 田立红; 丁列明
Original assignee: Yifang Biotechnology Shanghai Co ltd; Betta Pharmaceuticals Co Ltd
Current assignee: Yifang Biotechnology Shanghai Co ltd; Betta Pharmaceuticals Co Ltd
Priority date: 2022-11-03
Filing date: 2023-11-03
Publication date: 2024-05-07

Abstract

The Bei Fu tenib or the pharmaceutically acceptable salt thereof is used for postoperative adjuvant therapy of non-small cell lung cancer, can remarkably prolong the disease-free survival time of a tested patient, has controllable adverse drug reaction, and can provide safe and effective postoperative adjuvant therapy selection for IB-IIIB stage non-small cell lung cancer patients.

Description

Bei Futi Nib for postoperative adjuvant treatment of non-small cell lung cancer

The present invention claims priority from a prior application filed on 11.03 2022, under the application number 202211372187.9, entitled "Bei Fu tinib for post-operative adjuvant treatment of non-small cell lung cancer", the entire contents of which are incorporated herein by reference.

Technical Field

The invention belongs to the field of medicines, and particularly relates to Bei Futi Ni for postoperative adjuvant therapy of non-small cell lung cancer.

Background

Lung cancer is one of the malignant tumors with highest morbidity and mortality in China. About 85% of lung cancers are non-small cell lung cancers (NSCLC), the major pathological type leading to lung cancer morbidity and mortality, and about 30% of NSCLC patients initially have resectable early-to-mid NSCLC. For early and middle stage NSCLC patients, surgical radical resection is an important local treatment means for achieving tumor cure. However, although NSCLC patients underwent complete tumor resection, the proportion of patients with recurrent disease or post-operative death was still high (from 45% of patients in stage IB to 76% of patients in stage III). Thus, guidelines for each country recommend post-operative adjuvant treatment for patients with stage IB-IIIB NSCLC who undergo complete tumor resection.

Adjuvant chemotherapy is the most widely used adjuvant therapy at present. In view of the relatively limited survival benefits (about 5% increase in 5-year survival rate) that can be achieved by adjuvant chemotherapy due to the relatively large side effects of chemotherapeutic agents, it is necessary to evaluate the stage, physical stamina, personal will, quality of life of patients before adjuvant chemotherapy is performed after complete resection of tumors in NSCLC patients, and to fully evaluate the functions of each organ, including lung, heart, liver and kidney, etc., and comprehensively evaluate the benefits and risks of adjuvant chemotherapy. Cisplatin-based dual regimens are recommended for adjuvant chemotherapy, with combinations including vinorelbine, gemcitabine, docetaxel, paclitaxel, albumin-bound paclitaxel, pemetrexed (for non-squamous cancers only), and etoposide, and for patients intolerant to cisplatin, carboplatin-based dual regimens may be used.

Epidermal Growth Factor Receptor (EGFR) gene mutations, such as the 19 Exon deletion (Exon 19 del) and the 21 Exon L858R point mutation, are common oncogene mutations in NSCLC. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the recommended first-line treatment for EGFR mutation-positive advanced non-small cell lung cancer. Previous studies of targeted therapy focused mainly on patients with advanced NSCLC, but in recent years, subsequent studies have found that targeted therapy against EGFR mutations also plays an important role in adjuvant therapy after complete resection of tumors in patients with early and mid NSCLC.

RADIANT study Selective access to EGFR IHC/FISH positive patients with stage IB-IIIA NSCLC were treated with erlotinib or placebo adjuvant for 2 years. The 973 patients in the co-group were randomized into either erlotinib or placebo groups at a 2:1 ratio with a primary endpoint indicator of DFS. The results show that erlotinib adjuvant treatment did not prolong DFS in patients, and that neither group had statistical differences in DFS and OS; analysis showed that EGFR IHC/FISH and KRAS had no predicted effect on both OS and DFS. Subgroup analysis for 161 EGFR gene mutant (19 Del and L858R) patients showed that median DFS (46.4 months vs.28.5 months, p= 0.0391) was better in the erlotinib group. RADIANT the results suggest that EGFR gene mutations may be effective predictors of EGFR-TKI.

SELECT study is the first prospective study reporting that EGFR mutant patients may benefit from erlotinib adjuvant therapy, and 100 patients post-operatively receiving conventional adjuvant chemotherapy or post-radiotherapy stage IA-IIIA NSCLC were treated with erlotinib for 2 years. The main endpoint index was 2 years DFS. The results showed that the patient had a 2 year DFS of 89% and the median DFS time was not reached. 62% of patients received erlotinib again after relapse with a median treatment time of 10 months, approaching the data for first line TKI treatment. This study suggests that 2-year erlotinib-assisted treatment of EGFR mutant positive NSCLC patients is feasible, but the study is a phase ii single arm study alone, and it is difficult to determine whether TKI post-operative treatment would benefit such patients before long-term follow-up results in a randomized control study.

ADJUVANT the study was the first post-operative adjuvant treatment study reporting EGFR-TKI contrast-based adjuvant chemotherapy for phase II-IIIB with EGFR mutated NSCLC in complete surgical excision. 222 completely resected NSCLC patients with phase II-IIIB EGFR mutations were randomized 1:1 into two groups, the test group received gefitinib for 2 years, the control group received vinorelbine in combination with cisplatin chemotherapy for 4 cycles. The results showed that the median DFS was significantly prolonged in the gefitinib group patients, with gefitinib group and chemotherapeutic group DFS of 28.7 months and 18.0 months, respectively (p=0.0054); the 3-year DFS rates for gefitinib and chemotherapy groups were 27% vs.34% (p=0.37), respectively. In terms of safety, the occurrence rate of adverse events in the gefitinib group and the chemotherapy group is 58% vs.80%, respectively, and the occurrence rate of adverse events of grade 3 or more in the gefitinib group is significantly lower than that in the chemotherapy group (12% vs. 48%). Gefitinib can be used as a better choice for postoperative adjuvant therapy of EGFR mutant II-IIIB NSCLC patients.

The EVAN study is a study of erlotinib versus vinorelbine/cisplatin for post-operative adjuvant treatment of stage IIIB EGFR mutant NSCLC patients. 102 patients with EGFR-sensitive mutant NSCLC in period IIIB after R0 excision are randomly divided into two groups, and the test group is treated by erlotinib for 2 years; the control group received 4 cycles of chemotherapy with the vinorelbine/cisplatin regimen. The results show that: the 2-year DFS rate was significantly increased in the erlotinib-treated group, 81.4% and 44.6% in the erlotinib-treated group and the chemotherapeutic group, respectively, p=0.0054; the erlotinib group had significantly prolonged DFS compared to the chemotherapeutic group, with median DFS of 42.4 months vs 21.0 months, p <0.0001, respectively. In terms of safety, the occurrence rate of adverse events in the erlotinib group and the chemotherapy group is 58% vs.65%; the most common adverse events in erlotinib and chemotherapy groups were rash and neutropenia, respectively; the occurrence rate of the adverse events of the grade 3 and above is 12% vs.26% respectively. Erlotinib adjuvant therapy for 2 years can reduce the risk of disease or death in stage IIIB NSCLC patients.

EVIDENCE the study was a multicenter, randomized, open III study of Excritinib and standard adjuvant chemotherapy for post-operative adjuvant treatment of II-IIIA stage with EGFR-sensitive mutant NSCLC, 29 home participation nationally. The study included 322 post-stage II-IIIB EGFR mutation positive subjects, randomized 1:1, with 125mg TID oral treatment of EGFR-TKI Excritinib given in the test group for 2 years, and standard adjuvant chemotherapy vinorelbine/cisplatin or pemetrexed/cisplatin given in the control group followed 4 cycles later until recurrence, intolerance or death. The primary study endpoints were DFS, and the secondary study endpoints were 3 and 5 year DFS survival, OS and safety. The research result shows that the curative effect of the Excritinib group for the NSCLC patient with EGFR gene sensitive mutation in postoperative adjuvant therapy is obviously better than that of a standard adjuvant chemotherapy group, and the postoperative adjuvant targeted therapy remarkably prolongs the disease-free survival time of the patient and has better safety. Median DFS in the icotinib group was 47.0 months, median DFS in the standard adjuvant chemotherapy group was 22.1 months (hr=0.36, 95% ci:0.24-0.55, p < 0.0001); the DFS showed that the icotinib group was superior to the standard adjuvant chemotherapy group by clinical feature analysis of each subgroup. The 3-year DFS rates for the icotinib group and standard adjuvant chemotherapy group were 63.9% and 32.5%, respectively.

From these previous studies, although the postoperative adjuvant treatment of part of EGFR-TKIs (gefitinib, erlotinib, icotinib) has shown some improvement more or less for EGFR mutation positive early-middle stage NSCLC patients, in view of the complexity of tumor treatment, and different EGFR-TKIs show great differences in postoperative adjuvant treatment of non-small cell lung cancer, so whether an EGFR-TKI can be applied to postoperative adjuvant treatment of non-small cell lung cancer and what effect it has after being applied to postoperative adjuvant treatment is not known, especially in terms of clinical effectiveness and safety.

The invention is based on the invention of EGFR-TKI Bei Fu tinib which is independently developed before the company and is used for postoperative adjuvant therapy, so as to provide a new medication choice for medical workers and patients.

Disclosure of Invention

The invention aims at providing the use of befutinib or a pharmaceutically acceptable salt thereof for preparing a medicament for treating lung cancer in a patient in need thereof, which is characterized in that the patient is in postoperative adjuvant therapy and the medicament comprises Bei Fu tinib in a unit dose of 25-125 mg.

In some embodiments, the lung cancer is in stage IB-IIIB.

In some embodiments, the stage IIIB lung cancer is stage IIIB (T3N 2M 0).

In some embodiments, the lung cancer is EGFR-sensitive mutated non-small cell lung cancer.

In some embodiments, the EGFR sensitive mutation is a 19 exon deletion or a 21 exon L858R mutation.

In some embodiments, the EGFR-sensitive mutation is not a 20 exon T790M mutation.

In some embodiments, the patient does not have tumor recurrence and/or metastasis prior to administration Bei Fu of tinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the patient has not received systemic anti-tumor therapy, such as chemotherapy, radiation therapy, or targeted therapy, prior to administration of Bei Fu of tenib or a pharmaceutically acceptable salt thereof; the targeted therapy includes administration of monoclonal antibodies and/or small molecule tyrosine kinase inhibitors.

In some embodiments, the Bei Fu tinib or pharmaceutically acceptable salt thereof is administered three times per day, twice per day, once per two days, once per three days, once per four days, once per five days, once per six days, once per week, once per two weeks, or once per three weeks, wherein the Bei Fu tinib is administered at a dose of 25-125 mg each time; preferably, the Bei Fu tenib is administered at a dose of 75mg or 100mg each time.

In some embodiments, the medicament comprises Bei Fu tinib in a unit dose of 75mg or 100 mg.

In some embodiments, the Bei Fu tenib or pharmaceutically acceptable salt thereof is administered stepwise, with a 75mg dose administered first daily followed by a 100mg dose administered daily.

In some embodiments, the 75mg dose is administered daily for 15-30 days.

In some embodiments, the Bei Fu tinib or a pharmaceutically acceptable salt thereof is administered by first administering a dose of 75mg once daily for 18-24 days, preferably for 21 days; a dose of 100mg is then administered once a day.

In some embodiments, the Bei Fu pharmaceutically acceptable salt of tenib is present in the form of a mesylate salt.

In some embodiments, the medicament is administered orally.

In some embodiments, the medicament is a tablet or capsule.

In some embodiments, the medicament comprises a diluent, a disintegrant, and a lubricant.

In some embodiments, the diluent is selected from microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol; the diluent accounts for 60-95 wt% of the medicine, preferably 65-95 wt%, 70-95 wt%, 75-95 wt%, 80-95 wt%, 85-95 wt% or 90-95 wt%; when the diluent is selected from a mixture of microcrystalline cellulose and mannitol, the microcrystalline cellulose is selected from the range of 10 to 90wt%, preferably from 20 to 85wt%, 25 to 80wt%, 25 to 75wt%, 30 to 65wt%, 35 to 60wt%, 40 to 55wt%, 45 to 55wt% of the diluent.

In some embodiments, the disintegrant is selected from sodium carboxymethyl starch, colloidal silica, or a mixture of sodium carboxymethyl starch and colloidal silica; the disintegrant is selected from 1-10wt%, preferably 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt% or 9wt% of the drug.

In some embodiments, the lubricant is selected from sodium stearyl fumarate, talc, or a mixture of sodium stearyl fumarate and talc; the lubricant is selected from the range of 0.5 to 5wt%, preferably from 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 1.8wt% or 2.0wt% of the medicament.

It is a further object of the present invention to provide a method of treating lung cancer comprising administering Bei Fu a-tenib or a pharmaceutically acceptable salt thereof as a post-operative adjuvant treatment to a patient in need thereof.

In some embodiments, the lung cancer is in stage IB-IIIB.

In some embodiments, the stage IIIB lung cancer is stage IIIB (T3N 2M 0).

In some embodiments, the Bei Fu-tenib or pharmaceutically acceptable salt thereof is administered three times per day, twice per day, once per two days, once per three days, once per four days, once per five days, once per six days, once per week, once per two weeks, or once every three weeks.

In some embodiments, the Bei Fu tinib or a pharmaceutically acceptable salt thereof is administered at a dose of 25 to 125mg per time; preferably, the Bei Fu tenib or a pharmaceutically acceptable salt thereof is administered at a dose of 75mg or 100mg each time.

In some embodiments, the 75mg dose is administered daily for 15-30 days.

In some embodiments, the Bei Fu tinib or a pharmaceutically acceptable salt thereof is administered orally.

In some embodiments, the Bei Fu tinib or a pharmaceutically acceptable salt thereof is in the form of a tablet or capsule.

In some embodiments, the tablet or capsule comprises a diluent, a disintegrant, and a lubricant.

In some embodiments, the diluent is selected from microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol; the diluent accounts for 60-95 wt%, preferably 65-95 wt%, 70-95 wt%, 75-95 wt%, 80-95 wt%, 85-95 wt% or 90-95 wt% of the tablet or capsule; when the diluent is selected from a mixture of microcrystalline cellulose and mannitol, the microcrystalline cellulose is selected from the range of 10 to 90wt%, preferably from 20 to 85wt%, 25 to 80wt%, 25 to 75wt%, 30 to 65wt%, 35 to 60wt%, 40 to 55wt%, 45 to 55wt% of the diluent.

In some embodiments, the disintegrant is selected from sodium carboxymethyl starch, colloidal silica, or a mixture of sodium carboxymethyl starch and colloidal silica; the disintegrant is selected from the range of 1 to 10wt%, preferably 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt% or 9wt% of the tablet or capsule.

In some embodiments, the lubricant is selected from sodium stearyl fumarate, talc, or a mixture of sodium stearyl fumarate and talc; the lubricant is selected from the range of 0.5 to 5wt%, preferably from 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 1.8wt% or 2.0wt% of the tablet or capsule.

Advantageous effects

Bei Fu tenib or pharmaceutically acceptable salt thereof in the invention has obviously improved treatment effectiveness and safety after being applied to postoperative adjuvant treatment of non-small cell lung cancer, particularly after adopting the administration mode of the invention, and most of adverse events or adverse drug reactions occurring in DFS (disease-free survival period) patients with non-small cell lung cancer in IB-IIIB stage can be obviously prolonged to be grade 1 or grade 2; grade 3 and above have low incidence and are more tolerable for most patients, such as rashes, diarrhea, elevated aminotransferases, anorexia, etc. Thus Bei Fu tinib, or a pharmaceutically acceptable salt thereof, can provide a safe and effective post-operative adjuvant treatment option for patients with stage IB-IIIB non-small cell lung cancer.

Definition and description

Bei Fu Tinib, having the following structure:

Postoperative adjuvant treatment: refers to chemotherapy that begins within 70 days after surgical treatment.

Stage IB-IIIB (T3N 2M 0) non-small cell lung cancer: disease staging was according to the united states joint cancer committee (AJCC)/international anti-cancer alliance (UICC) 8 th edition lung cancer staging standard.

Adverse events (ADVERSE EVENT, AE) refer to: all adverse medical events that occur after a subject receives a test drug may be manifested as symptoms, signs, disease, or laboratory exam abnormalities, but are not necessarily causally related to the test drug.

Adverse events occurring in humans (whether or not drug related) include the following:

Adverse events occurring during use of the drug;

adverse events caused by overdose of drug (whether intentional or unintentional);

adverse events caused by abuse of drugs;

Stopping adverse events caused by medication;

Adverse events that may be caused purely by patients taking part in the study (e.g., adverse events or serious adverse events caused by discontinuation of antihypertensive drugs during the elution period), even though not related to study medication, must be reported as adverse events.

Serious adverse events (Serious ADVERSE EVENT, SAE) refer to: adverse medical events that occur after a subject receives a test drug and meet one or more of the following criteria:

Leading to death;

life threatening;

needs hospitalization or prolongs hospitalization time;

resulting in permanent or significant disability or loss of function;

Causing congenital anomalies or birth defects;

Important medical events.

Important adverse events are: in addition to serious adverse events, any adverse events that occur that lead to the adoption of targeted medical measures (e.g., withdrawal, dose reduction, and symptomatic treatment) and obvious abnormalities in hematological or other laboratory tests.

Adverse Drug Reaction (ADR) refers to: refers to any adverse or undesirable reaction to the human body that occurs in a clinical trial that may be associated with the trial drug. There is at least one reasonable possibility of causal relationships between the test drug and adverse events, i.e. correlation cannot be excluded.

EGFR: epidermal growth factor receptor

NSCLC: non-small cell lung cancer

OS: total life cycle

DFS: disease-free survival period

PD: disease progression

R0: complete excision of

EGFR mutation positive NSCLC and diagnostic method:

In 2004, activating mutations in exons 18-21 of EGFR were reported to be associated with responses to EGFR-TKI therapy in NSCLC (Science [ Science ] [2004], volume 304, 1497-1500;New England Journal ofMedicine [ New England journal of medicine ] [2004], volume 350, 2129-2139). It is estimated that these mutations are prevalent in about 10% -16% of NSCLC patients in the united states and europe, and about 30% -50% of NSCLC patients in asia. Among the two most significant EGFR activating mutations are the deletion of exon 19 and the missense mutation in exon 21. Exon 19 deletions account for approximately 45% of known EGFR mutations. Eleven different mutations resulting in three to seven amino acid deletions were detected in exon 19, and all of these mutations were centered on the consistently deleted codons of amino acids 747-749. The most significant deletion of exon 19 is E746-A750. The missense mutation in exon 21 accounts for about 39% -45% of known EGFR mutations, with the substitution mutation L858R accounting for about 39% of the total mutations in exon 21 (j. Thorac. Oncol. [ journal of chest oncology ] [2010], 1551-1558). The skilled artisan will recognize mutations in EGFR that are associated with improved response to EGFR-TKI therapy.

Currently, there are many methods for detecting EGFR activating mutations. These methods include tumor tissue-based diagnostic methods and plasma-based diagnostic methods. Typically, EGFR mutation status is first assessed using a tumor tissue biopsy sample derived from the patient. If a tumor sample is not available, or if the tumor sample is negative, a plasma sample can be used to assess EGFR mutation status. A specific example of a suitable diagnostic method for detecting EGFR activating mutations, in particular for detecting exon 19 deletions or L858R substitution mutations, is the human EGFR gene mutation detection kit (fluorescent PCR method, xiaomen Aide Biotechnology Co., ltd.).

Detailed Description

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In the examples below, unless otherwise indicated, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer; the raw materials and the reagents can be obtained in a commercially available mode.

Unless otherwise specified, the "Bei Fu tinib or a pharmaceutically acceptable salt thereof" is used in the present invention in an amount of "Bei Fu tinib", for example, "Bei Fu tinib or a pharmaceutically acceptable salt thereof" is used in an amount of 25.0 mg/time/day, which means 25.0 mg/time/day in an amount of "Bei Fu tinib", and if converted to Bei Fu tinib pharmaceutically acceptable salt, is 25mg/M _{Bei Fu Tinib}*M_{bei Fu pharmaceutically acceptable salts of tenib}, wherein M _{Bei Fu Tinib} represents a molecular weight 567.26 of Bei Fu tinib, M _{bei Fu pharmaceutically acceptable salts of tenib} represents a molecular weight of Bei Fu tinib pharmaceutically acceptable salt, and Bei Futi nimesulfonate is used as an example, is 29.2 mg/time/day.

Examples 1-Bei Futi Nimesylate Capsule

(1) The pharmaceutical composition of the Bei Futi nimesulfonate capsule of 25mg gauge comprises: 29.2mg Bei Futi mg of methanesulfonate (calculated as Bei Fu tinib 25.0 mg), 60.0mg mannitol (200 SD), 62.8mg microcrystalline cellulose (PH 112), 4.8mg sodium carboxymethyl starch (DST), 1.6mg colloidal silicon dioxide and 1.6mg sodium stearyl fumarate, and filling with No.2 hydroxypropyl methylcellulose hollow capsule shells. The prescription is shown in the table:

Bei Futi composition of capsule of nimesulfonate

Component (A)	Percentage (%)
		Bei Futi Nimesylate	18.3
Mannitol (mannitol)	37.5
		Microcrystalline cellulose	39.2
Carboxymethyl starch sodium	3.0
		Colloidal silica	1.0
Stearyl sodium fumarate	1.0
		Hydroxypropyl methylcellulose hollow capsule (I)	--

The preparation method of the capsule containing the components comprises the following steps:

And (3) batching: raw materials and auxiliary materials are respectively weighed.

Premixing: about half of the mannitol was added to the mixer hopper, followed by sequential addition of Bei Futi nimesulfonate and the remaining mannitol for premixing for 10min at 10rpm.

Sieving: sieving the premixed material once.

Mixing: mixing the sieved materials by a mixer, wherein the rotating speed is set to be 10rpm, and the mixing time is 20min.

Filling the capsule: according to the theoretical loading amount of the product, the No. 2 hydroxypropyl methylcellulose hollow capsule (I) is used for filling the capsule.

(2) The components and the preparation method of the Bei Futi nimesulfonate capsule with the specification of 50mg are the same as those of the Bei Futi nimesulfonate capsule with the specification of 25mg, except that the dosage of each component is doubled.

Examples 2-Bei Futi stability of the Nimesylate Capsule

Taking Bei Futi nimesulfonate capsules with 25mg specification prepared in example 1 as an example, the stability of a preparation sample obtained by the prescription process under high temperature, high humidity and illumination is studied, the preparation sample is placed for 30 days under the condition of 75% of high humidity, the sample has obvious moisture absorption phenomenon, and other detection indexes have no obvious change; the product is placed for 30 days under the conditions of high temperature of 40 ℃, high temperature of 60 ℃ and illumination of 4500Lx, moisture content tends to increase, and other detection indexes are not changed obviously. The detailed results are shown in the following table:

Stability of Bei Futi Nimesylate Capsule

EXAMPLE 3 clinical Studies

Bei Fu Multi-center, randomized, control, double blind, double mock, phase III clinical study of Ecritinib control for post-operative adjuvant treatment of EGFR-sensitive mutation-positive IB-IIIB (T3N 2M 0) stage non-small cell lung cancer

The research method comprises the following steps:

The study was a multicenter, randomized, control, double-blind, double-mock, phase III clinical study, of 570 subjects following complete excision (R0) of non-small cell lung cancer (NSCLC) in stage IB-IIIB (T3N 2M 0) positive for Epidermal Growth Factor Receptor (EGFR) sensitive mutation, at 1: the ratio of 1 was randomly assigned to Bei Fu or to the icotinib group. The random grouping procedure employs a central random system-interactive network response system (IWRS), and the layering factors include: stage of disease (IB/II/III), mutation site (19 del/21L 858R).

Purpose of investigation

Primary purpose and endpoint

Critical secondary objective and endpoint

Other secondary purposes and end points

Primary inclusion and exclusion criteria

Group entry criteria

The subjects must meet all of the following inclusion criteria to qualify for participation in the study:

1. Voluntarily signs written informed consent, and can understand and follow the test protocol requirements.

2. The age at the time of signing the informed consent is greater than or equal to 18 years old.

3. Primary non-small cell lung cancer (NSCLC) was histologically diagnosed, and the histology was predominantly non-squamous cell carcinoma (including mixed cancers based on adenocarcinoma components).

4. Brain Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scans must be performed prior to lung cancer ablation and the absence of brain metastases is confirmed. For patients not examined prior to surgery, groups can still be entered if brain MRI or CT scans are performed prior to the first use of the test drug and the absence of brain metastases is confirmed.

5. The pathology of the primary lung cancer after surgical complete excision (R0) proved to be non-small cell lung cancer subjects in IB, II, IIIA and IIIB (T3N 2M0 only) stage, and the disease stage was according to the United states Joint Committee for cancer (AJCC)/International anticancer Union (UICC) 8 th edition of lung cancer stage criteria.

Complete resection procedures include anatomical lobectomy (including compound lobectomy), partial lobectomy (for partial early lung cancer), total lobectomy or broncho-or (and) pulmonary angioplasty lobectomy (including compound lobectomy), total lobectomy and systemic mediastinal lymph node cleaning. And simultaneously meets the following requirements: (1) All incisional edges including bronchi, arteries, veins, peribronchial tissue and tissue near the tumor are negative; (2) A phylogenetic or phylloxera lymph node sweep must include 6 groups of lymph nodes, 3 of which are from intrapulmonary (leaf, she Jianhuo segments) and portal lymph nodes, and 3 of which are from mediastinal lymph nodes including subcarina lymph nodes; (3) The mediastinal lymph nodes excised or marginal lymph nodes excised from lung lobes, respectively, cannot have extranodal invasion; (4) the highest lymph node resected must be negative under the scope.

6. The tumor tissue specimens after operation are provided and detected as EGFR sensitive mutations (exon 19 deletion or L858R mutation) through a central laboratory, and other EGFR site mutations can exist alone or coexist, including the group of coexisting T790M mutation positive persons.

7. Patients who were fully recovered from surgery at randomization (any post-operative wound must be fully healed) should be treated with adjuvant within 4-10 weeks of surgery.

8. Eastern tumor tissue co-ordinated group (ECOG) Physical Status (PS) score 0 or 1 and no worsening 2 weeks before study drug first administration, with a minimum expected survival of greater than 12 weeks.

9. Voluntarily agreeing to employ routine sufficiently effective contraceptive measures for the whole study period and 3 months after the last administration [ for females: 1. contraceptive methods by oral administration, injection of contraceptive or hormone implantation; 2. an intrauterine device or intrauterine system; 3. barrier contraceptive method: condom or occlusion cap (diaphragm or cervical/dome cap) with spermicidal effect. For men: 1. condom with spermicidal effect; 2. surgical sterilization (e.g., bilateral orchiectomy, bilateral vasectomy); female patients who are possible for pre-menopausal fertility (1. Do not undergo bilateral tubal ligation, hysterectomy, bilateral ovariectomy; 2. Last menstruation to screening < 2 years) need to exclude pregnancy (i.e., pregnancy test negative within 7 days prior to first administration); and is in a non-lactation period.

Exclusion criteria:

subjects were not eligible to participate in the study if they met any of the following exclusion criteria:

1. There are unresectable or metastatic disease and pathology reports showing that the surgical incision is positive under the microscope or there is an extranodal violation, or there is a lesion left at the time of surgery. Subjects who received only wedge-shaped resections.

2. Lung superior sulcus cancer.

3. The lung cancer operation is performed on a right lung total excision patient.

4. Other malignancies besides the disease studied were seen within 5 years prior to the first administration. Except for malignant tumors that heal after treatment (including but not limited to fully treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell skin cancer, or ductal carcinoma of the breast treated by radical surgery).

5. Systemic anti-tumor therapies including chemotherapy, radiation therapy or targeted therapies (including but not limited to monoclonal antibodies, small molecule tyrosine kinase inhibitors), immunotherapy, research therapies, and the like are received prior to the study into the group.

6. Within 3 weeks prior to the first administration of study medication, patients had undergone major surgery (including primary tumor surgery, craniotomy, thoracotomy or laparotomy, etc., excluding vascular access establishment procedures), defined as surgery grade 3 and grade 4 as specified in the medical technical clinical application management methods administered on 1 month 11 of 2018.

7. The research drugs receive traditional Chinese medicine and Chinese patent medicine preparations taking antitumor as indications within 14 days before the first administration.

8. After the study has begun, it is still necessary to receive either form of systemic or local anti-tumor therapy (including maintenance therapy with another drug, radiation therapy, and/or surgical resection).

9. Clinically significant cardiovascular disease, including:

Qtcf interval >450ms (male) or >470ms (female), symptomatic bradycardia (heart beat <45 beats per minute) or other significant ECG abnormalities judged by the researcher (e.g. complete left bundle branch block, III degree block, II degree block, PR interval >250 msec).

B. the ultrasonic cardiography examination shows that the Left Ventricular Ejection Fraction (LVEF) is less than or equal to 50 percent.

C. Researchers judged clinically uncontrollable hypertension (e.g., blood pressure >160/100mmHg; note that if isolated readings were elevated, but that researchers judged clinically significant or controllable hypertension were optional).

The following conditions were found within 6 months prior to the first dose:

a. congestive heart failure (New York Heart disease Association grade III or IV).

B. Arrhythmia or abnormal conduction requiring medication. And (3) injection: drug-controlled atrial fibrillation/atrial flutter subjects, and pacemaker-controlled arrhythmia subjects may be selected.

C. Severe/unstable angina, coronary/peripheral bypass grafting, or myocardial infarction; (note: severe angina pectoris is Canadian cardiovascular society grade III or grade IV).

D. cerebrovascular accident or transient ischemic attack and transient myocardial ischemia.

10. Past history of combined Interstitial Lung Disease (ILD), drug-induced interstitial lung disease, radiation pneumonitis requiring hormonal treatment, or clinical evidence of combined active interstitial lung disease.

11. Patients who have had a history of thrombosis, a history of cerebral infarction, or who currently have a high risk of thrombus, COMPASS-CAT scoring.

12. Any clinical evidence suggests that patients with severe active infection, or any severe underlying disease that may affect the subject undergoing treatment for the regimen, such as active bleeding-prone patients, have active hepatitis b, hepatitis c or tuberculosis, syphilis, human Immunodeficiency Virus (HIV) antibody positivity.

Remarks: active hepatitis b and c are defined as follows:

active hepatitis B, positive for hepatitis B surface antigen (HBsAg), and HBV DNA quantification higher than or equal to the lower limit of detection (based on local laboratory detection values).

Active hepatitis C, hepc Ab results positive and HCV RNA positive (standard on local laboratory detection values).

13. Subjects suffering from active Gastrointestinal (GI) disease, or at risk of perforation of the GI tract, or other diseases capable of significantly interfering with the absorption, distribution, metabolism or excretion of the test drug. Including but not limited to: inability to take drugs orally, uncontrollable nausea or vomiting, intestinal obstruction, inflammatory bowel disease or extensive intestinal resection with chronic diarrhea, crohn's disease, ulcerative colitis or chronic diarrhea.

14. An abnormality in any of the following laboratory indicators occurred:

absolute Neutrophil Count (ANC) < 1.5X10 ⁹/L.

Platelet count (PLT) < 100×10 ⁹/L.

Hemoglobin (Hb) < 90g/L (note: to achieve the required hemoglobin level, transfusion is allowed, but needs to be done at least 14 days prior to screening).

Alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) is greater than 2.5 times the Upper Limit of Normal (ULN).

Total bilirubin > 1.5 times ULN.

Serum creatinine (SCr) > 1.5 times ULN or creatinine clearance < 50ml/min (calculated according to the Cockcroft-Gault formula).

The International Normalized Ratio (INR) or Activated Partial Thromboplastin Time (APTT) > 1.5 times ULN (note: if the subject is undergoing anticoagulant therapy, then the INR must be within the target range required for the disease being treated, as judged by the investigator).

15. The study drug Bei Futi, ecotinib and any component of its formulation had a history of allergy or suspected allergic symptoms.

16. The combination of a strong inhibitor or inducer of CYP3A is required during the period of use or study within 1 week prior to the first administration of the test drug.

17. Patients still using warfarin (allowed to use low molecular heparin sodium) within 7 days prior to the first dose.

18. Is being enrolled in a clinical study and is being treated with a study drug or study device, or is being enrolled in a clinical study and is being treated with a study drug or study device within 4 weeks prior to the first administration, or is scheduled to participate in any other clinical trial during the course of the study.

19. Live vaccine was inoculated 180 days before the first administration.

Note that: allows for vaccination with seasonal influenza inactivated virus vaccines for injection, novel coronavirus inactivated vaccines, but does not allow for vaccination with attenuated live influenza vaccines (e.g.)。

20. Researchers believe that compliance with a regimen may be affected or that subjects are signed with informed consent (e.g., history of psychosis or drug abuse, alcoholism, or other addiction), or any other disease or condition of clinical significance that is unsuitable for participation in the present clinical trial (e.g., abnormal outcome in the laboratory, clinically active diverticulitis, intra-abdominal abscess).

The usage amount is as follows:

bei Futi nimesulfonate capsule, specification: 25 mg/grain and 50 mg/grain.

The specification of the Icotinib hydrochloride tablet is as follows: 125 mg/tablet.

Bei Futi Nimesylate capsules, taken orally once daily, starting at a starting dose of 75mg for 21 consecutive days; if no serious side effect or no platelet decrease of grade 2 or more and/or no headache of grade 2 or more occurs, the dosage is adjusted to 100mg once daily after 21 days. Administration may be on an empty stomach or after a meal, until the disease recurs or intolerant toxicity or treatment occurs for up to 3 years (disease recurs including local recurrences and/or distant metastasis).

The Icotinib hydrochloride tablet is orally taken, 125mg (1 tablet) each time, three times a day, on an empty stomach or taken with food until the disease recurs or intolerant toxicity appears or treatment is performed for 2 years (disease recurrences include local recurrences and/or distant metastasis).

Dose adjustment

Adverse events should be closely monitored during the course of drug study and adjusted as needed to enable patients to tolerate treatment, and the reduction principle after adverse reaction is shown in the following table.

Dose adjustment principle of research medicament after adverse reaction

Note that: the above grades all refer to severity scores according to the United states cancer institute-adverse events common terminology standard version 5.0 (NCI-CTCAE 5.0).

* The stable and controllable thrombus is as follows: the laboratory test index D-dimer value did not continue to increase or decrease; the clinical symptoms are improved or not aggravated. The dosage adjustment standard of the# Bei Fu tinib capsule is 100 mg-75 mg-50 mg.

The dose adjustment criteria for the # icotinib tablet was resumption of the original dose after suspension of the drug.

For medications that are stopped due to adverse events, they should not be taken orally. Withdrawal from the study occurred beyond 21 days due to adverse events.

Efficacy assessment

Effectiveness index:

1) Main therapeutic effect index

DFS

2) Secondary efficacy index

DFS rate of 3 years, 5 years

OS Rate 5 years

OS

Security assessment

The security assessment mainly includes: physical examination, vital signs, 12-lead electrocardiogram, laboratory examination (blood routine, serum biochemical, blood clotting test, urine routine, serum pregnancy, virologic test, etc.), echocardiography, adverse events.

The severity of adverse events was reported, ranked and recorded according to NCI CTCAE version 5.0.

Stage 1: light weight; asymptomatic or mild; only for clinical or diagnostic purposes; treatment is not required;

2 stages: a medium degree; less local or non-invasive treatment is required; instrumental activities of daily living comparable to age are limited;

3 stages: serious or medically significant but not immediately life threatening; hospitalization is required or the hospitalization time is prolonged; disability is caused; the activities of the daily living of individuals are limited;

4 stages: life threatening; emergency treatment is required;

5 stages: death of

Not all adverse events include all classes. Therefore, some adverse events may be selectable at less than five levels. Grade 5 (death) does not apply to all adverse events, so there will be no such option at the adverse event.

Statistical method

In general, continuous variables are statistically described by mean, standard deviation, median, quartile (Q1, Q3), maximum, minimum, etc.; the classification variables are described by indexes such as frequency, percentage and the like. All summary analyses will be presented based on the treatment group, with combined presentation if necessary.

Staging analysis

A life cycle analysis was performed when the population reached about 2/3DFS events (118 cases) at stage IIA-IIIB (T3N 2M 0). The consumption function is Lan-Demets α consumption function of O' Brien-Fleming boundary. Nominal alpha (double sided) was 0.012 at the time of the interim analysis, and if the interim analysis did not reach a positive result, the final analysis was 0.0462. If the number of events actually occurring during the interim analysis is not equal to 118, alpha is adjusted based on the number of events actually occurring to control the class I error.

	Information ratio (event number)	Critical value (HR)	P value (double side)
				Analysis in DFS period	67％(118)	0.6298	0.0120
DFS final analysis	100％(177)	0.7410	0.0462

If there is a statistical difference between the two groups of stage IIA-IIIB (T3N 2M 0) populations, then the complete bilateral 5% alpha is transferred to the two groups of stage IB-IIIB (T3N 2M 0) populations for testing. The group of stage IB-IIIB (T3N 2M 0) will also be subjected to a life cycle analysis at about 2/3DFS events (139 cases). The consumption function is Lan-Demets α consumption function of O' Brien-Fleming boundary. Nominal alpha (double sided) was 0.012 at the time of the interim analysis, and if the interim analysis did not reach a positive result, the final analysis was 0.0462. If the number of events actually occurring during the interim analysis is not equal to 139 cases, the adjustment of α is performed based on the number of events actually occurring to control the class I error.

	Information ratio (event number)	Critical value (HR)	P value (double side)
				Analysis in DFS period	67％(139)	0.6448	0.0120
DFS final analysis	100％(208)	0.7524	0.0462

Description of the embodiments

The following clauses describe specific embodiments of the present invention.

1) Use of befutinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of lung cancer in a patient in need thereof, wherein said patient is in post-operative adjuvant therapy and said medicament comprises a unit dose of Bei Fu tinib of 25-125 mg.

2) The use according to embodiment 1, wherein the stage of lung cancer is stage IB-IIIB.

3) The use according to embodiment 1 or 2, wherein the lung cancer is EGFR-sensitive mutated non-small cell lung cancer.

4) The use of embodiment 3, wherein the EGFR sensitive mutation is a 19 exon deletion or a 21 exon L858R mutation.

5) The use according to embodiment 3 or 4, wherein the EGFR sensitive mutation is not the 20 exon T790M mutation.

6) The use according to any one of embodiments 1-5, wherein the patient does not have tumor recurrence and/or metastasis prior to administration of Bei Fu tinib or a pharmaceutically acceptable salt thereof.

7) The use according to any one of embodiments 1-6, wherein the patient has not received systemic anti-tumor therapy, such as chemotherapy, radiation therapy or targeted therapy, prior to administration of Bei Fu of tenib or a pharmaceutically acceptable salt thereof; the targeted therapy includes administration of monoclonal antibodies and/or small molecule tyrosine kinase inhibitors.

8) The use according to any one of embodiments 1-7, wherein the Bei Fu tinib or pharmaceutically acceptable salt thereof is administered three times per day, twice per day, once per two days, once per three days, once per four days, once per five days, once per six days, once per week, once per two weeks, or once per three weeks, wherein the Bei Fu tinib is administered at a dose of 25-125 mg each time; preferably, the Bei Fu tenib is administered at a dose of 75mg or 100mg each time.

9) The use according to any one of embodiments 1 to 8, wherein the medicament comprises Bei Fu tinib in a unit dose of 75mg or 100 mg.

10 The use according to any one of embodiments 1-9, wherein Bei Fu tinib or a pharmaceutically acceptable salt thereof is administered stepwise, first with a dose of 75mg per day, followed by a dose of 100mg per day.

11 The use according to embodiment 10, characterized in that the number of days for administering a 75mg dose per day is 15-30 days.

12 The use according to any one of embodiments 1 to 11, wherein Bei Fu tinib or a pharmaceutically acceptable salt thereof is administered by first administering a dose of 75mg once a day for 18 to 24 days, preferably for 21 days; a dose of 100mg is then administered once a day.

13 The use according to any one of embodiments 1 to 12, characterized in that the Bei Fu pharmaceutically acceptable salt of tennini is present in the form of a mesylate salt.

14 The use according to any one of embodiments 1 to 13, wherein the medicament is administered orally.

15 The use according to any one of embodiments 1 to 14, wherein the medicament is a tablet or capsule.

16 The use according to any one of embodiments 1 to 15, wherein the medicament comprises a diluent, a disintegrant and a lubricant.

17 The use according to embodiment 16, characterized in that the diluent is selected from microcrystalline cellulose, mannitol or a mixture of microcrystalline cellulose and mannitol; the diluent accounts for 60-95 wt% of the medicine, preferably 65-95 wt%, 70-95 wt%, 75-95 wt%, 80-95 wt%, 85-95 wt% or 90-95 wt%; when the diluent is selected from a mixture of microcrystalline cellulose and mannitol, the microcrystalline cellulose is selected from the range of 10 to 90wt%, preferably from 20 to 85wt%, 25 to 80wt%, 25 to 75wt%, 30 to 65wt%, 35 to 60wt%, 40 to 55wt%, 45 to 55wt% of the diluent.

18 The use according to embodiment 16, characterized in that the disintegrant is selected from sodium carboxymethyl starch, colloidal silica or a mixture of sodium carboxymethyl starch and colloidal silica; the disintegrant is selected from 1-10wt%, preferably 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt% or 9wt% of the drug.

19 The use according to embodiment 16, characterized in that the lubricant is selected from sodium stearyl fumarate, talc or a mixture of sodium stearyl fumarate and talc; the lubricant is selected from the range of 0.5 to 5wt%, preferably from 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 1.8wt% or 2.0wt% of the medicament.

20A method of treating lung cancer comprising administering Bei Fu a-tenib or a pharmaceutically acceptable salt thereof as a post-operative adjuvant therapy to a patient in need thereof.

21 The method of embodiment 20, wherein the lung cancer is in stage IB-IIIB.

22 The method of any one of embodiments 20-21, wherein the lung cancer is EGFR-sensitive mutated non-small cell lung cancer.

23 The method of embodiment 22, wherein the EGFR sensitive mutation is a 19 exon deletion or a 21 exon L858R mutation.

24 The method of any one of embodiments 22-23, wherein the EGFR sensitive mutation is not the 20 exon T790M mutation.

25 The method of any one of embodiments 20-24, wherein the patient does not have tumor recurrence and/or metastasis prior to administration of Bei Fu tinib or a pharmaceutically acceptable salt thereof.

26 The method of any one of embodiments 20-25, wherein the patient has not received systemic anti-tumor therapy, such as chemotherapy, radiation therapy or targeted therapy, prior to administration of Bei Fu of tenib or a pharmaceutically acceptable salt thereof; the targeted therapy includes administration of monoclonal antibodies and/or small molecule tyrosine kinase inhibitors.

27 The method of any one of embodiments 20-26, wherein Bei Fu tenib or a pharmaceutically acceptable salt thereof is administered three times per day, twice per day, once per two days, once per three days, once per four days, once per five days, once per six days, once per week, once every two weeks, or once every three weeks.

28 The method according to any one of embodiments 20-27, wherein the Bei Fu tenib or pharmaceutically acceptable salt thereof is administered at a dose of 25-125 mg per administration; preferably, the Bei Fu tenib or a pharmaceutically acceptable salt thereof is administered at a dose of 75mg or 100mg each time.

29 The method of any one of embodiments 20-28, wherein Bei Fu tenib or a pharmaceutically acceptable salt thereof is administered stepwise, with a 75mg dose administered daily followed by a 100mg dose administered daily.

30 The method of embodiment 29, wherein the 75mg dose is administered daily for 15-30 days.

31 The method according to any one of embodiments 20-30, wherein Bei Fu tinib or a pharmaceutically acceptable salt thereof is administered by first administering a dose of 75mg once a day for 18-24 days, preferably for 21 days; a dose of 100mg is then administered once a day.

32 The method according to any one of embodiments 20-31, wherein the Bei Fu pharmaceutically acceptable salt of tennini is present in the form of a mesylate salt.

33 The method according to any one of embodiments 20-32, wherein the Bei Fu tinib or a pharmaceutically acceptable salt thereof is administered orally.

34 The method according to any one of embodiments 20-33, wherein the Bei Fu tinib or a pharmaceutically acceptable salt thereof is present in the form of a tablet or capsule.

35 The method of embodiment 34, wherein the tablet or capsule comprises a composition comprising a diluent, a disintegrant, and a lubricant.

36 The method of embodiment 35, wherein the diluent is selected from microcrystalline cellulose, mannitol, or a mixture of microcrystalline cellulose and mannitol; the diluent accounts for 60-95 wt%, preferably 65-95 wt%, 70-95 wt%, 75-95 wt%, 80-95 wt%, 85-95 wt% or 90-95 wt% of the tablet or capsule; when the diluent is selected from a mixture of microcrystalline cellulose and mannitol, the microcrystalline cellulose is selected from the range of 10 to 90wt%, preferably from 20 to 85wt%, 25 to 80wt%, 25 to 75wt%, 30 to 65wt%, 35 to 60wt%, 40 to 55wt%, 45 to 55wt% of the diluent.

37 A method according to embodiment 35, wherein the disintegrant is selected from sodium carboxymethyl starch, colloidal silica, or a mixture of sodium carboxymethyl starch and colloidal silica; the disintegrant is selected from the range of 1 to 10wt%, preferably 2wt%, 3wt%, 4wt%, 5wt%, 6wt%, 7wt%, 8wt% or 9wt% of the tablet or capsule.

38 The method according to embodiment 35, wherein the lubricant is selected from sodium stearyl fumarate, talc, or a mixture of sodium stearyl fumarate and talc; the lubricant is selected from the range of 0.5 to 5wt%, preferably from 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 1.8wt% or 2.0wt% of the tablet or capsule.

The invention has been described in detail in connection with the specific embodiments and exemplary examples thereof, but such description is not to be construed as limiting the invention. It will be understood by those skilled in the art that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, and these fall within the scope of the present invention. The scope of the invention is defined by the appended claims.

Claims

1. Use of befutinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of lung cancer in a patient in need thereof, wherein said patient is in post-operative adjuvant therapy and said medicament comprises a unit dose of Bei Fu tinib of 25-125 mg.

2. The use according to claim 1, wherein the stage of lung cancer is stage IB-IIIB.

3. The use according to claim 1 or 2, wherein the lung cancer is EGFR-sensitive mutated non-small cell lung cancer.

4. The use of claim 3, wherein the EGFR sensitive mutation is a 19 exon deletion or a 21 exon L858R mutation.

5. The use of claim 3 or 4, wherein the EGFR sensitive mutation is not the 20 exon T790M mutation.

6. The use according to any one of claims 1 to 5, wherein the patient does not have tumor recurrence and/or metastasis prior to administration of Bei Fu tinib or a pharmaceutically acceptable salt thereof.

7. The use according to any one of claims 1-6, wherein the patient has not received systemic anti-tumor therapy, such as chemotherapy, radiation therapy or targeted therapy, prior to administration of Bei Fu tinib or a pharmaceutically acceptable salt thereof; the targeted therapy includes administration of monoclonal antibodies and/or small molecule tyrosine kinase inhibitors.

8. The use according to any one of claims 1-7, wherein said Bei Fu tinib or pharmaceutically acceptable salt thereof is administered three times per day, twice per day, once per two days, once per three days, once per four days, once per five days, once per six days, once per week, once per two weeks or once per three weeks, wherein said Bei Fu tinib is administered at a dose of 25-125 mg each time; preferably, the Bei Fu tenib is administered at a dose of 75mg or 100mg each time.

9. The use according to any one of claims 1 to 8, wherein the Bei Fu pharmaceutically acceptable salt of tenib is in the form of a mesylate salt.

10. The use according to any one of claims 1 to 9, wherein the medicament comprises a diluent, a disintegrant and a lubricant.