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US 20170224667A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0224667 A1 AZUMA et al. (43) Pub. Date: Aug. 10, 2017

(54) CANCER CHEMOPREVENTIVE AGENT (30) Foreign Application Priority Data (71) Applicants: Arata AZUMA, Mitaka-shi, Tokyo Oct. 15, 2014 (JP) ...... 2014-210690 (JP); KDL, Inc., Chiyoda-ku, Tokyo Publication Classification (JP) (51) Int. Cl. (72) Inventors: Arata AZUMA, Tokyo (JP); Yukiko A6II 3/448 (2006.01) MIURA, Tokyo (JP) A6II 45/06 (2006.01) (52) U.S. Cl. CPC ...... A61K 31/4418 (2013.01); A61K 45/06 (21) Appl. No.: 15/519,360 (2013.01) (22) PCT Filed: Apr. 21, 2015 (57) ABSTRACT (86) PCT No.: PCT/UP2015/062117 Provided is a medicine for cancer chemoprevention, the medicine being characterized by containing, as an active S 371 (c)(1), ingredient, pirfenidone or a pharmaceutically acceptable salt (2) Date: Apr. 14, 2017 thereof. Patent Application Publication Aug. 10, 2017 US 2017/0224667 A1

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CANCER CHEMOPREVENTIVE AGENT lead to an increase in lung cancer risk (non-patent document 2-3). Although a certain number of new compounds have TECHNICAL FIELD been reported to show chemopreventive activities, none of 0001. This invention is in the field of cancer chemopre them has shown effects in human. (patent document 1-6). vention. More precisely, this invention is to provide the 0008 Pirfenidone, 5-methyl-1-phenyl-2-(1H)-pyridone, method of cancer chemoprevention using the drug contain is widely known as an effective drug for the prevention and ing pirfenidone as a pharmacological active ingredient. treatment for diseases relevant to fibrosis (patent document 7), and especially useful for the treatment such as fibrosis There are also provided the use of pirfenidone for the lesions, transmissibility warts, contact-related dermatitis, a production of a medicament containing pirfenidone for keloid, pulmonary fibrosis, the fibrosis enlargement of the cancer prevention, and methods for cancer chemoprevention prostate, restoration and prevention of nephrosclerosis and comprising administering an effective amount of pirfeni So forth, or post-Surgery burn injury, and Alzheimer's dis done for cancer prevention to mammals including human. ease. Pirfenidone was first approved as pirespaR) 200 mg tablet for the treatment of idiopathic pulmonary fibrosis in BACKGROUND ART Japan in 2008 by the present inventors. In addition, it was 0002 Cancer is the number one cause of death in our approved for the treatment of idiopathic pulmonary fibrosis country and a disease which occupies a high rank as cause in Europe in 2010, and NDA was filed in the United States of death in the developed world. in 2014. 0003 For the treatment of cancer, there are surgery, 0009 Pirfenidone is expected to inhibit cancer growth, radiotherapy, and immune therapy, and these because pirfenidone inhibits beta type variation growth are appropriately combined and then applied. Rapid prog factor (transforming growth factor-B) and epithelium mes ress has been made in cancer treatments, especially in drug enchyma transition (EMT). Burghadtt et al. reported that therapy. Molecular target drugs are currently available in pirfenidone inhibited proliferation of the malignant glioma addition to chemotherapeutic drugs and they have dramati cells (non-patent document 4). Kozono reported the inhibi cally improved the outcome in some cancers. Drug therapy tory effects on fibrosis caused by pancreatic cancer (non is the sole treatment method for patients who developed patent document 5). systemic metastasis, but there is a limitation in their effec 0010 Idiopathic pulmonary fibrosis is often associated tiveness. Therefore, new drug is needed. with lung cancer and Such patients can be considered to be 0004 Recently cytostatic anticancer agents such as anti at high risk of developing lung cancer. Surgery of lung agiogenesis, which inhibit cancer growth indirectly by cancer of the patients with idiopathic pulmonary fibrosis is inhibiting angiogenesis as well as cytotoxic agents which known to cause a development of a serious acute exacerba inhibit cancer cell growth directly. Supporting drugs such as tion. There is a report that this acute exacerbation was antiemetic drugs and G-CSF, which reduce side effects inhibited by pre-treatment with pirfenidone (non-patent caused by chemotherapeutic agents have been available. document 6). 0005. Furthermore, cancer painkillers improve the qual ity of life (QOL) of the patient and, as a result, help CITATION LIST improvement of the cancer treatment. 0006. On the other hand, trials to prevent cancer have Patent Literatures been widely investigated. The 12 cancer prevention method 0011 Patent literature 1 JP2014-55196A including Smoking cessation, the intake of lots of vegetables, 0012 Patent literature 2JP2014-50390A moderate drinking, and lifestyle improvements including a 0013 Patent literature 3.JP2010-138192A limit of salt intake has been issued by the Japanese Cancer 0014 Patent literature 4 JP2012-510965A Association and the activity of cancer prevention is enlight 0.015 Patent literature 5 JP2006-510658A ened. In addition, aggressive intervention with drugs for preventing cancer, so-called "cancer chemoprevention' are 0016 Patent literature 6.JP2002-510667A sought and investigated. This is accomplished not only with 0017 Patent literature 7 JPH02-215719A animal experiments but also in clinical studies. Inspection of Non-Patent Literatures toxicity and effectiveness in cancer prevention and decisions of optimum doses are necessary for cancer prevention 0018 Non-patent literature 1 Advani P. Moreno-Aspitia studies. It is very difficult to develop a chemopreventive A. Current strategies for the prevention of breast cancer. agent because of the evaluation difficulty including decrease Breast Cancer (Dove Med Press). 2014; 6: 59-71. in incidence rate in humans as well as in animal models and (0019 Non-patent literature 2 IARC. IARC Handbook the optimal dose finding with less toxicity. of Cancer Prevention Volume 2 "Cartenoids, IARC Press, 0007. Several clinical trials of the compounds, mainly Lyon (1989). natural compounds, which were found to have their chemo 0020 Non-patent literature 3 Greenberg A. K., Tsay J. preventive effects in animal models, were conducted for C., Tchou-Wong K. M., Jorgensen A. Rom W. N. Chemo Subjects who have high risk factor of carcinogenesis such as prevention of lung cancer: prospects and disappointments in Smoking, colon polyp and so forth based on systemic human clinical trials. Cancers (Basel). 2013; 5: 131-48. epidemiological studies in humans. The only compounds 0021 Non-patent literature 4 Burghardt I, Tritschler F. with confirmed chemopreventive effects are tamoxifen and Opitz CA, Frank B, Weller M, Wick W. Pirfenidone inhibits raloxifen in prevention in breast cancer (non-patent refer TGF-beta expression in malignant glioma cells. Biochem ence 1). A chemopreventive effect of B-carotene on lung Biophys Res Commun. 2007: 354: 542-7. cancer was reported in animal studies, but no effects on lung 0022. Non-patent literature 5 Kozono S. Ohuchida K. cancer were found in Smokers and no-Smokers, and it rather Eguchi D, Ikenaga N. Fujiwara K. Cui L, Mizumoto K. US 2017/0224667 A1 Aug. 10, 2017

Tanaka M. Pirfenidone inhibits pancreatic cancer desmopla 0034 (8) The medicament of cancer chemoprevention sia by regulating stellate cells. Cancer Res. 2013; 73: according to any one of (1) to (7) further comprising any 2345-56. other pharmaceutical active drug as a concomitant drug. 0023 Non-patent literature 6 Successful Resection of 0035 (9) The medicament of cancer chemoprevention Lung cancer with idiopathic pulmonary fibrosis treated by according to (8) wherein said any other pharmaceutical pirfenidone during perioperative period. Jap J. Thorac Surg. active drug is a drug which prevents carcinogenesis, inhibits 2013; 66, 890-893. indirectly growth of cancer and/or directly inhibits growth of CaCC. SUMMARY OF INVENTION 0036 (10) The medicament of cancer chemoprevention method of cancer chemoprevention according to (8) wherein Technical Problem said any other pharmaceutical active drug is used as adju 0024. The aim this invention is to provide a medicament vant chemotherapeutic drug. of cancer chemoprevention. 0037 (11) An oral or parenteral pharmaceutical compo sition comprising an effective amount of pirfenidone Solution to Problem together with one or more pharmaceutically acceptable additive(s). 0025. The present inventors had hypothesized that pir 0038 (12) A method of cancer chemoprevention which fenidone might have a cancer chemoprevention activity comprises a step of administering an effective amount of based on the results that show that pirfenidone can normal pirfenidone for cancer prevention to mammals including ize damaged tissue such as inhibitory effects on Scars, in human. addition to its antifibrotic action. Thus, the present inventors 0039 (13) A method of cancer chemoprevention which evaluated the cancer chemoprevention effect of pirfenidone comprises a step of administering an effective amount of in idiopathic pulmonary fibrosis patients who are said to pirfenidone for cancer prevention to a Subject who has a high have a high risk factor of carcinogenesis. The patients were randomly assigned to a pirfenidone group and a non-pir risk factor of carcinogenesis. fenidone group, and the pirfenidone group was observed for 0040 (14) The method of cancer chemoprevention more than 12 months. As a result, the present inventors have according to (13), wherein said high risk factor of carcino found that pirfenidone has a cancer chemoprevention activ genesis is idiopathic pulmonary fibrosis. ity and accomplished the present invention. This efficacy 0041) (15) The method of cancer chemoprevention was not explained by its effectiveness on idiopathic pulmo according to any one of (12) to (14), wherein any other nary fibrosis, and is therefore a novel activity of pirfenidone. pharmaceutical active drug is further administered as a 0026. To describe more specifically, the present invention concomitant drug. is as follows: 0042 (16) The method of cancer chemoprevention according to (15), wherein said any other pharmaceutical 0027 (1) A medicament of cancer chemoprevention active drug is a drug which prevents carcinogenesis, inhibits which comprises pirfenidone or pharmacologically accept indirectly growth of cancer and/or directly inhibits growth of able Salt thereof as a pharmaceutical active ingredient. CaCC. 0028 (2) A medicament of cancer chemoprevention 0043 (17) The method of cancer chemoprevention which comprises 5-methyl-1-phenyl-2-(1H)-piridone as a according to (15), wherein said any other pharmaceutical pharmaceutical active ingredient. active drug is used as adjuvant chemotherapeutic drug. 0029 (3) The medicament of cancer chemoprevention according to (1) or (2) wherein said medicament is for cancer chemoprevention of Solid cancer. Advantageous Effects of Invention 0030 (4) The medicament of cancer chemoprevention 0044 According to the favorable findings of the present according to (3) wherein said solid cancer is selected from invention as mentioned above, it provides a cancer chemo the group consisting of a brain tumor, spinal cord tumor, oral prevention of Solid carcinoma Such as a brain tumor, spinal cancer, pharyngeal cancer, cancer of nose, cancer of larynx, cord tumor, oral cancer, pharyngeal cancer, cancer of nose, thyroid cancer, lung cancer, breast cancer, a mediastinum cancer of larynx, thyroid cancer, lung cancer, breast cancer, tumor, a mesothelioma, cancer of esophagus, stomach can a mediastinum tumor, a mesothelioma, cancer of esophagus, cer, duodenal Small intestine cancer, colon cancer, GIST. stomach cancer, duodenal Small intestine cancer, colon liver cancer, cholangiocarcinoma, a gallbladder cancer, pan cancer, GIST, liver cancer, cholangiocarcinoma, a gallblad creatic cancer, kidney cancer, urinary tract cancer, bladder der cancer, pancreatic cancer, kidney cancer, urinary tract cancer, adrenal tumor, prostate cancer, testicular cancer, cancer (renal pelvis cancer, ureter cancer), bladder cancer, cervical cancer, endometrial cancer and ovarian cancer. adrenal tumor, prostate cancer, testicular cancer, cervical 0031 (5) The medicament of cancer chemoprevention cancer, endometrial cancer and ovarian cancer. according to (3) or (4) wherein said solid cancer is lung 0045. In other embodiment of the present invention, there CaCC. are also provided the use of pirfenidone for the production 0032 (6) The medicament of cancer chemoprevention of a medicament containing pirfenidone for cancer preven according to any one of (1) to (5) wherein said medicament tion, and methods for cancer chemoprevention comprising is for cancer chemoprevention for a subject who has a high administering an effective amount of pirfenidone for cancer risk factor of carcinogenesis. prevention to mammals including human. 0033 (7) The medicament of cancer chemoprevention 0046. The medicament of the present invention provides according to (6) wherein said high risk factor of carcino prevention of cancerogenesis in healthy human with a high genesis is idiopathic pulmonary fibrosis. risk of cancer, and patients with idiopathic pulmonary US 2017/0224667 A1 Aug. 10, 2017

fibrosis, idiopathic interstitial pneumonia, COPD, Helico lack of exercise, lack of vegetables and lack of fruit, salt bacter pylori-positive gastritis, hepatitis C virus-positive intake, Helicobacter pylori infection, hepatitis C (HCV) and hepatitis and cirrhosis. hepatitis B (HBV) infection, humans papilloma virus (HPV) infection, type I human T cell virus (HTLV-I) BRIEF DESCRIPTION OF THE DRAWINGS infection, Epstein-Barr virus (EBV) infection, exogenous hormone use, hormone replacement therapy (HRT), oral 0047 FIG. 1 shows time course of unaffected rate of lung contraceptive (OC). Smoking (actively) is a risk factor for cancer in patients with idiopathic pulmonary fibrosis treated oral cavity and pharyngeal cancer, esophagus cancer, stom with/without pirfenidone. ach cancer, colorectal cancer, liver cancer, pancreatic cancer, larynx cancer, lung cancer, cervical cancer, ovarian cancer, DETAILED DESCRIPTION OF THE bladder cancer, renal cancer, and myeloid leukemia; Smok PREFERRED EMBODIMENTS ing (passively) and pulmonary fibrosis are risk factors for 0048. The active ingredient contained in the medicament lung cancer (non-Smoker); drinking alcohol is a risk factor of this invention is 5-methyl-1-phenyl-2-(1H)-pyridone (pir for oral cavity and pharyngeal cancer, esophagus cancer, fenidone) represented by the structure (1) or its pharmaceu colorectal cancer, liver cancer, and female breast cancer, tically acceptable salt thereof. being overweight and obesity are risk factors for colorectal cancer, pancreatic cancer, postmenopausal breast cancer, endometrial cancer, and kidney cancer, lack of exercise is a (1) risk factor for colorectal cancer, breast cancer, and endome trial cancer; lack of vegetables and lack of fruit are risk factors for esophagus cancer, stomach cancer, and lung cancer; salt intake is a risk factor for gastric cancer, Heli cobacter pylori infection is a risk factor for stomach (non cardiac part) cancer; hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are a risk factor for liver cancer; human papilloma virus (HPV) infection is a risk factor for 21 oral cavity cancer, oropharyngeal cancer, anal cancer, penile HC cancer, vaginal cancer, Vulval cancer, and cervical cancer, type I human T cell leukemia virus (HTLV-I) infection is a The pharmaceutically acceptable salts include salt(s) with risk factor for adult T cell lymphoma/leukemia (ATL); acid and alkaline. As an acid forming the salt with pirfeni Epstein-Barr virus (EBV) infection is a risk factor for done, there are hydrochloric acid, Sulfuric acid, phosphoric nasopharyngeal cancer Burkitt lymphoma, Hodgkin lym acid, p-toluenesulfonic acid, and methanesulfonic acid. As phoma; and use of exogenous hormones, hormone replace the alkaline salt of pirfenidone, there are sodium salt and ment therapy, and oral contraceptive (OC) are risk factors potassium salt. for breast cancer in women. 0049. The medicament of the present invention can be 0053 Recently, a genetic test is also used as a method to used for cancer chemoprevention. The term "cancer chemo know the cancer-causing risk. There is no need to limit, but prevention” means preventing the development of cancer by onset genes of cancer include AFP, BAGE, BCL2, CA-125, drugs. The present invention is a class of "cancer chemo CALCA, CD44, CEA, CGA, c-Kit, c-met, c-myc, COX2, preventive drug. “Effective dose of cancer chemopreven CyclinD1, Cytokeratin-19, Cytokeratin-20, Cytokeratin-7. tion' in the present invention means the dose for presenting E2F1, E2F3, EEF1A2, EGFR, EVI-1, FGFR2(K-sam), the preventive effect on the targeted disease, i.e. cancer GAGE, Gli1GPC3, HBV, HCCR, HCGbeta, HCV, Her-2/ preventive or preventing the development of malignancy, or neu, HIF1C, HnRNPA2/B1, HPV, hTERT, HTLV, L-myc, the dose detecting the cancer chemopreventive effect. MAGE-A1, MAGE-A12, MAGE-A3, A6, MAGE-A4, 0050. The medicament of the present invention is used MDM2, MDR-1, MMP-2, MMP-9, Mucin1, Mucin4, for cancer chemoprevention for human with risk factors of Mucin7, NCOA4, N-myc, NSE, ProGRP, PSA, PSMA, carcinogenesis. More preferably, although not particularly RCAS1, SCC, survivin, Thyroglobulin, VEGF-A, VEGF-C limited, the medicament of this invention is used for healthy and WT-1. Mutated genes include P53, K-RAS, H-RAS, human with a high risk of cancer. This invention is also used N-RAS, BRAF, APC, and EGF receptor gene, and Methyl for the patients who suffer from a cancer in order to enhance ation genes includes APC, ATM, BRCA1., DCC, E-Cad anti-cancer activity with combination of cancer treatment herin, H-cadherin, hMLH1, p14, p.15, p16, RAR-Beta2. drugs. RASSF1A, RB1, TIMP3.VH. These genes are used for 0051. The “subjects with risk factors of carcinogenesis' genetic screenings. Patients can be identified as treatment means healthy human with a high risk of cancer, and patients candidates for the medicament of the present invention with idiopathic pulmonary fibrosis, idiopathic interstitial based on these genetic screenings. pneumonia, COPD Helicobacter pylori-positive gastritis, 0054 The medicament of the present invention can be hepatitis C virus-positive hepatitis and cirrhosis. used for treatment of patients suffering from cancer by using 0052. There is no need to limit the high risk factors of pirfenidone or its pharmaceutically acceptable salt alone or cancers, but there are provided the factors including Smok combination with other pharmaceutical active drugs in order ing (actively), Smoking (passively), hyperplasia and meta to prevent malignant alteration of cancer or to enhance plasia of organs Such as the pulmonary bronchus, liver, Suppression of cancer growth. fibrosis Such as idiopathic pulmonary fibrosis, air pollution, 0055. There is no need to limit the pharmaceutically occupational revelation Such as chrome, arsenic, nickel, or active ingredients for combinations with pirfenidone, but asbestos, drinking alcohol, being overweight and obesity, more preferably there are provided compounds and drugs US 2017/0224667 A1 Aug. 10, 2017

which prevent carcinogenesis, inhibit indirectly growth of (Advan, Emarc, Nolvadex, etc.), dexamethasone (Orgad cancer, and/or directly inhibit growth of cancer. Especially, rone, Dexamethosasone Elixir, Methaderm), toremifene combination of pirfenidone with chemotherapeutic drugs (Toremifane, Fareston), bicalutamide (Casodex), flutamide which directly inhibit growth of cancer is used for prevent (Odyne, Flutamide, Flutamerck), prednisolone (predniso ing recurrence of cancer or secondary cancer. Combination lone, Predonine, Predovan, etc.), fosfestrol (Honvan), mito of pirfenidone with chemotherapeutic drugs are more spe tane (Opeprim), methyltestosterone (Enarmon, Enerfa), cifically useful as an adjuvant therapy. medroxyprogesterone (HySron, Progeston), mepitioStane 0056. As for the chemopreventive drug, there are no (Thioderon), leuprorelin (Leuplin), and letrozole (Femara); clinical available drugs, but there are provided the com and biological response modifiers such as interferon C. (IFN pounds which are known to show chemopreventive activi O, OIF. Sumiferon, etc.), interferon B (IFN-Mochida, ties in animal models. Those includes , not particularly Feron), interferon Y (Imunomax y, OH-Y, Biogamma), inter limited, but more preferably are carotenoids such as B-caro leukin (Imunace, Celeuk), ubenimex (Bestatin), dried BCG tene, C-carotene, lycopenes, luteins, fucoxanthins; vaccine (Immunobladder, ImmuCyst), and lentinan Such as retinoic acids, 13-cis-retinoic acid, 9-cis-retinoic (Lenakat, Lentinan). As for the morecular target drugs, there acid, fenretinide, ethylate, acitretin, N-ethyl-retinamide, and are provided ibritumomabtiuxetan (Zevalin), imatinib targretin ; anti-oxidants such as tocopherol, Vitamin E, (Glivec), everolimus (Afinitor), erlotinib (Tarceva), gefitinib Selenium and N-acetyl cystein; green tea components such (Iressa), gemtuzumab ozogamicin (Mylotarg), Sunitinib as catechins; and NSAIDS Such as aspirin, Sulindac, piroxi (Sutent), cetuximab (Erbitux), Sorafenib (Nexavar), dasat cam, and indometacin. inib (Sprycel), (Amnolake), trastuzumab (Her 0057. As for the compounds indirectly inhibit growth of ceptin), (Vesanoid), panitumumab (Vectibix), bort cancer, there is no need to limit, but more preferably are eZomib (Velcade), lapatinib (Tykerb), and rituximab provided anti-agenesis drugs such as bevacizumab (Avastin) (Rituxan). and thalidomide (Thaled). 0059. As for the adjuvant therapeutic drugs, there are 0058. There is no need to limit, but are provided chemo provided UFT (-uracil)+leucovorin, wherein “+” therapeutic drugs and molecular targeted drug as cancer means combination, (Xeloda), FOLFOX treatment drug which directly inhibit growth of cancer. As therapy (5---leucovorin-i-), XELOX for the chemotherapeutic drugs, there are provided alkylat therapy (capecitabine--Oxaliplatin) for colorectal cancer, cis ing agents such as (Ifomide), platin or -- or , and UFT (Endoxane), (Dacarbazine), (Te (tegafur-uracil) for non small cell lung cancer; TS-1 (tega modar), (Nidolan), (Busulfex, Mablin), fur-gimeracil-oteracil potassium), oral fruoropyrimidines (procarbazine hydrochloride), (Alk Such as UFT(egafur-uracil), mytomycin C+oral fruoropy eran), and ranimustine (Cymerin); anti metabolites such as rimidines, and 5-fluorouracil--leucovori for gastric cancer, enocitabine (Sanrabin), capecitabine (Xeloda), CMF therapy (cyclophosphamide----5-fluorou (Mifrol), (Leustatin), (Gemzar), cyt racil), AC therapy ( such as and arabine (Cylocide), ocfosphate (Starasid), tegafur -cyclophosphamide), taxans Such a paclitaxel and (Atyron, Aftoful, Tefseal, Futrafur, Lunasin), combination of , oral furuoropyrimidines such as UFT, anti-estro tegafur and uracil (UFT), combination of tegafur, gimeracil gens such as tamoxifen and tolemifen, aromatase inhibitors and oteracil potassium (TS-1), (Furtulon), Such as anastroZole, exemestane, and letrozole, goserelin, (Aranon G), (Hydrea), fluo luteinizing hormone-releasing hormones (LH-RH) com rouracil (5-FU, CalZonar, Bennan, Lunachol, Lunapon), pounds such as leuprorelin acetate, anti-HER2 monoclonal (Fludara), (Alimta), antibodies such as trastuzumab and pertuzumab, anti-VEGF (Coforin), (Leukerin), methotrexate monoclonal antibodies such as bevacizumab, and low (Methotrexate), and trifluridine.tipiracil hydrochloride molecular target compounds such as everolimus, lapatinib, (LonSurf); and Sorafenib for breast cancer; interferon C. for liver cancer; anticancer antibiotics Such as actinomycin D (Cosmegen), --5-fluorouracil for esophageal cancer, gemcitabine, (Aclacinon), (Calsed), TS-1 (tegafur-gimeracil-oteracil potassium), and capecit (Idamycin), epirubicin (epirubicin hydrochloride, Farmoru abine for biliary tract cancer; radiation+5-fluorouracil, bicin), Zinostatinstimalamer (Smancs), 5-fluorouracil--leucovori, 5-fluorouracil-doxorubicin-i-my (Daunopmycin), doxorubicin (Adriacin), (Pino tomycin C, and gemcitabine for pancreatic cancer; TC rubin, Terarubicin), (Bleo), peplomycin (Pepleo), therapy (taxans--cyclophosphamide) for ovarian cancer, (Mitomycin), (Novantron), and radiation for uterine cancer; and paclitaxel-gemcitabine-- liposomaldoxorubicin (DOXil); plant alkaloids Such as iri cisplatin for bladder cancer. notecan (Campto, Topotecin), (VePesid, Lastet), (Halaven), sobuzoxane (Perazolin), docetaxel 0060. The medicament of the present invention can be (Taxotere), nogitecan (Hycamtin), paclitaxel (Taxol), pacli administered as pirfenidone alone, but preferably adminis taxel injection (Abraxane), Vinorelbine (Navelbine), vin tered as oral or non-oral pharmaceutical composition, which cristine (Oncovin), (Fildesin), and are prepared by the known methods. (Exal); platinum compounds such as oxaliplatin (Elplat), 0061. As for the appropriate pharmaceutical composition carboplatin (Carboplatin, Carbomerck, Paraplatin), cisplatin for oral administration, for example there are provided (IA-call, Conabri, Cisplatin, etc.), and (Aqupla); tablets, capsules, fine granules, granules, liquid and solu hormonal agents such as anastroZole (Arimidex), exemes tions, and syrups. As the appropriate pharmaceutical com tane (Aromasin), estramustine (Estracyt, Biasetyl, Proesta), position for non-oral administration, for example there are ethinylestradiol (Prosexol), chlormadinone (Aptacor, Papa provided injections, Suppositories, inhalations, ophthalmic cor, Prostal, Prostat, etc.), goserelin (Zoladex), tamoxifen Solutions, nasal drops, ointments, creams, patches and so US 2017/0224667 A1 Aug. 10, 2017

forth. As for the preferable dosage form of the medicament pneumonia, and one patient of descquamative interstitial of this invention, there are pharmaceutical compositions for pneumonia). The patients in the pirfenidone group received oral administration. pirfenidone for 12-75 months (an average of 27.9+14.7 0062. The pharmaceutical composition of this invention months). As a result, the incidence of lung cancer in the is prepared by adding one or more pharmacologically or pirfenidone group was 2, whereas in the non-pirfenidone pharmaceutically acceptable additive(s) such as a diluting group it was 49. The duration of observation period in the agent, a disintegrating or collapsing agent, a binder, a pirfenidone group was 65.5+42.6 months, whereas in the lubricant, a coating agent, a pigment, a diluent, a basis, a control group it was 57.1+37.5 months. In addition, among dissolving or a solubilizing agent, a tonicity adjusting agent, 73 deaths in the non-pirfenidone group, 11 (4.7%) patients a pH modifier, a stabilizer, a aerosolized agent and an died by lung cancer, whereas among 29 deaths in the adhesive, but they are not limited to these. pirifenidone group, one (1.2%) patient died by lung cancer. 0063 As for the preparation of the pharmaceutical com These data indicate the chemopreventive effect of pirfeni position for oral administration including tablets, capsules, done on lung cancer. granules, and fine granules, diluting agents such as lactose, 0068 Results are shown in Table 1 and FIG. 1. crystalline cellulose, and starch; lubricants such as magne sium Stearate and talc, binders such as hydroxypropyl cel TABLE 1. lulose and polyvinylpyrrolidone; disintegrator Such as car boxymethylcellulose calcium, low substituted Result of lung cancer prevention through pir?enidone hydroxypropylmethylcellulose; and coating agents such as Pirfenidone Non-pirfenidone hydroxypropylmethylcellulose, macrogol, and silicone res group group p-value" ins can be used as needed. As for the preparation of the Number of patients 87 232 NS pharmaceutical composition for ophthalmic solutions, tonic Observation period 655 - 42.6 57.1 37.5 NS ity adjusting agents such as Sodium chloride, potassium (months) (range: 13-215) (range: 12-252) chloride and concentrated glycerin; buffering agents such as months months Treatment (months) 27.9 14.7 Sodium phosphate, sodium acetate, boric acid, and (range: 12-75) monoethanol amine; stabilizers such as Sodium citrate and months disodium edetate; preservatives such as benzalkonium chlo Incidence of lung 2 (2.3%) 49 (21.1%) <0.0001: ride and p-hydroxybenzoic ester, Surfactants such as poly cancer, N (%) Sorbate 80, and polyoxyethylene hydrogenated castor oil; Deaths, N (%) 29 (33.3%) 73 (31.5%) NS and pH modifiers such as diluted hydrochloric acid and Death by cancer, N (%) 1 (1.1%) 11 (4.7%) NS sodium hydroxide can be used as needed. The pH of the "Chi-squared test ophthalmic Solutions of the invention, not particularly lim *p < 0.05 ited, but is more preferably in the range between 4 and 8. which is permitted as an ophthalmic solution. 0069 FIG. 1 shows time course of incidence of lung 0064. Effective dosage of the medicament of this inven cancer in patients with idiopathic pulmonary fibrosis treated tion, not specifically limited, and is decided according to with/without pirfenidone. The accumulated incidences of conditions such as patient conditions, age, and body weight, lung cancer in patients with idiopathic pulmonary fibrosis route of administration, and kinds of active ingredient drug. not treated with pirfenidone after 1, 5, and 10 years were In one embodiment, when pirfenidone is administered 0.9%. 18.3%, and 26.8%, whereas in patients treated with orally, the daily dose is in the range from 50 mg to 3000 mg. pirfenidone after 1, 5, and 10 years the accumulated inci preferably 10 mg to 1000 mg, and is administered one time dences of lung cancer were 0%, 2.5%, and 6.4%. to several times a day. The above described dosage is for 0070 The risk factors of incidence of lung cancer were exemplification and can be adjusted arbitrarily. analyzed using logistic regression analysis. As for the vari 0065. The dosage regimen is adjusted when the medica ables, backgrounds such as age, sex, number of packs of ment of the present invention is used for cancer chemopre cigarettes Smoked per day by the number of years the person vention alone or with combination of other treatment drugs has Smoked (pack year), current Smoking, pulmonary for chemoprevention. Specifically, the optimal dosage regi emphysema, stage of idiopathic pulmonary fibrosis, lung functions (% vital capacity (VC), and forced expiratory vol men of pirfenidone is determined based on each of the ume in 1 second as percent of forced vital capacity: FEV combined treatment drugs. The dose of pirfenidone is pref 1%), respiratory function (carbon monoxide lung diffusing erably lowest dose which is more effective and less toxic, capacity; % DLCO), and arterial oxygen partial pressure since the medicament of the present invention is used for (PAO); home oxygen therapy (use/no use), pirfenidone prevention, and hence duration of the treatment is long. (use/no use), prednisolone (use/no use), N-acetyl cysteine (use/no use) and so forth were used. As a result, pack year, EXAMPLES current Smoking and pulmonary emphysema were found to 0066. The following examples are set forth so as to be factors which significantly increase the risk factors of provide a complete disclosure and description of how to incidence of lung cancer, while pirfenidone, N-acetyl cys make and use the present invention. The scope of the present teine and lung function (FEV 1%) were found to be factors invention is not limited to the following examples. which significantly decrease the risk factors of incidence of 0067. A total of 319 idiopathic pulmonary fibrosis lung cancer. Then, the factors affecting the incidence of lung patients that did not develop lung cancer were randomly cancer were analyzed using multivariate Cox proportion allocated into two groups. 87 in the pirfenidone group (83 hazard mode. The results are presented in Table 2. Four idiopathic pulmonary fibrosis, four nonspecific interstitial variables were found as affecting factors. Among them, pneumonia) and 232 in the non-pirfenidone group (213 current Smoking and pack year were the factors increasing idiopathic pulmonary fibrosis, 18 nonspecific interstitial the risk of lung cancer, whereas treatment with pirfenidone US 2017/0224667 A1 Aug. 10, 2017 was only factor decreasing the risk of lung cancer. This done as a pharmaceutical active ingredient. In another Supports the lung cancer protective efficacy of pirfenidone. embodiment, there are provided the use of pirfenidone for the production of a medicament containing pirfenidone for TABLE 2 cancer prevention, and methods for cancer chemoprevention comprising administering an effective amount of pirfeni Risk of lung cancer in patients with idiopathic pulmonary fibrosis# done for cancer prevention to mammals including human. 1-11. (canceled) 95% 12. A method of cancer chemoprevention which com confidence interval prises a step of administering an effective amount of pir Variable Hazard ratio LCL UCL p-value fenidone for cancer prevention to mammals including human. Pirfenidone O.128 O.O31 0.535 00048* Current Smoking 1122 1.037 1.213 O.OO41* 13. A method of cancer chemoprevention which com Pack years 2.629 1.457 4.743 O.OO13* prises a step of administering an effective amount of pir % of Pulmonary 1021 1.003 1.038 0.0219* fenidone for cancer prevention to a subject who has a high function (% VC) risk factor of carcinogenesis. #Hazard ratio and 95% confidence interval (95% CI) in multivariate Cox proportion hazard 14. The method of cancer chemoprevention according to model analysis *p < 0.05 claim 13, wherein said high risk factor of carcinogenesis is LCL: Lower confidence limit idiopathic pulmonary fibrosis. UCL: upper confidence limit 15. The method of cancer chemoprevention according to claim 12, wherein any other pharmaceutical active drug is 0071 Cancer micro environment plays a great role in further administered as a concomitant drug. growth of cancer and malignant alteration of cancer cells. 16. The method of cancer chemoprevention according to Especially, fibroblast and mesenchymal stem cell in stromal claim 15, wherein said any other pharmaceutical active drug tissue of cancer, epithelial-mesenchymal transition (EMT) is a drug which prevents carcinogenesis, inhibits indirectly from cancer cells, or mesenchymal stem cell-derived acti growth of cancer and/or directly inhibits growth of cancer. vated cancer-associated fibroblast (CAF) are heavily 17. The method of cancer chemoprevention according to involved in cancer progression and malignant alteration of claim 15, wherein said any other pharmaceutical active drug cancer cells. Pirfenidone inhibits transforming growth fac is used as adjuvant chemotherapeutic drug. tor-3 (TGF-B), which activates the cancer micro environ 18. A method of cancer chemoprevention which com ment, resulting in suppression of activated CAF and pre prises a step of administering an effective amount of vention of cancer under a pre-cancerous stage. This 5-methyl-1-phenyl-2-(1H)-piridone for cancer prevention to Pirfenidone's efficacies on prevention of cancer can be mammals including human. confirmed by known experimental methods. 19. A method of cancer chemoprevention of lung cancer which comprises a step of administering an effective amount INDUSTRIAL APPLICABILITY of pirfenidone for cancer prevention to mammals including 0072 This invention provides the medicament for treat human. ment of cancer chemoprevention which comprises pirfeni