US 20200121788A1 IN (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0121788 A1 MASSIMINI et al. (43 ) Pub . Date : Apr. 23 , 2020 ( 54 ) ABITUZUMAB FOR THE TREATMENT OF A61K 31/44 (2006.01 ) COLORECTAL CANCER A61P 35/00 (2006.01 ) (52 ) U.S. Cl. ( 71) Applicant: Merck Patent GmbH , Darmstadt (DE ) CPC ... A61K 39/39558 (2013.01 ) ; CO7K 16/2848 ( 2013.01 ) ; CO7K 16/2863 ( 2013.01 ) ; CO7K ( 72 ) Inventors: Giorgio MASSIMINI, Darmstadt (DE ) ; 16/22 (2013.01 ) ; A61K 31/4745 ( 2013.01 ) ; Ilhan Celik , Zwingenberg (DE ) ; Josef A61K 31/513 ( 2013.01 ) ; A61K 2039/505 Straub , Seeheim - Jugenheim (DE ) ; Rolf ( 2013.01) ; A61K 31/519 ( 2013.01 ) ; A61K Bruns, Darmstadt ( DE ) 33/243 (2019.01 ) ; A6IK 38/179 ( 2013.01) ; A61K 31/44 ( 2013.01) ; A61P 35/00 ( 2018.01 ) ; ( 73 ) Assignee: Merck Patent GmbH , Darmstadt (DE ) CO7K 2317/76 ( 2013.01) ; A61K 31/7072 ( 21 ) Appl. No .: 16 /657,828 ( 2013.01) ( 22 ) Filed : Oct. 18 , 2019 (57 ) ABSTRACT Methods of treatment of colorectal cancer can include the Related U.S. Application Data administration of the anti - alpha - v integrin (receptor ) anti (60 ) Provisional application No. 62 / 748,114 , filed on Oct. body Abituzumab . Preferably , the methods of treating col 19 , 2018 . orectal cancer can include treating Stage II - IV colorectal cancer, metastatic colorectal cancer , left - sided colorectal Publication Classification cancer and /or left- sided metastatic colorectal cancer, involv ( 51) Int. Ci. ing the administration of said Abituzumab to patients in need A61K 39/395 ( 2006.01 ) thereof. Abituzumab is also useful for the manufacture of a COZK 16/28 ( 2006.01 ) medicament for treating colorectal cancer , preferably col COOK 16/22 ( 2006.01 ) orectal cancer as defined herein . Abituzumab is further A61K 31/4745 ( 2006.01 ) useful for the manufacture of a medicament for treating A61K 31/513 ( 2006.01 ) colorectal cancer in combination with suitable targeted A61K 31/7072 ( 2006.01) therapy concepts , such as growth factor or growth factor A61K 31/519 ( 2006.01) receptor targeting monoclonal antibodies , and / or chemo A61K 33/243 ( 2006.01 ) therapy . A61K 38/17 ( 2006.01 ) Specification includes a Sequence Listing . mo 20 Submucosa Patent Application Publication Apr. 23, 2020 Sheet 1 of 11 US 2020/0121788 A1 ROAD IT!!! Subset Fig . 1 Patent Application Publication Apr. 23, 2020 Sheet 2 of 11 US 2020/0121788 A1 M 3 ** Fig . 2 Fig . 3 Patent Application Publication Apr. 23, 2020 Sheet 3 of 11 US 2020/0121788 A1 Randomized phase il part 5338 Abluzumab 1,000 mg every 2 weeks + Soc 2 Fig . 4 Patent Application Publication Apr. 23, 2020 Sheet 4 of 11 US 2020/0121788 A1 KHASiruan in : 3 ) Randorismo ( 26) located to abituzumal 500173 Allocated to returnabinoiochi cocinab u vinoteoan ( 73 ) Donec accated interverter Donceive allocated * Did not receive allocied Intervention ( 2 ) Lost to folk - p19isy Los tonowa ini ) Discontinued intervention 107 Disexso progresa33 - Disease progress (0-10 ) -Deprogression ( 2 ) Adverse event marceptabi koly attem Muldew but Survival data . - Dia.costante iuxcity without -Utacceptable toxicity without cose reochon ( 2 ) Analysedior ITpoulation ( +33 Bigios to virstwe surgery: ... 17 ( 2 Analysed in ITT Beniculation ( 332 Fig . 5 Patent Application Publication Apr. 23, 2020 Sheet 5 of 11 US 2020/0121788 A1 A Abituzumab 500 mg ?? *** per ?? Fig . 6A Patent Application Publication Apr. 23, 2020 Sheet 6 of 11 US 2020/0121788 A1 Suzumab 500 mg Pionsbilityofsurvival 3 2 goan 7 tuzumab 1000 rg 7 : ?? Fig . 6B Patent Application Publication Apr. 23, 2020 Sheet 7 of 11 US 2020/0121788 A1 20 Fig . 7 Patent Application Publication Apr. 23, 2020 Sheet 8 of 11 US 2020/0121788 A1 wwwwwwwww wwwwwww -- nie Fig . 8 Patent Application Publication Apr. 23, 2020 Sheet 9 of 11 US 2020/0121788 A1 Abituzzo 500 YO (KROSS 185 % C1030-100 ] .. yummm 5 1 *** Jonas moment Fig . 9 Patent Application Publication Apr. 23 , 2020 Sheet 10 of 11 US 2020/0121788 A1 ? 0 017 06 34 0 3 3 23 27 Overal survival (months ) 25AN . Atidex120 1080p Fig . 10A Patent Application Publication Apr. 23 , 2020 Sheet 11 of 11 US 2020/0121788 A1 3 0 my X 3 Fig . 10B US 2020/0121788 Al Apr. 23, 2020 1 ABITUZUMAB FOR THE TREATMENT OF [0006 ] In both cancer of the colon and rectum , chemo COLORECTAL CANCER therapy may be used in addition to surgery in certain cases . In rectal cancer , chemotherapy may be used in the neoad CROSS - REFERENCE TO RELATED juvant setting. APPLICATIONS [0007 ] If cancer has entered the lymph nodes , adding the chemotherapy agents fluorouracil or capecitabine increases [0001 ] The present application claims the benefit to the life expectancy. If the lymph nodes do not contain cancer , provisional application 62 / 748,114 , filed on Oct. 19 , 2018 , the benefits of chemotherapy are controversial. If the cancer which is incorporated by reference in its entirety . is widely metastatic or unresectable , up to now , treatment is mainly palliative . Typically in this setting , a number of REFERENCE TO A SEQUENCE LISTING different chemotherapy medications may be used . Chemo therapy drugs for this condition may include capecitabine , [0002 ] The present application incorporates by reference fluorouracil, irinotecan , leucovorin , oxaliplatin and UFT . the material in the ASCII text file “ 2019-10-07 - P18-218_ Preferably , fluorouracil may be administered as its Prodrugs , ST25.txt ,” created on Oct. 7 , 2019 , having a size of 7878 such as Capecitabine and / or 5 -Fluorocytosine . Another type bytes , which is submitted herewith . of agent that is sometimes used are the epidermal growth factor receptor inhibitors . BACKGROUND OF THE INVENTION [0008 ] While a combination of radiation and chemo therapy may be useful for rectal cancer, its use in colon Field of the Invention cancer is not routine due to the sensitivity of the bowels to [0003 ] Methods of treatment of colorectal cancer can radiation . Just as for chemotherapy , radiotherapy can be comprise the administration of the anti- alpha - v integrin used in the neoadjuvant and adjuvant setting for some stages ( receptor ) antibody Abituzumab . Preferably , such methods of rectal cancer. relate to treating colorectal cancer , Stage II - IV colorectal [0009 ] However , the indication colorectal cancer (CRC ) is cancer , metastatic colorectal cancer, left - sided colorectal known and widely understood in the art. Preferably , col cancer and / or left - sided metastatic colorectal comprising the orectal cancer is a heterogeneous indication disease that can administration of said Abituzumab to patients in need preferably be distinguished by characteristics, including , but thereof. More preferably , such methods relate to treating not limited to the location of origin , the kind of tissue colorectal cancer , preferably the above given kinds or stages affected and /or the stage of the disease as it develops. of colorectal cancer , said methods comprising the adminis [0010 ] The staging of colorectal cancer is widely known tration of the anti - alpha - v integrin ( receptor) antibody Abitu and understood in the art . Preferably , the different stages of zumab additionally to an existing treatment or treatment development are divided in four or five categories , prefer regimen for said kinds or stages of colorectal cancer. Thus, ably four categories. The earliest stage colorectal cancers are Abituzumab may be used for the manufacture of a medica preferably categorised “ stage 0 ” ( a very early cancer) , and ment for treating colorectal cancer , preferably colorectal then range from stages I ( 1 ) through IV ( 4 ). As a rule , the cancer as defined herein , and / or Abituzumab for the manu lower the number, the less the cancer has developed , pro facture of a medicament for treating colorectal cancer in gressed and /or spread . A higher number , such as stage IV , combination with suitable targeted therapy concepts , such as preferably means cancer has spread more . And within a growth factor or growth factor receptor targeting monoclo stage , an earlier letter preferably means a lower stage . nal antibodies , and / or chemotherapy . Although each person's cancer experience is unique, cancers with similar stages tend to have a similar outlook and are Discussion of the Background often treated in much the same way. [ 0004 ] Colorectal cancer ( preferably also known as colon [0011 ] The staging system most often used for colorectal cancer , rectal cancer and /or bowel cancer ) is when cancer cancer is the American Joint Committee on Cancer ( AJCC ) develops in the colon or rectum (parts of the large intestine ). TNM system , which is based on 3 key pieces of information : It is due to the abnormal growth of cells that they generally [ 0012 ] The extent (size ) of the tumor ( T ) : How far has have the ability to invade or spread to other parts of the body. the cancer grown into the wall of the colon or rectum ? [ 0005 ] To date , treatments used for colorectal cancer may These layers , from the inner to the outer layers as include some combination of surgery , radiation therapy , shown in FIG . 1 , include : chemotherapy and targeted therapy . Cancers that are con [0013 ] The inner lining (mucosa ), which is the layer fined within the wall of the colon may be curable with surgery while cancer that has spread widely are usually not in which nearly all colorectal cancers start . This curable with management focusing on improving quality of includes a thin muscle layer (muscularis mucosa ) . life and symptoms. Five -year survival rates in the United [0014 ] The fibrous tissue beneath this muscle layer States are around 65 % . This , however , depends on how ( submucosa ) advanced the cancer is , whether or not all the cancer can be [ 0015 ] A thick muscle layer (muscularis propria ) removed with surgery, and the person's overall health . Globally , colorectal cancer is the third most common type of [0016 ] The thin , outermost layers of connective tis cancer making up about 10 % of all cases .