Platinum-resistant cancer treatment

Abstract

A compound of formula I or a pharmaceutically acceptable salt or ester thereof is provided for the treatment of cancer wherein (i) the cancer is one that has the characteristic of being a type prone to being or becoming refractory or resistant to platinum drug based therapy and (ii) the treatment is with a dose of between 1 mg/m 2 and 30 mg/m 2 of compound per patient body surface area per administration. Method of treatment and novel dosage forms are also provided. Particularly treated are ovarian cancers, particularly those expressing a-folate receptors, including epithelial ovarian, fallopian tube or peritoneal cancer.

1 . A method of treating cancer comprising administering to a patient in need thereof a compound of formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof for the treatment of cancer wherein
 (i) the cancer is one that has the characteristic of being a type prone to being or becoming refractory or resistant to platinum drug based therapy and 
 (ii) the treatment is with a dose of between 1 mg/m 2  and 30 mg/m 2  of compound per patient body surface area per administration. 
 
     
     
         2 - 21 . (canceled) 
     
     
         22 . A method for treating a patient suffering from a cancer that has the characteristic of being a type prone to being or becoming refractory or resistant to platinum drug based therapy and wherein the treatment is with a dose of between 1 mg/m 2  and 30 mg/m 2  of compound per patient body surface area per administration of a compound of formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof for the treatment of cancer. 
     
     
         23 . (canceled) 
     
     
         24 . A method as claimed in  claim 22  wherein the treatment with the compound of the formula I is given in combination with a regimen administering a therapeutically effective amount of one or more further anticancer agents. 
     
     
         25 . A method as claimed in  claim 24 , wherein the treatment comprises administering a composition comprising the compound of the formula I and the one or more further anticancer agents. 
     
     
         26 . A method as claimed in  claim 24 , wherein the compound of the formula I and the one or more further anticancer agents are administered separately. 
     
     
         27 . A method as claimed in  claim 24 , wherein the administration of the compound of the formula I and the administration of the one or more further anticancer agents are separated by 12 hours. 
     
     
         28 . A method as claimed in  claim 24 , wherein the administration of the compound of the formula I and the administration of the one or more further anticancer agents are separated by 24 hours. 
     
     
         29 . A method as claimed in  claim 24 , wherein the administration of the compound of the formula I and the administration of the one or more further anticancer agents are separated by 36 hours. 
     
     
         30 . A method as claimed in  claim 24 , wherein the administration of the compound of the formula I and the administration of the one or more further anticancer agents are separated by 38 hours. 
     
     
         31 . A method as claimed in  claim 24 , wherein the administration of the compound of the formula I and the administration of the one or more further anticancer agents are performed on alternate weeks of a 7 day dosing schedule. 
     
     
         32 . A method as claimed in  claim 24 , wherein the administration of the compound of the formula I and the administration of the one or more further anticancer agents are performed on alternate weeks of a 14 day dosing schedule. 
     
     
         33 . A method as claimed in  claim 24  wherein the one or more further anticancer agents used in this combination therapy are selected from Cisplatin, Carboplatin, Doxorubicin, Bevacizumab Gemcitabine, Topetecan, Paclitaxel, Docetaxel, Etoposide, Nanoparticle albumin-bound paclitaxel, Lynparza (olaparib), Rubraca (rucaparib), Zejula (niraparib). Tecentriq (atezoizumab), Bavercio (avelumab). 
     
     
         34 . A method as claimed in  claim 24  wherein the treatment includes combinations of the compound of formula I administered together with a regimen administering bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan. 
     
     
         35 . A dosage form of a compound of formula I 
       
         
           
           
               
               
           
         
       
       comprising a single dosage unit containing said compound or a pharmaceutically acceptable salt or ester thereof characterised in that the amount of said compound in the dosage unit is between 0.5 mg and 40 mg. 
     
     
         36 - 49 . (canceled) 
     
     
         50 . A method of treating cancer comprising administering to a patient in need thereof a compound chosen from formula I 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts or esters thereof, wherein
 (i) the cancer is one that has the characteristic of being a type prone to being or becoming refractory or resistant to platinum drug based therapy; 
 (ii) the treatment is with a dose of from 1 mg/m 2  to 30 mg/m 2  of compound per patient body surface area per administration; and 
 (iii) the dose is administered intraperitoneally (IP). 
 
     
     
         51 . A method for treating a patient suffering from a cancer that has the characteristic of being a type prone to being or becoming refractory or resistant to platinum drug based therapy and wherein the treatment is with a dose of from 1 mg/m 2  to 30 mg/m 2  of compound per patient body surface area per administration of a compound of formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof for the treatment of cancer, wherein the dose is administered intraperitoneally (IP). 
     
     
         52 . A method as claimed in  claim 51  wherein the treatment with the compound of the formula I is given in combination with a regimen administering a therapeutically effective amount of one or more further anticancer agents. 
     
     
         53 . A method of treating cancer comprising administering to a patient in need thereof a compound chosen from formula I 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts or esters thereof, wherein
 (i) the cancer is one that has the characteristic of being a type prone to being or becoming refractory or resistant to platinum drug based therapy; 
 (ii) the treatment is with a dose of from 1 mg/m 2  to 30 mg/m 2  of compound per patient body surface area per administration; and 
 (iii) wherein at least one side effect associated with classical thymidylate synthase inhibitors or alpha folate receptor antibody drug conjugates is not observed. 
 
     
     
         54 - 73 . (canceled) 
     
     
         74 . A method of treating cancer comprising administering to a patient in need thereof a compound chosen from formula I 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts or esters thereof, wherein
 (i) the cancer is one that has the characteristic of being a type prone to being or becoming refractory or resistant to platinum drug based therapy; 
 (ii) the treatment is with a dose that achieves a concentration of about 0.5 μM or greater of the compound for at least 72 hrs. 
 
     
     
         75 - 99 . (canceled) 
     
     
         100 . A method of treating cancer comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof wherein
 (i) the cancer is one that has the characteristic of being a type prone to being or becoming refractory or resistant to platinum drug based therapy and 
 (ii) the treatment is with a dose of between 1 mg/m 2  and 30 mg/m 2  of compound per patient body surface area per administration.