Prodrugs and medical uses thereof
The invention relates to nitrogen mustards bearing substituted piperazine carboxamide and their corresponding pharmaceutically acceptable salts as cytotoxic agents that target tumours and methods of use thereof, alone or in combination with other cancer treatments.
1 . A method for the treatment of a solid, metastatic cancer affecting a Human patient, wherein said solid cancer is selected from a group consisting of breast cancer and pancreatic cancer, comprising a step of administering an effective amount of 2-((2-bromoethyl) (5-(4-ethylpiperazine-1-carbonyl)-2-(methylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate or a pharmaceutically acceptable salt, solvate, or stereoisomer of said compound, wherein presence of a hypoxia gene expression signature has been assessed and confirmed in said solid metastatic cancer, and wherein said patient has previously been treated with a radiotherapy, chemotherapy, and/or an immunotherapy.
2 . The method of claim 1 , wherein the compound is administered to said Human patient who has been previously treated with a compound selected from a group consisting of carboplatin, cisplatin, miboplatin, nedaplatin or oxaliplatin.
3 . The method of claim 1 , wherein the compound prevents drug resistance, immunological escape, relapse, or metastasis of said cancer in said Human patient.
4 . The method of claim 1 , wherein the compound is formulated for parenteral, intratumoral, trans-arterial embolization, or oral administration.
5 . The method of claim 1 , wherein the compound is administered at a dose comprised between 40 and 10,000 mg/m 2 .
6 . The method of claim 1 , wherein the compound is administered to said Human patient, simultaneously or sequentially, with another therapeutic agent or therapy.
7 . The method of claim 6 , wherein the other therapy is radiotherapy.
8 . The method of claim 6 , wherein the other therapy is chemotherapy.
9 . The method of claim 1 , wherein the hypoxia gene expression signature is assessed using pimonidazole (PIMO+) staining or an equivalent assessment.
10 . The method of claim 1 , wherein the chemotherapy is cisplatin.
11 . The method of claim 8 , wherein the chemotherapy is selected from cisplatin, carboplatin, paclitaxel, gemcitabine, docetaxel, doxorubicin, gemcitabine: nab-paclitaxel.
12 . The method of claim 1 , wherein said solid cancer is triple negative breast cancer or pancreatic ductal adenocarcinoma.
13 . A method for the treatment of a solid, metastatic cancer affecting a Human patient comprising:
selecting said solid metastatic cancer from a group consisting of breast cancer and pancreatic cancer;
assessing a homologous recombination and DNA repair mechanism status of said solid cancer and confirming said solid cancer has a hypoxia gene expression signature; and
administering an effective amount of 2-((2-bromoethyl) (5-(4-ethylpiperazine-1-carbonyl)-2-(methylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate or a pharmaceutically acceptable solvate, or stereoisomer thereof in said cancer.
14 . The method of claim 13 , wherein said hypoxia gene signature has been confirmed for said solid cancer using pimonidazole (PIMO+) staining or an equivalent assessment.
15 . The method of claim 13 , wherein the compound is administered to said Human patient, simultaneously or sequentially, with another therapeutic agent or therapy.
16 . The method of claim 15 , wherein the other therapy is selected from cisplatin, carboplatin, paclitaxel, gemcitabine, docetaxel, doxorubicin, gemcitabine or nab-paclitaxel.
17 . The method of claim 16 , wherein the said 2-((2-bromoethyl) (5-(4-ethylpiperazine-1-carbonyl)-2-(methylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate or a pharmaceutically acceptable solvate, or stereoisomer thereof is administered in a combination therapy with radiotherapy.
18 . The method of claim 15 , wherein the said 2-((2-bromoethyl) (5-(4-ethylpiperazine-1-carbonyl)-2-(methylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate or a pharmaceutically acceptable solvate, or stereoisomer thereof is administered in a combination therapy with another compound selected from carboplatin, cisplatin, miboplatin, nedaplatin or oxaliplatin.