Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention generally relates to pharmaceutical compositions and methods for treating cancer, and particularly to a combination therapy with a gallium complex.
• Tris(8-quinolinolato)gallium(in) is an organic gallium complex that has been suggested to be useful in certain types of cancer.
• US Patent No. 7,919,486 discloses and claims the use of tris(8-quinolinolato)gallium(III) and related compounds for the treatment of melanoma.
• the present invention provides a method of treating breast or colorectal cancer in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) and 5-fluorouracil or a prodrug thereof.
• the present invention provides a method of treating breast cancer in a patient in need of such treatment comprising administering to the patient a
• the present invention provides a method of treating cancer (e.g., lung cancer or renal cell carcinoma) in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) and a second drug that is gemcitabine or temsirolimus.
• cancer e.g., lung cancer or renal cell carcinoma
• a second drug that is gemcitabine or temsirolimus.
• the present invention provides a method of treating prostate cancer in a patient in need of such treatment comprising administering to the patient a
• the present invention provides a method of treating cancer (e.g., melanoma or glioblastoma) in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) and temozolomide.
• cancer e.g., melanoma or glioblastoma
• temozolomide e.g., melanoma or glioblastoma
• the present invention provides a method of treating cancer (e.g., multiple myeloma, MDS) in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) and lenalidomide or thalidomide.
• cancer e.g., multiple myeloma, MDS
• administering comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) and lenalidomide or thalidomide.
• the present invention provides a method of treating cancer (e.g., non-small cell lung cancer) comprising administering to a patient in need of treatment sequentially first with a therapeutically effective amount of a compound of Formula (I) (e.g., tris(8-quinolinolato)gallium(ni)), and then a therapeutically effective amount of erlotinib.
• a compound of Formula (I) e.g., tris(8-quinolinolato)gallium(ni)
• the present invention provides a method of treating cancer (e.g., non-small cell lung cancer) comprising administering to a patient in need of treatment sequentially first with a therapeutically effective amount of paclitaxel, and then a
• a compound of Formula (I) e.g., tris(8- quinolinolato)gallium(III)
• compositions and kits comprising a therapeutically effective amount of a compound of Formula (I) below, particularly tris(8-quinolinolato)gallium(III), and a second anti-cancer drug as described above are also provided.
• Figure 1 is a combination index plot illustrating the additive to synergistic activity between tris(8-quinolinolato)gallium(III) and 5-FU in the breast carcinoma cell line ZR-75-1.
• Figure 2 is a combination index plot illustrating the additive to synergistic activity between tris(8-quinolinolato)gallium(III) and paclitaxel in the breast carcinoma cell line ZR- 75-1.
• Figure 3 is a combination index plot illustrating the additive to synergistic activity between tris(8-quinolinolato)gallium(III) and 5-FU in the colorectal adenocarcinoma cell line LoVo.
• Figure 4 is a combination index plot illustrating the additive to synergistic activity between tris(8-quinolinolato)gallium(III) and docetaxel in the prostate carcinoma cell line LNCaP-1.
• Figure 5 is a combination index plot illustrating the additive to synergistic activity between tris(8-quinolinolato)gallium(III) and temsirolimus in the lung carcinoma cell line A549.
• Figure 6 is a combination index plot illustrating the additive to synergistic activity between tris(8-quinolinolato)gallium(III) and gemcitabine in the lung carcinoma cell line A549.
• Figure 7 is a combination index plot illustrating the additive to synergistic activity between tris(8-quinolinolato)gallium(III) and temozolomide in the malignant melanoma cell
• Figure 8 shows the combined growth inhibitory activities of tris(8- quinolinolato)gallium(III) and lenalidomide against the multiple myeloma tumor cell line RPMI-8226.
• Y axis % control;
• X axis Concentration (uM).
• Figure 9 shows combination index plots illustrating antagonism (circle) between erlotinib and tris(8-quinolinolato)gallium(III) in lung carcinoma cell line A549 treated sequentially first with erlotinib and then with tris(8-quinolinolato)gallium(III); and synergism (square) when treated in the reverse sequence.
• Figure 10 shows combination index plots illustrating antagonism (square) between paclitaxel and tris(8-quinolinolato)gallium(III) in lung carcinoma cell line NCI-H322M treated sequentially with tris(8-quinolinolato)gallium(III) first and then with paclitaxel, but synergism (circle) between the two drugs when used in a reverse sequence.
• Figure 11 shows a combination index plot illustrating the antagonism between doxorubicin and tris(8-quinolinolato)gallium(III) in colon cancer LoVo cell line.
• Figure 12 shows a combination index plot illustrating antagonistic activity between tris(8-quinolinolato)gallium(ni) and paclitaxel in the colorectal adenocarcinoma cell line LoVo.
• the present invention provides a method of treating cancer by a combination therapy.
• the method comprises treating a cancer patient in need of treatment with
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof; and simultaneously or sequentially (2) a second anti-cancer drug as described below.
• the phrase "treating . . . with . . .” means administering a compound to the patient or causing the formation of a compound inside the patient.
• pharmaceutically acceptable salts refers to the relatively non-toxic, organic or inorganic salts of the active compounds, including inorganic or organic acid addition salts of the compound.
• a method of treating breast cancer or colorectal cancer in a patient comprising (1) administering to the cancer patient in need of treatment a therapeutically effective amount of a compound of Formula (I):
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof; and simultaneously or sequentially (2) administering to said cancer patient a therapeutically effective amount of 5-fluorouracil or a prodrug thereof (e.g., capecitabine, SI or tegafur).
• a therapeutically effective amount of 5-fluorouracil or a prodrug thereof e.g., capecitabine, SI or tegafur.
• the method comprises administering a therapeutically effective amount of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof to a cancer patient who is under treatment of 5- fluorouracil or a prodrug thereof (e.g., capecitabine, SI or tegafur), or administering a therapeutically effective amount of a 5-fluorouracil or a prodrug thereof (e.g., capecitabine, SI or tegafur) to a cancer patient who is under treatment of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof.
• a therapeutically effective amount of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof e.g., capecitabine, SI or tegafur
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in simultaneous or sequential combination with 5-fluorouracil or a prodrug thereof (e.g., capecitabine, SI or tegafur) for treating breast cancer or colorectal cancer.
• the present invention provides a use of 5-fluorouracil or a prodrug thereof (e.g., capecitabine, SI or tegafur) for the manufacture of a medicament useful in combination with a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for treating breast cancer or colorectal cancer.
• a method of treating breast cancer in a patient comprising (1) administering to the cancer patient in need of treatment a therapeutically effective amount of a com ound of Formula (I):
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof; and simultaneously or sequentially (2) administering to said cancer patient a therapeutically effective amount of paclitaxel or a prodrug thereof (e.g., Abraxane ®
• the method comprises administering a therapeutically effective amount of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof to a breast cancer patient who is under treatment of paclitaxel or a prodrug thereof, or administering a therapeutically effective amount of paclitaxel or a prodrug thereof (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)) to a cancer patient who is under treatment of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof.
• a therapeutically effective amount of paclitaxel or a prodrug thereof e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in simultaneous or sequential combination with paclitaxel or a prodrug thereof (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)) for treating breast cancer.
• paclitaxel or a prodrug thereof e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)
• the present invention provides a use of paclitaxel or a prodrug thereof for the manufacture of a medicament useful in combination (simultaneous or sequential) with a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for treating breast cancer.
• a method of treating prostate cancer in a patient comprising (1) administering to the cancer patient in need of treatment a therapeutically
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof; and simultaneously or sequentially (2) administering to said cancer patient a therapeutically effective amount of docetaxel.
• the method comprises administering a therapeutically effective amount of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof to a prostate cancer patient who is under treatment of docetaxel or a prodrug thereof, or administering a therapeutically effective amount of docetaxel to a cancer patient who is under treatment of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof.
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in combination (simultaneous or sequential) with docetaxel for treating prostate cancer.
• the present invention provides a use of docetaxel for the manufacture of a medicament useful in combination (simultaneously or sequentially) with a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for treating prostate cancer.
• a method of treating lung cancer comprising (1) administering to the cancer patient in need of treatment a therapeutically effective amount of a compound of Formula (I):
• the method comprises administering a therapeutically effective amount of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof to a lung cancer patient who is under treatment of gemcitabine, or administering a therapeutically effective amount of gemcitabine to a lung cancer patient who is under treatment of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof.
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in combination (simultaneously or sequentially) with gemcitabine for treating lung cancer.
• the present invention provides use of gemcitabine for the manufacture of a medicament useful in combination (simultaneously or sequentially) with a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for treating lung cancer.
• a method of treating cancer comprising (1) administering to the cancer patient in need of treatment a cancer (e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors) in a patient comprising (1) administering to the cancer patient in need of treatment a cancer (e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)) in a patient comprising (1) administering to the cancer patient in need of treatment a cancer (e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)) in a patient comprising (1) administering to the cancer patient in need of treatment a cancer (e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)) in a patient comprising (1) administering
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof; and simultaneously or sequentially (2) administering to said cancer patient a therapeutically effective amount of temsirolimus.
• the method comprises administering a therapeutically effective amount of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof to a cancer patient (e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)) who is under treatment of temsirolimus, or administering a therapeutically effective amount of temsirolimus to a cancer patient (e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)) who is under treatment of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof.
• a cancer patient e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)
• a cancer patient e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in combination (simultaneously or sequentially) with temsirolimus for treating cancer (e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)).
• cancer e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)).
• the present invention provides use of temsirolimus for the manufacture of a medicament useful in combination (simultaneously or sequentially) with a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for treating cancer (e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)).
• cancer e.g., non-small cell lung cancer, renal cell carcinoma, or neuroendocrine tumors (e.g., pancreatic neuroendocrine tumors)
• a method of treating cancer e.g., melanoma or brain tumor such as glioblastoma
• administering to the cancer patient in need of treatment a thera eutically effective amount of a compound of Formula (I):
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof; and simultaneously or sequentially (2) administering to said cancer patient a therapeutically effective amount of temozolomide.
• the method comprises administering a therapeutically effective amount of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof to a cancer patient (diagnostic with e.g., melanoma or brain tumor such as glioblastoma) who is under treatment of temozolomide, or administering a therapeutically effective amount of temozolomide to a melanoma patient who is under treatment of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof.
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in combination
• temozolomide for treating cancer (e.g., melanoma or brain tumor such as glioblastoma).
• cancer e.g., melanoma or brain tumor such as glioblastoma.
• the present invention provides use of temozolomide for the manufacture of a medicament useful in combination
• cancer e.g., melanoma or brain tumor such as glioblastoma.
• a method of treating cancer e.g., multiple myeloma or
• MDS myelodysplastic syndromes
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof; and simultaneously or sequentially (2) administering to said cancer patient a therapeutically effective amount of lenalidomide or thalidomide.
• the method comprises administering a therapeutically effective amount of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof to a cancer patient (e.g., having multiple myeloma or MDS) who is under treatment of lenalidomide or thalidomide, or administering a therapeutically effective amount of lenalidomide or thalidomide to a cancer (e.g., multiple myeloma or MDS) patient who is under treatment of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof.
• a cancer patient e.g., having multiple myeloma or MDS
• a cancer patient e.g., multiple myeloma or MDS
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in combination (simultaneously or sequentially) with lenalidomide or thalidomide for treating cancer (e.g., multiple myeloma or MDS).
• the present invention provides use of lenalidomide or thalidomide for the manufacture of a medicament useful in combination (simultaneously or sequentially) with a compound of Formula (I) above or a pharmaceutically acceptable salt thereof for treating cancer (e.g., multiple myeloma or MDS).
• the present invention provides a method of treating cancer (e.g, non-small cell lung cancer) comprising administering to the cancer patient in need of treatment se uentiall , first a therapeutically effective amount of a compound of Formula (I):
• cancer e.g, non-small cell lung cancer
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof (e.g., tris(8-quinolinolato)gallium(III)), and then a therapeutically effective amount of erlotinib.
• M is a metal ion
• R 2 represents hydrogen
• R 1 is CI
• R 2 is I
• a pharmaceutically acceptable salt thereof e.g., tris(8-quinolinolato)gallium(III)
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof (e.g., tris(8- quinolinolato)gallium(III)) for the manufacture of a medicament useful in a sequential combination with erlotinib for treating cancer (e.g., non-small cell lung cancer), wherein the compound of Formula (I) above or a pharmaceutically acceptable salt thereof (e.g., tris(8- quinolinolato)gallium(III)) is administered first and erlotinib is administered second.
• a pharmaceutically acceptable salt thereof e.g., tris(8- quinolinolato)gallium(III)
• the present invention provides a method of treating cancer (e.g., non-small cell lung cancer) comprising administering to the cancer patient in need of treatment sequentially, first a therapeutically effective amount of paclitaxel or a prodrug thereof (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)), and then a thera eutically effective amount of a compound according to Formula (I):
• cancer e.g., non-small cell lung cancer
• a therapeutically effective amount of paclitaxel or a prodrug thereof e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)
• R 1 represents hydrogen, a halogen or a sulfono group SO 3 M, in which M is a metal ion, and R 2 represents hydrogen, or R 1 is CI and R 2 is I, or a pharmaceutically acceptable salt thereof (e.g., tris(8-quinolinolato)gallium(III)).
• the present invention provides a use of a compound of Formula (I) above or a pharmaceutically acceptable salt thereof (e.g., tris(8-quinolinolato)gallium(III)) for the manufacture of a medicament useful in sequential combination with paclitaxel or a prodrug thereof (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)) for treating cancer (e.g., non-small cell lung cancer), wherein paclitaxel or a prodrug thereof (e.g., Abraxane ® (paclitaxel protein- bound particles for injectable suspension)) is administered first and the compound of Formula (I) above or a pharmaceutically acceptable salt thereof (e.g., tris(8- quinolinolato)gallium(III)) is administered second.
• paclitaxel or a prodrug thereof e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)
• cancer e.g
• the compound of Formula (I) is tris(8-quinolinolato)gallium(III).
• Tris(8-quinolinolato)gallium(III) also known as tris-(8-hydroxyquinoline)gallium, is a gallium complex compound first made by Professor Bernhard Keppler and is disclosed in, e.g., US Patent No. 5,525,598.
• a patient having cancer is identified or diagnosed, and such patient is treated with a therapeutically effective amount of an anticancer drug such as 5-FU or a prodrug thereof (e.g., capecitabine, tegafur, SI), paclitaxel or a prodrug thereof (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)), docetaxel, gemcitabine, temsirolimus, temozolomide, lenalidomide, thalidomide and erlotinib in combination with (simultaneously or sequentially) a
• an anticancer drug such as 5-FU or a prodrug thereof (e.g., capecitabine, tegafur, SI), paclitaxel or a prodrug thereof (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension)), docetaxel, gemcitabine, temsirolimus, temozolomide, len
• a compound of Formula (I) such as tris(8- quinolinolato)gallium(III).
• the compound of Formula (I) such as tris(8-quinolinolato)gallium(III) and the other anti-cancer drug(s) can be administered at about the same time, or separately according to their respective dosing schedules or regimens.
• the gallium compound and the other anti-cancer drug(s) can be administered in the same pharmaceutical composition or in separate dosage unit forms.
• the compound tris(8-quinolinolato)gallium(III) can be administered, e.g., orally at a dosing of from 0.1 mg to 3000 mg at, e.g., four times a day, while the other anti-cancer drugs can be administered at a dose and dosing schedule as provided in the FDA-approved prescribing information.
• the drugs in sequential combination are administered according to their pharmacokinetic profiles such that the second drug is administered after the plasma level of the first drug is substantially reduced or removed.
• the pharmacokinetic parameters of tris(8-quinolinolato)gallium(III) is disclosed in Hofheinz et al, International Journal of Clinical Pharmacology and Therapeutics, 43 (12): 590-591 (2005).
• the therapeutically effective amount for each active compound can vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, adverse events, and the like, as will be
• the amount of administration can be adjusted as the various factors change over time.
• Suitable oral formulations can be in the form of tablets, capsules, suspension, syrup, chewing gum, wafer, elixir, and the like.
• Pharmaceutically acceptable carriers such as binders, excipients, lubricants, and sweetening or flavoring agents can be included in the oral pharmaceutical compositions. If desired, conventional agents for modifying tastes, colors, and shapes of the special forms can also be included.
• the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and safflower oil.
• the pharmaceutical compositions can be in lyophilized powder in admixture with suitable excipients in a suitable vial or tube.
• the drugs Before use in the clinic, the drugs may be reconstituted by dissolving the lyophilized powder in a suitable solvent system to form a composition suitable for intravenous or intramuscular injection.
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) such as tris(8-quinolinolato)gallium(ni) as well as a therapeutically effective amount of a second drug chosen from the group of capecitabine, tegafur, SI, paclitaxel, a prodrug of paclitaxel (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension), docetaxel, gemcitabine, temsirolimus, temozolomide, lenalidomide and thalidomide.
• a compound of Formula (I) such as tris(8-quinolinolato)gallium(ni)
• a second drug chosen from the group of capecitabine, tegafur, SI, paclitaxel, a prodrug of paclitaxel (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension), docetaxel, gem
• the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I) such as tris(8-quinolinolato)gallium(III) and a therapeutically effective amount of capecitabine, tegafur, SI, temsirolimus, temozolomide, lenalidomide or thalidomide.
• a compound of Formula (I) such as tris(8-quinolinolato)gallium(III) and a therapeutically effective amount of capecitabine, tegafur, SI, temsirolimus, temozolomide, lenalidomide or thalidomide.
• the composition can be in an orally administrable form (e.g., tablet or capsule or syrup etc.) with a therapeutically effective amount (e.g., 0.1 mg to about 3000 mg) of tris(8- quinolinolato)gallium(III) and a therapeutically effective amount (e.g., from 0.1 mg to about 2000 mg) of a second anti-cancer drug as described above.
• a therapeutically effective amount e.g., 0.1 mg to about 3000 mg
• a therapeutically effective amount e.g., 0.1 mg to about 3000 mg
• a therapeutically effective amount e.g., from 0.1 mg to about 2000 mg
• the second anti-cancer drug is temsirolimus, temozolomide, lenalidomide or thalidomide, and the
• composition includes temozolomide at 5 mg to about 250 mg, or 25 mg of temsirolimus, or 50 mg to 250 mg of lenalidomide, or 5 mg to 25 mg of thalidomide, or 10 mg to 500 mg of capecitabine, or 10-200 mg of SI, or 10-200 mg of tegafur.
• a pharmaceutical kit comprising, in a compartmentalized container, (1) a unit dosage form of a compound of Formula (I) such as tris(8-quinolinolato)gallium(III); and (2) a unit dosage form of a second drug chosen from the group of capecitabine, tegafur, SI, paclitaxel, a prodrug of paclitaxel (e.g., Abraxane ® (paclitaxel protein-bound particles for injectable suspension), docetaxel, gemcitabine, temsirolimus, temozolomide, lenalidomide and thalidomide, preferably from the group of tegafur, SI , temsirolimus , temozolomide, lenalidomide and thalidomide.
• a compound of Formula (I) such as tris(8-quinolinolato)gallium(III)
• a second drug chosen from the group of capecitabine, tegafur, SI, paclit
• the amount of a therapeutic compound in the unit dosage form is determined by the dosage to be used on a patient in the method of the present invention.
• tris(8-quinolinolato)gallium(ni) is in a tablet or capsule or any other suitable form at an amount of, e.g., 0.1 mg to about 3000 mg per unit dosage form.
• the kit further includes a second anti-cancer drug as described above in a unit dosage of from about 0.1 mg to about 2000 mg in a tablet or capsule form or in lyophilized powder.
• the second anti-cancer drug is temsirolimus, temozolomide, lenalidomide or thalidomide
• the kit includes a capsule of temozolomide of 5 mg to about 250 mg, or a vial of 25 mg of temsirolimus in lyophilized powder, or a capsule of 50 mg to 250 mg of lenalidomide, or a capsule of 5 mg to 25 mg of thalidomide, or 10 mg to 500 mg of capecitabine in an oral dosage form such as tablet or capsule, or 10-200 mg of SI in an oral dosage form, or 10-200 mg of tegafur in an oral dosage form.
• the kit further comprises instructions for using the kit in the combination therapy method in accordance with the present invention. EXAMPLE 1
• the cells were removed from their culture flasks using trypsin solution pooled in a sterile conical tube and centrifuged at 350xg for 5 minutes at room temperature. Pelleted cells were re-suspended in complete media and then counted with a Neubauer Bright-Line® hemacytometer and trypan blue viability stain.
• the cell suspensions were diluted (based on live cell counts) using complete media to yield a final suspension density (cells/ml) based on previously determined seeding densities for each cell line for a 72 hour 96-well plate assay.
• the tissue culture treated plates for EC50 testing were seeded at a density specified below in Table 1 and incubated overnight at 37°C in a 5% C0 2 , 95% air humidified atmosphere to allow the cells to attach.
• the top concentration mixture (2x final treatment concentration) was made in sterile 1.5 ml microcentrifuge tubes and then directly transferred to the first well of the treatment dilution plates.
• Tris(8-quinolinolato)gallium(in) (a fine, medium yellow colored powder; lot Q04014, M.W. 502.19, >95% parent) was obtained from Niiki Pharma, Inc. in Parafilm ® -sealed screw capped clear glass vials and stored at -20°C in a covered box to prevent exposure to light.
• 5- Fluororuracil was manufactured by TEVA Parenteral Medicines and supplied in vials at a concentration of 50 mg/ml (384.4 mM) in aqueous solution.
• Docetaxel manufactured by Fluka was weighed out (1.6 mg) and a 2,000 ⁇ solution was made by adding 0.990 ml 100% DMSO and intermittently vortexing for 1 -15 seconds.
• Paclitaxel (a fine, white powder; lot TECH600600-A, M.W. 853.9, 99% parent) was manufactured by Cedarburg Hauser and supplied in an amber glass screw cap vial sealed with Parafilm ® . It was stored at -20°C in a covered box to protect from exposure to light. Paclitaxel (2 mM clear, colorless stock solution in 100% DMSO) was made previously and stored at -20°C in a covered box to protect from exposure to light. One vial of 2 mM paclitaxel stock solution was quickly thawed in hand just prior to use. The 2mM stock solution was diluted lOOOx in complete media ( ⁇ 0 ⁇ 2 mM Paclitaxel + 9.990 mL media) to yield a 2 ⁇ working stock solution.
• Temsirolimus (a white, medium particulate powder; lot BTM-104, M.W. 1030.29, >99% purity) was obtained from LC Laboratories (product # T-8040) and supplied in an amber glass vial. It was stored in the dark at -20°C and sealed with Parafilm® to limit exposure to light and humidity. Temsirolimus (6.1 and 8.1mg) was weighed out and 100 and 200mM clear, colorless stock solutions were made by adding 59.2 and 39 ⁇ , respectively of 100% DMSO.
• Temozolomide (a very light pink tinted granular powder; lot 7BTR042, M.W.
• the antiproliferative activity of the test agents was evaluated using the MTT Cell Proliferation Assay Kit (ATCC catalog # 30-1010K).
• the MTT assay is based on the reduction of yellow tetrazolium MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) by metabolically active cells forming purple formazan crystals.
• the purple formazan is solublized with detergent and quantified spectrophotometrically at 570 nm.
• Cells in the log phase of growth were seeded at the indicated densities listed in Table 1 above into 96-well culture treated plates in 0.1 mL of complete media in all wells except for one column reserved for the media only control.
• test agents were serially diluted in complete culture media (+1% DMSO where appropriate) and added to each well in a volume of 0.1 mL for a total final volume of 0.2 mL/well (0.5% DMSO final, where used). Cells were exposed to test agents for 72 hours. Following the exposure to test agents, 0.1 mL of culture supernatant was carefully removed from all wells of each plate and 0.01 mL of MTT reagent was added to each well. The plates were returned to the incubator for four hours. Following the incubation period, kit supplied detergent reagent (0.1 mL) was added to all wells. The plates were wrapped in plastic wrap to prevent evaporation and allowed to sit at room temperature in the dark overnight. The absorbance at 570 nm was measured the following day using a SpectraMAX Plus plate reader (Molecular Devices).
• the plate blank signal average was subtracted from all wells prior to calculating the Percent of Control. Percent of Control values were calculated by dividing the absorbance values for each test well by the No Drug Control average (column 11 values; cells + vehicle control) and multiplying by 100. Plots of Compound Concentration vs. Percent of Control were analyzed using the 4-parameter equation to obtain EC5 0 values and other parameters that describe the sigmoidal dose response curve.
• Combination Index (CI) values to assess synergy.
• the Fractional Affect (Fa) was calculated from the Pecent of Control (from SoftMax® Pro) using the formula: 1 -(Percent Control/100).
• the dosage, fractional affect and molar ratio of compounds tested in combination were entered into the CompuSyn ® software for evaluation of the presence/absence of synergy.
• CompuSyn assigns a Combination Index (CI) value which rates the level of compounds' affect on proliferation.
• CI values below 1 indicate the presence of synergy and CI values above 1 indicate antagonism.
• CI values close to 1 indicate an additive affect. See Chou, Pharmacol. Rev., 58(3):621-81 (2006).
• Table 2 below summarizes the CI values of the synergistic combinations.
• Figures 1-8 are combination index plots illustrating the synergistic activity between tris(8-quinolinolato)gallium(III) and the above other drugs.
• the antiproliferative activity of tris(8-quinolinolato)gallium(III) and lenalidomide against the human multiple myeloma tumor cell line RPMI 8226 was determined with Promega's Cell Titer-Glo ® assay.
• the human tumor cells were placed in a 96-well microculture plate at the appropriate density for 96 hours of total growth time. After 24 hours of incubation in a humidified incubator at 37°C with 5% C0 2 and 95% air, serially diluted test agents in growth medium were added to each well. After 96 total hours of culture in a C0 2 incubator, the plates were processed with Cell Titer-Glo (Promega #G7571) according to manufacturer's instructions.
• Luminescence was detected using a Tecan GENios microplate reader. Percent inhibition of cell growth was calculated relative to untreated control wells. All tests were performed in duplicate at each concentration level.
• the IC50 value for the test agents was estimated using Prism 3.03 by curve-fitting the data using the following four parameter-logistic equation: tilling
• Top is the maximal % of control absorbance
• Bottom is the minimal % of control absorbance at the highest agent concentration
• 7 is the % of control absorbance
• IC50 is the concentration of agent that inhibits cell growth by 50% compared to the control cells
• n is the slope of the curve.
• Figure 9 shows the combined growth inhibitory activities of tris(8-quinolinolato)gallium(III) and lenalidomide against the multiple myeloma tumor cell line RPMI-8226.
• Y axis % control
• X axis Concentration ( ⁇ ).
• adding lenalinomide at a constant amount potentiates the tris(8-quinolinolato)gallium(III) effect.
• the IC 50 goes from -0.9 with tris(8-quinolinolato)gallium(ni) alone down to 0.5 with lenalidomide.
• A549 and NCI-H322M human tumor cell lines were obtained from the American Type Culture Collection (ATCC) and the National Cancer Institute (NCI), respectively.
• Cell cultures were established using standard in vitro culture methods and cell line supplier's recommended media and supplements in 175cm 2 Greiner ® tissue culture-treated flasks. All cell cultures were incubated in a humidified 37°C, 5% C02, 95% air environment. The cells were sub-cultured regularly to maintain log phase growth. On the day of EC50 plate seeding, the cells for each line were processed and seeded into 96-well cell culture-treated plates one cell line at a time.
• Erlotinib was obtained from LC Laboratories. A 40mM stock solution was made. This solution was immediately diluted 1 :80 into cell line-specific complete media (100 ⁇ 40 mM erlotinib into 7.9 ml media). This was then serially diluted 1 :4 in complete media containing 1.25% DMSO, across nine wells of a 96-well dilution plate for a total of ten concentrations ranging from 250-0.002 ⁇ .
• Paclitaxel was manufactured by Cedarburg Hauser. A 2,000 ⁇ clear, colorless stock solution was made using 100% DMSO. This was diluted l ,000x in complete media for a top concentration of 2,000 nM (0.1% DMSO) in the first well of a 96-well dilution plate. This was then serially diluted 1 :4 in complete media across nine wells of the dilution plate for a total of ten concentrations ranging from 2,000 - 0.008 nM. The antiproliferative activity of the test agents was evaluated using the MTT Cell Proliferation Assay Kit (ATCC catalog # 30-1010K).
• kit supplied detergent reagent (0.1ml) was added to all wells.
• the plates were wrapped in plastic wrap to prevent evaporation and allowed to sit at room temperature in the dark overnight.
• the absorbance at 570nm was measured the following day using a SpectraMAX Plus plate reader (Molecular Devices).
• Absorbance values were converted to Percent of Control and plotted against test agent concentrations for ECso calculations using SoftMax® Pro (version 5.2, Molecular Devices). The plate blank signal average was subtracted from all wells prior to calculating the Percent of Control. Percent of Control values were calculated by dividing the absorbance values for each test well by the No Drug Control average (column 11 values; cells + vehicle control) and multiplying by 100. Plots of Compound Concentration vs. Percent of Control were analyzed using the 4-parameter equation to obtain EC50 values and other parameters that describe the sigmoidal dose response curve.
• Fractional Affect was calculated from the Percent of Control (from SoftMax® Pro) using the formula: 1 - (Percent Control/100).
• the dosage, fractional affect and molar ratio of compounds tested in combination were entered into the CompuSyn ® software for evaluation of the
• CompuSyn ® assigns a Combination Index (CI) value which rates the level of a combination of compounds' effect on proliferation.
• CI values below 1 indicate the presence of synergy and CI values above 1 indicate
• test drug tris(8-quinolinolato)gallium(in)
• erlotinib tris(8-quinolinolato)gallium(in)
• Figure 9 shows a combination index plots illustrating the antagonism (circle) between erlotinib and tris(8-quinolinolato)gallium(III) in lung carcinoma cell line A549 treated with erlotinib first for 48 hours, washed, and then treated with tris(8-quinolinolato)gallium(III) for 48 hours, and the synergism (square) between the two drugs in A549 cell line treated with tris(8-quinolinolato)gallium(ni) first for 48 hours, washed, and then treated with erlotinib for 48 hours. This demonstrates the importance of correct treatment sequence.
• test drug tris(8-quinolinolato)gallium(ni) ("test drug") and paclitaxel
• Figure 10 shows a combination index plots illustrating the antagonism (square) between paclitaxel and tris(8-quinolinolato)gallium(III) in lung carcinoma cell line NCI-H322M treated with tris(8-quinolinolato)gallium(III) first for 48 hours, washed, then treated with paclitaxel for 24 hours, washed, and then cultured in fresh media for 24 hours, and the synergism (circle) between the two drugs in NCI-H322M cell line treated with paclitaxel first for 24 hours, washed, and then treated with tris(8-quinolinolato)gallium(III) for 48 hours, and washed and then cultured in fresh media for 24 hours.
• Human tumor cell line LoVo was obtained from the American Type Culture
• Test agents such as tris(8-quinolinolato)gallium(III) and paclitaxel were prepared as described above in Example 3. Doxorubicin was obtained from Teva Parenteral
• the antiproliferative EC50 activity of the test agents was evaluated using the MTT Cell Proliferation Assay Kit (ATCC catalog # 30-1010K), and the data was analyzed as described above in other examples. Table 6 below summarizes the CI values of the combinations.
• Figure 11 shows combination index plot illustrating the antagonism between doxorubicin and tris(8-quinolinolato)gallium(ni) in colon cancer LoVo cell line.
• Figure 12 shows combination index plot illustrating antagonistic activity between tris(8- quinolinolato)gallium(III) and paclitaxel in the colorectal adenocarcinoma cell line LoVo.

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