METHODS OF TREATING CANCER
Disclosed is (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride effective as a vascular disrupting agent. (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs, and in particular to its use in treating cancer.
1 . A method of treating cancer in a mammal in need of such treatment, comprising administering to the mammal an effective amount of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine, or a pharmaceutically acceptable salt thereof, and an effective amount of one or more chemotherapeutic agents chosen from antiangiogenic agents and cytotoxic agents.
2 . The method of claim 1 , wherein the pharmaceutically acceptable salt is (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride.
3 . The method of claim 2 , wherein the effective amount of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is administered at a dose of not more than about 4.5 mg/m 2 .
4 . The method of claim 2 , wherein the effective amount of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is administered at a dose of not more than about 3.3 mg/m 2 .
5 . The method of claim 2 , wherein the effective amount of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is administered at a dose of not more than about 2.7 mg/m 2 .
6 . The method of claim 2 , wherein the effective amount of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is administered at a dose of not more than about 2.1 mg/m 2 .
7 . The method of claim 2 , wherein the effective amount of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is administered at a dose of not more than about 1.5 mg/m 2 .
8 . The method of claim 2 , wherein the effective amount of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is administered at a dose of not more than about 0.5 mg/m 2 .
9 . The method of claim 1 , wherein the chemotherapeutic agent is an antiangiogenesis agent.
10 . The method of claim 9 , wherein the antiangiogenesis agent is chosen from penicillamine, Tetrathiomolybdate, trientine, British Anti-Lewisite, dimercaptosuccinic acid, clioquinol, pyrrolidine dithiocarbamate, alpha-lipoic acid, L-taurine, pyrrolidine dithiocarbamate, an NSAID, and brucillamine.
11 . The method of claim 9 , wherein the antiangiogenesis agent is chosen from bevacizumab, sunitinib, sorafenib, vatalanib, semaxanib, ZD6474, SU6668, AG-013736, AZD2171, and AEE788.
12 . The method of claim 9 , wherein the antioangiogenesis agent is bevacizumab.
13 . The method of claim 12 , wherein the effective amount of bevacizumab is administered at a dose of not more than about 25 mg/m 2 .
14 . The method of claim 12 , wherein
(a) (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is administered at a dose of between about 2.1 mg/m 2 and about 3.3 mg/m 2 , and
(b) bevacizumab is administered at a dose of between about 10 mg/kg and about 15 mg/kg.
15 . The method of claim 1 , wherein the chemotherapeutic agent is chosen from temozolomide, dacarbazine, BCNU, CCNU, vinorelbine, teniposide, irinotecan, daunomycin, idarubicin, cytarabine, gemcitibine, capecitibine, carboplatin, and oxaliplatin.
16 . The method of claim 1 , wherein the chemotherapeutic agent is carboplatin and wherein the effective amount of carboplatin is administered at a dose that provides the subject an AUC of not more than about 6 mg/mL (min).
17 . The method of claim 1 , wherein
(a) (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride is administered at a dose of between about 2.1 mg/m 2 and about 3.3 mg/m 2 , and
(b) carboplatin is administered at a dose that provides the subject an AUC of between about 4 mg/mL (min) and about 6 mg/mL (min).
18 . A unitary pharmaceutical composition comprising:
a pharmaceutically acceptable carrier;
an effective amount of (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine, or a pharmaceutically acceptable salt thereof; and
one or more chemotherapeutic agents chosen from antiangiogenic agents and cytotoxic agents.
19 . The unitary pharmaceutical composition of claim 18 , wherein the antiangiogenesis agent is chosen from penicillamine, Tetrathiomolybdate, trientine, British Anti-Lewisite, dimercaptosuccinic acid, clioquinol, pyrrolidine dithiocarbamate, alpha-lipoic acid, L-taurine, pyrrolidine dithiocarbamate, brucillamine, and NSAIDs.
20 . The unitary pharmaceutical composition of claim 18 , wherein the chemotherapeutic agent is chosen from temozolomide, dacarbazine, BCNU, CCNU, vinorelbine, teniposide, irinotecan, daunomycin, idarubicin, cytarabine, gemcitibine, capecitibine, carboplatin, and oxaliplatin.