Treatment of cancer using hypoxia activated prodrugs
Inventors
Curd, John G. • Kroll, Stewart • Matteucci, Mark • Hart, Charles P. • Duan, Jian-Xin • SUN JESSICA D, null
Assignees
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Publication Number
US-8946275-B2
Publication Date
2015-02-03
Expiration Date
Abstract
Cancer can be treated by administration of a hypoxia-activated prodrug, such as TH-302, alone or in combination with other anticancer agents and/or radiation therapy. In combination therapy, the hypoxia-activated prodrug and another anti-cancer agent or radiation therapy may be administered within the same 24-hour period, and administration of the hypoxia-activated prodrug may be completed prior to beginning administration of the other anticancer agent or radiation therapy.
Core Innovation
The patent describes cancer therapy using hypoxia activated prodrug TH-302, including TH-302 as N,N′-bis(2-bromoethyl)phosphorodamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester. The background rationale is that tumor hypoxia drives resistance, and a hypoxia targeting agent such as TH-302 is used to address this hypoxia-related problem in cancer treatment.
A core treatment concept is administering TH-302 and also administering a therapeutically effective dose of an anticancer drug that is not a hypoxia activated prodrug, with the non-HAP anticancer drug beginning after TH-302 administration is completed. The patent characterizes this as a non-contemporaneous administration schedule, with a post-completion delay window beginning 30 minutes to 8 hours after TH-302 dosing is completed.
The patent also describes TH-302 pharmaceutical formulations as stable liquid compositions that include ethanol and a nonionic surfactant in an amount effective to act as a stabilizer. This formulation approach is presented with TH-302 in relatively high concentrations, and it is described as aimed at reducing precipitation and/or degradation, supporting administration as an intravenous (IV) infusion as described in the document.
In addition, the patent provides combination regimen concepts in which TH-302 monotherapy or combination therapy is used for specific tumor types described in the document, including melanoma and small cell lung cancer (SCLC). The non-HAP agents listed in the claim set include chemotherapeutic agents such as docetaxel, gemcitabine, pemetrexed, and doxorubicin, and the document further addresses safety/tolerability themes by describing prophylactic topical or oral agents for mucositis/skin toxicity and associating increased toxicity with contemporaneous administration relative to delayed non-contemporaneous scheduling.
Claims Coverage
The partial claim set includes two independent claims: one method-of-treatment claim and one pharmaceutical formulation claim. Across these independent claims, the inventive features focus on a non-contemporaneous scheduling relationship between TH-302 and an anticancer drug that is not a hypoxia activated prodrug, and a stable liquid formulation of TH-302 using ethanol and a nonionic surfactant stabilizer.
Non-contemporaneous TH-302 followed by a non-HAP anticancer drug within a delay window
A method of treating cancer comprising administering TH-302 intravenously in a specified mg/m2 range and administering a therapeutically effective dose of an anticancer drug that is not a hypoxia activated prodrug, where administration of the non-hypoxia activated prodrug begins 30 minutes to 8 hours after administration of TH-302 is completed.
TH-302 liquid formulation with ethanol and nonionic surfactant stabilizer
A pharmaceutical formulation comprising TH-302 as an active ingredient in an amount of about 50 mg/ml to about 300 mg/ml, a nonionic surfactant in an amount effective to act as a stabilizer, and ethanol as a carrier.
Overall, claim coverage centers on TH-302 cancer therapy using a non-contemporaneous administration schedule relative to non-hypoxia activated anticancer drugs, and on a defined stable liquid TH-302 formulation using ethanol and a stabilizing nonionic surfactant.
Stated Advantages
Documented Applications
No documented applications found
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