Compositions for treating cancers having acquired resitance to prior chemotherapeutic and targeted drugs using carboxyamidotriazole orotate
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Publication Number
US-9089570-B2
Publication Date
2015-07-28
Expiration Date
Abstract
This invention provides methods and compositions useful for treating early and late stage metastatic cancer to prevent or treat acquired resistance due to gene amplification or mutation in response to chemotherapeutic and/or targeted drugs. In particular, the methods and compositions include carboxiamidotriazole orotate (CTO) alone or in combination with specific regimens of chemotherapeutic and/or targeted drugs designed to overcome the genomic resistance raised to prior therapy.
Core Innovation
Carboxyamidotriazole orotate (CTO), including CTO as an orotate salt of carboxyamidotriazole (CAI), is used in a pharmaceutical composition to prevent or overcome acquired resistance to chemotherapeutic drugs and targeted drugs. The acquired resistance is described as arising due to gene amplification or mutation in metastatic and/or refractory cancers. The composition includes an effective amount of CTO defined by a patient’s body surface area range.
The document describes CTO as a “multiple TKI” pathway inhibitor intended to inhibit TKI pathways associated with acquired resistance. The rationale connects CTO with inhibition across multiple signaling activities such as calcium channel-mediated calcium influx, calcium mobilization, VEGF expression/secretion, and phosphorylation of STATs, CrkL, Akt, and Erk1/2, together with pathway relevance to EGFR, HER2/ERBB2, VEGFR, IGF-1R, MET, NF-kB, and KRAS/BRAF/PI3K/AKT/mTOR. This multi-pathway inhibition is positioned as supporting the prevention or overcoming of resistance to chemotherapeutic and targeted drug regimens.
The document further reports clinical Phase I observations in multiple cancer types, including improved progression-free survival, partial responses, and stable disease. Tumor response is evaluated using criteria including RECIST and Macdonald Criteria. Example patient situations are described with reported tumor mutations and reported CTO dosing ranges, supporting the proposed use of CTO in combination with prior therapies or regimen contexts aimed at addressing acquired resistance.
Claims Coverage
The provided claim set includes two independent claims. Across them, the core coverage centers on pharmaceutical compositions using carboxyamidotriazole orotate to prevent or overcome acquired resistance due to gene amplification or mutation, with dose defined by body surface area, and with targeted drugs specified in at least one independent instance.
Carboxyamidotriazole orotate composition for resistance prevention and targeted resistance context
A pharmaceutical composition of an effective amount of carboxyamidotriazole orotate that prevents or overcomes acquired resistance to chemotherapeutic drugs and targeted drugs due to by gene amplification or mutation, wherein the effective amount of the composition is in the range 50 mg/m2 to 1500 mg/m2 based on the patient's body surface.
Erlotinib targeted composition
The pharmaceutical composition of claim 3 wherein the targeted is erlotinib.
Overall, the independent claim coverage establishes CTO (carboxyamidotriazole orotate) as the active composition for preventing or overcoming acquired resistance linked to gene amplification or mutation, with body-surface-area based dosing, and includes at least one independent instantiation specifying erlotinib as the targeted drug.
Stated Advantages
Prevents or overcomes acquired resistance to chemotherapeutic drugs and targeted drugs due to gene amplification or mutation.
Improved progression-free survival, partial responses, and stable disease are reported in Phase I observations.
Documented Applications
Use of CTO in a pharmaceutical composition to prevent or overcome acquired resistance to chemotherapeutic drugs and targeted drugs in metastatic and/or refractory cancers driven by gene amplification or mutation.
Clinical evaluation/application in Phase I studies across multiple cancer types, with tumor response assessment using RECIST and Macdonald Criteria.
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