Sorafenib or regorafenib troxacitabine phosphoramidate prodrug combination therapy for liver cancer
Inventors
ALBERTELLA, Mark • Eneroth, Anders • Klasson, Björn • Öberg, Fredrik • ÖHD, John
Assignees
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Publication Number
US-10960017-B2
Publication Date
2021-03-30
Expiration Date
Abstract
Combination therapy with sorafenib or regorafenib and a phosphoramidate prodrug of troxacitabine with the formula: where Y is C1-C8 straight or branched chain alkyl, X is H, halo, C3-C4cycloalkyl or C1-C4alkyl and Z is H or fluoro, or a pharmaceutically acceptable salt thereof, shows surprising utility in the treatment of liver cancer or liver metastasis.
Core Innovation
The invention relates to a method for treatment of liver cancer or liver metastasis in a subject in need thereof. The method administers, as combination therapy, a targeted therapeutic agent that is an isotope of sorafenib together with a phosphoramidate prodrug of troxacitabine, together with pharmaceutically acceptable salts.
The disclosure addresses liver cancer types including hepatocellular carcinoma and intra-hepatic cholangiocarcinoma, and liver metastases. It states a purported synergy between the kinase inhibitor component and the defined troxacitabine phosphoramidate prodrugs, including a greater-than-additive anti-proliferative effect.
The phosphoramidate prodrug of troxacitabine is defined by structural formula constraints with variables Y, X, and Z, including stereochemistry at phosphorus and specified substituent possibilities. The document also references efficacy evaluation using in vitro synergy assay and in vivo xenograft evaluation.
Claims Coverage
The independent claim is clm-00001, and it includes 2 inventive features centered on the combination drug selection and the structural constraints for the troxacitabine prodrug, together with pharmaceutically acceptable salts.
Treatment of liver cancer or liver metastasis with sorafenib isotope plus troxacitabine phosphoramidate prodrug
A method for treatment of liver cancer or liver metastasis comprising administering to a subject a targeted therapeutic agent that is an isotope of sorafenib in combination with a phosphoramidate prodrug of troxacitabine, with pharmaceutically acceptable salts.
Troxacitabine phosphoramidate prodrug substituent constraints (Y, X, Z)
The phosphoramidate prodrug of troxacitabine includes Y as C1-C8 straight or branched chain alkyl, X as H, halo, C3-C4 cycloalkyl, or C1-C4 alkyl, and Z as H or fluoro, or a pharmaceutically acceptable salt thereof.
Liver cancer subtype coverage (HCC or intra-hepatic cholangiocarcinoma)
The method is applied to liver cancer that is either hepatocellular carcinoma or intra-hepatic cholangiocarcinoma.
Liver metastasis origin limitation (colorectal cancer)
The method is applied to liver metastasis wherein the liver metastasis originates from colorectal cancer.
Daily same-day dosing schedules (QD, BID, TID)
The sorafenib isotope and the phosphoramidate prodrug of troxacitabine are each administered daily on the same day using QD, BID, or TID dosing schedules.
Same-day dosing separation constraint (at least 6 hours apart)
The sorafenib isotope dosage units and phosphoramidate prodrug of troxacitabine dosage units are administered at least 6 hours apart on the same day.
Alternating administration during monotherapy cycles with treatment-free periods
The sorafenib isotope and the phosphoramidate prodrug of troxacitabine are alternately administered during monotherapy cycles of 1-28 days, with treatment-free periods of 1-28 days in between.
The claim coverage centers on administering an isotope of sorafenib together with a phosphoramidate prodrug of troxacitabine defined by the specified Y, X, and Z constraints and pharmaceutically acceptable salts for treating liver cancer or liver metastasis. Additional refinements include liver cancer subtypes and metastasis origins, plus administration timing constraints involving same-day dosing, separation between administrations, and alternating monotherapy cycles with treatment-free periods.
Stated Advantages
Purported greater-than-additive anti-proliferative effect (synergy) between the kinase inhibitor component and the troxacitabine phosphoramidate prodrugs.
Hypothesized enhanced activation via sorafenib or regorafenib-induced hepatic hypoxia.
Documented Applications
Treatment of liver cancer or liver metastasis in a subject in need thereof.
Application to hepatocellular carcinoma (HCC) or intra-hepatic cholangiocarcinoma.
Application to liver metastasis originating from colorectal cancer.
In vitro evaluation of synergy using MacSynergy II.
In vivo xenograft evaluation using xenograft models including Hep3B xenograft.
Assessment using endpoints OS, PFS, DFS, RR, and QoL.
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