Combination therapy with an anti-hyaluronan agent and therapeutic agent

Abstract

Provided herein is combination cancer therapy effected by administering a polymer-conjugated hyaluronidase, and a tumor-targeted taxane, and optionally a further chemotherapeutic agent such as a nucleoside analog. The combination therapy can be used in methods of treating cancers, and in particular solid tumor cancers.

What is claimed is: 
     
         1 . A method for treating cholangiocarcinoma, comprising administering to a subject:
 a) a composition comprising a soluble PH20 hyaluronidase, wherein the soluble PH20 hyaluronidase is PEGylated; and   b) a composition comprising a nucleoside analog, wherein:   the subject has cholangiocarcinoma;   the soluble PH20 hyaluronidase comprises a sequence of amino acid residues that has at least 95% sequence identity to the sequence of amino acid residues set forth in SEQ ID NO: 4; and   the composition comprising the PEGylated soluble PH20 hyaluronidase and the composition comprising the nucleoside analog are administered separately in two compositions or are administered in a single composition.   
     
     
         2 . The method of  claim 1 , wherein the compositions are administered sequentially. 
     
     
         3 . The method of  claim 1 , wherein the soluble PH20 hyaluronidase comprises a sequence of amino acids that has at least 98% sequence identity to the sequence set forth in SEQ ID NO: 4. 
     
     
         4 . The method of  claim 1 , wherein:
 the hyaluronidase is a truncated PH20; and   the truncated PH20 comprises a sequence of amino acids that contains amino acids 36-464 of SEQ ID NO:1, or comprises a sequence of amino acids that has at least 95% sequence identity to a sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1 and retains hyaluronidase activity.   
     
     
         5 . The method of  claim 4 , wherein the truncated PH20 comprises a sequence of amino acids set forth in any of SEQ ID NOS: 4-9, 47, 48, 150-170 or 183-189, or a sequence of amino acids that exhibits at least 98% sequence identity to a sequence of amino acids set forth in any of SEQ ID NOS: 4-9, 47, 48, 150-170 or 183-189 and retains hyaluronidase activity. 
     
     
         6 . The method of  claim 1 , wherein the PEGylation moiety is a polyethylene glycol (PEG), and the PEG is a branched or linear PEG. 
     
     
         7 . The method of  claim 1 , wherein:
 the hyaluronidase is administered in a dosage range amount of between or about between 0.01 μg/kg to 15 μg kg (of the subject); or   the hyaluronidase is administered in a dosage range amount of between or about between 10 to 10,000 Units/kg (of the subject).   
     
     
         8 . The method of  claim 1 , wherein the nucleoside analog is a purine or pyrimidine analog or derivatives thereof. 
     
     
         9 . The method of  claim 8 , wherein the nucleoside analog is selected from among fluoropyrimidine, 5-fluorouracil, 5-fluoro-2′-deoxycytidine, cytarabine, gemcitabine, troxacitabine, decitabine, Azacytidine, pseudoisocytidine, Zebularine, Ancitabine, Fazarabine, 6-azacytidine, capecitabine, N4-octadecyl-cytarabine, elaidic acid cytarabine, fludarabine, cladribine, clofarabine, nelarabine, forodesine, and pentostatin, or derivatives thereof. 
     
     
         10 . The method of  claim 1 , wherein the nucleoside analog is administered in a dosage range that is between about 100 mg/m 2  to 2500 mg/m 2  body surface area of the subject. 
     
     
         11 . The method of  claim 1 , wherein the compositions are administered orally, intravenously (IV), subcutaneously, intramuscularly, intra-tumorally, intradermally, topically, transdermally, rectally, intrathecally or sub-epidermally. 
     
     
         12 . The method of  claim 1 , wherein the compositions are administered intravenously or subcutaneously. 
     
     
         13 . The method of  claim 1 , wherein the hyaluronidase is administered prior to, simultaneously, sequentially or intermittently with the nucleoside analog. 
     
     
         14 . The method of  claim 1 , wherein the frequency of administration of the hyaluronidase is twice weekly, once weekly, once every 14 days, once every 21 days or once every month. 
     
     
         15 . The method of  claim 1 , wherein 30% or more of the tumoral area in a tumor biopsy from the subject expresses hyaluronan (HA). 
     
     
         16 . The method of  claim 15 , wherein 50% or more of the tumoral area in the tumor biopsy expresses HA. 
     
     
         17 . The method of  claim 1 , wherein the nucleoside analog is gemcitabine. 
     
     
         18 . The method of  claim 1 , wherein the nucleoside analog is 5-fluorouracil.