Patent Application: US-99751309-A

Abstract:
this invention provides herbal compositions useful for increasing the therapeutic index of chemotherapeutic compounds . this invention also provides methods useful for improving the quality of life of an individual undergoing chemotherapy . furthermore , this invention improves the treatment of cancer by administering the herbal composition phy906 in combination with one or more chemotherapeutic compounds to a mammal undergoing such chemotherapy .

Description:
mixtures of botanical extracts have been widely used throughout the world for the management of disease and are gaining increased acceptance in western countries ( 2 - 5 ) . the use of traditional chinese medicine ( tcm ) is based on many chemical components in an herbal preparation that interact and act simultaneously through multiple molecular targets and cellular mechanisms . these multiple components serve various functions ; some may be responsible for efficacy while others may decrease toxicity or increase bioavailability . chinese herbal formulations are perhaps the best - known botanical medicines to have been derived from empirical observations in humans over the millennia . the claimed indication of a given chinese medicinal preparation is sometimes multiple rather than single . this is not surprising since many phytochemical ingredients in a formulation can exert actions at multiple targets and biological pathways . phy906 , a decoction of a mixture including four herbs , was established more than 1500 years ago for the treatment of diarrhea , abdominal spasms , fever , headache , vomiting , nausea , extreme thirst , and subcardial distention ( 6 ) . our studies showed that phy906 not only reduced chemotherapy - induced toxicities , including body weight loss and mortality , but it also enhanced the antitumor efficacy of a broad - spectrum of anticancer agents . in one embodiment , the four herbs that constitute phy906 are scutellaria baicalensis georgi ( scute baical skullcap root ), paeonia lactiflora pall . ( white peony root ), glycyrrhiza uralensis fisch . ( licorice root ), and ziziphus jujube mill . ( date fruit ); with a ratio of 1 . 5 : 1 : 1 : 1 , respectively . each of the four herbs of phy906 is reported to possess a distinct pharmacological profile ; these include anticancer and antiviral activity , hematological and immunological stimulation , analgesic activity , liver protection , and appetite improvement ( 7 ) . phy906 has proven to be efficacious in enhancing the therapeutic indices of a variety of anticancer agents including , but not limited to cpt - 11 , 5 - fu , cpt - 11 / 5 - fu / lv , vp - 16 , l - oddc and oxaliplatin / 5 - fu / lv in colorectal cancer ; sorafenib , capecitabine , thalidomide , and cpt - 11 in liver cancer ; and capecitabine , oxaliplatin , gemcitabine and gemcitabine / oxaliplatin in pancreatic cancer in vivo animal models . for example , phy906 has proven to be a useful adjunct of camptosar ® ( cpt - 11 , irinotecan ) for the treatment of advanced colorectal cancer . cpt - 11 is a water - soluble derivative of camptothecin ( an antitumor alkaloid isolated from camptotheca acuminata ) that exhibits a wide spectrum of antitumor activity because of its inhibition of dna topoisomerase i ( 8 ) . cpt - 11 is a component of some of the most widely used chemotherapy treatment regimens ( e . g . the “ saltz ” regimen [ cpt - 11 plus 5 - fluorouracil / leucovorin ], ifl , folfiri , aio ) for colorectal cancer ( 9 , 10 ) . diahrrea has long been recognized as one of the most common limiting side effects associated with cpt - 11 use , regardless of the schedule of administration ( 11 - 13 ) . it causes two types of diarrhea : ( a ) early acute diarrhea that occurs soon after cpt - 11 administration and ( b ) late - onset diarrhea that occurs usually after an average period of 6 days . in about 40 % of patients , this side effect is classified grade 3 ( serious ) or grade 4 ( life - threatening ) according to the national cancer institute common toxicity criteria ( 14 ) . high - dose loperamide is considered standard treatment for cpt - 11 - induced diarrhea in europe and the us , but the success of this approach is limited ( 15 ) . in preclinical studies , when phy906 was used in combination with cpt - 11 in mice bearing colon 38 tumors , the antitumor efficacy of the combination was greater than that of cpt - 11 alone , and the toxicity ( as measured by body weight loss and mortality ) seen with phy906 + cpt - 11 was reduced over that seen with cpt - 11 alone ( 16 ) . although the effects of phy906 on cpt - induced diarrhea were not directly measured , the reduction by phy906 of body weight loss induced by cpt - 11 acts as a “ surrogate ” marker for diarrhea reduction . in mice bearing colon 38 tumors and treated with a high dose of cpt - 11 , phy906 proved to be much more effective in reducing body weight loss than other “ antidiarrheals ” including loperamide and the chinese herbal formulations tj - 14st , tj - 15 , and phy915 ( 17 ) . on the basis of the above , and other , preclinical studies , an fda - approved , phase i / iia , multicenter , randomized , double - blind , placebo - controlled , cross - over dose escalation , safety study in patients with advanced , refractory colorectal cancer in which the combination of cpt - 11 plus 5 - fluorouracil / leucovorin ( 5 - fu / lv ) supplemented by phy906 or placebo was used as first - line treatment , was launched in 2002 . the trial was terminated earlier than expected when the oncology community in the united states adopted a new first - line chemotherapy that included the agent eloxatin ® ( oxaliplatin ) for advanced colorectal cancer and patient recruitment rates slowed . phy906 was shown to be safe with no serious adverse events ( saes ) attributed to the study drug . phy906 was found to have no appreciable effect on the metabolism of cpt - 11 or 5 - fu in controlled metabolic testing ( pharmacokinetic study ). fifteen of seventeen patients treated showed either a partial response or stable disease after two courses of treatment . reduction of diarrhea / nausea / vomiting induced by cpt - 11 treatment was observed in the cross - over , internal , patient controls . phy906 reduced the amount of loperamide necessary to treat cpt - 11 - induced diarrhea . at a dose of 1 . 2 g / day , phy906 reduced the severity of diarrhea by one grade and , at a dose of 2 . 4 g / day , it reduced nausea / vomiting by one grade ( 18 , 19 ) . recently , a phase i / ii study of the use of phy906 in combination with the chemotherapeutic agent xeloda ® ( capecitabine ) in patients with advanced hepatocellular carcinoma ( hcc , primary liver cancer ) ( 20 ) . both doses of phy906 ( 600 mg or 800 mg given orally twice per day on days 1 - 4 and days 8 - 11 ) with capecitabine ( 750 mg / m 2 given orally twice per day on days 1 - 14 ) were well tolerated in hcc patients . the dosing regimen of phy906 ( 800 mg given orally twice per day on days 1 - 4 and days 8 - 11 ) with capecitabine ( 750 mg / m 2 given orally once per day on days 1 - 14 ) was used in the phase ii study . the results of the study were ( n = the number of patients ): ( a ) among 27 evaluable hcc patients in us sites , 14 . 8 % ( n = 4 ) achieved minor response , 51 . 9 % ( n = 14 ) had stable disease , and 33 . 3 % ( n = 9 ) had progressive disease at the end of two treatment cycles ; ( b ) the median survival time was 9 . 2 months ( n = 27 ) for all patients ; ( c ) for child - pugh a patients ( n = 20 ), median survival time was 10 . 9 months ; ( d ) asian patients ( n = 12 ) had a higher median overall survival time ( 16 . 5 months ) than non - asian patients ( 6 . 2 months , n = 15 ) [ p = 0 . 03 ]. in addition , the severity of side effects , particularly diarrhea and fatigue , in this study were much lower than those reported in the pivotal phase iii study used for the fda approval of nexavar ® for hcc . hepatocellular carcinoma ( hcc primary liver cancer ), a common tumor worldwide , with a varying geographic incidence , is frequently encountered in southeast asia and sub - saharan africa ( 25 , 26 ) . once considered a rare tumor in the united states ( u . s . ), western europe , and australia , its incidence has been rising in the u . s . in fact , a 48 % increase in the incidence of hepatobiliary cancers has occurred between the years 1993 and 2000 from 15 , 000 to 20 , 200 in the year 2000 ( 27 , 28 ) . indeed , el - serag and mason have recently reported an increase in the incidence of hcc in the united states , mostly in the african - american population ( 3 ) . until recently , there was no fda - approved treatment for this disease . in late 2007 , nexavar ® ( sorafenib ), a multiple tyrosine kinase inhibitor ( 31 ) previously approved for the treatment of renal cell cancer , was approved for the treatment of advanced unresectable hcc ( 30 ) . however , advanced hcc remains one of the most difficult to treat cancers . sutent ® is an oral , small - molecule , multi - targeted receptor tyrosine kinase inhibitor . a tyrosine kinase is an enzyme that can transfer a phosphate group from atp to a tyrosine residue in a protein . thus , a tyrosine kinase inhibitor interferes with cell communication and growth and may prevent tumor growth . sutent ® is the malate salt of sunitinib ; i . e ., sunitinib malate . the active ingredient of sutent ® is sunitinib , the chemical name of which is n -[ 2 -( diethylamino ) ethyl ]- 5 -[( z )-( 5 - fluoro - 1 , 2 - dihydro - 2 - oxo - 3h - indol - 3 - ylidine ) methyl ]- 2 , 4 - dimethyl - 1h - pyrrole - 3 - carboxamide . the terms “ sutent ®” and “ sunitinib ” are used interchangeably throughout this application . in early 2006 , sutent ® was approved by the fda for the treatment of renal cell carcinoma and gastrointestinal stromal tumors that are resistant to treatment with gleevec ®. sunitinib was the first cancer drug simultaneously approved for two different indications ( 21 ) . sunitinib has become the standard of care for both of these cancers , and is currently being studied for the treatment of many others . sutent ® acts by inhibiting cellular signaling through its targeting of multiple receptor tyrosine kinases ( 22 - 24 ) . these include all platelet - derived growth factor receptors and vascular endothelial growth factor receptors which play a role in both tumor angiogenesis and tumor cell proliferation . the simultaneous inhibition of these targets leads to both reduced tumor vascularization , cancer cell death , and tumor shrinkage . a study was conducted in which immune - deficient ncr “ nude ” mice bearing hepg2 ( human hepatocellular carcinoma ) tumors were treated with phy906 alone , sutent ® alone , or with the combination of phy906 and sutent ®. phy906 was administered twice per day at a dose of 500 mg / kg for four days beginning on day 1 , and was continued on a 4 days on , 3 days off schedule . sutent ® was given once per day . two doses of sutent ® were used , 40 mg / kg and 80 mg / kg . as can be seen in fig1 , phy906 by itself had slight effect on the tumor growth rate over the 10 - day period of observation . sutent ® alone significantly reduced the tumor growth rate at both doses employed with the 80 mg / kg dose being the most effective . when the combination of phy906 and sutent ® was used , not only was the growth of the tumors stopped , but the size of the tumors appeared to be decreased from pretreatment levels by five days and the rate of tumor growth appeared to remain depressed for the 10 - day period ; this observation was seen at both doses of sutent ®. it can be concluded that ( a ) phy906 potentiates the antitumor activity of sutent ®, and ( b ) the combination of phy906 and sutent ® is very effective as a chemotherapeutic treatment in this liver cancer animal model system . the positive results from these preclinical studies demonstrate that phy906 can be used as an adjuvant for a broad - spectrum of different types of chemotherapeutic agents in anti - cancer therapy . the cancers include , but are not limited to , colorectal cancer , liver cancer , hepatocellular carcinoma , and pancreatic cancers . the methods of the present invention can be used to improve the quality of life of patients including mammals under chemotherapy . specifically , this invention relates to the dosing and scheduling of phy906 in potentiating the therapeutic index of a broad - spectrum of cancer chemotherapeutic agents by the herbal composition phy906 . all applications , patent , and publications referenced herein are incorporated by reference to the same extent as if each individual application , patent , and publication was specifically and individually indicated to be incorporated by reference . specifically , the disclosures of wo 01 / 66123 , wo 06 / 053049 , u . s . pat . no . 7 , 025 , 993 , us 2005 / 0196473 , and us 2003 / 0211180 are incorporated herein by reference in their entirety for all purposes . furthermore , the following references and their contents are herein incorporated by reference in their entirety for all purposes : 1 . garcia m , jemal a , ward e m , center m m , hao y , siegel r l , thun m j . global cancer facts & amp ; figures 2007 . atlanta , ga . : american cancer society , 2007 . 2 . okada f ( 1996 ). kampo medicine : a source of drugs waiting to be exploited . lancet 348 : 5 - 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