WO2010014250A1

WO2010014250A1 - Prediction of cancer therapy based on cathespin b levels

Info

Publication number: WO2010014250A1
Application number: PCT/US2009/004424
Authority: WO
Inventors: Stewart Chipman; Jack Singer; Fred Oldham; Bruce Bandstra
Original assignee: Cell Therapeutics, Inc.
Priority date: 2008-08-01
Filing date: 2009-07-31
Publication date: 2010-02-04

Abstract

Disclosed are methods for predicting the outcome of treatment for various types of cancers in males and females, comprising the determination of serum or plasma levels of catB prior to selecting the cancer therapy.

Description

PREDICTION OF CANCER THERAPY BASED ON CATHESPIN B LEVELS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of the filing date of United States Provisional Patent Application No. 61/137,638 filed 08/01/08, the disclosure of which is hereby incorporated herein by reference. BACKGROUND OF THE INVENTION

[0001] The past 20 years have been witness to a significant increase in options for cancer treatments, including advancements in biological and chemotherapeutic agents . Given this plethora of new treatments, selecting a therapy that provides the greatest benefit with the least harm to the patient is challenging.

[0002] It is important to select an appropriate treatment regimen from the onset of treatment because inadequately treated cancers can progress to a more advanced stage, or mutate, resulting in a different target that is more refractory to current treatment regimens. Both situations reduce the chances for a positive patient outcome. Currently, cancer treatment selection is based on a number of factors including the type of cancer, cancer stage at diagnosis, and the presence of tumor related markers . SUMMARY OF THE INVENTION

[0003] A first aspect of the present invention is directed to a method of predicting the outcome of a cancer treatment regimen for treating patients, diagnosed with a cancer of epithelial origin, comprising the determination of serum or plasma cathepsin B (catB) levels, wherein a patient with a serum or plasma catB level of about 65 nanograms per milliliter (ng/ml) or greater is indicative of a better outcome when the patient is treated with a polymer-conjugated anti-cancer drug, versus treatment with an unconjugated anti-cancer drug. On the other hand, a patient with a catB serum or plasma level less than 65 ng/ml, indicates no difference in efficacy between treating said patient in need thereof with a polymer-conjugated anti-cancer drug, or an unconjugated anti-cancer drug.

[0004] In addition to utilizing serum or plasma catB levels for predicting treatment outcome, the invention optionally envisions treating a patient with a catB serum or plasma level of about 65 ng/ml or higher, with a polymer-conjugated anti-cancer drug.

[0005] A second aspect of the present invention is directed to a method of treating a patient identified as having a low catB level, and who is diagnosed with a cancer, wherein the cancer is characterized as being of an epithelial origin, and wherein said catB levels are artificially elevated to serum or plasma levels of about 65 ng/ml or greater, and wherein treatment comprises delivering to said patient in need thereof a combination therapy comprising a polymer-conjugated anti-cancer drug and a therapy that elevates serum or plasma catB levels.

[0006] While not intending to be bound by any particular theory of operation, Applicant believes that catB, an enzyme associated with the separation of an anti -cancer drug from a polymer carrier, results in an increase in the amount of the unconjugated anti-cancer drug in the cancerous tissue. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Fig. 1 is a graph depicting survival in patients exhibiting either a high or low serum level of catB, and treated with comparator drugs.

[0008] Fig. 2 is a graph depicting survival in patients exhibiting a low serum level of catB, and treated with either paclitaxel conjugated to poly-glutamate (i.e., paclitaxel poliglumex (PPX) ) or comparator drugs.

[0009] Fig. 3 is a graph depicting survival in patients exhibiting a high serum level of catB, and treated with PPX or comparator drugs . [0010] Fig. 4 is a graph depicting survival in patients exhibiting either a high or low serum level of catB, and treated with PPX.

[0011] Fig. 5 is a graph depicting the correlation between increasing estrogen levels and the elevation in catB activity. DETAILED DESCRIPTION

[0012] The present invention is directed to a method that involves predicting the outcome of a cancer treatment regimen, which is based on blood serum or plasma levels of catB. Thus, in one embodiment of the invention, serum or plasma levels of catB are determined in patients diagnosed with cancer, and in need of a cancer treatment regimen. While it is contemplated that predicting the outcome of all cancer treatment regimens could be guided by determining the serum or plasma levels of catB, it is especially useful when dealing with a prognosis for epithelial cancers .

[0013] CatB is a widely expressed cysteine protease that has been reported to have a role in a variety of physiological and pathological functions including maintenance of the central nervous system (Felbor et al., PNAS, 99 (12) : 7883-7888 (2002)), antigen presentation (Blum et al., PNAS, 85:3975-3979 (1988)), prohormone processing (Shinagawa et al., PNAS, 87:1927-1931 (1990)) and tumor invasion (Berquin et al., Adv. Exp. Med. Biol., 389:281-294 (1996)).

[0014] CatB levels, elevated with respect to control levels, are often indicative of a poor prognosis for a variety of cancers including breast cancer, colorectal cancer and nonsmall cell lung carcinoma (Lah et al., Clin. Can. Res., 6:587-504 (2000); Skrzydlewska, et al., World J. Gastroenterol. , 11 (27 ) :4225-4229 (2005); Werle, et al., Cancer, 89(11) : 2282-2291 (2000)). In the present invention however, the inventors have surprisingly discovered that cancer patients with increased blood serum or plasma catB levels have a better prognosis when treated with polymer-conjugated anti -cancer drugs compared to the non- polymer conjugated form of the drug.

[0015] CatB circulates in the blood as a pro-enzyme, without enzymatic activity (Mort et al. , Biochem. <J. , 233:51-63 (1986); Mach et al., Biochem. J., 253:437-442 (1993)) . CatB levels can be measured in blood serum or plasma utilizing a variety of assays such as an enzyme linked immunosorbent assay (ELISA) or a Western blot analysis. In an exemplary embodiment, catB levels are measured in blood serum utilizing an ELISA kit such as the Human Pro-Cathepsin B

Quantikine" ELISA kit (R&D Systems , Minneapolis, Mn). [0016] As used herein, the term "serum or plasma level of catB" refers to the amount of catB present in a blood serum or plasma sample. For the purposes of distinguishing a high catB serum or plasma level from all other catB serum or plasma levels, a catB level of about equal to or greater than 65 ng/ml is considered a high serum or plasma catB level. By contrast, a catB serum or plasma level less than 65 ng/ml is considered a low serum or plasma catB level.

[0017] Thus, patients with "high levels of endogenous catB, " as the phrase is used herein, have a blood serum or plasma catB level (measured, e.g., with a commercially available ELISA kit) of about 65 ng/ml or greater of serum or plasma, plus or minus (±) the error of the assay. Patients with "low levels of endogenous catB, " as the phrase is used herein, have a blood serum or plasma catB level (measured, e.g., with a commercially available ELISA kit) that is less than 65 ng/ml, e.g., about 64 ng/ml of serum or plasma, to below the limits of detection, ± the error of the assay. [0018] The invention contemplates using blood serum or plasma that is obtained from whole blood, and may contain additional components such as anticoagulants and preservatives, that are added prior to, at the time of or after blood collection. Whole blood may be obtained by any medically approved method including, but not limited to venipuncture . Methods for obtaining serum or plasma from whole blood are well known in the art and will not be further discussed herein.

[0019] As previously stated, it is envisioned that the present invention will be especially useful in predicting a treatment outcome for cancers with an epithelial origin. Such cancers typically arise from epithelial cells . Epithelial cells form the tissues that line and cover the body, including outer surfaces and inner surfaces such as the lining of body cavities and the covering of organs. The vast majority of cancers have an epithelial cell origin.

[0020] As used herein, the term "epithelial cancer" refers to any cancer arising from the various epithelial cells (e.g., squamous cells, adenomatous cells, and transitional cells) . Epithelial cancers include, but are not limited to cancers of the ovaries, breast, prostate gland and lung. In an exemplary embodiment, the cancer is lung cancer. In another exemplary embodiment, the cancer is non- small cell lung cancer (NSCLC) . [0021] In one aspect of the invention, patients diagnosed with cancer and treated according to methods of the present invention have high blood serum or plasma levels of endogenous catB . As used herein, the term "endogenous catB" refers to naturally occurring catB levels, as opposed to catB levels that are achieved as a result of manipulating physiological parameters (e.g., hormone therapy) . In this aspect, one would predict that a patient given a cancer treatment regimen comprising a polymer-conjugated anti-cancer drug would have a more positive outcome than similarly situated patients treated with an unconjugated anti-cancer drug.

[0022] As used herein, the term "polymer-conjugated anti-cancer drug" refers to a class of anti-cancer drugs that share the feature of having been conjugated to a polymer backbone. The nature of the polymer backbone is such that it can increase both passive and active tumor targeting, as well as acting directly as an anti-cancer drug itself. [0023] One component of the polymer-conjugated anti-cancer drug, also referred to in the art as a polymeric prodrug, is the polymer-drug linker. This linker allows both the attachment to and ultimate release of an anti-cancer drug from a polymer carrier (Duncan, The Pharmaceutical Journal, 273:485-488 (2004)). Overall, the attachment of an anti -cancer drug to a polymer allows the polymeric prodrug to remain inert when circulating in the blood stream, but then allows for separation of the drug from the polymer carrier at the site of the tumor.

[0024] Designing polymer-drug linkers and synthesizing polymeric prodrugs are well known in the art (Duncan, The Pharmaceutical Journal, 273:485-488 (2004); Duncan, Nature Reviews, 2:347-360 (2003)) The nature of the polymer-drug linker dictates, to a certain extent, the type of enzyme required to cleave a drug, for example, an anti -cancer drug, from its polymer carrier.

[0025] A number of polymeric prodrugs have already been tested in early phase clinical trials, including polyglutamate-paclitaxel (e.g., PPX, CT-2103 and Xyotax™) , N- (2-hydroxypropyl )metharylamide (HPMA) copolymer-doxorubincin (e.g., PKl; FCE28068), HPMA copolymer-doxorubincin-galactosamine (e.g., PK2 ; FCE28069) , HPMA copolymer-paclitaxel (e.g., PNU166945), HPMA copolymer camptothecin (e.g., MAG-CPT/PNU166148) , HPMA copolymer platinate (e.g., AP5280 and AP5346), polyglutamate-camptothecin (e.g., CT-2106) and PEG-camptothecin (e.g., Prothecan®) . Of these, those that are designed with the HPMA linker have been proven to be cleavable by catB . Duncan, The Pharmaceutical Journal, 273:488 (2004). In addition, the results from the examples provided herein suggest that polyglutamate-paclitaxel is also cleaved by catB . [0026] The invention envisions the use of any polymer-drug conjugate that includes a polymer linkage capable of being cleaved by catB, such that the anti-cancer drug is released from the polymer carrier. In an exemplary embodiment, the polymer-drug conjugate comprises a drug conjugate possessing an HPMA linker. In another embodiment, the drug is HPMA copolymer-paclitaxel . In yet another embodiment, the drug is a paclitaxel drug conjugate.

[0027] As used herein, the terms "paclitaxel drug conjugate," "conjugated paclitaxel" and "paclitaxel conjugate" refer to any of the taxol drugs, conjugated to a polymer backbone. In an exemplary embodiment, the polymer backbone is polyglutamate .

[0028] In another aspect of the invention, a patient diagnosed with cancer constitutes a patient with low levels of endogenous catB. In this aspect, one would predict that such patients treated with a polymer-conjugated anti-cancer drug would fare no better than those treated with an unconjugated anti-cancer drug.

[0029] A further aspect of the invention includes optionally providing to a patient, diagnosed with a cancer, a cancer treatment regimen comprising a polymer-conjugated anti-cancer drug. In an exemplary embodiment, the polymer-conjugated anti-cancer drug is a conjugated paclitaxel .

[0030] Paclitaxel conjugates are well known in the art. Methods for conjugating paclitaxel to polymer backbones are described in Li et al., U.S. Patent 6,441,025. Polymer backbones may be synthesized in accordance with several types of standard techniques, including chemical and recombinant processes. For example, a homopolymer of glutamic acid may be prepared in a two-step process, in which (i) glutamic acid is treated with phosgene or an equivalent reagent, e.g. diphosgene, at a temperature of from 15°C to 70⁰C to form an N-carboxyanhydride (NCA), and (ii) ring-opening polymerization of the N-carboxyanhydride is effected with a base to yield poly- (glutamic acid) . Suitable bases include alkoxides, e.g. alkali metal alkoxides such as sodium methoxide, organometallic compounds and primary, secondary or tertiary amines, for example butylamine or triethylamine . See, U.S. Patent 5,470,510. Additional methods for chemically synthesizing poly (amino acids) are well-known in the art and will not be further described herein.

[0031] The paclitaxel conjugated drugs of the present invention are multiple taxane skeleton molecules while traditional paclitaxel (i.e., unconjugated paclitaxel) is a single taxane skeleton molecule. The amount of drug conjugated to the polymer is variable. At the lower end, the drug polymer conjugate may comprise from about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21% about 22%, about 23%, about 24%, to about 25% (w/w) of drug relative to the mass of the conjugate. At the high end, the drug-polymer conjugate may comprise from about 26%, about 27%, about 28%, about 29%, about 30%, about 31% about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, to about 50% or more (w/w) of drug relative to the mass of the conjugate.

[0032] Similarly, the number of molecules of drug conjugated per molecule of polymer can vary. At the lower end, the drug-polymer conjugate may comprise from about 1, about 2 , about 3 , about 4 , about 5 , about 6 , about 7 , about 8 , about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, to about 20 or more molecules of the drug per molecule of polymer. At the higher end, the drug-polymer conjugate may comprise from about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35., about 36, about 37, about 38, about 39, about 40 about 41, about 42, about 43, about 44, about 45, about 46 about 47, about 48, about 49, about 50, about 51, about 52 about 53, about 54, about 55, about 56, about

57, about 58, about 59, about 60 about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, to about 75 or more molecules or more of drug per molecule of polymer. [0033] To provide at least one meaningful comparison between the conjugated and unconjugated paclitaxel drugs, each taxane skeleton molecule in the conjugated drug is calculated as one paclitaxel (i.e., unconjugated paclitaxel) equivalent. [0034] An exemplary paclitaxel conjugate, suitable for use in the present invention is poliglumex (PPX) , which is fully described in U.S. Patent Application Publication No. 2007/0167349. PPX is paclitaxel conjugated to poly- (1-glutamic acid) . PPX has an average MW in the range of about 35,000 to about 40,000 Da, but does not exceed 75,000 Da, with about 35% to about 37% weight to weight (w/w) paclitaxel loading.

[0035] The optional treatment aspect of the invention also contemplates the use of two or more drugs, each conjugated to the same type of polymer, as well as mixtures of two or more drugs, each conjugated to a different polymer. In certain embodiments, two or more different drug moieties may be conjugated to a single polymer. The invention also contemplates administration of other cancer drugs (e.g., carboplatin) in addition to the drug conjugate and/or hormone therapy.

[0036] Paclitaxel drug conjugates, including PPX may be delivered or administered by any therapeutically suitable means. For example, administration may be parenteral or oral. In preferred embodiments administration is intravenous . [0037] Compositions include the conjugate and a pharmaceutically acceptable carrier. As used herein, pharmaceutically acceptable carriers include solvents (e.g., buffered aqueous medium), dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents (e.g., glucose) and the like. Pharmaceutical compositions containing the conjugates suitable for intravenous use include sterile aqueous solutions or dispersions, as well as sterile powders that can then be reconstituted in an aqueous solution. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol, suitable mixtures thereof, and vegetable oils. Suitable injectable solutions may be prepared by incorporating an appropriate amount of the conjugate into an appropriate solvent, optionally with various other ingredients as listed above. Solutions may be sterilized by filtration. Dispersions may be prepared by incorporating the conjugate into a sterile vehicle containing the dispersion medium and any other ingredients from those listed above. Sterile powders may be prepared by vacuum drying and freeze-drying techniques, yielding a powder of the conjugate and any additional desired ingredients from a previously sterile-filtered solution thereof.

[0038] Pharmaceutical compositions may be delivered or administered in an appropriate dosage and for a suitable duration and frequency. Dose and duration of administration are typically determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. The appropriate dosage and treatment regimens are designed to achieve a therapeutic benefit (e.g. an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival) . Examples of different ranges of dosage and administration schedules are provided in U.S. Patent 5,670,537 (disclosing dosages and administration schedules for taxol). [0039] In an exemplary embodiment, a patient in need thereof receives a paclitaxel conjugate such as PPX by intravenous infusion. Intravenous infusion may be for any appropriate time period, which is readily determinable by one of ordinary skill in the art. For example, infusions may last for about one to about 24 hours, although shorter or longer infusion times also fall within the scope of the invention. [0040] In some embodiments of the invention, patients in need of such treatment receive a paclitaxel conjugate, on a bi-weekly or other clinically useful schedule, at dose levels typically used for the particular conjugate involved. As previously described, a meaningful comparison between multiple taxane skeleton molecule therapies and other single taxane skeleton molecule therapies can be expressed as paclitaxel equivalents. For example, for dosing purposes, each taxane skeleton in a taxane conjugate molecule is calculated as one paclitaxel equivalent. The dose level generally ranges from about 175 to about 250 mg/m² paclitaxel equivalents. In other exemplary embodiments, patients in need of such therapy are treated with a paclitaxel conjugate such as PPX, in an amount of about 200 to about 250 mg/m² paclitaxel equivalents every 21 days or about once every 3 weeks . In yet another exemplary embodiment, patients in need of such therapy are treated with a paclitaxel conjugate such as PPX, in an amount of about 175 mg/m² paclitaxel equivalent every 21 days or about once every 3 weeks. In yet other embodiments, patients in need of such therapy are treated with a paclitaxel conjugate such as PPX, in an amount in excess of about 250 mg/m² paclitaxel equivalents every 21 days or even in excess of about 275 mg/m² paclitaxel equivalents every 21 days.

[0041] The production and secretion of catB is the result of a complicated regulatory pathway. In some cancer patients, catB Levels are less than 65 ng/ml of serum or plasma. For example, post-menopausal women and men tend to have catB levels less than 65 ng/ml of serum or plasma.

[0042] While there may be numerous reasons for the low levels, these levels can be artificially elevated via the administration of various therapies, such as hormone therapy. As the term is used herein, "artificially elevated, " when applied to serum or plasma catB levels, refers to levels of about 65 ng/ml or greater that are achieved by the administration of a therapy, as opposed to levels of about 65 ng/ml or greater that are present in the serum or plasma of patients who are not administered a catB elevating therapy, such as hormone therapy. Thus, in another embodiment of the invention, hormone therapy is provided in order to artificially elevate catB levels to be about equal or greater than 65 ng/ml of serum or plasma. In an exemplary embodiment, the hormone therapy comprises estrogen therapy.

[0043] "Estrogen therapy, " as used herein, refers to administration of an estrogenic substance that will increase levels of estrogen in the patient, thus leading to an increased level of catB. As used herein, "estrogen" includes, but is not limited to, any of the naturally occurring mammalian estrogens and congeners thereof, e.g., estradiol and its organic esters (e.g., estradiol benzoate, estradiol cypionate and estradiol valerate) , estrone, diethylstilbestrol , piperazine estrone sulfate, ethinyl estradiol, mestranol, polyestradiol phosphate, estriol, estriol hemisuccinate, quinestrol, estropipate, pinestrol, estrone potassium sulfate, and tibolone, estrogen metabolites, e.g., 17-β-estradiol, estrogen analogs, natural compounds with estrogenic activity, e.g., phytoestrogens, such as genestein or isoflavone, estrogen agonists, e.g., selective estrogen receptor modulators with some agonistic activity (e.g., tamoxifen) , and other substances capable of interaction with cell surface estrogen receptors. These estrogens and estrogenic substances may be natural or synthetic. [0044] Estrogen or estrogenic substances can be formulated by any means compatible with mammalian physiology and the selected route of delivery. These methods are well known in the art. See U.S. Pharmacopeia National Formulary, United States Pharmacopeal Convention, Inc., pp. 530-541 (1990). [0045] Estrogen therapy can be administered by any suitable route such as locally, orally, systemically, intravenously, intramuscularly, mucosally, or transdermally (e.g., a patch). The estrogen therapy may be administered on a regular (e.g., a daily/weekly) basis, and may be intermittent or substantially continuous with respect to the paclitaxel conjugate therapy. Typical dose ranges depend on the compound and the characteristics of the patient. The daily dose of the estrogen is typically based on the amount of a given preparation necessary to maintain serum or plasma estrogen levels equal to or greater than 30 pg/ml when estrogen or its metabolites are used. As used herein, the daily dose of estrogen will also be based on the amount needed to maintain serum or plasma catB levels about equal to or greater than 65 ng/ml .

[0046] Treatment regimens include, but are not limited to, hormone replacement therapy, such as estrogen/progesterone therapy at 0.3 mg/1.5mg, 0.45 mg/l.5mg, 0.625 mg/2.5 mg, or 0.625 mg/5.0 mg daily. In an exemplary embodiment, therapy may comprise estrogen therapy at 0.15 mg, 0.3 mg, 0.625 mg or 1.25 mg once or twice daily. In another exemplary embodiment, hormone replacement therapy comprises 10 mg estrogen three times daily. An example of estrogen is Premarin^® (Wyeth Pharmaceuticals, Inc., PA). In some embodiments, the estrogen/progesterone combination is accomplished by administration of Prempro^® (Wyeth Pharmaceuticals, Inc., PA). [0047] Once a patient, diagnosed with a cancer and initially determined to have a low serum or plasma catB level, has the catB level elevated to about 65 ng/ml or greater, one would predict that a cancer treatment regimen comprising a polymer-conjugated anti-cancer drug would provide a more positive outcome versus a cancer treatment regimen comprising an unconjugated anti-cancer drug. Thus, a further aspect of the invention includes a combination therapy comprising the administration of a hormone therapy and a polymer-conjugated anti-cancer drug.

[0048] The methods of the invention do not require that each component of the combination therapy is delivered by the same route or even at the same time. In some aspects of the invention however, a polymer-conjugated anti-cancer drug and hormone therapy are given at the same time by the same route of administration. In an exemplary embodiment, the hormone therapy comprises estrogen therapy, and is administered transdermally (e.g., by a patch) or orally (e.g., daily tablet, capsule or pill) so as to be substantially continuous over the duration of the polymer-conjugated anti-cancer treatment course .

[0049] It is to be understood that the at least 2 components of the combination treatment (i.e., the polymer-conjugated anti-cancer drug and the hormone treatment) may comprise all possible combinations, so long as catB levels are at about 65 ng/ml or greater. In an exemplary embodiment, a patient diagnosed with a cancer of epithelial origin, who presents with a low serum of plasma catB level, is administered a combination therapy comprising the administration of PPX as previously described, combined with the administration of estrogen, as previously described. [0050] In order to fully illustrate the present invention and advantages thereof, the following specific example is given, it being understood that the same is intended only as illustrative and in no way limitative. Example 1

[0051] In order to understand the relationship between catB levels and overall survival (OS) in patients treated with either a conjugated or unconjugated cancer therapy, the pre-treatment serum from such patients was analyzed to determine the baseline level of catB. At the end of the trial, catB levels were correlated to OS and the cancer regimen.

[0052] The experiments and results presented in example 1 describe the correlation between serum levels of catB, and treatment with PPX versus a comparator drug, as measured by OS. Two phase III studies, enrolling a total of 781 patients with NSCLC and a poor performance status (PS2) , were conducted. In one study (STELLAR 3), patients were divided into two treatment groups, the experimental group received PPX (210 mg/m² plus carboplatin AUC 6, every 3 weeks) and the control group received paclitaxel (225 mg/m² plus carboplatin AUC 6, every 3 weeks) . In the other study (STELLAR 4) , the experimental group received PPX (175 mg/m², every 3 weeks) and the control group received gemcitabine (1000 mg/m² on days 1, 8, and 15, every 4 weeks) or vinorelbine (30 mg/m² on days 1, 8, and 15, every 3 weeks).

[0053] In order to study the effect of catB levels on survival among the various treatment groups , catB was measured in pretreatment, stored serum using a standard ELISA assay with a high degree of specificity. The median value for all sera thus assayed was 65 ng/ml . The OS of patients with less than the median value (i.e., <65 ng/ml) was compared to the OS of patients with catB levels equal to or greater than the median value (i.e., _j>65 ng/ml). The results from both phase III clinical trials were combined and a composite analysis performed. These results are presented in Figs. 1-4. [0054] Results from the above study indicated a statistically significant difference in OS, in patients treated with comparator drugs, between those patients with high levels of catB versus low levels of catB (Fig. 1) . Patients with low levels of catB do not appear to fare any- better when treated with PPX versus comparator drugs (Fig. 2). However, there is a trend towards better OS in patients with high levels of catB, treated with PPX versus comparator drugs (Fig. 3). Patients treated with PPX, regardless of their catB status experienced similar OS rates (Fig. 4). Example 2

[0055] A study was conducted to examine the effect of estrogen on catB activity in human tumor xenografts. To study this effect, HT-29 human colorectal cancer (CRC) and H460 NSLCL cells (both from the ATCC) were transplanted s.c. into female CD nu/nu mice. Placebo or 0.17, 0.36, 0.72 τng/60 days of 17β Estradiol (E2) controlled release pellets (IRA) were implanted s.c. on day 0 and after 5 days human tumor fragments were transplanted. On day 5, 21, 28 and 35 after pellet implant, blood and tumors were collected (5 mice/time point) . [0056] The effects of estrogen treatment on catB activity was determined as follows: proteins were extracted by homogenization in catB buffer in a ratio of 1 ml of buffer per 100 mg of tissue. The test utilized the ability of catB to digest the synthetic substrate Z-Arg-Arg-AMC . Released AMC was determined fluorometrically at an excitation wavelength of 390 nanometers (nm) and an emission wave-length of 460 nm. The activity of catB was quantified versus an AMC standard curve. The results from these studies are presented in Fig. 5.

[0057] The results from the above study indicate that increased levels of estradiol result in increased catB activity. This was true for both the HT-29 and H460 tumor models . [0058] INDUSTRIAL APPLICABILITY

[0059] The present invention has industrial applicability in the field of cancer treatment.

[0060] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims .

Claims

1. A method for predicting the outcome of a cancer treatment regimen based on catB levels, comprising: determining whether the serum or plasma level of catB of a patient diagnosed with a cancer is about equal to, greater than or less than 65 ng/tnl, wherein a serum or plasma level of catB that is about equal to or greater than 65 ng/ml indicates that treatment with a polymer-conjugated anti-cancer drug will be more effective than treatment with an unconjugated anti-cancer drug, and wherein serum or plasma catB levels less than 65 ng/ml indicates that treatment with a polymer-conjugated anti-cancer drug will be no more effective than an unconjugated anti-cancer drug, and wherein said cancer is of epithelial origin, and optionally wherein a patient with a catB level in serum or plasma of about 65 ng/ml or greater is provided a cancer treatment, said cancer treatment comprising the administration of a polymer-conjugated anti-cancer drug.

2. The method of claim 1, wherein the cancer is lung cancer.

3. The method of claim 2, wherein the lung cancer is non-small cell lung cancer.

4. The method of claim 1, wherein the polymer-conjugated anti-cancer drug is a paclitaxel conjugate, administered in a dosage amount of about 175 to about 250 mg/m² paclitaxel equivalents .

5. The method of claim 4, wherein the paclitaxel conjugate comprises paclitaxel poliglumex.

6. The method of claim 5, wherein the paclitaxel poliglumix is delivered intravenously.

7. A method for treating a patient, diagnosed with a cancer of epithelial origin, comprising: determining whether the serum or plasma level of catB of said patient is about equal to, greater than or less than 65 ng/ml, wherein a serum or plasma catB level less than 65 ng/ml is artificially elevated to be about equal to or greater than 65 ng/ml, and wherein said patient with an artificially elevated catB serum or plasma level of about 65 ng/ml or greater is provided a cancer treatment, said cancer treatment comprising the administration of a polymer-conjugated anti-cancer drug.

8. The method of claim 7, wherein the cancer is lung cancer.

9. The method of claim 8, wherein the lung cancer is non- small cell lung cancer.

10. The method of claim 7, wherein the artificial elevation of catB is accomplished by the administration of a hormone therapy.

11. The method of claim 10, wherein the hormone therapy is estrogen therapy.

12. The method of claim 11, wherein the estrogen therapy comprises the administration of 17β estradiol.

13. The method of claim 10, wherein the polymer-conjugated anti-cancer drug is a paclitaxel conjugate.

14. The method of claim 13, comprising the administration of said hormone therapy in combination with the administration of about 175 to about 250 mg/m² paclitaxel equivalents of the paclitaxel conjugate.

15. The method of claim 14, wherein the hormone therapy comprises 17β estradiol and the paclitaxel conjugate is paclitaxel poliglumex.