AU2015203646A1 - Folate-targeted diagnostics and treatment - Google Patents

Abstract

Methods of detecting and assessing functionally active folate receptors on tumors and treatment associated with those tumors are described. Also described are methods of selecting ovarian and lung cancer patients for therapy with a folate-vinca conjugate by 5 identifying functionally active folate receptors on the tumors of the patient. Also described are methods and compositions for treating folate receptor expressing epithelial tumors with a folate-vinca conjugate in combination with doxorubicin such as pegylated liposomal doxorubicin in which the tumors include ovarian, endometrial or non-small cell lung cancer tumors, including platinum-resistant ovarian tumors and platinum 10 sensitive ovarian tumors. Also described are methods of treating platinum-resistant ovarian cancer using a folate-targeted drug, in the absence or presence of selecting the patient by identifying functionally active folate receptors on the tumors of the patient.

Description

- 1 FOLATE-TARGETED DIAGNOSTICS AND TREATMENT The present application is a divisional application of Australian Application No. 2010278734, which is incorporated in its entirety herein by reference. This application claims the benefit of United States provisional 5 applications 61/230,595, filed 31 July 2009; 61/346,444, filed 19 May 2010; and 61/351,022, filed 3 June 2010, each of which is incorporated herein by reference in its entirety. TECHNICAL FIELD This invention relates to methods and compositions for detecting and 10 assessing functionally active folate receptors on tumors and treatment associated with those tumors. The invention further relates to methods and compositions for selecting ovarian and lung cancer patients for therapy with a folate- vinca conjugate by identifying functionally active folate receptors on the tumors of the patient. The invention also relates to methods and compositions for treating folate receptor expressing epithelial 15 tumors with a folate-vinca conjugate in combination with doxorubicin such as pegylated liposomal doxorubicin in which the tumors include ovarian, endometrial or non-small cell lung cancer tumors, including platinum-resistant ovarian tumors and platinum sensitive ovarian tumors. The invention also relates to methods and compositions for treating platinum-resistant ovarian cancer using a folate-targeted drug, in the absence or 20 presence of selecting the patient by identifying functionally active folate receptors on the tumors of the patient. BACKGROUND AND SUMMARY An important adjunct to targeted drug therapies is the co-development of 25 diagnostic tests to provide information on the presence or absence of the molecular target in question. For example, selection for therapy with Herceptin@ (trastuzumab) is guided by such a diagnostic test, the HercepTest@, a semi-quantitative immunohistochemical (IHC) assay that measures human epidermal growth factor receptor 2 (HER2) expression to aid in selecting patients for treatment with Herceptin*. 30 However, the HercepTest* does not detect functionally active epidermal growth factor receptors (i.e., receptors that bind epidermal growth factor) because antibodies to the - 1 a epidermal growth factor receptor are used to detect the presence of epidermal growth factor receptors on fixed tissues, not the capacity of those receptors to bind epidermal growth factor. Following a study with "lIn-DTPA-folate, to detect folate receptors on the tumors of 5 ovarian cancer patients, studies were initiated to develop a technetium-99m ('t'c)-based folate linked radiopharmaceunca Advantages of a techneiumr-based agent inclde. ready availability of molybdenum/technetinn9m generators, 2)aptimal energy 0) ke) idetedon in gam 'a counters and 3) short half'-ife, in this regard "TcdEC20 C20) having the formula NH HN Cg 0 N H -S ws developed. Technei-991m -labeled EC20 t"T EC20) provides realtime noninasive detection of Assues expressing folate receptors capable of binding to folate. 0 The term EC20 is commonly used to identity the nonradioactive reagent lacking a radionucide: Na I-N com4)0 NH H H 0" N EC20, However EC20 is also commonly used to identify the radioactive drug 15 Substance "Y TcC20, which is the substance administered to patients. See Examples 2 and 3, below, In the context of administration to patients for detecting and assessing issues expressing folate receptors capable of binding to folate, ECZ0 is used herein to denote tne radioactive drug substance 9"AcEC20, or a pharmaceuticallyacceptable salt thereofit will be appreciated that the substance may be present in solution or suspension in an ionized fonn 20 including a deprotonated form Folaetargeted drgs have been developed and are being tested in clinical trials as cancer terapeutes, EC145 comprises a highly potent inca alkaloid cytotoxic mtydrazide (DAVLBIf, conjugated to folate The EC145 molecule targets the folate receptor found at high levels on the surface of epheli alumors inchiding noasnal cell ung cacinomas ,NSCL ovarian endonetial and renal cancers, and others inciding fallopian tube and primary peritoneal carcinoma Without being bound 5 bytheoryg it is believed that ECI45 binds to turnors that express the folate receptor delivering the vinca moiety directly to cancer cells while avoiding normal tissue Upon binding. EC145 enters the cancer cell via endocytosis, releases DAVIBH and causes cell death by inhbiting forrnaion of the itotic required for cell division- EC45 has the Chemical Abstracts Registry Number 742092-031 and the following formula. (mI q H C- ,j /" H 4 0, N NA\OVNY 2 N ~. C co c C4 EC045 As used herein, in the context of trattmr the term EC145 means the conipound or a 5 phannaceutically acceptable salt thereot. as indicated above; and the compound may be present in solution or suspension in an ion ed fnrm, including a protonated fom Applicants have demonstrated tha filate-radioactive imaging agent conjugates capable of to folate receptorscan be used to target a radionuclide to umos including ovarian umios or to lung tumors and to further to concentrate the 20 radionuclide in the tumor. Surprisingly, Applicants have discovered that the presence of a thresholdlevel of functionary active folate receptors may be indicative of a clinical benefit to the patie4t Thus. in accordance with the invention, a method of determining the presence of active folate receptors on tumors of patients is herein described. In addition methods for selecting parents for therapy with EC145 are described wherein a patient can be selected for 25 therapy based on a predicted clinical benefit to the patient resultingirom detection of a threshold evel of functionally active folate receptors on the patients tumor(s) The clinical benefit to the patient includes progression4ree survival of the patient ability to receive four or more cyces of therapy with B0 4 innhition of tumor growth, stable disease, a panial response of the tumor to therapy, and/or a complete response of the tumor to therapy -4 Accordingly, the detection of functionally active folate receptors (which may include but is not lmied to determining a threshold level of expression of functionally active fnlate receptors) can be used to determine if EX145 is indicated for the treatmentot a patient with ovarian cancer or iung cancer This noninvasive method can be used by medical personnel as an maid in trtrapy with conjugates with ovarian or lung tumors bearing the relevant functionally active folate receptor mtolecul ar target. Applicants have further demonstrated treatment of plainunWentn ovarian tumors, including metastatic tumors in patients with a combination of ECl145 and pegylated liposomal doxorbicin. Applicants have demonstrated that thi cambinaion therapy is 0 advantageous over the treatment of the patients using pegylated liposorral doxorubicin without EC145 EC20) may or may not be used in conjunction with this treatment, In one aspect of the invention, a method for detecting functionally active folate receptors in patients with tumors is provided. in anoer aspect of the inyendon, there is provided a method for detenining 5 the presence of fnctionally active to late receptors on a tumor such as an ovarian tumor or ng tumor, including primary and metastatic tumors. of' a patient comprising the step of administering to the patient a compositon comprising EC20. in another aspect of the invention, there is provided a method of determining whether EC145 is indicated for the treatment of a patient wih a tumor such as an ovarian 0 tumor or a lung tumor, the method comprisina the step of determining whether functionally active folate receptors are present on the tumor of the patient wherein EfC145 is indicated for the treatment of the patient wih the tumor if functionally active folate receptors are present on the tumor. ini primary and neta:tatic tumors 1n another aspect there is provided a method of determining whether EC 145 is 25 indicated fur the treatment of a patient with an ovarian tumor or a lung tomor the method comparing the step of administering to the patient FC20 wherein ECI 45 is indicated for the treatment of the patient with the tumor if the tunmor of the patient has functionally active foate receptors wherein the functinaiiy active fblate receptors are capable of detection with EC20, In a father aspect of the invention, trs provided a method ofieteruining whether EC 145 is indicated for the treatment of a patient with an ovarian tumor or a iung tumor the method comprising tie step of adnlisterng to the patient EC20, wherein EC145 is indicated for the treatment of the patient with the tumor if the radioactive signal produced by the EC20 upon binding to the tumor compared to the background radioacti ve signal produced by the EC20s indicative of a clinical benefit to the patient. in a further apect of the ino ee is provided a method of preditng a response of an ovarian tumor or a hng tunor of a patient to therapy with EC145, the method 3 compri ingithe steps of a) administering to the patient EC20 wherein the EC20 produces a radioactive Siagnal; b) quantifying the radioactive signal produced by the BC20 upon binding of the EC20 to the tmor: ( c) quantifying the background radioactive signal produced by the EC20; d) comparing the radioactive signal produced upon binding of the EC20 to the tumor to the background radioactive signal; and e) predicting the response of the tumor to the therapy based on the comparison 5 In an additional aspect of the invention, there is provided a method of treatment of folate receptor expressing epithelial tumors in a patient in need thereof comprising administering a therapeutic amount of EC-145 in combination with a therapeutic amount of doxorubici n. In an additional aspect of the invention, there is prodded a method of 0 treatment of folate receptor expressing epithelial tumors in a patient i need thereof compriin A stering a utic amount of ECD45 in combination wih a therapetui amount of pegyiated liposomal doxorubicin. In an additional aspect of the invention there i provided a method of treatment of platinmresistant ovarian cancer in a patient in need thereof comprising 25 administering a therapeutic amount of E143 in combination wvith a therapeutic amount of pegvy ated liposcomal doxorubicin. in an additional aspect of the invention, there is provided a method of tUa trment of platinitisensitiye ovadan cancer in a patient in need thereof comprising administering a therapeutic amount of EM145 in combination with a therapeutic amount of h) pegyiated liposomal doxorubicin. in a further aspect of the invention there is provided a method of obtaining a clinical benefit compared to treatment with a therapeutic amount of pegylated liposomtal doxorubicin in the treatment of piatinun resistant ovarian cancer in a patient in need thereof -6 comprising adrninisteinng a therapeutic amount of 1145 in combination with a therapeutic aniount of pegylated iiposonal doxorubicin. In another aspect, a method of dem nweher a patient with a tmnor has htunctroailv active folate receptors present on the tumor of the patient is provided. The 5 method comprises the step of administering an effective amount of EC20 to the patient for detection of the functionally active folate receptors. in yet another aspect the tumor is an ovarian tumor or a hng tumo In another ilhistrative aspect, the tumor is a primary tunor or a ietastatic umor In another e.ibodhnent, the funtionally active folate receptors are detected visually. In still another aspect, the Visual detection of functionally active folate 0 receptors is used to determine folate receptor status of the patient, llustratively, the folate receptor status of the patient is selected from the group consisting of EC20++, EC20+, and EC20, In this ilhustrative aspect, the folate receptorstatus may be EC20++ and treatment with EC145 is indicated In another aspect. EC20++ status correlates with a clinical benefit to the patient and the clinical benefit may be disease control rate or overall disease response 5 rate. BRIEF DESCRIPTION OF THE DRAWINGS F[I 1 Planar imace of a Patient After Administration of "Tc-EC20PFlate Prior to the mTc1TBC20 iming rocedure patients receive one IV injection of 0.5 mg of 0 folic acid, followed, within I to 3 minutes by a I to 2 miL injection of 1 mg of EC20 labeled with 20 to 25 mCt of techneiums99n Approxmately I to 2 hours post-injection of )VTecEC20 mid-thigh to head. anterior and posterior planar images are acquired. Arrows indicate approximate location of the tumors (lesions). In this example, two areas containing foate reeptor positive tumors are indicated, 25 IlG 2. Planar Image of a Patient After Adntinistration of eC-olata Prior to the ""Te-EC20 imaging procedure, parents receive one IV injection of 05 rg of flijc acid, followed, within I to 3 minutes, by a to 2 mL injection of 014e of EC20 labeled with 20 to 25 mCi of technetium99m. Approximately I to 2 hours post-injection of Tc-EC20.nid-thigh to head, anterior and. Posterior Planar images reacquired Arrows 30 indicate approximate location of the tumors (lesions). In this example, two areas containing folate receptor positive turinrs are indicated.

FIKIC 3, Planar knace of a Patient After Adinistration of "TcC20-clate Prior to the 9 "TBC20 imaging procedure, patients receive one IV injection of 0.5 mg of folic acid followed, wihin 1 to b nutes, y a I to 2 ml. ejection of 0.1 mg cf EC20 labeled with 20 to 25 mCiof technetium--99m. Approximately I to 2 hours post-injection of 5 VTe EC20, miduhigh to head anterior and posteror planar images are acquired Arrws indicate approximate location of the tumors (lesions). In this example, two areas containing flate receoptor positive tumors are indicated. FI. 4. Planar Iage of a Patient After Administration of 9"'1EC20-Folate, Prior to the 9 "Tc-EC20 making procedure, parents receive one W injection of 0,5 mg of 0 folic acid, followed, within I to 3 invites, by a 1. to 2 ml injection of 0, t mg of EC20 labeled with 20 to 2 mCi of technetium-9 Pm Approximately 1 to 2 hours post-injection of -Tc-EC20 i th.igh to head, anterior and posterior paqanages are acquired. Arrows indicate approximate location of the tumors lesionss. In this example, one area containing a folate recep tor positive turror is indicated, 5 FI. 5, Planar Imace of a Patient After Adrmnnistration of Tc-Ed2-Foite Prior to the TcFC20 imaging procedure, patients receive one IV injection of 8 5 mg of fblic acid, followed within I to 3 minutes b a I to 2 rnL injection of 01 mg of [C20 labeled with 20 to 25 mCi of technetium-99ry Approximately 1 to 2 hours post-iij cion of TcEC20 mid-thigh to head. anterior and posterior planar images are acquired, Arros 0 indicate approximate location of the tumors (lesions) In this example, six folate receptor positive lesions are indicated. FIGi 6, CT Scan Inage of the Same Patient For Which the Planar iae s Shown in FIG. 5. Regions of interest (high intensity image area withitumor lesion) are indicated by the two ellipses Images were measured prior to commencement of treatment 25 with FC145 to yield the following sizes: Tiumor I - 34 mn Tumor 2 --- 25 mm FIG. 7. ( Scan frage of the Sa-me Patient For Which the Planar mage Is Shown in FIG, I Regions of interest (high intensity image area within tumor lesion) are indicated by te two ellipses llmages were measured after 8 weeks t2 cycles) of treatment with EC145 to yild the following tumor sizes(percent size chang )Tumor --- 15 mm 30 t.56%- Tuor 2 -- 0 irinti 60%vc) FIG. 8. Exemplary 16 week treatment regimen with EG45. FI Tumor Response of Non-Small CellLung Carcinoma and Ovarian Cancer Tumors to Treatment. '[umors were di-e into two groups, folate--receptor positive and falate'receptor negative (separated by the vertical dotted line in the figureybased on Making results after administration of ""Te EC2O according to the methods described in Example 16. The change in size of each tumor after treatment by the method of Examnple I8 or Example 19 is indicated by the individual bars in the graph, As described in Examiple 21, 5 the manincrease in size for all tumors that were folate-receptor posing based on the method desrnbed in Example 16 was significantly less than the mean increasein size for all tumors that vere flate-receptor negative,7% versus 33%. respectively. FIG. 10. SPECT and. planar images shving E720 uptake in target lesions. "-I.EC20 allows the physician to obtain a. real-imne assessment of receptor expression. 0 Panels A 13, and C compare (T SPECT and planar images from an ovaran cancer patient (patient 035. study EC-WV-2) shown r t I'ceEC20 uptatke in ad minbasses (ht arrows) Panel A - CT scan; Panel B -SPECT image showing 5 TcEC20 uptake; Panel B planar image showing T WEC20 uptake Fi: G I1 shows the KaplanMekir curves for progression free survival (PFS) at 5 the interim analysis in stud yt EC .FV-04 for patients treated with ECI 45 in combination with pylated liposomal dox(orbic 14 P h LD)and for patients treated with pegylated liposomal doxorubicin alone ILD alone FIG, 12 shows Kapian-Meier curves for progaression free survival (PFS) time in Study E(C-FV-04, an ongoing phase 2 trial in women wih platinon-esistant ovarian 0 cancer, at the time of the interim analysis, for subjects enroled at sizes with nuclear inging capabilies who were scanned with 1EC20 prior to study treatment and assessed as EC20 positive (EC20+ status) prior to study treatment (EC 145 in combination with PL) versus PLD alone)t. Fi 13 shows Kaplan--Meier curves for overall survival (OS) time in Study 25 ECB-O2 a trial in women with advanced ovarian and endonetrialcancers who were scanned with EC20 prior to study treatment and assesed as EC20 positive (EC20++ status) compared to those assessed as EC20+ status or ECO status prior to study treatment, TIhis curve shows the utiliy of selecding patients who benefit from the single agent EC145 in highiv refractoiry ov arian cancer patients. 30 FI 14 shows Kaplan-Meer curves for overall. survival (OS) time in Study ECFV-04 an ongoing phase 2 trial in women with platinum-resstant ovarian cancer at the time of the interim analysis, for patients treated with EC145 in combination with pegylated -4 1posomtl- doxoimbicin (E045 + P11)and for patients treated with pegylated liposomal doxonubicin alone PLD alone FIG, 15 shows the synergistcrelationship between EC145 and doxorubicin in the. inhibition of growth of KB tninor cells in vivo as described in Example 7 dta points that 5 fall below the line represent synem.g st FIG. 16 shows the effects on tunor growth and responses (PR partial response CR = complete response. Cores) from the study in mice bearing M109 tumors described in Example for the following groups: mM1 control C45 2 pmo"kg (ci DOXI. 7 ng/k dy EC145 2 pmol/kg + DOXIL, mg/kg: e) DOXIL, 4 mg/kg and 0 (f) ECl45, 2 pmol/kg + DCXILI 4 mg/kg. FIG. 17 shows the effects on weight change from iti study in mice bearing M109 tumors described in Exanple 8 for the following groups; (a) M1.09 control (b) EC145 2 pmonkg; (c) DOXIL, mg/pkg: (d) EC145, 2 pmok/1 + DOXL? mg/kg; (e) DOXIL. 4 rng/kg; ar d) EC145. 2 pmofg DOXIL, 4 rng/kg, 5 DEFINITIONS In accordance with the invention. "functionally active folate receptors" means folate receptors expressed on an ovarian or a lung tunor at a tumor to background ratio of at least about i bor greater The term also can be used to mean a signal from tunors detectable visually(e gused to identf an EC20±± patient as described below) The presence of 0 "functionally active folate receptors" (ise. a tnor to background ratio of at least about L2 or greater or a sgnal from tumors detected visually correlates wilb a clinical benefit to a patient selected for therapy with E-C145, the clinical benefit including progressionree survtalof the patient, overall survival of the patient'ability to receive four or more cycles of therapy with EC 145,.inhibition of tumor growth. stable disease, a paial response, and/ar a complete 25 response, In accordance with the invention. 'tumor to background ratio means the ratio of the radioactvesignal produced by EC2O upon bind-ing to a tumor compared to the background radioactive signal produced by the foiate-radioactihe imaing agent Mthe patient. 30 in acCordance with the invention "clinical benefit" means a re-sponse o a patient to treatment with ECl45 where te response includes progresson-tee survival of the patient overall survival of the patient, ability to receive four or moe cycles of therapy (egg, I 0 fo-ur weeks of therapy) with ECI 45. inhibition of tumor growth, stable disease, a partial -spoise. andtior a complete response, [i accordance with the invention, "ihibition of rumor growth* meas reduction in tumor size complete disappearance of a tumor, or growth of a patient tumor of 5 tess than 30% over the course of therapy with EC145, In accordance with the invention, Ntabie disease" means no material progression of disease in a patient over the course of therapy with EQ 145. in accordance with the invention, "a partialresponse" means a decrease in tumor size of 30% or greater in a patient treated with EC 145. J In accordance with the invention "a complete response means the disappearance of detectable disease in a patient treated with EC145, DETAILED DESCRIPTION OF ILLUS'TRATIVE EMBODIMENTS in any of the various disclosures above te allowing fethue.es may be present 5 where app cable providing additional embodiments of the invention. Another embodiment is described wherein the method further comprises the step of administering to the patient an unlabeled folate, such as folic acid or a salt thereof, prior to administration of EC20 in the form of a complex with a radionuclide. Another embodiment is described wherein EC 145 isd for the 0 treatment of the patient with the tumor if the radioactive signal produced by EC20 upon binding to the tumor compared to the backgrtround radioactive s ig':nal produced by the EC2)0 is indicative of a clinical benefit to the parent Another embodiment is described wherein the clinical benefit is progression, free survival of the. patient 25 Another embodiment is described wherein the clinical benefit i iinhibitionf f tumor growth. Another embodiment is described wherein the clinical benefit is selected fhum the iroup consisting stable disease, a partial response and a compete response Another embodiment is described whereinthe level of expression of the 30 fuIonally active folate receptors is quantified based on a tumor to background rato of the radioacte signal produced by the EC20 to the background radioactive signal, Another embodiment is described wherein the tumor to background ratio is at least about i 2.

Another em n is described wherein dhe tumor to background ratio is at least about 1.3, Another embodiment is described wherein the turr to background ratio s at least about 14 5Another embodiment is described wherein the tunmor is an ovarian tumo. Another embodiment is described wherein the tumor is a platinum-resistant ovarian tumor, Another embodiment is described wherein the tumor is a han tumor Another embodiment is described wherein the tumor is a nonsmall cel 0 carcinoina of the lung, Another embodiment is described wherein either the EC145, the EC2,or both are in a pareiteral dosage torin Another embodiment is described wherein the dosage form is selected from the group consisting of itradertal subcutneous intramuscular intraperitonea. 5 ravenous and intrathecaL Another embodiment is described wherein the ECJ45 is in a composition and wherein the composition further comprises a pharmaceutical acceptable carrier, Another embodiment is described wherein the. compositionom prison the EC20 further comprises a pharmaceutical acceptable carrier, 0 Another embodiment is described wherein the phamnaeutiealy acceptable carrier is a liquid carrier. Another embodiment is described wherein the iquid career is selected from the group consisting of saline, glucose alcohols, glycols. ese aides, and a combination thereof, IS Another embodiment is described wherein the EC145 administered in a therapeutically effective amount Another embodiment is described wherein the EC20 is administered in a therapeutically effective amount. For EC20, a therapeuticaily effective amount denotes a diagnostically effective amount, 30 Another embodiment is described wherein the eTective amount ranges trotn. about I ng to about i mg per kilogram of body weight Another embodiment is described wherein the effective amount ranges from about 100 ng to about 500 pg per kilogra-m of body weight Another embodmt is described wherein the effective amount ranges from about 100 ng to about 50 p kilogram of body weight. Another embodi ment is described wherein the tumnr is a pri Iary tunor, Another embodiment is described wherein the tumor is a metastasized tumor 5Another eibodinet is described wherein the EC20 is radiolabeled usiria a cheating agent and a reducing agent Another enoden is described whereii the cheating agent is sodiurn ul -) gI ucohepIonate. Another enbodimntu is described wherein the reducing agent is tin (H) 0 choAride dehydrate. Another embodiment is described fiurher comprising the step of administering to the patient doxorubicin. One embodiment is wherein the doxoruhicin is in the forn ot a pegyl ated liposoat doxorubicin (PLLD) For any method or use described here fix oC20; or a pharmaceuticaly 5 acceptable sait thereof an alternative embodiment is a folate-radioactiye imaging conjugate having as the complexed radionuclidea cation of a radionuclide selected trom the group consisrig of isotopes of gallium, indiun, copper; technetiunt, and rhenium. For all of the eniodiments, any applicable combination of embodiments is also contemplated. Any applicable combination of the abovedescribed embodituents is 0 considered to be in accordance with the inventiot In accordance with the invent, EC20 can be used to target a radionud ide to ovarian tumors or to lung tumors and further to concentrate the radionuclide in the tumor for use in detecting functional y active foate receptors on the tumors. Surprisingly Appliants have discovered that a hreshold level of fakte receptor expression on the tumor (e. the 25 presence of functionally active ftolate receptors on the tumor) correlates vith a clinical benefit to a parent selected for therapy with EC4N Thus, in accordance with the invention a method of determining the presence of functionally active folate receptors on tumors of patients is herein described i addition, methods are provided for selecting patients for therapy with [C:45 wherein a patient can he selected for therapy based on a predicted 30 ceinial benefit restdtun. from detection of a threshold level of functionally active folae receptors on the patients tumor. The clinical benefit to the patient includes progression4ree survival of the patient overall survival of the patient, ability to receive four or more cycles of therapy with EC45, inhibition of tnor gro .h stable disease a partial response of the -13 tumor to therapy, and/or a complete response of the tumor to therapy. The threshold level of folate receptor expressing can heb for example, a tumor to background ratio of at least about 1.2. at least about 1.3 or at e about 1.4, or can be detected visually (eg. visual detection used to identify an EC20++ patient as described below) Accordiney the detection of 5 functionally active folate receptors (ie, a threshold level of fblate eceptor expression detected as a tumor background ratio or detected visually, for example) can be used to determine if EC145 is indicated for the treatment of a patient with an ovarian tumor or a lmg tumor, In one embodiment, the method is applicable to tumor types having 0 functionally active folate receptors includina ovarian tumors or ung tumors. In another illustrative embodiment. the method is applicable to platinunuresistant ovarian tumors. In vet another embodiment the method is applicable to nan-smal celtlung carcinomas In another illustrative embodiment, the tumor can be a primary tumor. In another entbodiment. he tumor can be a metastasized tumo 5 In one embodeent, the method described herein is us ed to quantify ftmeti onal y active folate receptors. In another ehodiment the method. described herein is used to quantify functionally active. folate receptors to determine if EC145 is indicated for the treatment of a patient with an ovarian tumor or a ug tumor inone. embodiment the patient optional 0 can be preinjected with untabeled folate and therinjected with ' BEC20 to determine a tunor to background ratio. In this embodiment, a tumor to background ratio is the ratio of the radioactive signal (eg. by SPECT/CTor SPECT imaging) produced by "fTeEC20iC upon binding to the tunconr copared to the background radioactive signal produced by the folate-radioactive imaging aent in the patient In this embodiment the tumor to backgroiId 25 ratio can be, for example at eabt aout 1.2. Ateratively the presence of a threshold level of functionally active folate receptors can be determined visuallxeg, to idendfy an EC20-+ patient as described below. The threshold level of expression of functional active folate receptors may correlate with a clinical benefit to the patient. The dinical beneft can include progression 30 free survival of the patient. overall survival of the patient ability to receive tour or more cycles of therapy with EC145 inhibition of mor growth stb disease ,a partial response of the tumor to therapy and/or a complete response of the tumor to therpy The detection of functionally active foltte receptors (eg, a threshold. level of folate receptor expression I 4 reflected in a tumor to background ratio of .2 or determined visuall, e g visual detection used identify an EC20++ patient as described below can be used to determine if EC145 is indicated for the treatment of a patnt t with an ovarintu m or a lung tumor in the above described embodiment the tumor to background ratio can be, for 5 example.,.2, U or 1.4, or detected visually n another illustrative embodiment the threshold level of functionally active folate receptors can be determined by visual examination of, for example, a predetermined region of a SPECT/CT or SPECT image and coding the intensity of"'c E(2t uptake as. for example, no uptaket mild uptake or marked uptake, and sel.cting Patients for therapy with - md -hptake or marked optake U In yet another enbodiment, a method of selecting a patient with an ovarian tumor or a lung tumor for therapy with a cniagate comprisinAg a folate linked to a vinca compound is descaned The method comprises the step of determine if functionally active folate receptors are present on the tumor of the patient wherein the patient is selected for therapy vdih the folatevoca compound conjugate if functionally active folate receptors are 5 detected on the. tumor, In another embodiment a method of selecting a patient with an ovarian tumor or a hing tumor for therapy wih a conjugate comprising a folate linked to a vinca compound is described. The method comprises the step of administering to the patient a composition coMprisin a folate linked to a radioactive imaging agent, wherein the patient is selected for 0 the therapy wth the conjugate comprising the folate inked to the vinca compound if the tumor of the patien has functionaY active fate receptorN wherein the functionally active folate receptors are capable of detection with the iC20, in another embodiment a method of selecting a patient with an ovarian tumor or a lung tumor for therapy with a conjugate comprising a folate linked to a vinca conpouid 25 is described. The method comprises the step ofadmiistering to the patient a cnjugate comprising a folate linked to a radioactive- mai aent, wherein the patient is selcted for therapy if the radioactive signal produced by the EC20 upon binding to the tumor compared to the backgrotud radioactive signal produced by the EC20 is indicative of a cinical benefit to the patient. 30 i one embodime.nt of the invention the EdIO can be administered to the patent in combination with unlabeled folate. "In combination with"rneans that he unlabeled vitamin can be either coadministered with the EC20 or the unlabeled folate can be preinjected before administration of the EC20 to improve inage quality. For e.x ample, the Ed20 can be administered in combination with about 0-5 ng unlabeled folate/kg of body weight to about 100 a unlabeled folae/k of body weight, or about Ig uieled folate&g of body weight to abWut 100 ma unlabeled iateg of body weight or Out 100 pg unlabeled folaikefg of body weight to about 100 rg unlabeled folate/kg of body weight, or about 100 pga unlabeled 5 folatekg of body weight to about 700 pg unlabeled folatetk o bony weight with an average patient having a body weight of about 70 kg. Another embodimenr a patient with a umor has functionally active foIate receptors presAnt on the nimor of the patient In one embodnent the tumor is an ovarian tumo or a lmg tumorn another embodiment the 0 tumor is a primary tumor or a metastatic tumor. In a further embodiment the method comprises adnuisterig to a patient an effective amount of Tc-EC20 for detection of the funetunnaily active fol ate receptors. In other embodiments of the methods described herein pharmaceutically acceptable salts of the conjugates described herein are described, Pharmaceutically 5 acceptable salts of the conjugates described herein include the acid addition and base salts thereof. Suitable acid. addition salts are formed from acids which fior non-toxic sats. Illustrative examples include the acetate, asparate. benzoate besylate. bicarbonatcarbonate. bisuiph ate/sulphate, borate. carsy late, citrate.disylate, esyiate ate, fumarate 0 ghIuceptate, gl uconate. giucuronate. hexafluorophosphate hibenzate, hydrochioride/hloride hydrobromider.nide, hydroindideiodide. isethionate, laate. irlalate. n aleate; maionate; mesylate. nmethylisulphate, naphthylate, 2-apsylate, n icoti nate, nitrate, ermt ae. oxal ate, palmitate, pamoate phospha'telydrogen phospharedihydrogen phosphate, saccharate, stearate succinate tartrate, tosylate and trifuoroacetate salts, 25 Suitable base sats of the couugates described herein are formed from bases which form nontoxic salt Illustrative examples incude the arginine; benzathine, calcium choline, dietiamine. didlamnineglyine.lysine magnesium mealmine famine, potassium, sodium, tromethmine and zinc salts. Ierrisalts of acids and bases may also be formed, for exampleemisuiphate and hemicalcium salts. 30 in various embodiments of the methods described herein, the EC145 may be administered alone orin combination with one or more other drugsor as any combination thereof) In one illustrative embodiment, the EO45 can be adminisered incombination with i6 doxorubicin, in one illustrative embodiment; the EC 145is administered in combination with pegytated liposomal doxonubicin as described in Example 20. in one embodtment, the conjugates described herein may be admijoistered as a formulation in association with one or more pharmaceu ticalty acceptable carriers The 5 carriers can be excipients. The choice of carrier ill to a large extent depend on factors such as the particular mode of admtnistration the effect of the carrier on solubility and stability and the nature of the dosage forn. PharnceuttcaI compositions suitable for the delvery of conjugates descihed herein and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found. ( for example, in Remington TheScience & Practice of Pharmacy, 21 th Edition (Lppincott Williams &Wilkins 2005) incorporated herein by reference in one illustrative aspect a armaceutically acceptable carrier includes any and all solvents dispersion media.coatingsantibacterial and antifuingal agents, isotonic and absorpton delaying agents, and the like, and coinnattons thereof, that are physiologicaly 5 compadle in some embodiments the carrier is stitalle for parenteral administration. Pharmaceutcally acceptable careers include sterile aqueous solutions or dispersions and sterile powers for the extemporaneous preparation ot sterile injectable solutions or dispersions. Supplementary active compounds can also be incorporated into compositions of the invention 0 in various embodiments, liquid formulations may include suspensions and soltions. Such formulations may comprise a carrier, tor example, water ethanol, polyethylene glycol, propylene glycol, methyicellulose or a suitable oil, and one or more emusand/or agents. u nations m so be prepared by the reconstitution of a solid, for exampedm a sachet 25 In one embodiment an aqueous suspension may contain the active materials in admixture with appropriate exci pients Such excipients are suspending agents, for example, sodium carboxymethylcelhulose, methyceliulose, hydroxypropylmethylcellulose sodium alginate polyvinyipyrrolidone gum tragacanth and gum acacia; dispersing or wettfig agents which may be a naturally-occurrmg phosphatide, for example, lecithin: a condensation 30 product of an alkylene oxide with a fatty acid. for exam ple polyoxyethylene stearate; a condensation product of etyene oxide with a long.. chain aliphatic alcohol, for example heptadecaethyleneoxycetanol a condensation product of ethylene oxide with a partial ester derived frorn fatty acids and a hexitolsuch aspolyoxyethylene sorbitol monooleate:or a I 7 condensation product of ethyene oxide with a partial ester derived from fatty acids and hexitol anhydrides. for example. potyoxyethyl ene sorbitan mnonoolea te. The aqueous suspensions onay also Cotain one or iore ptreservatives fthyl, n propyL or p-hydroxybenzoate; or one or more coloring agents, 5 In one illustratve enibodinxent. dispeAblae owdeis and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent. suspending agent and one or more preservatives, Additional excipients. fAr ample, coloing agents mayaso be present Suitable emnulsifying agents nay be naturallyvoccuring gums tor example. 0 gum acacia or guim tragacanth; naturalixoccurrg phosphatides, for example, soybean lecithin; and esters including partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mnono-odeate, and condensation products of the said partial esters with ethyl ene oxide, for example; poiyoxyeth ylene sorbitan mon ooleate. ither embodiments isotonic agent, for example , sugars, polyakoho such 5 manitol, sorbitol or sodium chloride can be included in the composition, Prolonged absorption of the timetable compositions can be brought about by including in the composition an agent which delay absorption, for example, nonostearate salts and gelain. In one aspect a conjugate as described herein may be administered directly into the blood stream, into m wusde or nto an integral organ Suitable routes for such 0 parenteral administration include intravenous intraarterial intraperitoneal, intrathecal. epidural. i tracerebroventriculaintraurethral intrasternal intracrandat itraturnoral, intramuscular and subcutaneous delivery, Suitable means for parenteral administration include needle i needing mnicroneede) in sectors. needletree sectors and infusion techniques, 25 In one illustrative aspect parenteral formultions are typically aqueous sohtutons which may contain carriers or recipients such as salts, carbohydrates and bufifering agents (preferably at a pH of from 3 to 91 but, for some applications., they may be more suitably formulated as a sterile non-aqueous solution or as a dried fbrm tobe used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. in other 30 embodiunsany of the, liquid formulations described hereinr be adapted for parental administration of the conjgates described herein W The preparation of parenteral fomulations under sterile conditions.for example by Iyophilizaton under sterile conditions. may readily be accomplished using standard pharmaceutcal techniques well known to those skilled in the 18 art. In one embodiment, the solubility of a con jugate used in the preparation of a parenteral formulation may be increased by the use of appropriate fomiation techniques. such as the incorporation of soliubiy- ernanci ges ii in various embodiments. formulations for parenteral administration may be 5 fornmlated to be for immediate and/or modified release in one illustrative aspect. active agents of the invention may be administered in a time release formulation, for example in a composition which includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a control lled release formulationincluding plants and microencapsulated delivery systems. Biodegradable, 0 biocompatible polymers can be used, such as ethylene vinyl acetate, polyaihydrides polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolyners (PGIA). Methods for the preparadon of such formations are generally known to those skilled in the art, In another enibodinent, the conjugates described herein or conmposition s comprising dhe conjugates may be continuously adlistered where 5 appropriate. In one embodiment, a kit is provided. If a combination of active compounds is to be administered, two or more pharmaceutical cornpositions may be combined in the form of a kit suitable for seqenti al administration or c-administration of the compositions. Such a kit comprises two or more separte pharmaceutical comEpositions. at least one of which 0 contains a conjugate described herein, and means for separately retaining the compositions, such as a cntainer, divided bottle, or divided foil packet, in another embodiment, compositions comprising one or more conijgates described herein, in containers having labels that provide instructions for use of the conjuigates for patient selection and/or treatment are provided. 25 In one embodiment 4 sterile injectable, soltions can be prepared by incorporating the active agent in the required amount in an appropriate solvent one or a combination of ingredients described above, as required, followed by filtered sterilization. lypical l.y dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a dispersion medium and any additional ingredients from those 30 described above In the case of sterile powders for the preparation of sterile injectable solutions, the preferred, methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously steile-filtered solution thereof, or the ingredients may be sterile-filtered together, (19 Ithe composition can be formulated as a solution. ncroem lsion, liposofme. or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for examnple.water, ethanol polyol. (for example.glycerol, propylene glycol, and liquid polyethylene giycol, and the liket and suitable mixtures thereof. 5 in one embodiment, the proper fluidity can be nuiritained, for exampWe. by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. An effective regimen for administering the E145 can be used, For example, the E 45 can be admAnistered as single doses, or can be divided and administered as a 0 multiple-dose daily regimen Further a staggered region for example, one to fie days per week can be used as a alternative to daily treatment, and for the purpose of the methods described herein, such intermittent or staggered daily regimen is considered to he equivalent to every day treatment and is contemplated, In one illustrative enbodiment the patient is treated with multiple injections ohe EC145 to ehniname the tumor, in one embodiment; the 5 patient is injected mutiple times (preferably about 2 up to about 50 times) with the FC145. for example, at 12-72 hour intervals or at 48-72 hour intervals., Additional injkctons of the E145 can be administered to the patient at an integral of days or months after the initial injections(s) and the additional inections can prevent recurrence of the cancer Any suitable course of therapy with the EC145 can be used in one 0 embodiment. individual doses and dosage regimens are selected to provide a total dose ad ministered during a month of about 15 ag. In one illustrative example, the EC21 45 is administered in a single daily dose administered five days a week in weeks 12 and 3 of each 4 week cycle with no dose administed in week 4 in an alternative example the ECI 45 is administered in a single daily dose administered three days a week of weeks I, and 25 3 of each 4 week. cycle. ; with no dose administered in weeks 2 and 4. The unitry daily dosage of the EC145 can vary significantly depending on the patient condition, the disease siae being treated, the molecular weight of the EC145, its route of administration and i issue distribution and the possibility of co-usage of other therapeutic treatments, such as radiation therapy or additional drugs in combination therapiesT The 30 effective amount to be administered to a patient is based on body surface area. nass, and physician assessment of patient condition. Effective doses can range, for e xamle from about 1 nagkg to about I mg/kg, from about Igg/kg to about 500 pg/kg. and from about 1 sg/kg to about 100 p-g/kg. These doses are based on an average patient weight of about 70 kg, The conjugates described herein can be administered ina dose of from about I a) ng/kg to about 1000 .g/kg, from about 10 ng/kg to about 1000 ggfg from about 50 5 ng/Ig to about 1000 pg/kg, from about 100 ng1g to about 1000 g/kg from about 300 ag/kg to about 1000 pg/kg from about I ng/g to about 500 ug/kg, from about1ng/kg to about 100 jg/kg, fon about pkgg to about 50 pgg, fom about I pgkg to about 10 pg/g from about 5 pg'g to ibout 500 g/kgg from about 10 g/kg to about t00 pgkg from about 20 jag/kg to about 2 00 pgg, from about 10 pg/kg to about 500 pgkgg ar from about 50 pg/kg 0 to aIout 0 pg&g The total dose may be administered in singer divided doses and may. at the physician discretion, fal outside of the typical range given herein These dosages are based on an average patient weight of about 70 kg The physician will readily be able to determine doses for subjects whose wci gjht falls outside this range such as infants and the elderly: The conjugates described herein may contain one or more chiral centers. or awy otherwise be capable of existing aaltnple stereoisomers. Accordingly it 1s to he understood. that the present in vention incldes pure tereoisomers as well as mixtes of Ntereoisomers, such as enantiomers diastereomers and enantiomerically or diastereomnerially enriched mixtures. The conjugated described herein inay be capable of 0 exisung as geometric isomers. Accordingly, it is to be understood that the present invention includes pure geometry isomers or mixtures of geometric isomers. it is appreciated that the conjugates described herein may exist in unsolvated forms as well as seated forms including hydrated forms, hn general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scone of the present 25 invenon. The conjugates described herein may exist in multiple crystalline or amorphous orrms. in general physical forum are equivalent for the uses contemplated by thpresent invention and are intended to be withinthe scope of the present invention. In another ebodment. compositions and/or dosage foruas for administration of E a45 e prpard5 with a purity of at least about 90% or about 95%. or ,30 about 96%, or about 97%, or about or or about 99%, or about 99.5% in another embodiment, coampositions and or dosage forms tor administration of EC145 are prepared 2f from LC('145 with a purity of at least 90%. or 95%, or 96%. or 97%. or 98% or 99%, or 99,5%, In another enbodimentco.positions and/or dosage fons for adrninis"atron of EC20 are preparedim FC20 with a purity of at least about 90%, or about 95% or about 5 % or about 97% or about 98%, or about 99% or about 995%, ha another embodinen compositions and or dosage forms for administration of EC20 are prepared from EC20 with a purity of at least 90% or 95%. or 97%. or 98% or 99%. or 995% In another embodiment, compositions and/or dosage fonns for administration of radiolahed fC20 are prepared from BC20 of with a radiochemicalpurity of at least about 0 90S, or about 95% or about 96%, or about 97% or about 98% or about 99%. or about 99.5%. in another embodiment; compositions and or dosage forms for adnrnstration of EC20 are prepared from fC20 with a purty of at least 90%, or 95%. or 96% or 97% or 98%, or 99%%, or NS As used erein, purity determinations inay be baseon weight peredage, 5 mole percentage. and the like. In addition, purityv determinations may be based on thre absence or substantial absence of certain determined components such as, but not limited to: lohe acid. disulfide conaining components not containing a inca drug, oxidation products.disultide components not conaining a folates and the like. It is also to be understood that purity determinations air applicable to solutions of the compounds and 0 compositions purified by the methods described beretr in those instances, purity measurements, including weight percentage and mol percentage measurements are related to the components of the solution exclusive of the solvent, The purity of the B1545 or the BC2T may be measured using any conventional technique including various chro atography or spectroscopic techniques. such 25 as high pressure or high performance liquid chromatography HPlPL nuclear magnetic resonance spectroscopy 'TLC, UV absorbance spectroscopy, fluorescence spectroscopy, and the like, In one aspect, patient response to treatment was characterized utliizing Response Evaluation Criteria in Solid 'Tumors (RECI1ST) criteria, llustratively, the criteria 30 have been adapted from the original W14,91 handbook (3), taking into account the measurement of the longest diameter for al target lesions: complete response (CR)-the disappearance of all target lesions: partial responseP MR)-at least a 30 decrease in the sum of the longest diameter of target lesions taing as reference the baseline sun longest 22I diameter; stable disease (SD- neither sufficient shrinkage to qualify for partial response nor sucient increase to ali forogressive disease, taking as reference the smallest sum longest diamener since the treaent stayed; progressive disease (PD) I ateast a 20% increase in the sumof the longest diameter of target lesions,takin as reference the smallest 5 sinm knges diameter recorded since the treatment stated or the appearance of one or more new lesions. Overall disease response rate (ORR) is calculated as the percent of patients who achieve a best response of CR or PR, Overall disease controlrate (DCR) is calculated as the percent of patients who achieve a best response of CR PR. or SD, In another embodtnent.the BC 145 is provided in a stele container or 0 package. in another embodiment EC20 is a sterile contamer or package. In one embodiment, a method is provided of determining whether EC145 is indicated for the treatment of a patient with one or more ovarian tumors or one or rnore ling tumors, the method comprising the step of determining a folaterceptor stats in a patient ovaria cancer Wherein the EC 14 is indicated for the treatment of the patient if the 5 folate<receptor status in the patient is posmivie. As used herein, when used in patients,the term "BC20" refers to EC,20. or pteroyl-D*glutarnyiLL2y diarmnopropiony aspr* i esteine or pterog I D- :iu -tatyiUr2--di1nnoroioy1-- as partvlt- cvseine compiexed to '"4 . Pr examplee. the term "'Tce EC 20" explicitly refers to the complex conta ining the radi oactive Folate-receptor status in the patient is positive if one or more tumrs in the patient have foate receptors capable of binding EC20 or if all tumors in the parent are capable of binding I20 in one illustrative example, the folate-radi active imaging agent con jugate is "WcEC20. At the time of the interim analysis described in Exanle 25, 25 below 913% of all ovarian cancer patents scanned with EC20 had been "positive" indicated by having at least one tmor lesion/area that binds EC20 versus 8.% of patients fhat were fully [EC20 "negative" In one embodiment a method is provided of assessing whether EC1 45 is indicated for the treatment of a patient wth one Or more ovarian tumors or one or noreig 30 tumors. The method comprises the steps ofvisually determining folate receptor status (egA EC20++ E(720+, or C20-) in. the patient herein folate receptor status is based on a measurement of the percentage of evaluated tumors that are folate receptor positive in the patient. and wherein the BC is indicated for the treatment of the patient when the folate :1 receptor status of the patient is EC2-i± In an llustrative embodiment EC20-- status means that the percentage of evaluated tumors in the patient that are folate receptor posive is about 100% In other illustative aspects, EC2Q+ status means that the percentage of evaluated tumors in the patient that are folate receptor positive is about 90%, about 80% or 5 about 70%. In another aspect. EC20 a semiquanitative imaging agent In this visual assessment embodiment (visual detection), lesions are evaluated visuaiiy to determine if the patient has a threshold level of funeionally actve folate receptors indicative of a linical benefit to the patient In one aspect leasions Q tumors) for analysis i each patient are selected by a radiologist according to PCIST (Oriteria. 0 Subsequently, a nuclear medicine physicianpise reader) assesses the uptake of the EC20 for each evaluable target lesion visually, and classifies the uptake as 'E1C2 positive' (marked uptake/muild uptake) or "EC20 negative" (no uptake), i one illustranve example the folate radioactive imaging agent conjugate is ~~T--EC20 I'he tenm "no uptake" imeatns that visual inspection or the target esion compared with the nearby tissue indicates that uptake of E7C20 5 in the arget lesion and uptake of EC20 in nearby tissue are not distinguishable The term "nild uptake" means that visual inspection of the target lesion compared with the nearby ueiat uptke of EC20 n te aget On and uptake of EC20 in nearby tissue are distingluishable. The terry "marked uptake" means that visual inspection of the target eSion compared with the nearby tissue indicates that uptake of EC2 in the target esion and 0 uptake of EC20 in nearby tissue are clearly distinguishable, n this embodiment, lesions can be evaluahie or non-eval uabie. In one embodinent, lesions ess than 1.5 cim in longest dimensionLL) ar considered "non evaluabie" unless the nuclear medicine leader identified them as having unegiivocal uptake of EC620 -in which case they are characterized as positive. Moreover, certain organs (ce-g 25 liver spleen. bladder and kidney hae an inherently high uptake of EC20. Target lesions located in these organs are considered. nonevaluable. In another embodiment. EC20 nonevaluable lesions i one of the following criteria: i defined as not imaged" or "not applicable" on 99mTc EC20 SPECT target lesion evaluation 2) as negative for EC0 uptake and less than 15 mm in diamter or 3) lesion 30 located in the liver, kidney/adnaJland. spleen, or bladder, EC20 evauie lesions fi one of the following criteria: 1) denied a-s pisive for EC20 uptake, 2) defined as negative for EC20 uptake and greater tmn or equal to 1 5 mm in diameter.

-24 In one embodiment, patients are assigned to groups (ife. assigned a status) based on the observation of EC20 positive lesions. EC20 negative lesionsand/or non evaluable lesions in the patient. The percentage of lesions that are EC20 positive in each patient is calculated as follo; EC20 positive lesions (number of EC20 positive lesions/ z nutiber of EC20 negative lesions + number of tinevauable lesions) in one illustrative example, patients are assigned to three groups denoted EC20+E EC20+ and E20- wherein about 100% of the lesions in the patients assigned to the EC20++ group ara EC pkositive from about 1% to about 99% of the lesions in th ients assigned to the EC20+group are EC20 positive and about 0% of the lesions in te patients assigned the EC20- group are 0 EC20 positive. In another illustrative example patients are assigned to three groups denoted EC2++; EC20+, and EC20 wherein about 90% of the lesions in the patients assigned to the EC20++ group are EC20 positive; from about 11% to about 89% of the lesions in the patents assigned to the EC20+ group are EC20 positive; and about ( to about 10% of the lesions in the patients assigned to the EC20 group are EC20 positive, 5In the above -described embodiment. if a patient is in the EC20-++ group -a clinical benefit of E 145 treatment is indicated, The clinical benefit to the patient includes progressionlree survi val of the patient, overall survival of the patient, ability to receive four or mine cycles Of therapy with EC 145. inhibition of tumor growth, stable disease a partial response of the patient to therapy, a complete response of the patient to diterapy disease O control the best result obtained is a complete response.a partial response or stable disease) and/or oveml disease response (ie. the best resu ltobtained is a complete response or a partial response). in one ilisatrative example, the clinical benefit for a patient being treated for non-sinall cell lung cancer is determined at 4 months after the beginning of the treatments In another illustrative example, the clinical benefit for a patient being treated for 25 ovarian cancer is determined at 6 months after the beginning of the treatment in one ilustrative example overall survival is the time to death for a given patient defined as the number of days from the first day the patient received protocol treatment (CIDI) to the date of the patient ' death. Ali events of death can be included regardless of whether the event occurred while the patient was still taking the study drug or 30 after the patent discon tined the study drug. If a patient has not died, then the data can be censored at te last study visit, or the last contact date. or the date the patent was last known to be alive, whichever is last.

;15-~ In an in vitro study described below in xamle 7. EB 145 and doxomibicin have been shown to synergstcdally inhibit the growth of human cancer KB tumor cells In a study in mice bearing the ladison 109 lung arcinoma 109) a folate receptor (FRN- over)eaxpressing spiytheli al tumor relatives resi stan t to chemotherapy 5 described below in Example S. it has been demonstrated that E145 in combination with pegylated iposomal doxorubicin (PLD), trade names Doxiland Caelyx> displayed an excellent ani t-umor effect and cure rate, with mild weight loss Accordtigl in one embodiment there is provided a method of treatment of a folate receptor expressing epitIheial tumor in a patient in need thereof comprising administeng a therapeutic amount of EC145 in 0 combination with a therapeutic amount of doxorubicin Anotherenibodirment is the use of 1C145 in combination with doxorubicin for the treatment of a folate receptor expressing epithelial tumor in a patient A further ernbodirnent is the use of PC1:45 for the manufacture of a medicament for the treatment in combination with doxorubicin of a folate receptor expressing epihelial tmnor hna patient. 5 A further eibodirent is a method of achieving a clincal benefit in the treatment of a folate receptor expressing epihelial tumor in a patient in need thereof comprising administering a therapeutic amount of EC145 in combination with a therapeutic amount Of doxorubicin uIn one embodiment, the clinical benefit is progression-tree survival. In another embodiment, the clinical benefit is overall sUrvival 0 For any of the above methods or usesin one embodiment, the doxorubicin is in the form of a pegylated liposomal doxoruhicin For any of the above methods or uses, an embodiment of a folate receptor expressing epithelia tumor is an ovarian, endometrial or non-small cell lung cancer NSCL.C) tumor. For any of the above methods or uses, another embodiment of a late receptor 25 expessing epithelial tumor is an ovarian tuaor. Ovadan cancer patients who respond to initial piatinum-containing systenic therapy, only to experience disease progression after a treatment-tree interval of less than 6 months, are consideredby con ventionM to have p/anrdignf disease These patients are considered to have failed prhnm) platinum therapy, An additional group of patients may 30 respond to initial platinum-containn systernic therapy anad progresslonger than 6 months after therapy. These patients may receive additionaI platinum-containing therapy l on to progress while on, or within 6 months of having received, secondary platinum therapy Also 426 deemed platinum resistant, these patients are considered to have failed xecondrv platinum therapy. Patients with platimunresistant disase have a limited number of therapeutic option". and often receive agents such as topotecan, gemcitabine, and pegyated liposomal 5 doxoruhicin(P.D) the latter approved in the United States under the trade name DoxiP tand elsewhere under the trade name Caelyx for the treatment of patients with ovarian cancer whose disease has progressed or recurred after piatinui-based chemotherapy: Indeed PID is frequenii used as treatment for patients with recurrent platinum-esistant ovarian cancer PLD is a polyethylene glyco liposomal encapsulation of doxorubicin an anthracycline 0 topoi somerase inhibitor known to have broad antitumor activity T'he liposomaa encapsuation provides altered pharmacokinetics over the parent compound, including a prolonged circulation hafilife(see Doxilt Package Iserix in one embodiment there is provided a method of treatments of platinuni resistant ovarian cancer in a patien in need thereof comprisirg administering a therapeuic 5 amount of ECI 45 in combination with a therapeutic amount of pegylated liposoral doxorubicin Another embodiment is the use of EC145 in combination with pegylated liposormal doxorubicin for the treatment f platinumresistant ovarian cancer in a patient. A further embodiment is the usof EC145 for the manufacture of a medicament for the treatment in combination with peglated iposomal doxorubicin of platinum-resistant ovatan 0 cancer in a patient A further embodimerit is a method of achieving a cliical benefit in the treatment of platinum--resistant ovarian cancer in a patient in need thereof comprising administering a therapeutic amountof EC 145 in combiation with a therapeutic amount of pegylated liposomal doxorubicin. In one embodiment, the clinical benefit is proagression-free 25 survival. in another embodiment, the clinical benefit is overall surviva. In a further embodiment of the invention, there is provided a niethod of treatment of platinum senutive ovarian cancer in a patient in need thereof comprising administering ih a terapeu tic amount of pegylated liposomal doxorubicin or doxorubicin which is not of the pegylated liposomal 30 forn.A further erhodiment is the use of EC145 for the ianufacture of a mnedicamemt for the treatment in combination with pegyIated liposomal doxorubicin or doxorubicirewhich is not of the pegylated liposomal form of platinm-sensitive ovarian cancer in a patient A further embodiment is a kit comprising a therapeutic amount of EC145 and a therapeutic amount of 4egyiated hposomal doxorubicin in separate containers. in another erodimen for any method, use okit the EC 145 is a coni pound having the fornula N S 14' N '- N 5 or a pharmaceuticaly acceptable salt therof A s used herein EQ45 ay be parent in solution or smspension in an ionized form. including a protonated form. (1 In one embodiment there s proYde an miethod of treatment of platinum msistant ovarian cancer in a patient in need thereof comprising admnistering a therapeutic an'oun of EC145 in cAmhinaton with a therapeutic amount of pegylated iposomat doxorubicin. In another embodiment, thereis provided use of BC 145 in combination with pegylated iposomaI doxorubicin for the treatment of pratnumresistar ovarian cancer in a 5 patient in another embodiment, there is provided the use of FC 145 for the manufacture of a medicament for the treatment in combination with pegylated liposomal doxorubicin of platinunresistant ovarian cancer in a patient. In a further embodimenthere is provided a method of obtaining a clinical benefit compared to treatment with a therapeutic amount of pegylated liposoma doxorubicin 20 in the treatment of platimmvresistant ovarian cancer in a patient in need thereof comprising administeing a therapeutc amount of EC 145 in combinaton with a therapeutic amount of pecylated liposonial doxrubicin. In one embodiment, the clinical benefit is progreson-free survival. ri another embodiment the clinical benefit is ovenalsurvivat. he utility of ECI45 in combination with pegylated liposonal doxomubicin in 25 treatment of piatinum-resistant ovarian cancer is demonstrate in the clinica trial results provided in the Examples below, as well as in the figures. For any method or use described above concerning the treatment of platinum resistant ovarian, cner using ECRiW in combination with pegylated liposomnal doxorubicin one embodiment is one wherein the purity of EC145 is at least 90%, Another embodinent is 28 one wherein the E0145 is provided in an aqueous sterile liquid fonnulation the components of which comprise monobasic sodium phosphate monohydrate dibasic disoditm phosphate dih ydrate, sodium chloride, potlassiumchloride and water for injection A further embodiment is one wherein the treatment further comprises a bowel 5 regimen A suggested progressive bowei regimen can be modified front Carney NT. Meier D Palliative care and end-of-life issues. Anaesthesiol CliinNorth America 200,18:183, in one enbodiment the bowel regimen comprises administering Docusate, 100 mg twice daily (iida and Senna. I tablet once daiy (qd) or b id In one embodiment, the bowel regimen comprises administering Docusate 0 100 mg b iAd, Senna, 2 tablets baid. and Bisacodyirectal suppositories. I- after breakfast. in one embodimnntthe bowi regimen comprises administering Docusate 100mg bid . Sena 3 tablets biAd and Bisacodyl rectal suppositories 3-4 after breakfast in one embodiment, the bowel regimen comprises administering Dcusate 100 ng bid. S 4iii tablets bid.. Lactulose or sorbitol. 15 ml. bid and Bisacodvl rectal 5 suppositories 3-4 after breakfast, In one embodiment the bowel regimen comprises administering Docusate, 100 mg bid., Senna, 4 tablets bid, Lactulose or sorbitol, 30 ml bi., and Bisacodyl rectal suppositories, 3-4 after breakfast In one embodiment, the bowe! regimen comprises administering Docusate. 0 100 mg b-iid, Senna, 4 tablets b. d Lactulose or sorbitol 30 onl old,, and Bisacodyl rectal supposi tories, 3-4 after breakfast For any method or use described above concerning the treatment of platinmresistant ovarian cancer using EC 1 45 in combination with pegylated liposoraidoxoubicin, an additional embodiment is one further comprising administering EC20 to the patient prior 25 to treatment and assessing the patient to have EC20++ status. in a frther embodiment there is provided a method of selection a patient for treatment as desNcribed in any method or use described above concerning the treatment of platimresistant ovarian cancer using [Cl 45 in combination with pegylated liposomal dmoxobin pri administering EC20 to the patient prior to treatment and assessing 30 the patient to haveCO±+ status. in a frther embodimentthere is provided a pharmaceuticalomposition comprising EC 15 in an aqueous steril liquid formulation the components otnwhich 419 cornprise monobasic sodium phosphate mronohvdrate, dibasic disodiurn phosphate dihydrate, sodiurn chloride, potassium chloride and water tormidyecon. ki a further embodiment there is provided a dosage uit comprise g EC145 drng product for intravenous adninistraton as 2 0niL of an aqueous sterile liquid 5 formulation p11 7A. which dosage uni contains i4 mghaL of EC 145 in one embodiment, the above dosage unit is an ampoue a sealed vial or a prefilled syringe. In another embodiment, the above dosage mit is a sealed via. Embodiments of the inventon are further described byv the foilowigi enumerated clauses: I 1 A method of deterninin g whether EC 145 is indicated for the treatment of a patient with an ovarian tumor or a tumor. the method comprising the step of deterninin g whether functionally active folate receptors are present on the tumor of the patient wherein the ECI145 is indicated for the treatment of the patient with the tumor if functionally active folate receptors are resent on the tumor. 2. The. method of clause 1 5 further comprising the step of administering to the patient BC2) for detection of the funcionady active folate receptors 3. The nethodr of clause 2 further comprising the step of administering to the patient an unlabeled folate prior to administration of the E3(20 4, The method or clause 2 orclause 3 wherein the EC145 is indicated for the treatment of the patient with te tuoar if the radioactive signal produced by the EC210 tpen binding to the tumor 0 compared to the background radioactive signal produced by the EC20 is indicative of a clial benefit to the patient. 5. The method of chase 4 wherein the clinical benefit is progress sion-free survival of the patient. 6. The method of clause 4 vhirein the clinical benefit is inhibition of tumor growth 7. The method of clause 4 wherein the clinical benefit is selected from the group consisting stable disease, a partial response, and a complete 25 response. S. The method of clause 4 wherein the lWel of expression of the functionallv active folate receptors is quantified based on a tumor to bckgrond ratio of the radioactie. m1i produced by the. EC2t0 to the background radioactive signal 9. The method of clause 8 wherein the tumor to background ratio is at least adtf2, 1.0, The method of clause 8 wherein the tumor to background ratio is at least about I 11E he method of clause 8 30 wherein the tuior to background ratio is at least about 1A 12, he method of anyone of clauses I to I wherein the tumor is an ovarian tumor. 1 The method of clause 12 wherein the tumor is a platinumresistant ovarian tumor, 14. The method of any one of causes I to 11 wherein the tumor is a lung tumor. 15. The method of clause 14 wherein the tumor is a 430 non-small cell carcinoma of the lung 16 The method of any one of clauses I to 15 wherein either the EOC45. the EC20, or both are in a parenteral dosage fm. 17 The method of clause 16 wherein the dosage frma is selected fror the group consisting of intrademal. subcutaneous, intramuscular intraperitoneal, intravenous, and intrathecal, 18. The method 5 of any one of clauses I to 17 wherehi the C1 45 is in a composition and wherein the composition further comprises a pharmaceutically acceptable carrier 19, The method of any one of clauses 2. to 18 wherein the composition comprising the EC22 further comprises a pharmnaceuticalIy acceptab e carrier. 9a. The method o clause 1 8 or 19 wherein the pharnaceutical Iy acceptable carrier is a liquid carrier: 9 OhIe method of clause 19a 0 wherein the liquid carrier is selected from the group consistIng of" Saline, gicose, alcohols, glycoIs.esters, amides and a combination thereof 20, The method of any one of clauses I to 19 whemin the EC145 is administered in a therapeuically effective amount. 21. The method of any one of clauses 2 to 20 wherein the EC20 is administered in a therapeutically effective amount. 21 a, The method of clause 20 or 21 wherein the effective amoun ranges 5 from about 1 ng to about I mg per kilogram of body weight 21 b, The method of clause 2ia wherein the effective amount ranges from about 100 ng to about 500 pg per kilogram of body weight. 2 lo, The method of clause 2 lb wherein the effective amount ranges from about l00 rg to about 50 p g per kiloram of body weight 1 i. The method of any one of clatises I to 21 c wherein the tumor is a primary tumor. 21 e. The method of any one of clauses I to 21c 0 wherein the tumor is a metastasized tmor. 21 The method of any one of clauses Ito 2Ie or clauses 24 to 2 5y wherein EC20 as the folate-radioactive imaging coriugate .s replaced by a compound having the formula H K Ii 0 ±NN N C$ 25 or a pharrmacetically acceptable sah thereof vherein M i.s a cation of a radionuclide 21 g The method of clause 21f wherein the folate-radioactive imaging conjugate is a compound having the formula 0Hy Oa phanweauically acceptable sA, thereof' 21h. The miO fdas2fwhrite folte-adoaciveimgin cojuateisa compound ha-ving teformrifaa 'N'HN N Kct'rH o o a pharmaceuticaly acceptale salt thereof 2 i, The methd of clause 21f or 21h wherein Mi is selected frmhe group cossigof -isotopes,, of galliamneindium, copper, technetium and rheniurn 21, The mnethod of clause 21heinMis an isotope of technetiam 2i1 T method o1ae tg or 2hu wherein the folaerradioactive ing agent vuojgate is.radiRlabc-ed using a cheating agent and a reduc.ig agent 21L The 0 metho clause 21.k wherein the ehelating agn i odiumnrhchpoae 21im, The method of enmse 1kq 211o2 whaererr" the" reducing agent Ws tin(11 chloridkdhyrae 21n. The mnetho..d of an.y one of clause I to 21m o lauses 24 to 25y nbyrtheir compning the step of adm-i-nistering to thIe patient a pegyIlated liposomal doxortibicinm 2'2. The mnethod of any one of clauses,- I to 21n further tmpriing thWe step of adminsering to the patient 15 doxorubicin. 21 The method of cas 2vhiereinh doxorubicin isN in the formn of a peglaedliosmaidoorbit24. A method of deem n h t-heE.J45 is indicated for t treatment ofa-aten with an varian wnumor or )uhng tutor the method Comprising Wbe step of administeringz.to d1e patit a composition comrrq'ising EC2l herei EX.'145 k indicatd foc the. treatmento the: patient With thle tumor f' the, tumor ofthe patient has 20 fnctionally active folate receptor wherein the functonally aciv oterceptors- ame capable of detecnton witvh EC20, 25. The method. of cl2s 4 11urthe,-r comprising the step of admniste.uring to) the patient an unlabeled foaepirt diitainof the ECT20. 25a. The method of clause 25 wherei EC145 is idcedfcot teatmnt of the patient with the -32 tumor if the radioactive signal produced by E a20 upon binding to the tumor compared to the background radioactive signal produced by EC2O is indicative of a clinical benefit to the parent 25A The method of clause 25a wherein the clinical benefit i.s progessionfee survival of the patient, 25c, The method of clause 25a wherein the clinical benefit is 5 inibitdon of tumor growth 25d The method of clause 25a herein the clinical benefit is selected from the group consisting stable disease, a partial resonseand a complete response, 25e,, The method of clause 25a wherein the ievel of expression of the functionary active folate recepto is quantified bascd on a tumor to background ratio of the radioactive signal produced by EC20 to the back ground radioactive signal 25f. The method of clause 25e 0 wherein the tumor to background rato is at least about i2. 25g The method of clause 25e wherein the tumor to background ratio is at least about i. 25h The method of clause 25e wherein the tumor to background ratio is at least about 1A 251 T of any one of clauses 24 to 25h wherein the tumor is an ovarian tunor 25j. The method of clause 25i wherein the tunor is a platinuresistant ovarian tumor 25kL The method of any one of 5 clauses 24 t 25h wherein the tunor is a lung tumor. 251, The method of any one of clauses 24 to 25i wherein the tumor is a non-snalR cell carcinoma of the lung, 25mn. The method of any one of clauses 24 to 251 wherein either EC 145, EC20. or both are in a parenteral dosage form. 25n The method of clause 25m wherein the dosage form -is sectd from the group consisting of intradermal/subcutaneous, itramuscular.intrapedttnaal ixavenous and 0 intrathecal. 25o. The method of any one of clauses 24 to 25n wherein ECi45 is in a composition and wherein the composition further comprises a pharmaceutically acceptable carrier. 25p, The method of any one of clauses 24 to 25o wherein EC20 further comprises a pharnaceutically acceptable carrier 25q. The method of clause 250 or 25p wherein the phannaceutically acceptable carrier is a liquid carrier. 25r. The method of clause 59 25 wherein the quid carrier is selected from the group consisting of saine, glucose, alcohols, glycols esters, aides, and a combination thereof, 25s. The method of any one of clauses 24 to 2r wherein EC145 is adminisered in a therapeutically effective amount. 25t. The method of any one of clause 24 to 25s wherein EC2 is administered i a therapeutically effective amount. 21w The method of clause 25s or 2St wherein the effective amount ranges 30 from about I n1g to about 1 i og per kilogaofb method of c se. 5u wherein the effective amount ranges from about 100 ng to about 500 pg per kilogramiof body weiAht 25w. The method of clause 2iv wherein the effective amount ranges from about 100 ma to about 50 pg per kilogram of body weight 2 The method of any one of clauses 24 to -33 25w wherein the tumor is a primary tumor. 25y. The method of any one of cla uses 24 to 25w wherein the tumor is a metastasized tumor. 2:6. The method clause 24 or 25 further conpising the step of admhaistering to the patient doxorubicin. 27. The method of clause 26 when do bicin is in the form of a pegyated liposomal doxorubicin 28. A method 5s of predicting a response of an ovarian tumor or a lung tu-ior of a patient to therapy with ECi45, the method comprising the steps of a) administering to the patient EC20 wherein the EC20 produces a radioactive signal; b) quantfif.n theradioative signal produced by the EC20 upon binding of the [20 to the tumo; c) quantifying the background radioactive signal produced by the EC0 d comparing the radioactve signal produced upon binding 0 of the [C 20 to the tumor to t background radioactive signal; and e) predicting the msponse of the tumor to t he rapy based on the comparison, 29. The method of any one of clauses .1 to 28 wherin 1A mg/month of the EC145 is administered 30 A method of treatment of platinum resistant ovarian cancer in a patient in need thereof comprising administering a therapeutic anoun of EC4 in combination with a therapeu tic amount of 5 pegyated Liposomal doxorubicnh. 3 1 Use of EC145 in combination with pegylated iiposomaI doxorubicin for the treatment of platinum-resstant ovarian cancer in a patient. 32. Ose of Ff145 for the manufacture or a medicament for the treatment in combination with pegyl ated liposomal doxorubicin of platinum-resistant ovarian cancer in a patient 33. A method of obtaining a clinical benefit compared t treatment Ah a therapeutic amount of 0 pegylated liposomal doxorubicn in the treatment of platinunwresistant ovarian cancer in a patient in need thereof emprising adrnnistering a a therapeutic amount of EC145 in combination with a therapeutic amount of pegylated liposomal doxorubicin. 34. The method of clause 33 wherein the clinical benefit is progression-free survival 35. Tha method of clause 33 wherein the cynical benefit is overall survival. 36, The method or use of any of 25 claises04 wherein the purity of ECI 45 is at least 90% 37 The method or use of any of clause\ 30 3 wherein thi C 4I is provided in an aqueous sterile iquid formulation the componentN of which comprise monobasic sodium phosphate monohydrate. dibasic disodium phosphtiate sodium chloride. potassiurn chloride aidwater for injection 38, The method or use of any of clauses 30-35 wherein the treatment further comprises a bowel 30 regimen. 39. The method or use of any of clauses 30-38 wherein the EC145 is adiniriistered as a bolus oer about 10 to 20 seconds. 40 The method or use of any of clauses 3039 further comprising adrinistering BC20 to the pin prior to treatment and assessing the patient to have EC20+-- status, 4 L A method of selecting a patient for treatment as -34 described in any one of clauses 30-39 compAsing administering EC20 to the patient prior to tratnent and assessing die patient to have E.C2 aistats 42, A pharmaceutical composition comprising EC145 in an aqueous sterile liquid tornulation die components of which comprise monobasic sodium phosphate monohydratedibasic disodiam phosphate 5 dihydrate, sodium chloride, potasSin chloride and water for injecion. 43 A dosage urnt compising E3C145 drug product for intravenous administration as 2.0 ni of an aqueous sterile liquid 7.4 which dosage unit contains - 1 h/t of EC145. 44 The dosage uit of clause 43 which is an ampouide a sealed vial or a prefiuled syringe, 45. The dosage unit of clause 44 which is a sealed vial. 46 A method of dtemning whether 0 patient with a tumor has funetionally active folate receptors present on the tunmor of the patient. the method comprising the step of administerng an effective amount of EC20 to the patient for detection of the functionally active foate receptos, 47, The method of clause 46 wherein te tumor is an ovarian tumor or a lung tumor. 48. The method of clauses 46 wherein the tunor is a primary tumor or a metasta tic tumor, 49. Themethod of any one or 5 clauses 1 2427 or 4643 wherein the functionally active folate receptors are detected visually 50 The method of clause 49 wherein the visual detecton of functionally active Relate receptors is used to determine folate receptor status of the patient 5 The method of clause 50 wherein the folate receptor status of the patient is selected from the group consisting of EC20. EC20+, and EC20, 52, The niethod of clause 51wherein the folae 0 receptor status is EC2O+ 53 The method of clause 52 wherein treatment with EC145 is indicated 54 The method of clause 52 wherein LC20±+ status correlates with a clinical benefit to the patient 55, The method ofclause 54 wherein the cinical benefit is disease control rate. 56. The method of clause 54 wherein the clinical benefit is overall disease response rate. 57 The method of clause 54 wherein the clinical benent is overall survival. 25 58 A method of treatment of a folate receptor expressing ephelialtunor in a patient in need thereof comprising adninisteringi a therapeutic amount of 1145 in combination with a therapeutic amount of doxorubicin. 59. The use of EC145 in combination with pegylated liposomal doxorubicn for the, treatment of a folate receptor expressing epithelial tumor in a patient. 60 The use of EC145 for the manufacture of a medicament for the treatment in 30 combination with pegylated liposomal doxorubicin of a flaite receptor expressing epithelial tumor in a patient. 61, A method of achieving a clinical benefit in the treatment of a folate receptor expressing epitielial tumor in a patient in need thereof comprising administering a therapeutic amount of EC145 in combination with a therapeutic amount of pegylated -35 Hiposonal doxorubicin, 62, The method of clause 61 in which the clinical benefit is progression-free survival. 63. The method of clause 61 in which the clinical benefit is overall survival. 64, The method or use of any of clauses 58 to 63 wherein the doxorubicit is in the form of a pegylated liposomal doxoruhicin65, T1he method or use of any of clauses 5 58 to 64 wherein the folate receptor expressing epithelial tumor is an ovarian, endometrial or non-small cell lung cancer (NSC L humor. 66. The method or use of clause 65 wherein the flate receptor expressing epithelia tUamor is an ovarian tumor, 67. The method or use of clause 64 wherein the folate receptor expressing e pithelaJ tumor is an ovaria, endometriaI or non-small cell lung cancer (N SOLO) rumor. 68 Ti he. method or use of clause 67 wherein the 0 folate receptor expressing epithelial tumor s an ovarian tumor 80A A method of determining whether EC145, or a phanmaceu ticaly acceptable salt thereof, is indicated for the treatment of a patient with an ovarian tumor or a lung tumor the ienod comprising the step of administering to the patient a composition comprising a EC20. wherein EC145 is indicated for the treatmenof the pArat with the tumor if the radioactive signal produced by 5 E7C(20 upon binding to the tumor compared to the background radioactive signal produced by E20 is indicative of a clinical benefit to the patient 8OB A method of selecting a parent with an ovarian tumor or a lung tmor for therapy with EC145 the method comprising the step of determining if functionally active folae receptors are present on the tumor of the patient wherein the patient is selected for therapy with EC145 if finctionally active folate 0 receptors are detected on the tumor, 80C, A method of selecting a patient with an ovarian tunor or a lung tumor for therapy with £145, the method composing the step of administering to the patient a composton comprising EC20 wherein the patient is selected for the therapy with £0145 if the rumor of the patient has functionally active folate receptors wherein the functionally active folate receptors are capable of detection with EC20. SoD. A 25 method of selecting a patient with an ovarian tumor or a hmg tumor for therapy with C145, the method compri sing the step of administering to the patient EC:2 wherein the patient is selected for therapy if the adioactive signal produced by £020 upon binding to the tumor compared to the background radiocive signal produced by EC20 is indicative of a cinical benefit to the patient. 81. The method of clause 80A, 80B, 80C or SOD further comprising 30 the step of administering to the patient an unlabeled foate prior to administration of the folatemadioactive imaging agent conjugate: 82. The method of clause S1 wherein £0145 is indicated for the treatment of the patient with the tumo the the radioactive signal produced by £020 upon binding to the tumor compared to the background radioactivec signal produced by -36 ECKis indicative of a clinical benefit to the patient. 83 The method of clause 8.2 wherein the lniscal benefit is progression-flee survival of the patient. 84 The. method of clause 82 wherein the clinical benefit is nhbition of tumor growth. 85 The method of clause 82 wherein the clinical benefit is selected from the group consisting stable disease, a partial 5 response and a complete response. 86 The method of cause 82 wherein the level of expression of the functionally active tblate receptors is quantified based on a tumor to background ratio of the radionctve signal produced by EC20 to the. background raioactive signal. 8 The method of clause 86 wherein the tumor to background ratio is at least about S.2, 88, The method of clause 86 wherein the tumor to backgroundratio is at least about 1.1 0 89, The method of clause 86 wherein the tumor to background ratioistlengt about 1 90, The method of any one of clauses 8ON 80B 8C 80D to 89 wherein the tumor is an ovarian tumon 91. The method of clause 90 wherein the tumor is a ovarian tumor, 92, The method of any one of clauses 80A, 801. SOC 80D to 89 wherein the. tumor is a lung tumor. 93. The meodid of any one of the clauses SOA 8013 80C, SOD to 89 wherein the 5 tumor s a non small cell carcinoma of the long 94, The method of any one of clauses BOA, 80B, SOC, 80D to 93 wherein eiher the EC 145n ECZ0 or both are in a parenteral dosage orn. 95 The method of clause 94 wherein the dosage form is selected from the group consisting of intranmuscular intraperitoneal intravenousand intrathecal, 96, The method of any one of clauses 80A SOB 80C SOD to 95 wherein EC45 0 is in a composition and wherein the composition further comprises a pharmaceuticay acceptable carrier. 97 The rnethod of any one of causes 80 801 S C 80D to 96 wherein the composition coEC2 further compares phamviaceutically acceptable carrier. 98 The method of clause 96 or 97 wherenthe pharmaceutically acceptable carrier is a liquid carrier 99 The method of clause 98 wherein the liquid carier is selected fromthe group 25 consisting of saline. glucose alcohol glycol s, esters, amides, and a coribination thereof 100 The method of any one Of clauses 80A80B, SOC. 80D to 99 wherein EC145 is administered in a therapeutically effective amount. 101. The method of any one of clauses 8A SOB. O0C S80D to 100 wherein EC20 is administered in a therapeutically effective amount. 102. The method ofclause 8OA SOB SOC, 8OD or 101 wherein the effective 0 amount ranes om ng w about . . rg per kilogram of body weight. 103 The method of clause 102 wherein the effective amount ranges from about 100 ng to about 500 pg per kilogram of body weight. 104 The method of clause 102. wherein tnee.tectiv'e amount ranges from about 100 ng to about 50 pg per kilogram of body weight. 105 The a-7 method of any one of cdauses SAO B3 80( 80D to 104 wherein the tumor is a primary tumor. 60 The method of any one of clauses 80A, 8B SOC 801 to 104 whemi the tumor is a netastasized umor 1 0 The method of inv one of causes 80A 80B C, 801) to 109 whemin EC20 as the folate-radioactive imaging conjugate is replaced by a compound 5 having the founua J0aH H NAIN HNHN -N 00. or pamacutcalyacceptableN,- sah thereof;vherein M! is a cation of a radio-nuclide. I IL The method of clause 010 where n the oatrdoctvimgg con uzgate sa compound 0 having the forn-uia NOHHN CH Co, N or a pharmaceutically acceptable salt there 12 Theen atod of cause 10 wcre.n th. Te e-radioa cla n* 10 w i e otraipoatve iman n onjgateCandhmponuua 4N HN Ca N 15 HI H lo NN or a phannaceutically ceptable sal thereof, 112. The merthod of clause -110 or 112 w herein iMls selected maig consgaisng of avping ofganium, inditmh cfopr ehn and rhniun 114. The, mthod oense13weinM is; anP isotope of tchnthn, 115, -38 The method of clause III or 112 wherein the folate-radioactive imaging agent coryugate is radioiabeled using a chelatin agent and aru agent I6. The method of cause Il5 wherein the chelaing agent is sodim tiglucoheptonate; 17. The method of clause 11 or il6 wherein the reducing agent is tin (Ii) chloride dihydrate. 118. The method of any one 5 of clauses 8 80B 80C 8D to 117 fuaher comprising the step of administering to the patient a pegylatedliposonma doxorubicin. 119. The method of any one of clauses 80A. SOB, 80C, SOD to 118 wherein 15 mg/nonth of the folate-vainca conju gate is administered, In another embodanent the methods described herein inchde the fotlowi a 0 examples The examples further illustrate additoal tetures of the varous embodiments of the invention desceibed herein. However, it is to be understood that the examples are i lustrative and are not to be construed as limiting other eibodiments of themenenon described hereina In addition, it is appreciated that other variationof the examples are included in the various embodiments otheivention described herein. 5 EXAMPLES EXAMPLE I Materials N' *>trifiuoroacetylpteroic acid Was purchasedt frEm prova AG. Schaffhausen, O Switzerland. Peptide synthesis reagents wer purchased fron Noval3iochem and Bacheni 99rnTc Sodium Pertechnetate was supplied by Syncor [ReO2en}2]( I was prepared according to Rousclhias (Rouschias, (d, Chem. Rev., 74: 531 (1974)). Cellulose plates and DEAE ion exchange plates were purchased from VT. Baker. DOXIL® was obtained from Ortho Biotecli Products, LPII Raritan. NJ 25 EXAMPLE 2 Preparation of EC20 EC20 was prepared by a polymersupported sequential apoach using the Fmoc-strategy ( Fmoc 9-fluorenyinethyloxycarbonyl Doe tertbutyloxycarbonyl; Dap 30 diarninopropionic acid; DMF dimnethylfornamide; D[PEA disopropylethylaride) E{'20 was synthesized on an acidsensitive Wang resin loaded withhnoc Cysthe 01 lBen zotriazole- i yoxttispyrrol idinophosphonium hexafluorophosphate (PyBOPwas applied as the activadng reagent to ensure efficient coupling using low eqjuivalents of amino -39 acids, Fmoc protecting groups were removed after every coupling step under standard conditions (20% piperidine in DM4 Coupling reactions i FmocAsp( PyBop, IPEA, DMF; ii) £oc-Dap(Fmoct() PyBop, DIIPEA DMiih i noc-DMlu-Odhu, PyBop DIPLA, DM FIv. N 0 '1iPA-- Pte4TOHI DIPEA, DMSO, After the last assembly step 5 the pepidewas cleaved fromt the polymeric support by treatment with 92% trifluoroacetic acid containing 2.5% ethanedithiol, 253% triisopropylsilane and 2,.5% deionized water, This reaction also resulted in siminultaneous removal of the t BBoe and trityl protecting groups. Finallythe trifhioroaceti moiety was removed in aqueous anrnoniun hydroxide to giv e EC20. 0 The EC20 product was puified by I li wsing an Xtera R11 8 30 x 300 mmr. 7 pm column f (Wtrs. mobie phase 32 eM HOi' ( eOH c gradient conditions starnag. with 99% A and 1% B, and reaching 89% A and I1% 13 in 37 rai by a flow rate of 20 mLnin Under these conditions, EC20 monomer typically eluted at 14,38 min whereas EC20 di sulfide diMer (minor contaminant) eluted at 16,8.3 mn EC20 analyzed by 5 electrospray-nass spectrometry. Major positive ion peaks (m/z, relative intensity)746A 100; 747.1 44; 556S8 32: 570.8 16. EXAMPLE 3 Preparation of the No"nRadioactive Reagent il and of ""Tc EC20, 0 EC20 kits were used for preparation of the FenEC 2 0 radioactive dag substance. Each kit contained a sterile, non-yroenicyophilized mixture of 0. m. EC20, 80 mrg sodi'um' tut-i)guoepoa 80 mng ti (HI) chloride dihydrate, and suiffi-,cnt sodiumhydroxide or hydrochlorie acid to adjust the pH to 6.8 ± 0.2 prior to lophilization. The iyophinized powder was sealed in a 5 ml- vial under an argon atmosphere The kits were then 25 stored fozen at 20'C until use or expiration (current shelf life is > 2 year The tin (ID chloride component is present to reduce the added "lcpertechnetate.ile the sodium u-giucoheptonate component is present to stabilize the reduced "Tc prior to its final chelaion to the E120 compound. 99neEC20 was prepared as folows (i-e. chelation of 99n're to EC2th 30 First a boiling water bath conUtining a partially submerged lead vial shield was prepared The top of an EC vial was swabbed wth0% ethanol to sanitize the surface and the vial was placed unsuitable shielding container. Using a shielded syringe with 2 ae de I miL. of sterile Sodium Pertechnetate 99n17c Iniecion (15 to 20 mCi) in 0 9% sodium -40 chloride was injected into the shielded vial, Before removal of the syringe from the vial a vol Ie of gas from the vial equal to the volume of pertechnetate added was withdrawn in order to normalize the pressure inside he vial. The vid was gently swirled for 30 seconds to ensure complete dissolution of the lyophilized powder. The vial was then placed into the lead 5 shield that was standing in the boiling water bath. The solution was heated for --18 minutes and then cooled to room temperature for a minium of 15 min This solution can be stored at room temperature (15-25*C) protected from light, hut it should be used within 6 hours of preparation, 0 EXAMPLE 4 Preparation of EC; 119 NH'" Yang resin bond 4~methoxytrityl (MTT)wprotected Cys-N NIt was reacted according to the following sequences P a noc-A sp(OtBu) OH PyBO DIEIIA; b, 20% 5 PiperidineLDMF 2) a, Eimocasp(OtuOH P y BOP i)P DIPE\ b.2% Piperidine/DMF; 3) a. Ermoc-Arg(Pf Phi 0 1 (yBOP, DIPEA. b, 20% PiperidinellDMR 4 ) a, moo.sp(Ot~u OH, PyBOP. DIPEA b 20% Piperidine/DMF, 5) a. Fmoc-Gh-OtBu, PyBOP. DIPEA; b 20% Piper6idine/DM 6) N 1TWFA-pteroic acid, PyBOP DIPEA. The MIT, T n, and Pbf proteeti lg grouv were removed with T-A/H20/TIPS/ED(92,5 :52.5:25 and the TEA J) protecting group was removedwith aqueous N1H40H at pH =93. Selected 1 NMR (D0) 6 (ppm) 8468 (s, I-, FA H 7)57 (d 2H 8A zA H2 &166,67 (d 21-1, j 9 hz FA 1-13 &i5) 440475 (in. 5H, 435 cn 2H), 4. I6 (in 3,02 3 . , 21. ) 2:55-2.95 (nu, 8H) 2.42 (m n 2.00-2.30 (W 2Hy 5 1 .90 (nL 2H) 1.48 im. 21 MS (ESI, m-+fnf 2046.

-41 EXA MPI 5 mng) andV8 pi of DINIPA were sequentiady added to a soat on of desacetyl vinblastine 5 hydrazide (prepa red according to Bamett et At k MedCe 21:88-96 i0 978) the disclosure of the fregoing is ncroaehrinin Is entirety by reference, In addition the enieyofthedslsrefe of the pulctoscited hnerein are also incorpor,'ated he"reinl by reeene)668 mng) in 5 i of DCMd at OWC The reaction was aloweidtowrtoom teipeatreandi stirred for 3 bowrs TLC (5%1 MeH in DCM). showed com-plete 0 conversion The mieewspurifieysilic gel hrmtgaphy (I1:9 MeOWDC"'<M " The co~nbined fractio,- ere evaporAed, redlissolved in DCM1\ and wvashed with 10%1N02C03, biige die'd (M%/gSO4) i ea oatd to 5R) mg (80%); HPLC :RT 1.2,651 inx 91% puro, III E vIR spectrumnsitntwt the assigned structureand MNS (ESI+), 9843 983, 982A4, 492A 499 .41,8, 5k EXkA MPN6 P11eptidyl fragment P-te-Olu-Asp-Arg Asp-Asp--Cys-OHl (Examiple 4) in Tif" 20 was treated ithd either the toslonate or pyridyidithio-acvated vinblastine (Example -5), as a yedlow s toresufting dwerei s rai 1 solution 6,5 underargoan en ztiret o ansed HJPLo C gve a70% yeld; selce H NMR (t0ed e 8.67 (a r Ha FoA Hr L0 (frence VLB (668 t i 3040 ( mr of VI al 1('), 7T35 (da 2cH1, w= 7ao H.e, tFA tro 12 &6;7X2r anS stir If B 34 30 75 (br 1H A i ). 61 (d 2H 8 Hz FA 25 Ifa3 t 6 rA e2ap V ae 14 &s 17o,5'e ri IVLB an A 5 (ih 10 VLBI 2CO 5.rie (dr VIL olefin)y a1dVLB HvAur 4, to50 ma(m %;H H-B 8 1). 382 mm.3H1 VLB C- -COiC& ,69 (s 3EVLB Cj, O-CH- 218 s, 3UH. VLB NC) 1,35 (br sl 1- VLB 3., 1A5 (in, 1I VIB HS), 09 (t 3EL J = 7FHz VLB 42.1'H 1 0.55 (t 31. J= 6 Hz, VLB 21); LCMS (tBSI ) n±f 1918., 5 EXAMPLE 7 In Vitro DrutgDrug CAmbination Assay with EC145 and Doxorubicin On day one KB tumor cells were trypsinized, suspended in flate deficient RPM i (FDRPMi)+± 5% fetal bovine serm, and counted using a hemacytonmeter. The cell suspension was diluted to a final concentration of 0.5 x I105 cells/miL and the dihned 0 suspension used to load six 24 well plates with I moL of cell suspension per wei 'The we s were then divided into test groups with four replicates per sample and allowed to attach to the plate overnight at 3YC, 5% CO 2 . On day two, EC145 and doxoruhiiconcentrations were prepared from 0,731 rmNI and 29 nN sterile stock solhtions, respectively a 2X the final concentrations and then 5 combined in their corresponding wels with either FDRENI or the alternate drug in a final volume of 500 ph The final concentration of EC145 in each individual well was 0 nML 2 nM nM 8 nM 6 4nl or32 nM. The final concentration of doxorubicin in each individual well was 0 nM, 12 .5 nM.25 nM, 50 nM, 100 nM. or 200 nM ourreplicates of each of the 36 cornb.inanons of C 45 concentration and doxorubicin concentration were 0 tested. Samples containing PCI45 were incubated far two hours, replaced with either FDRPM [ or the appropriate concentrations of doxorubicin and then incubated a totalof 72 hours. Samples of doxorubicin only were incubated for 72 hours uninterrupted. Afterwards. spen incubation medium in each well was replaced with 500 gL of I yCi/niL 'Htthy.idine in FDRPMI; cells were incubated for four additional hours. After the incubation, the ibeling 25 solution was aspirated and the cells were washed twice with PBS. 500 pL of I0% trichloroacetic acid (ICA)was then added to each well and the plates were stored at 4C until they were processed. Cells were processed by spiraling TCA and adding 500 pL of ()25 M NaOR. 450 uL of sample from each wel was then transfened to individualvy-labeled liquid 30 scinillation vials, vortexed with 3 iL of Ecolite cocktail, and then counted in a liquid scintilation counter CPM results were then tabulated and percent control values calculated, 4>4 Isobologram Drug Synergy Method g syn y was determined by the isobologram method, In his method IC60 vauese foecast fm e percent of control values, These data can be graphed as nM values or as eqivnalents by setting Ote IC60 of each single agent equal to I and all 5 cornlhinadonal KI as a traction thereof, Combination data points that fall on the hune represent an additive dadra interaction; whereas data points that fall below or above the line represent synergism or antagonism, respectively As showing graph in FIG 15 IC60 vales for ECI45/doxomhicin combinations fell wei below the linesuggesting that EC145 and doxonbicin have a strong synergistic relationship in KB cells. 0 EXAMPLE 8 Study of ECi45 and DUKA® tPDL) Alone or in Combination in Balble- Mice bearn g Subcutaneous M109 Tumors Maintained on olate Deficient Diet 5 Balb/e female mice purchased front Flalan (Indianapolis. IN) were housed (5 animals/caget in standard nolvearbonaze shoebox cages with sanichips bedding and wire top. The cages were replaced with clean cages every two weeks., The animals wene housed throughout the study period in an environmental controlled room. The room temperate settings rangedfrm 7(F to 74' F. The relative humidity of the room ranged front 30% to 0 70- L.ight thners were set to provide a 12-hour light! 2-hour dark photopeiod., The animals were observed dani for health. The animalswere initally fed Test Diet #00434 produced by Harlan Teklad (Madison, WI). Beginning one week after dosn. the animals were switched to Standard Rodent Diet PMI 5000 manufactured by PM I Labdiet (Richmond, IN') The animaal feed and 25 drinking water were provided ad lizuim throughout the study period, Tunor implantation N 109 (Madison-109 long carcinoma cells) tumor cells were grown in folate deficient R.PMI 1640 with 5% 1B at37 Cin a 5% CO. humidified atmosphere. M109 30 tumor cells (I x 10% cells per anmal) were inoculatedsubeutancousl 9 days post start of the folate deficient diet, Mice were dosed after the tumors reached between 70- 100 mm.

-44 Preparation of dosing dru solutions and dosAng Dosing solutions were prepared by weighing appropriate amounts of each compound. reconstitudng/dissolving in PBS p-I 74). sterile filtering the drug soliion through a 0.22 pm. )VDF syringe tdter, and freezing aliquots for each day of dosing at -20NC 5 Doses were administered i n n a vlrume of 200 pL Evaluation TAunor size was monitored and body weight measured 3 nmes/week Attention was given to gross animal morphology and behavio Euthanasia was performed if 0 the mice lost> 20% of weight or w-en iithe tumorS reached a size of 1500 m'. Euthanasia was also performed at the researcher s discretion ifniee lost a lot of weight ir a short duration or when nice were approaching moribund conditions Results and Condusions 5 The effects on tumor growth and responses PR pardal response. CR complete response n Cures) are ilustrated in FHOO RE 16. and the eiects on weight change are illustrated in FIGURE 17, respectively, for the following groups: {a) N-flO9 control; (b) U3C145, 2 molkgc) DOXIL 7 mg/kg: d E145. 2 pmol/kg + DOXIL, 7 ung;; (el) DOI4 ; (f) EC 145 2 iol/kg + DOXI 4. ni/kg. The results for each 0 group are further described below: ECO145 at 2 pmol/kg TIW x 2 doses displayed good anti-tumor effect with 3 of the 5 mice cured of visible tumor: Mice in this group had no weight loss during the dosti period Qc Doxil at 7 og/kg, q7d x 2 doses displayed marked anti-tumor effect 5 with 4 of 5 cures Mice in this group did experience slight weight loss (2- 8% during the dosing period, (d) EC0145 at 2 rnoi/kg 'IW x 2 combined with Dcxii at 7 mg/kg q7dx2 doses also displayed good anti-tumor effect with 3 of 5 cures, Mice in this group had slight weight loss (1 - 6%) during the dosing period. ne animal died during dose 5 due to 30 unknown causes- his animal nad a partial response at this time; (e) Doxil at4 mg/kgi q7d x 3 doses displayed marked anti anor effect with 1 complete response ands 3 cures. Three mice in this group also experienced -45 polonged weight loss 2- 10% upon completion of dosing. but eventually regained their weights (f) E0 0145 at 2 pmol/kg, IW x 2, combined with Doxii at 4 mg/kg q7d x 3 doss displayed excellent anti-tumoreffect with 5 of 5 cures. Nice in this group had a 5 mild weight los of 0 to 5% ding and after the dosing perod. EXAMPLE 14 Study of ECI45 in Patiems with Advanced Ovarian and Endometrial Cancers The protocol for this study (is smsn marized at 0 h top/www cli nicaltrial s.gcov/ct2hhow/NCT0050774 I7term.=Endocyte&.ank= 3 which is incorporated by reerence herein EXAMPLE .15 Study of EC 145 in Patients with Progressive Adenocarcinoina of the ung 5 The protocol for this study (EC-FV-3) is summarized at http :bwww clini caltrials. go v/ct2/show/NCT005 11485 terrm=Endocyte&rank=7 which is incorporated by reference herein EXAMPLE 16 0 Tumor Inaej tin Protoco. usi "Tc EC20 9 Tc'-EC2O doucnand~m~m a performeithin 0 21 days but not les than 7 days prior to the initiation of EC 145 treatment 25 Pior to te EC20 imaging procedure, patients received one IV injection of 035 mg of folic acid, followed, within I to 3 minutes. by a I to 2 m.L i jwection of 0. mg of EC20 labeled with 20 to 25 mCi of technetum*99m. If possible folic acid supplements were discontinued within a week of administration of T\ EC20o Folic acid was administeredby IV inaction approximately I to 3 minutes IG prior to administration of mTc.EC20. Folic acid was injected as a~ slow IV push followed by 5 to, C 1. of nomi;nal saline ia a fee-aowing indwelling IV catheter in an upper extremity vein (eg, antecubital fossa) or appropriate indwelling A. access, -46 'lTc-EC20 was administered in a volume of approxiatly - to 2 L -viaa tree flowing indwelling IV catheter. *TcEC20 may be administered in the same line as the fili acid "Tc-EC20 was administered over a period of approximately 30 seconds. followed by 5 to 10 mL injections of normal saline. The injected radioactive dose was 5 between 20 and 25 mCi, Image Acqdisition Approximately I to 2 hiu postanjection of**Tc-EC2, mid-thigh to head, anteinor and posterior planar Wages were acquired lmMedately after planar images were 0 acquired SPECT (or SPECT/YCT3 images of the anatomic region known to contain the tumor as identified by the patient's conventional Wage werequired, If the anatonic region containing the tumor was not previously identified, SPECT (or SPECT)OD images of the chest/abdomen and abdomen/pelvis were acquired. 5 Planaraging A mid-thigh to head, antenor and posterior planar images were acquired according to the following required parameters: I. aging Area: Mid-thigh to head 2., Camera: Dual or triple headed detector large field of view (FOV) LEHR parallelhole colimators. 3.) Matrix: 256 x 1024 minimum. 4) Energy Window: 15%- -- 20% 5,) Energy 0 keV: 140. and 6.) Scan S p -ed 8 10cm/minute Representative planar images are shown in FIGIRES I., 2; 4, and 5. Tumor locations are indicated by the arrows added to the images. SPECI [agin g 25 F or optimal imaing of the body, the arnms we-re elevated over the head if tolerated by the patient For optimal imaging of the head and neck the armsere motioned along the sides. ages of the region known to contain he target lesions as identified by conventional image wer obtained, inmediately after the planar images were acquired; 30 If all target lesions are not in the FOV for the first image acquisition, addttonal imaging was performed to obtain- an image of all target lesions. SPECT/CT may 47 be used in place of plain SPEC- -T using the attenuation correction parameters listed below, Data was reconstruted at the highest pixel resolution using iterative reconstruction (a Wiininnun of 6 tendons is recomended. SPECT is reconstructed into3orthogonal planes: transversesagittal and coronal. 51ages of the region known to con tari 6he the target lesios were acquired according to the following required parameters: 1.) Canmera: Dual or triple-headed detector large FOV LEHR parallel-hole colbmators 2, lotal Projections: 120 -- 128 :4 Matri 128 x 128 4) Orbit Type: Circular or Eliptical 5.) Ofbit: 180 degrees per head with a dual detector camera OR 120 degrees per head with a triple detector camera 6) Time per Stop: 40 0 seconds/stop 7.) Total Number of Stops: 60 to 64 projections per head for a dualbhead camera or 40 to 43 projections per head for a triple-head camera 8.) Energy Window: 15% -20% 9 Energy ke 140 5 Acquisition of CT iages using SPECT/(l' equipment foiowed the Society of Nuclear Medicine Procedure Guideline for SPECT/CT Imaging, CTinages were acquired only for the purposes of attenuation correct on/anatomitc localization (AC/AL) unles s the CT component of the combined SPECT/CT system was capable of providing diagnostic images with image quality and 0 resoltin that met or exceeded that of available dedicated diagnostic CT equiment CT images were acquired using a 256 x 256 iniun maiNxa iaximnur 7.5-mi slice thickness, spiral cquisition, at 40 kVp and 80 mA during normal (tidal) respiration AC/AL. CT sinograms were constructed with filtered backprojecion at the full F)V The filtered back projection was either 2dirnensionai after appropriate portions of the 25 spiral CT data were collected into axial or tilted planes or fully dimnsional Standard kerels were used for attenuation correction. CT may be refornattedinto three orihogonal planes: transverse, sagittal, and coronal. See FIGUR ES 6 and 7, -48 EXAMPLE 17 TurnorAto Hackgaround Measurement ECU2{ 3&oed,t Sale For both the planar images and the SPECI/2T or SPECT ages, the nuclear 5 medicine physician coded the intensity of uptake for each target lesion (eT T T T If a lesson was not in the S>ECT region, code as not imaged, I No uptake No uptake as compared to background. 2. Mild UptakeUptake increased sighmiy as compared to background. 3.Marked Uptake: Uptake s ignifticanti y increased as compared to hackgaround. 0I For any area showing uptake that does not correspond to a radiographic abnormality including organs the nuclear medicine physician documented thelocation and coded the intensity of uptake using the same coded scale. 5 SPECT images were analyzed semiquantatveiy using a tumor-to background (TB) ratio. For each target lesion e. T, *T2 1 ) a region of interest (RO) was drawn over the areas of maxurn aevity within the lesion that corresponds to the radiographic abnormality; The region was used to provide the tumor measurement. Foreach target lesion, an R of the corresponding miar image location available in the normal 0 appearing conralateral area was drawn, If the region was an area showing uptake. an R01 of norma tissue adjacent to the leson was drawn. This region was used to provide the background measurement. For any area showiz uptake that did not correspond to a radiographic abnornality, including organs, the location was documented and an ROI was drawn over the 25 area of maximum activity within the area of uptake, An ROI of the corresponding mirror image location available in the normal -appearing contralateral anatomy was drawn, If the contraiateral site was an area showing uptake, an ROT of normal tissue adjacent to the lesion was drawn. The tunor-to-normai tissue background (TAB) ratio for each lesion is 30 calculated from the mneasurerient derived from each ROI pair, -49 EXAMPLE Ig Patient Selection and T t Regimen with EC3.45 Lung Timnor Patient Selection Criteria 5Patients had advanced progressive. adenocarcinoma of the lung, had previously received two or more cytotoxic. agent containing ekemotherapeutic regimens, had a performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG)scale.. were at least 4 weeks fher prior therapy and recovered(to baseline) from associated acute toxicities Patients also had radiographic evidence of measurabledisease and mor than one oI area of. tmor that was aso identified as "EC20 positive" (ie.. a tumor-to-background ratio A 1L2), Treatment Regimen was h4 1a olus jinjection. on E~l 45 (1 mninjection) administered intravenously as a hlsijcino 5 M. T. W. Thb and F during weeks I to 3 in each 4-veek cycle. No treatmentwas administered in week 4 (total dose adrunsistered to the patient was 15 mg/month). This cyle was repeated twice in the induction phase. This phase was followed by the maintenance phase which consisted of injections of 2.5 mginjection, administered intraenausi a bohis injection. on M. F of weeks I and 3 of the 4Week cycle. No treatment was administered 0 in weeks 2 and 4 (total dose administered to the patient was15 mg/month See FIOURE 8 for a graphical description of the dosing schedule EXAMPLE 19 Treatment of Patients with EC145 combined with "Tc EC20 monitoring 25 Patients were screened prior to the begrmingp of administration of EC145 using the methods of EXAMPLE 16 EC 145 was administered to the patients folowing the igimen described in EXA MPLE I. TABLE I Population Fully eligible patients (all All treated patients (icludes patients with screening CT 11 pts with screening C' 28 within 28 days of onset of days range 29-39d) before EC 145 therapy) receiving EC145) Endpoint n = 29 n = 42 -o Clinical Benefit 31% 9) 25% (11) Disease Control Rate at 8 41% (12.) 357% (15) weeks RECISTresponse I PR 1 PR Table shows that patients treated with EC 45 derived clinical benefit (defined as the ability to receive 4 or more cycles of therapy) at rates greater than 20%, thus the primary endpoint for the study was achieve. * RECIS. Complete Response (CR): Disappearance of all target lesions 5 * RECIST Partial Response (PR) At least a 30% decrease in -he s ounf thelongest dimension (LD of target lesions, taking as reference the baseline sum LD * RECIST, Stable Disease (SD) Neither sufficient shrinkage to qualify fbr PR fior sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatmnt started 0 *RECIST, Progressive Disease (PD): At least a 20% increase in the sum of the LID of targe t lesions, taking as reference tile smallest sum LD recorded since the treatment started or the appearance of one or more new lesions TABLE 2 Population All patients rece giving 3/4" line patients with 100% EC 145 as3 or 4 line W of tumors showing EC20 therapy uptakie Endpoint n = 20 n I I Clinical Benefit 40%(8) 45% (5) Disease Control Rate at 8 50% (10) 66%:(7) weeks RE response I PR I PR 15 The pri mary endpoint criterion requires response rate of ' 20% Subset analysis of patients receiving EC145 as Y', or 4' line therapy indicates a clinical eneit rate of 40% In patientswith E'0 uptake (indicating FR expression) in ail tumors, the clinical benefit rate increases to 45% 20 TABLE 3 Population3/ in patients with 100% 31 ne parents with of tumors showing EC20 heterogenous EC20 uptake uptake i e.W at least one EC20> negative tor mass) Endpoint n ii 6 Clinical Benefit 45% (5) 33% (2) Disease Control Rate at 63,6% (7) 33% (2) 8 weeks RECIS response I PR The primary endpoint criterion requires response rate of 20% EXAMPLE 20 5Trainen Regimen with EC145 and DOXL@ (PDLx Ovariai Cancer On the days on which subjects receivEC 45 and pegylated iposona doxorubicin (PLD) [C 45 was administered at least 45 minutes prior to the administration 0 of PLD. After the E(45 is adniistered, the Whub was flushed, and when at least 45 minutes had elapsed the PLD was administered via the same IV hub used for adnmnistering EC 145 15 EC145 was administered through an IV line (peripheral or indweliing catheters are acceptable) as a bolus injection oer approximately 10 to 20 seconds. ECI 45 was not mixed with any other drug solution during adminitraion and the IV hub was flushed with apprmmately 10 cc of sterile normal saline solution (or a flush amount per institutional standard of care) both before and immediately y after aministradon of EC 145 EC145 (25 20 nmi was administerd on MondayWednesday. and Friday ofweeks I and 3 of each 4-week cycle. No therapy was administered during weeks 2 and 4. The schedule for each subsequent cycle after cycle I was identical to that of the rst cyele; Calulaionan. Dli axof EL)Dose PL vas administered IV at a dose of 50 mg/nl For subjects whose measured body weight was greater than thei ideal body weight, the dose of PLD was calculated on. the basis of ideal body weight (JBW) After the subject's height in centimeters 5 was determined, IBW was calculated as folks 3W = -4 j 0 -kg + k for each centimeter over 152 cm Body surace area (IBSA) in square meters is then calculated as follows: BSA (in= e (cn) x IBW (kvg]/ 3600n alternately BSA (m the square roof ([height (cm) x IBiW (kg W3600) 0 PE>)vas administered at a rate of I rag/min to imniriue the risk of infusion reactions. If no infusionrelated adverse reactions were observed, the rate of the infusion was increased to complete administration of the drug over I hour. The risk of cardiotoxide increased with the cumulative dose of doxorubicin. The recommended ifezime maximum dosage of conventional doxorubii was as Roliows; 5 Adults < 550 nr/i Adulis > 70 years of age Consider curmulative. dose of < 300 ng/m (Cancer Chemotherapy Manua published by Walters KluwerfHealth (0 Ldniversity of Utah August 2006) 0 The subject received a dose of PLD once every 28 days on day I (for a recommended minimum of 4 courses) unti the maximum allowable cuiulauve dose of 550 mg/02i was attained as long as the subject did not exhibit disease progression, did not show evidence of cardiotoxicit and continued tolerate treatment, The peylated liosomal doxoruhicin used in this study is a mixture 25 comprsing liposomes containing doxorubicin or a salt thereof where the liposomes comprise a poiyethylene g I ycol modified surface. in illustrative samples, the peggIa ted liposonmal doxorubicin was DOXIL® DOXIL@ is doxorubicin F01 encapsulated in STNALTH@ liposome carriers. STEALTH® i@iposone carriers were composed of N4carbonyk methioxypolyethylene glycol 2000) 2 distearoyl-sn-gl)ycero-ephosphoethanol amine sodium 30 sal (MIPE>DSPE). 3.19 mg/n ; fuly hydrogenated soy phosphatidylkholine (HSPCt 9.58 mghnL: and cholesterol 3.19 nafmg/mi Each ml. also contained ammonin sulfate; approximately 2 mg; histidine as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose to maintain isotonicity. Greater than 90% of the drug was encapsulated. in the STEALTH@ liposomies. EXAMPLE 21 5 Tumor response in NSC d ad Ovarian Cancer valuable lesions Using the imaging methods described in EXAMPLE 16, tumors were imaged during the treatment described in EXAM PLE 18 or EXAMPLE 9, The percentage size change for each imaged tumor is shown in FGURE 9. [he data showit folate-receptor positive tmors (selected based on. use of the "YTc420 imaging method designed herein) 0 have a mean inease in size of ov 79b cotoed t the mean increase in size of 33% shown for the folate -receptor negative tumors (lesions). Wbile certain embodiments of the present inention have been described andlor exemplified above it is contemplated that considerable variation and modification thereof are possible. According the present invention is not limited to the particular 5 embodiments described andior exemplifed herein, EXAMPLE 22 EC45 for injection (EC145 Drg Product)Specification and Representative Result Storage/Handlina instructions; t ore at -20X 5 I potect from light Appearance Yllow Soti YeloW S oen Identity M9-% at 959A ± 959N Purty > 90 0 % 95 6% La r destdvdual Ox nation Product % 4 Largest Individual Related Substance <4 % P0% ECi45 Content 90 110% label contest % TUd Related Subsances, 1410 IA% pH 6 --7.8 7.6 Osmolality TB:ns A4 * Steri i v pass Pas ndotoin NT 19 E c1 El.~iJvia Particulate Matter I0 nucron NMT 6000' B 08 / via 2 micron NMT 600/ia 5 / viQ Residual Solvents 1% Volume n Container 8 I .$L in Vial 20 mI vial EXAMPLE 23 EC145 drug product (DP) for rravenous V) ad(tinstration is provided as 5 21) aL of an aqueous sterile liquid formation, pH 71 in single-use clear glass vials with F!mteelf coated rubber stoppers and is tored frozen under argon. Each vial contains 1 4 mghnmL of BC 145. The quantitative composition of the drug product is shown in the table below Single vials are u sed to provide ia t mgolus close of ECI45i BC 145 Drug Product Conmponents Am~urper vial, Function r ad ) EC45 Activn he e 2 Sodi m phosphate. pH control. SP 1 monobasic monohvdratc tonicity 2USP 214 dibasi c dihd rate Ton city Sxdhum chkoncde Tonickty USP' 16 12 Potass----chlorid-------t--------- .... ... wIQ o2 A 10 EXAMPLE 24 Reprsentative Bowel Regimen for Treatment/Prevention of Consipaton Constipaton/ileus was noted as a potentally serious adverse even in the Phase Itial of EC 145. especially in those subjects who received concomitant opioid 15 analgesia.

A suggested progressive bowelregimen (Modified from Carney NMT', Meier DE. Palliative care and end-of-ife issues. Anaesthesiol Clin North America 200 183 for subjects who receive therapy with EC145 should parallel that used for subjects who receive opiold therapy in which clnicians can progress throu higher steps until an effective z regimnen is tound: Step I Docusate, 100 mg twice daily (hi .d. and Senna. I tablet once daily (%d) or bd. Step 2: Docusate l0 ng bid, Senna2tablets hid., and Bisacodvl rectal suppositories - after breakfast. 0 Step 3: Docusate. 100 mg bidA Senna, 3 tablets bid., and Bisacodyi rectal supposioris 3 -4 after breakfast, Step 4: Docusate. 100 rmg b i-t Senna 4 tablets bi.d.. L.acvulose or sorbitol. 15 mL bid., and Bisacodyi rectal suppositoies 4 after breakfast Step 5: Docusate 100 mg b.io Senna 4 tablets bid. Lactulose or sorbitoL 5 30 nil b id, and Bisacodyi rectal supposltOries 34 ater breakfast. Step 6: Docusate. 100 rag b it Senna 4 tablets b~i d. Lactolose or sorbitol. 30 ml qi.d,, and Bisacodyl rectal suppositories 34 after breakfast, EXAhdPIE 25 0 PRECEDENT: A randomized phase 11 trial conpuring £0145 and pegylated liposomal doxombicin (PL) in combinatn versus I alone in subjects with pLdi.,-es.istat ovarian cancer (ECATM4). Background: EC145 a con jugate of folic acid and desacetyvinblastne hydrazide binds with 25 high affinityto the foate receptor (FRA found on. > 90% of epithelial ovarian. cancers. This example reports interim data on an international randomized, phase 2 study of ECI1454 PL) compared with PLD alone, in women with plaonuvmresstant varian cancer, An independent Data Safety Monitoring Board (DS MB) has conducted a pre specified interim Malysis on FFS and safety with results reported herein. 30 Methods: Women I 18 with ECOG PS of 1-2 and <2 prior systemic cylotoxic regions werandom to re V 4(5 rmg IY weeks 1 and 3)+ PLD f50 mg/n IBW IV q 28 days) or PL) (50 mg/n IBVV N 28 days) alone until progression or death.

56 Results: The interim analysis occurred after the 46th even out of a planned study total of 95 progressionsor deaths Demtographic characteristics at screens such as age, cancer type. residual tumor after debulking, prior therapy, CA- 125 and time from diagnosis were balanced 3 between arms RECIST mean sum tmodength was longer for the conbinatioin arm (122.7mm vs., i .3mm). There was no statistical difference between study arms with regard to total adverse, events, serious adverse events or the number of subjects reporting at least one treatment-emergent drug-related serious adverse vent sting in discontinuationI The table below displays the results of the interim analysis of PFS and the Kaplan Meer curve 0 can be found in FII 11. Patient ECI 45 + PLD PLD Hazard Ratio Pv aue Population PFS ( vees FS oeeks) EC::-FV:04 Study 24,0 11 0497 0,014 At the interim; there is also a trend toward benefit in overall survival for the combinatIo, arn with HRa - 0.1> P val ue of 0 064) 5 Conclusions; Results indicate a greater than doubling in median PFS for women with platium-resistant ovarian cancer recei vin g ECi145 and PI1D over those receiver PUD alone. These iterin data suggest that EC I 45 and iPD is the first combination to snow a statistically significant increase in progression free survival over standard therapy in women with platinum-resistantovarian cancer 20 Kaplan-Meler curves for progression free survival time in the ongoing phase 2 trial in women withplatinum-resistant ovarian cancer, at the tirne of the interim analysis, for subjects enrolled at sites with nuclear imaging capabiities who were scanned with EC2-0 prior to study treatment and scored as EC20 positive (EC20++ status) prior to study treatment 25 (EC145 n combination with PLD versus PLD alone) are shown in FIG. 12, Response to Therapy at the interim according to RE$ LUersion 1.0) is shown in the following table. Scan frequency and timing of assessments (every 6 weeks for 24 weeks, then every weeks for the balance of thestudy paticipatise were equaltfor each 30 arm, RECAST .Confirmed EC 145'LD PLD Response to Treatiment n=54 n= 17 Complete Response (CR) 0 (0W%) 0 R0O% Partial Response (PR) 9 (167% 4 (18 Stable Disease (SD) 33 (61.1%) 12 (44A%) Progressie Disease. (PD) 12 (22.3%) 11 (407%) OveraLl Disease Control 42 77.8%) 16 (59.3% (SD+PR+CR) FIG. 14 shows a Kaplan-Meier graph of Overall Survival (IS) for paients trated vith ECl45 in combnadrn with PLD versus those receiving PLD alone At the time 5 of the pre-specified interim analysis median overall survival was tending toward statistical sigificance with hazard ratio of 0425 (dtais char . The protocol for this trial is summarized at http bwwwelinicaltrials. go vi2Nshow/NCT0072.2592i7term=p atinum~resistant-i-varian -can 0 cer&rank=2 which is incorporated by reference herein EXAMPLE 26 Kaplan-Meler curves for overall survival time in Study EC-PV-02, a trial in women with advancedovaran and endometrial cancers who were scanned with EC20 prior 15 to study treatment and assessed as EC20 positive (EC2+ status compared to those assessed as EC20 status or [EC72(-status prior to study treatment are shown in FG, 13. This curve examines the utility of selecting patients who benefit from the single agent EC145 in highly retractory ovarian cancer patients. 20 EXAMPLE 27 EC20 Patient Scanning Procedure. Following completion of screening procedures and confirmation of elHiility all one intravenous injecton of 05 mg of folic acid followed within 1-3 minutes by a l-2 mL injection of 0 1 mg of EC20 labeled with 202---5 mCi of technetin-9 Patients then underwent SPECT imaging (mid 25 fhigh to head, posterior andanterior images -- 2 hours following injection of EC20. Target lesions were selected by the radiologist according to REcIST (vi 0) criteria, Subsequently, nuclear medicine physici an s assessed EC20 uptake for each target lesion visually. and classed the uptake as positive" (rIakedhniid uptake) or ~negative"(no uptake). 5 EXAMPLE 28 EC20 Lesion Scoring Procedure. Lesions less than 1.5 em in longest dimension (lO) were considered "nonevaluabi"unless the nuclear medicine reader identified- then'i as Iavi ng unequivocal uptake of EC2, in which case they were characterized as "positive. Since certain organs (le, liver, spleen, bladdeand kidney have 0 an inherentrf high uptake of EC20, target lesions located in these organs were considered "non-evaluable) All evaluablesions were categorized into two mutually exclusive groups;) EC20+ uptake of EC20) and 2) R720 (neg) (no uptake of EC20). Change in lesion size was compared between the2 groups uing analysis of variance (ANOVA a 5 treatment response was determined esians with at least a 20% reduction in sure were classified as responded (mPR and those with at least a 20% increase in size were classified as progressive disease (PD. Lemons not meeting either the mxPR or PD criteria were classitied as stable (SD The percentages of mPR, SD, and PD lesions were. compared between the E720+ and EC20(neig groups using Fisher's exact test The quantitative 0 percent change in tumor size was measured using the. Pearson correction coefficient. EXAMPLE 29 EC20 Patient Scorng Procedure A subject score was calculated by dividing the total number of EC20+ lesons by the total number of lesions (evaluable and 25 nonevahuabie) Patients were categorized into three mutually exclusive groups: Group I EC20++ (100% EC20-positive, target lesions) Group 2: EC20 ( 9-,-9% -C20-positive target lesions) Group; FfC20-uey (% or no EC20 positive. target lesins For example; the "subject score" for a subject with one EC20+lesion and two 30 Ef2{-(neg lesions (three target lesions in total) would be 33% (1 of 3 lesions positive placing the subjects in the EC20- group, A subject with all target less FfC20 positive would beate.orized as EC20+ (3 of 3 lesions are Posiive).

-nl The best overall response was determined for each subject using RECIST v LO (Therasse. 000) RECIST overall response rae (ORR) and disease control razes (CR/PR/SD) were calculated for each of the 3 populations, F-or these analyses. subjects who came off study prior to evaluation were considered non--responders Overall survival was 5 analyzed using Kaplan-Meier techniques and Cox proportional hazards models (Kaplani 1958; ManteL 1966 Due to sample size considerations the EC204 and EC2 -(neg) were pooed for the survival analyses, Sample sets for ORR and DCR included all evaluabie subjects (intent to treat as well as a subset of subjects who failed less han or egnal to 3 prior lines of therapy. Due to 0 a restriction in sample size only intent to treat (TIT) is included for the survival analysis, EXAMPLE 30 Patient Demographics. Forty-five ovarian cancer subjects were evaluated. Key demographic and disease characteris tics are shown in the table below, Overall subjects 5 were highly pretreated prior to entering the E(>FV-02 study with a median number of 4 prior chemotherapeutic regimens (range of I to M4 regimens). Eighty percent of subjects had tumor burden > 5 cm in D Demographics of Patients Ireated with EC20 EC-FV-02 Nof o subjects MedIa pe (ears)6 -- - - - P--rmancee--a-us 171 24 (S!§{ tametria a Ovarian 3 5 (%) ......... P..it..n..

'60 Dsease burden --- -- --- -- --- -- --- -- -- --- -- --- -- -------- -- -- --- -- ----- --- -- -- --- -- --- ----- -- --- -- -- --- -- -- --- --- -- - K ew 9 2% EXAMPLE 31 Lesion Assessment ForPfive protocoielgiesubjects with a total of 216 RECIST-defined target 5 tumors (ie Mestons") were included in this retrospective analysis b low) One hundred and forty-five 4S/216; 67% of the lesions were considered EC20 "evaluable," Of these! i i1 C77 ad EO2 h Apositive uptake. Of the 71 lesions considered "non-evaluable 45 lesions were present in organs with high background uptake; 15 lesions did not have suicieie.nt SPECT data for interpretation; and i lesions that were smaller than L5 cm in size 0 wore coded with uptake as none As shown in the table below, 145 lesions were classfied with unequivocally positive or "negative" uptake of EC20. These lesions were included in lesion analysis, One-hundred and eleven esons were EC20+ and 34lesions were. EC20-(neg) Evaluable and Non-Evaluable Lesions Leson Grouping N(% I t nmber of'P RLCSI'dhe les-iiuns 1 a1 m", 71 NroniExaita bie i.esions NoSI4XA dat (% Nkzaativcelesion < 1.5en a IISn Lesons found in organs with hi h ba k round 45 63%; I~sr\- I . 067%f Negative EC 204(:e&)) 34' 23% 15 Bighty-seven percent of the subjetst ha -uI (T ptake observed visuallyin at le-ast I arget lesion. EC20dneg) lesions wre slightly larger in size than the EC2O+ lesions (2.8ecm versus 24 en, respectively [p =0.01) -61 EXAMPLE 32 As shown in the table below 59%b (n=65) of the EC20+ lesions exhibited 5 stable disease (SD or nodifed panial respos (PR as compared to a 27% SD rate in the EC20ineg) population These findings indicate tht EC20h uptake diemnte ewe lesions that exhibited a modified PR or SD (p0)Q after exposure to EO45 versus lesions that, at best exhibht SD All of the lesions in the modified PR group were EC2{0 Lesions Response to EC145 Therapy by EC20 Uptake EC20+ Ct Change i Lesion Sie n (% Number of evaluable lsons 100%) 34 (100%) MPR 11 (10%) 0 (0%h) SD 540049%) 9(27%) PD 4 25(73%) naPR + SD 6 59% 9 (27%) 0 EXAMPLE 33 The DCR for all enwduable subjects regardless of EC20 status wa .2% (Thle below) The DCRK increased with LC20 positivity. EC20++ subjects had the h h"st 5 DOC followed by EC20+ and EC20-(neg) subjects: 5 36% and 33%, respectively Ihe ORR across all subjects was 5% Consisent wih the DCR analysis the ORR in the EC20+ subgroup was tie highest at 14%, wit the other 2 groups at 0%. In the subgroup ofess heavily treated subjects that had faied :5 3 prior therapies, DCR fo the EC20++ group was 86% versus 50% and 0% in the EC20+ and EC20(neg roups respectively. 20 EC20 Percent Positive --- -------- c- rnim 1t hoITT' - -ud'~ h r ~rr AU L(0++ EC2t+ E t0+ EC + EC2t Onea ligb 10w% IS99% EC20(ng 10% 189% /% a i't PoP v Poitive Posi Pi Posit R- 1i n=45----- =4 n=41--- (n----=7 ( (= 2)IM 4%III (2 ;_% ( TI4M 0 (0) 14 Of (3 %0) SD 5(% (16 50 33%. 8 29% (2 %" 1 (N) ) 0% (0 PD (/0% 5%(6 43% (6) 63%, (15 7 1% (5' (1 1 (0%X (21 .... ... .... ... .... ...... ... .... ... .... .. ) Results from this exploratory study of subjects treated with EC45 showed a trend for greater survival in the group with 100% positive lesions. The median overall sur viva in these subjects was 634 weeks vass 21 weeks insubjects wjtri less than 100% 5 positive tumors (hazard ratio = 0.6 p 0071) EXAMPLE 34 EC2 Chemistry M anufactui.ing and Controls Mianufacttre 0 EC20 is synthesized using standard Fmocbased solid phase peptide syntesis chemistry as described above and in the diagram below Starting with resin bound cystele. protecting group removal is followed by coupling ofehe amino acid residue using standard reagents., After the last coplinPg and deprotection. the peptide is cleaved fon the resin. Crude product is precipitated and isolated by filtration. The purity of crude EC20 is about 5 90% Crude EC20 is purified by preparatve column chronmatography EC20 is preciptaed and isolated by tilration, The pudty of the final drug substance is A 97%. PNress Flow Diagram H--Cys(Trt)-2 chlorotrityl resin Adtd Fmoc-Asp4OtBu H4 and reagents to couple 1'Coupling Confirm coupling with Kaiser test Deprotect with anso 2 n od 4" Cu 1 n 3' andee ci in Add next amino acid residue and reagents to couple aThree cycles)~ 4C Conftrm coupling, wit Kaiser test Repeat with next residue Deprotect and cleave De>protect Cleave peud fro Filter, Wash afnd Dry Purify crude solid Elute EC20 Pool fractions Pwr hcatdon of EC20 Preci pitateafhiter and dry Store under Atrozen at a-20"C C h aracterizatiomn EC20 drug substance has been characterized by H and 1 "C NMR analysis, by o spectroscopy. arino acid analysis,. and peptide conten All methods 5 confirmed the structure shown abovc. Process.ela ted im pur iesa EC2O is purified by column chromatography to ensure that no starting materials orreagents used in the preparation of EC20 are present in the EC20 dng substance. Residal solvent levels are assessd by CC analysis of the isolated drug substance. 10 h specficatn ftanC i ow i the tab l below Attribute Test Method L.imit A ppearance Visual Inspection Yelkoffoiwhite pocwder identity ESMS MEI 746 2 1 Purity RP AP 1 95.0% WNdividual Specified hnpuities RP4iPLC A .0% F 0% H 1.0% -64 P1 I TV Individual UnspecifiedRAPC RP-HPLC i0 irapurities Total hnpurities RPMiPLC 20% content % Nitrogen 0% Moisture KarlFischer 100% Endotoxin USP <85> 2.0 EU/mg Microbial Enorneration USP <61> < 1 C11 T?100 mg Methanol (as Chromatography 5 (5 pg MeOl / rg API Acetonite C Lpg ACN/img API Hydrazne 1. micrognnn A PI EC20 Drug Substance is stored at -20 W in amber glass bottles with butyl rubber stoppers Stability data show thatkd u substance is stabe under these conditions for more than 24 months. EXAMPLE 35 Description and Composition o the Investigational Medicinal Drug Product The medicinal product is a Vit for the preparation of T- EC20 The pmduct is a lyopili zed sterile, light yellow solid. 10 Quan tiy per v ial of E720 Dig P product lngredilent Quantity per vial (mr. EC20 Dnre Substance 0.00 Sodium au-DGlucoheptonate Dihydrate 80 (U ucohepton ate Tin (l) Chloride Dihvdrate (SnC 2H O (R08( The preparation of the final dosage f T E2for inetion, is carried out at the clinical trial site in accordance w standard practices for Tc-ased d.iagnostic agent -65 The EC20 drug product is a single use vial that contains al the components necessary to prepare an effectivedmaging agent by the addition of sterile sodium pertechnetate. The drug substance is formulated with Tin (11 chloride, and soiume gieohneptoaae in the anounts shown in the table below The fornmdation istypical for 5 agents that utilise metastable technetium as a source of radioactivity. The EC20 drug product chelate technetiumand when an aqueous solution of freshly prepared retastable technetium Is used to reconstitute the EC20, the technetiun is chelated and the imaging agent is formed. EC220 DP? components ass or CncMolaronRafio InkoCA af 2R, f o Comonnt Activity recon sdtnm 80 m 28x 02 1 8M TUO55 glucoheptonate +8N 0 Tin (II) chloride 80 p 5 xC 035 x l0 M 686 "-Tcl ~ ~ ~ ~ ~ - I c I U4 " Ax V " 0 Biatch Forr.nuia The batch formula is provided in tb table below for the typical 2000 vial batch of EC20 Dug Product EC20 Batch Formula gredient I QuanttY Sdun -- ) - Giucoheptonate Dihydrate (ilucohepton ate 160 g Tn MY Chloride D_'ihvrate (SCC-i-t016 g Sterile Water For Imection (SWEi S Nitrogen (nert atmosphere A needed Hydrochloric acid 4 Sodiumn H ydroxide 10a 46 NC2O DP Fill Prmcess The manufacturing process is perfonned under a nitrogen or argon a trnosphere, 5 EC2O Drug Product Manufacturing Process and Controls Disso v t GH n e.natec SWIK naUl (iduride solution r epared in nC using deoxygenated SWFH E Drug Subsance webed and i ade as a solid io Tind s k an |ouhA{n Solulion oft adjusted Dilution to Batch Sire Sterile Am O INl and Szopoer I yophilize C20 )rug Product inpected ad Laxilcd Preparanon of G nhcrsepmaw scuo!i The empty fornmulation vessel is weighed wci th a 10 suitable stir bar. Deoxygenated SWNFis added to the pro-weighted fomudation vessel, Gucoheptonate is added to the formulation vessel using a glas fune. The weighing container and nnel are rinsed wJth deoxgenated S WE and the rinses added to the fonulation sohitinn.

-67 S praratian A :l/2eisruusiondhe SnCi 2BO is weighed into an appropriately sized flask. The SnCT 2114O is dissoled in deoxygenated 02M HIM. Frepar'wan of the EC20 soba/n: The SnCht2HO solution is slowly transferred to the 5 prepared Glucoheptonate sohtior. with continuous stirring The appropriate amount of EC20 (calculated from the known peptide content is transferred the Glucoheptonate / SnC1 solution. IM NaOH and/or0.M H is slowly added until the p1H reaches 6.8 ±0,2, The solution is diluted t the desiredtarget weight 0.25% with deoxygenated SWIl and stirred for a minimum of 5 minues. A prefiltration bioburdten sample is draiwn hrm the 0 formulatio vessel using aseptic technique and placed into a sterile Continer with sterile Cap closure The firation apparatus, two sterile filters in series, and receving vessel are set up and the EC20 fonrulation soluon is filtered into an appropriate receiving g vessel through the 0.22 micron. sterile filter using a peristaltic pump. A post-filtration filter i ntegritv test is performed. if the recorded pressure, fils, t est is repeated one fine. Ifit fails a second 5 time, new filters may be installed and the process can be repeated Plun undwpperig Filning and stoppering is carried out aseptically in a Class 3003 finling area All containers, vessels miin g devices and utensils which contact the product or materials going into the product are propedy cleaned and sterilzed or depyrogenated, Setup 0 and fill checks are performed gravinietrically based on calculated density. The vials are filled and stoppered. Stoppers are placed in the lyophilisation position (half seated before the vials are removed from the work station. Lyophilizer trays are loaded into the chamber onto shelves and then Chilled to 45 * 3 *C. Once the product is frozen he vacuum pump evacuates the chamber, The drying cycle is terminated msanuall y by closing the vacu un 25 pump valve after holding a shelve temperatreof 30 -C 35 "C for 3 10 hours, The shelf stoppern mechanism is activated after purging the cianmber to 7 -- 10 mnnlg with filtered nitrogen. When all vials are stoppered the chamber is back filled with filtered nitrogen to atmospheric pressure and the product trys are removed from the chamber anid capped with aluminum seals. Vials are labelled after capping and stored at -OP "C i 3C. ) 0l -68 NC2O Drug Product Excipients Specificatdons Ingredient Specfication Li mnn Result T s p Chlorid N 1-,S P NA apcbi Dhydrate (SnC 2 AgH Nuapphca e applOcable Assa, HLC 98 1.02% 100% Solution 0PAqueous Pass solutionl is clear and colorless Sodiun a- D Ghoheptonate Diydrae pH5 2.8% 8.7 (Klucoheptonate~LDTA . 1 P/m ~ LOD2GA CFU'" -)% < 100 El~/n Bloburden < 10 Endotoxit EU.g -4 ------- Bsobnrden and Endotoaxin were deterred prior to using te- glucoheptonate as an ex en AU other assay results were obtained from the vendors certificate of analysis 5> EXAMPLE 36 Typical Conversion of' Vinblastine Sulfate into Desacetyivinbiastine Hvdrazide dso

NCI

Materias Vinblastine Sul it SP FW= 909.05 g/moie: Methanol'anhydrous Hvdrazine: 10 anhydrous; FW =32 ghmol; De-ionized water; Ethyl acetate; C C grade; Tlene; L/C grade; Monobasic sodium phosphate:990%; FW = 120 g/mole; Dibasic sodium phosphate; 469 n1990%; FW = 142 g/mole; Sodium chloride; reagent grade; FW = 58A g/mcde; Sodium slfate: anhydrous %norbomenitarboxylli acid. Procedure 5 The reaction extractive work-up and isohaion are run under a nitrogen or argon atmosphere. Pressure filters are used to remove te sodium sulfate and capture the product The sodnim chloride sohtions used in the quench and wash ae spared with nitrogen or argon until the dissolved oxygen level is not more than 0.9 pprn, Vinbiastine sulfate and anhydrous methanol are charged to an argon purged 0 reactor, INorhorene-carboxylic acid and anhydrous hydraz.ine are added to the reactor, The mixture is stirred and after the solids dissolve, heat the mixture to around 60 'C, By HPLC analysis, when the reaction is complete. it is cooled, quenched and extracted into ethyl acetate- After drying, the product is talized from ethbi acetate and toluene, Th solids are dried under vacuu.n overnight at roonI temperature. 5 The buffered NaCi contains: 10 0 g NaCI, 7, 10 -7.30 g NlakItP0 4 . 4.40 4,.0 g of NalPO 4 and 90 nL of water. The solution is spared with arion or nitrogen (dissolved oxygen content < 0.9 ppmt The typical isolated yid is 50 60 %6 of the the-oretcal maximum, EXAMPUI 36 Steps 2 and of the EC 145 Process -zK 3 ,Nll 4 5Step 2and Step 3 Rocs Mneltrials Desbet~i astnehydrazide: FAW=768,9 g/nol; 20, g 26,7 mmiol, Mixeid Carbonate (3 FW=384, g/moA 103 g, 278 m Ao AcetoriWe: q : riethyla>n FW=10 g/m2 167 g,264 maiol;Na2Po47JlH(: 4184g;EC119: 29g 28,6utnrinokl 0,5 N IRA, 10 g :WFit g,,, Procedure Note that all of the water used in this process is WFi, Purge an appropriate vessel with Argon. Chare 20.5±3 g of des 5 acetylvinblastne h.ydraide; this charge is potency adjusted. ie. if the poten cy were 90,0%, the charge would be 22.8 g Chage 10 g 7 a of Mixed Carbonate (potency adjusted Charge 800±30 ml- of acetonitrie and 29±l1 g of triethylamine. Mix under Argon at 10 4*C for 2028 hours. Take a sampe for HPECC45-CMC-AM4000.erion 2 3), The expected result is the ratio of CDSi to hydrazide > 25:1, If not. contiie miNin under Argon 0 at 10 14V for 2 -4 hours and sample again. Spare 780~820 m of water vvh Argont unti the dissolved oxygen level is less than 0,9 ppm' reccord dissolved oxygen level. Dissolve 47,8 0 5 g of odim p1hosphate dibasic heptahydte in the deoxygenated wuter. To a suitable container; add 2918+15 g of 5 ECiF9 (charge is potency adjusted Add the sodium phosphate solution to Ite I 119 and mix under Argon, Measure thec solution's pH and adjust the p to 5.8 - 6.2 wi 5 > N HCI if necessary Add the buffered EC1 19 sobution to the reaction nrie. Mix under Argon at 0 20-25C for 60-75 minutes, Iake a sample for UPLC (EC 145 -CMC-AMO00L version 2.3) if the ratio of ECI .4 to CDS >25:1, proceed. if not, continue miixinig under Argon ai 20-25 C and sample again l the ratio of EC145 to CDS1 > 25:1proceed. If not, add an additionall g of EC I 19 aid mix under Argeon at 2025'C for 30 minutes and sample again. 25 Prepare 6 9 U L 7- 1 L of 25 mM phosphate buffer 185i 195 mM NaCL pH 7,2 -- 75 made from waterspaged with Argon until the dissolved oxygen level is less than 0,9 ppm. Dilute the reaction mixture with this buffer. If the mixture develops more than a faint haze. the product solution needs to be filtered (Whaian Polycap TC75 or TC150 0 45 or 1.micron)this filtration may be done while loading the product onto the Biotage 30 columlm Liquid (hromatographic Purficaton Use a Biotage I50 CI8 cartridge This size cartridge can accommodate a reactionixt twice the size of the one curneti described. 5 Cuun preparation: a Flush the column with i. 12 I 3 L of acetonutrile ii. 12 -13 Luo 80% acetonitrile and 20% water (v/v) iiv. 12 - 13 L of 50% acezontrile and 30% water (V/V) 0 iv. 12 L ofl 0% acetonitrile and 9(0% water (v/v) Poification: Prepare a 25 nAM phosphate buffer(83 i95 mmol NaClEpH 73 TS Sparge the buffer with argon until ie dissolved oxygen content is 09 ppm. 5 Prepare: 41 L of i0% acetonitrile in buffered saline ( 11s): 13 L of 16% acetonitrile in buffered saline (svv 52 L of 27% acetonitr e in buffered saline (v/vt Check the dissoled oxygen content of the mobile phase solutions If the dissolved oxygen content is greater than 0.9 ppn, spare the mobile phase with argon or nitrogen until the dissolved oxygen level is 0.9 pp. 0 Fush the column with 26 27 Fof the 10% acetonitrile mobile phase Load the product solution onto the colunn Elute the product using the flowing sequence of mobile phases: i 14 L of the 10% acetonitrile mobile phase. i. 13 L of the 16% acetonitrile moile phase. 25 11R 51 -52 1 of the 2.7% acetonittile mobile phase Notes: An inline v detector is helpful:Product should come out startir at 15 19 L of the 27% acetonitrile nile phase with a band ,-idth of 8 - 13 L. Fracton Evahuation 30 i -PLC Method ECI 45-CMCIP-000 1. iA Passing fraction =O 97M0% ECI 45 and no impuity 0.8% PosTRun Column ifeatment The column can be reused once. If the column. will be used for a second run. perform id i Flush column. with 12 3 L of 1:1 acetonitilc-ater. 5 it ush column with 20 -22. L of acetonitrile iii Repeat column preparation steps it iv Ultra-itration Spare csA. water with argon or nitrogen until the dissolved oxygen level is 0 less than 0.9 ppm Piassing chromatography fractions are combined and diluted with an equivalent volume of sparged water. Assemble an ultra ration apparatus using a Millipore regenerated cellulose membrane with nominal MW cutoff 0 1000 (catI CDUFO02LA) and rinse it with 9 L of deoxygenated water. Start ultra-ilration of the product solution. Maintain a backpressure of 30-501 psi Continue ultra-filtration until the retentate vouei 2 5 to 3 L. Add I I to 12 l of deoxygenated water Continue ultra-filtration until the retentate volume i2 to 3 L Add II to 12 L of deoxygenated water, Continue utra-filtration until the reten. volume is 2 to 3 L, Add 8 to 10 Cd ofdeoxgenated wate. Continue the utra filtration unt I he retentate volume is 2 L. The ultra-filtration endpoint must he determined by anayin a sample of the reentate via CC and concentration. The specification is S 50 0 micrograms of acetonitrile per milligram of EC i45 f not achieved perform another cycle of the ultra-filtration The Al solutions concentration must be adjusted so that the packaged material is 6 to 2img/mL. At the completion of the ulra-fiItrationthe apparatus will be 25 rinsed with I lier of water Therefre, continue ultra-filtration or add water as necessary Once the product solution is out of the ultra-filration apparatus, rnse the ultrafitration apparatus with 1 L of deoxygenated water and combine with the product solution. After the rinse is conibined with the product solution, this solution must be 30 filtered through a 0.2 micron absolute filter, and this filtrte ia packaged (performed under an inert atmospheree. The yield of isolated product is 50-60% of the theoretical maximum-

Claims (12)

1. 2. The method of claim I further compising the step of administering to the patient EC20 for detection of the functionally active foate receptors
2. 3. The method of claim2 further conrising the step of administering to the patient an unlabeled folate prior to administration of the E ia
3. 4. The method of claim 2 or claim 3 wherein the EC145 isindicated far the treatment of the patients ith the tunor if the radioactive signal produced by the EC20 upon bindin a to the tumor compared to the backgrounc radioactive signal produced by the EC2O is indicative of a dinical benefit to the patient, 5 5. The method of clain 4 wherein the clinical benefit is progression ree survival of the patient. 6i The method of claim 4 wherein the clnicalbenefit is inhibition of tumor growth I. The method of claim 4 wherein tie clinical benefit is selected fronmt the 0 group consisting stable disease, a partial response, and a complete response.
4. 8. The method of clan 4 wherein the level of ex pression of the functionally active folate receptors is quantied based on a turor to background ratio of the radioacive signal produced by the EC20 to the background radioactive signal
5. 9. The method of claim 8 wherein the tumor to background ratio is at 25 least about 1.2, 10 The method of claim 8 wherein the tumor to background ratio is at least about 13,
6. 11. The method of claim 8 wherein the tumor to background naio is at least about 1 .4 30 12, The method of daim 4 wherein the turner is an ovarian tumor. 3. he method of claim 12 wherein the tumor is a piatinm-resistant ovarian tunor.
7. 14. The method of claim 4 wherein the tumor is a lung tumor. 1i The method of claim 14 wherein the tmor is a non-small cell carcinoma of the hing& 6. The method of daim 4 wherein eidier the EC145, the EC20, or both are in a parenteral dosagefnm 5 I7 The method of claim .16 wherein he doage form is selected froi the group consitin g of intradernal, subcutaneous, intramscular. imraperitoneal, intravenous, and intrathecal. I 8 The method of daiN 17 wherein the EC1.45 is in a composition and wherein the composition further comprises a pharmaceutical acceptable canie. 0 19 The method of claim 4 whemein the composition comprising the EC20 further comprises a pharmaceutical acceptable carrier:
8. 20. The method of cla 4 where the EC145 is administered in a therapeutically eff ective amount. 21, The method of claim 4 whereindie £220 is administered in a 5 therapeutically effective amount 22 The method of claim 1 further comprising the step of administering to the patient doxorubicin, 21 The method of clim 22 wherein the doxorubicin is in the form of a pegylaed ipus omai doxorubi c1.1 0 24 A method of deterrdning whether EC 145 is indicated for the treatment of a patient with an ovarian tumor or a lung tumor, the method comprising the step of adinitering to the patient a composition comprising EC20 wherein the EC145 is indicated for the treatment of the patient with the tumor if the tumor of the patient has functionally active folte receptors wherein the functionally 25 active folate receptors are capable of detection with Ed20. 25 The method of daim 24 further comprising the step of administering to the patient an unlabeled folate prior to administration of the EC20 26 The method claim 24 or 25 further comprising the step f administering to the patient doxorubicin. 30 27. The method of claims 26 wherein the doxorubicin is inthe forin of a pegyl ated liposomnal doxorubicin. 28 A method of predicting g a response of an ovarian tumor or a lung tumor of a patient to therapy with EC145 the method comparing the steps of a) admnistering to the patient E!C0 wherein the EC20 produces a radioactive iagnal; b) qantifyg the radioactive siby the C20 upon binding of the EC20 to the tumor, 5 C) qanifying the background radioactive signal produced by the EC20; d) comparing the radioactive signal produced upon binding of the EC20 to the tumor to the background radioactive signal; and e) predicting the response of the tumor to the therapy based on the comparison. ) 2 The method of any one of claims 1, 24 and 28 wherein. 15 mng/month of the BC 145 is administered 30 A mnethod of treatment of piatinuntresistant ovarian cancer in a patient in need thereof comprising a initering a therapeutic aicont of EC145 in combination with a therapeutic amount of pegyla ted lposomai doxorubicnr 5 31. Use of E 145 in combination with pegylated liposomal doxorubicin for the treatment of platinum-resistant ovarian cancer in a patient. 32 Lse of El 145 for the manufacture of a mtedicament for the treatment in combination with pegyned liposomal doxorbicin oflatinunvesistant ovarian cancer in a patient 0 33 A method of obtaining a clinical benefit compared to treatment with a therapeutic amount of pegylated liposal doxoruhicin in the treatment of platinum -resistint ovarian cancer itt a patient in need therof comprising a inseigaatherapetic amount of BC 145 in combination with a therapeune amount of pegylated liposomal doxoriicin. 34 The method of claim 33 wherein the clinical benefit is progressioniree 25 survival, 31 The method of daim 33 wherein the clinical benefit is overall survl. 36 The method or use of any of claims 30-35 wherein the purity of EC145 is at least 90%. 37 'The method or use of any of claims 30-35 wherein the EC145 is 30 provided in an aqueoussterile liquid formulation the components of which comprise monobasic sodium phosphate monohydrate, dibasic disodium phosphate dihdrate, sodiun chloride potassium chiortde and water for injeeton 38 The rnethod or use of any of claims 30-35 wherein he treated further comprises a bowel regimen,
9. 39. The method or use of any of caims 30,35 wherein the EC.I 45 is administered as a bolus over about 10 to 20 seconds. 5 40, The method or use of any of claims 3035 further comprising administerin g EC20 to the patient prior to treatment and assessing the patient to have EC20+status. 41 A method of selecting a patient fo.r tratment as described in any one of cims 3035 corn prising administering EC2.0 to the patient prior to treatment and 0 assessing the patient to have EC20+ status. 42, A pharmaceutical composition comprising EC 145 in an aqueous sterile liquid formulation the components of which comprise ranobasc sodiurmi phosphate monohydrate dibasic di sodium phosphate dihydrate, sodium chloride, potassium chloride and water r injection, 5 43. A dosage unit comprising EC 145 drug product r intravenous administration as 2.0 mL of an aqueous sterile liquid fomiulation, ph14 7. which dosage unit contains 1 4 mgnBL of EC 15.
10. 44. The dosae. unit of claim 43 whbch is an ampoule, a sealed vial or a prefilled syringe 0 45 The dosage unit of claim 44 which is a sealed vial. 46 A method of deterni.nirg whether a patient wi th a tumor has functionay av f e receptors present on the tumor Of the patient, the method comprising the step of administering an effective amount of EC20 to the patient for detection of the functionally active folate receptors, 25 47 The method of aim. 46 wherein the tumor is an ovarian tumor or a lung tumor. 48, The method of caims 46 wherein the tumor is a primary tumor or a netasafic tumanor 49 The method of any one of claims 1-3 24-25. or 46-48 wherein the 30 funedionally active folate receptors are detected visually. 50S The method of daim 49 wherein the visual detection of functionally active folate receptors is used to detemune folate receptor status of the patient. 08 5i [he method of claim 50 wherein the folate receptor status of the patient is selected from the group consisttog of EC20++, EC20+ and EC20, 52 The method of caim 5i wherein the folate receptor status is ETC20+. 5 1 The method of claim 52 wherein treatment with EC 45 is indicated, 5 54 The method of claim 52 wherin EC20++ status correlates with a clinical benefit to the patient. 55 The method of claim. 54 wherein the clinical benefit is disease control rate,
11. 56. The method of claim 54 wherein the cRnica benefit is overall disease 0 response rate, 5 'the method of claim 54 wherein the clinical benefit is overall survival. 58, A method of treatment of a folate receptor expressing epithelial turner in a patient in need thereof comprising admsterng a therapeutic amount of EC145 in combination wit a theapeutc arnount of doxerubicin. 5 59 The use of EXC145 in combination with pegylated tiposomal doxorubcin for the treatment of a folate. receptor expressing epithelial tumor in a patient. 60 The use of EC 145 for the manufacture of a medicament for the treatment in combination with pegylated ipsownal doxorubicin of a folate rceoptor expressing epithelial tumor i a patient 0 61. A method of achieving a clinical benefit in the treatment of a folate receptor expressing epihelial tumor in a patient in need thereof comnprisin g admaisteng a therapeutic amount of EC145 in combination with a therapeutic amount of pegylated iposomal doxorubicin. 62, The method of claim 61 in which the clinical benefit is progressions 25 free survival. 63 The method of claim 61 in which the clinical benefiis overall stirvval.
12. 64. The method or use of any of claims 58 to 63 wherein the doxorubicin is in the form of a pegylated liposomal doxoruMii. 30 65, The method or use of any of claims 58 to 63 wherein the tolate receptor expressing epithelial tumor is an ovarian, endometrial or non-small cell hmg cancer (NSCLCy tumor; 66 The rnethod or use of claim 65 wherein the folate receptor expressing epithelial tumor is an ovarian tumor. 67, The method or use of claim 64 where the foate receptor expressing epiheial tumor is an ovarian. endometrial or non-small cd kung cancer (NSCIC) tumor. 5 68, The method or use of claim 67 wherein the elate receptor expressing epithelial tumor is an ovarian tumor,