WO2013083809A1

WO2013083809A1 - Prevention of adverse effects caused by epcamxcd3 bispecific antibodies

Info

Publication number: WO2013083809A1
Application number: PCT/EP2012/074855
Authority: WO
Inventors: Sabine STIENEN
Original assignee: Amgen Research (Munich) Gmbh
Priority date: 2011-12-09
Filing date: 2012-12-07
Publication date: 2013-06-13
Also published as: AR089114A1; AU2012350429A1; UY34504A; TW201322985A

Abstract

The present invention relates to a glucocorticoid (GC) for use in the amelioration, treatment and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by an EpCAMxCD3 bispecific antibody, wherein the administration of the GC is started prior to the administration of the EpCAMxCD3 bispecific antibody. Kits comprising a GC, an EpCAMxCD3 bispecific antibody and instructions for use indicating that the GC is to be employed for the treatment, amelioration and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by said EpCAMxCD3 bispecific antibody in a patient, are also disclosed.

Description

Prevention of adverse effects caused by EpCAMxCD3 bispecific antibodies

Antibody-based cancer therapies require a target antigen firmly bound to the surface of cancer cells in order to be active. By binding to the surface target, the antibody can directly deliver a deadly signal to the cancer cell or indirectly by, for example, recruiting a cytotoxic T cell, if it is a bispecific antibody. In an ideal treatment scenario, a target antigen is abundantly present and accessible on every cancer cell and is absent, shielded or much less abundant on normal cells. This situation provides the basis for a therapeutic window in which a defined amount of the antibody-based therapeutic effectively hits cancer cells but spares normal cells.

The epithelial cell adhesion molecule (EpCAM) is found on most human adenocarcinoma, including cancers of colorectal, breast, lung, gastric, bladder, prostate, ovarian, and pancreatic origin. For instance, in colorectal cancer, more than 98% of patients show an intense and frequent expression of EpCAM on cancer cells in the primary tumor (P. Went et al., Br. J. Cancer 94: 128 (2006)). EpCAM is not lost from cancer cells when they de-differentiate and progress to the metastatic stage. In some cancers, such as breast, ovarian and certain squamous cell carcinomas, EpCAM expression is either de novo or highly upregulated compared to normal epithelial tissues. When EpCAM expression is knocked down in cancer cells by anti-sense or siRNA, cells cease to proliferate, move and invasively grow in soft agar. Conversely, ectopic expression of EpCAM in quiescent cells confers these properties, and leads to their serum growth factor-independent growth (M. Munz et a/., Oncogene 23: 5748 (2004)). EpCAM has been added to the list of cancer stem cell markers (J.E. Visvader and G.J. Lindeman, Nat. Rev. Cancer 8: 755 (2008)). Cancer stem cells are thought to constantly repopulate tumors and to be responsible for chemoresistance and tumor relapse. EpCAM expression has been found on cancer stem cells derived from breast, colon, prostate, liver and pancreas tumors. EpCAM is currently being targeted by several antibody-based therapeutic approaches.

Though binding domains like antibodies are an effective means in treating many disorders, in particular cancer, their administration is not necessarily devoid of side effects. Adverse effects may cause a reversible or irreversible change in the health status of a patient. As adverse effects could be harmful and undesired, it is highly desirable to avoid them. However, though it is known that a medicament can cause adverse effects, its prescription and administration could not be avoided or is accepted, since the medicament has an outstanding beneficial therapeutic effect or may even be life-saving. In clinical trials, a general distinction can be made between adverse effects (AEs) and serious adverse effects (SAEs). Specifically, adverse effects can be classified in 5 grades in accordance with the Common Terminology Criteria for Adverse Events (CTCAE). Grade 1 relates to mild AE, grade 2 to moderate AE, grade 3 to severe AE, grade 4 to life-threatening or disabling AE, while grade 5 means death related to AE.

An adverse effect commonly observed in antibody therapy is the occurrence of infusion- related side effects, such as the cytokine release syndrome ("CRS"). Other adverse side effects described to be associated with CRS are e.g. fatigue, tachycardia, hypertension, and back pain.

Adverse events have not only been observed with antibodies binding to the T cell receptor but also with an EpCAMxCD3 bispecific antibody called MT1 10 (=AMG 110 = solitomab). MT1 10 is a bispecific single chain antibody construct (BiTE®) binding to EpCAM on most solid cancers of epithelial origin and to CD3 on T cells. MT1 10 has shown high anti-tumor activity in various preclinical models including a human colorectal cancer (CRC) xenograft.

MT1 10 is presently under investigation in a dose-escalating phase 1 trial in patients with advanced adenocarcinoma of the lung, small cell lung cancer, gastric cancer including adenocarcinoma of gastro-esophageal junction, colorectal cancer, metastatic breast cancer, hormone-refractory prostate cancer, ovarian and endometrial carcinomas. In order to evaluate safety and tolerability of the anti-EpCAM x anti-CD3 bispecific single chain antibody, the compound has been administered by long-term continuous infusion. Only very sporadically patients developed fever, chills or other infusion reactions after start of the infusion. Almost no substantial systemic cytokine levels could be found. However, a transient elevation of liver enzymes has been observed upon start of infusion of the EpCAMxCD3 bispecific single chain antibody, as well as certain gastrointestinal reactions such as diarrhea, gastroenteritis, abdominal pain and nausea/vomiting.

It is however difficult to design an EpCAMxCD3 bispecific antibody-based therapy, which does not cause hepatic and/or gastroenterological reactions or, to put it differently, it is desired to provide EpCAMxCD3 bispecific antibody-based medical therapies with increased patient tolerability, i.e., reduced or even no undesired adverse effects such as hepatic and/or gastroenterological reactions.

Though pharmaceutical means and methods which allow "adapting" a patient to an EpCAMxCD3 bispecific antibody prior to the actual therapy with an EpCAMxCD3 bispecific antibody were shown to be beneficial for avoiding undesired side effects - particularly unwanted increase in liver parameters - (see WO 201 1/033105), certain adverse events could unfortunately not be prevented by these measures.

Thus, the technical problem underlying the present invention was to provide means and methods to overcome the above problems.

The present invention addresses this need and thus provides embodiments concerning means and methods for use in the amelioration, treatment and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by (the administration of) an EpCAMxCD3 bispecific antibody in a patient. These embodiments are characterized and described herein and reflected in the claims.

It must be noted that as used herein, the singular forms "a", "an", and "the", include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a reagent" includes one or more of such different reagents and reference to "the method" includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein. The term "and/or" wherever used herein includes the meaning of "and", "or" and "all or any other combination of the elements connected by said term."

Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

The term "about" or "approximately" as used herein means within ±20%, preferably within ±15%, more preferably within ±10%, and most preferably within ±5% of a given value or range.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term "comprising" can be substituted with the term "containing" or "including" or sometimes when used herein with the term "having". When used herein "consisting of" excludes any element, step, or ingredient not specified in the claim element. When used herein, "consisting essentially of does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein, any of the terms "comprising", "consisting essentially of" and "consisting of may be replaced with either of the other two terms.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.

***

In view of the adverse events described in the sections above, particularly the adverse hepatic effects and/or the adverse gastroenterological effects observed with the administration of EpCAMxCD3 bispecific antibodies, the finding that these adverse effects can be mitigated or even avoided if the administration of the EpCAMxCD3 bispecific antibody is preceded by the administration of a glucocorticoid, is definitely remarkable.

Specifically, the present inventors observed that those patients, to whom an EpCAMxCD3 bispecific antibody was administered, encountered hepatic and/or gastroenterological side effects, and, further, that these side effects could be alleviated or even prevented by means of a therapy in which the administration of a glucocorticoid is started prior to the administration of the EpCAMxCD3 bispecific antibody. Accordingly, the present invention establishes for the first time that glucocorticoids such as dexamethasone mitigate or even avoid hepatic and/or gastroenterological adverse effects which might occur in the course of a treatment with EpCAMxCD3 bispecific antibodies, specifically when the glucocorticoid treatment is started prior to the antibody treatment (see also the Example section).

Glucocorticoids (GCs) are still the most widely used immunosuppressive agents for the treatment of inflammatory disorders and autoimmune diseases. Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell, including humans. These compounds are potent anti-inflammatory agents, regardless of the inflammation's cause. Glucocorticoids suppress, inter alia, the cell-mediated immunity by inhibiting genes that code for the cytokines IL-1 , IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-γ. Cortisone which belongs to the group of GCs is an important therapeutic drug which is used to fight many ailments ranging from Addison's disease to rheumatoid arthritis. Ever since the discovery of its anti-rheumatic properties, which led to its acclaim as a wonder drug, many derivatives of cortisone with enhanced properties to better fight a specific ailment have been produced. Cortisone belongs to a group of steroids known as corticosteroids. These steroids are produced by the adrenal cortex, which is the outer part of the adrenal glands, near the kidneys. The corticosteroids are divided into two main groups: the glucocorticoids, which control fat, protein, calcium and carbohydrate metabolism, and the mineralocorticoids controlling sodium and potassium levels. Cortisone belongs to the former group, i.e. to the GCs. Cortisone and its many derivatives are used for a variety of diseases. Cortisone also helped to make organ transplants a reality due to its ability to minimize the defense reaction of the body towards foreign proteins present in the implanted organ and thus damage the functionality of the implanted organ. However, despite clinical use during more than 50 years, the specific anti-inflammatory effects of GC on different cellular compartments of the immune system are not yet clear. GCs affect nearly every cell of the immune system, and there is growing evidence for cell type-specific mechanisms.

In a first embodiment, the present invention relates to a glucocorticoid (GC) for use in the amelioration, treatment and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by (the administration of) an EpCAMxCD3 bispecific antibody in a patient, wherein the administration of the GC is started prior to the administration of the EpCAMxCD3 bispecific antibody.

As outlined above, several unwanted adverse effects frequently accompany a therapy with an EpCAMxCD3 bispecific antibody. The present invention remedies these disadvantages and provides glucocorticoid(s) for use in the amelioration, treatment and/or prophylaxis of hepatic and/or gastroenterological adverse effects in a patient, wherein said patient is subject to therapy with an EpCAMxCD3 bispecific antibody, and wherein the administration of the GC is started prior to the administration of the EpCAMxCD3 bispecific antibody.

Also, the present invention relates to a method of amelioration, treatment and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by an EpCAMxCD3 bispecific antibody, said method comprising administering to a patient in need thereof a glucocorticoid (GC), wherein the administration of the GC is started prior to the administration of the EpCAMxCD3 bispecific antibody. It will be understood that in the context of the present invention, the term "method" includes a "dosage regimen" to be used in a method of the present invention.

Furthermore, the present invention relates to the use of a glucocorticoid (GC) in the manufacture of a medicament for the amelioration, treatment and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by an EpCAMxCD3 bispecific antibody in a patient, wherein the administration of the GC is started prior to the administration of the EpCAMxCD3 bispecific antibody.

In the context of the present invention "administration of an EpCAMxCD3 bispecific antibody" or "administering an EpCAMxCD3 bispecific antibody" or any other grammatical form thereof means that the EpCAMxCD3 antibody is in the form of a pharmaceutical composition, optionally comprising a pharmaceutically acceptable carrier. Accordingly, it is to be understood that a pharmaceutical composition comprising an EpCAMxCD3 bispecific antibody is administered to a patient, preferably a human patient.

Likewise, in the context of the present invention "administration of GC" or "administering a GC" or any other grammatical form thereof means that the GC is in the form of a pharmaceutical composition, optionally comprising a pharmaceutically acceptable carrier. Accordingly, it is to be understood that a pharmaceutical composition comprising GC is administered to a patient, preferably a human patient.

The term "administering an EpCAMxCD3 bispecific antibody" in all of its grammatical forms means administration of an EpCAMxCD3 bispecific antibody (in the form of a pharmaceutical composition) either as the sole therapeutic agent or in combination with another therapeutic agent, i.e. in co-administration with other medicaments or drugs, for example, other medicaments for treating EpCAM positive epithelial cancer cells in a patient.

The term "glucocorticoid" means compounds that bind, preferably specifically, to the glucocorticoid receptor. Said term includes compound(s) selected from the group consisting of cortisone, Cortisol (hydrocortisone), cloprednol, prednisone, prednisolone, methylprednisolone, deflazacort, fluocortolone, triamcinolone, (including triamcinolonacetonide) , dexamethasone, budesonide, betamethasone, cortivazol, paramethasone, flusticasonepropionate, triamcinolonacetonide, fluticasone (including flusticasonepropionate), beclometasone, and/or fludrocortisone including pharmaceutically acceptable derivatives thereof. The term "pharmaceutically acceptable derivatives" includes salts (such as acetates), esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatisation. The present invention is however not limited to the above mentioned specific GCs. It is envisaged that all substances which already are or will be classified as a "glucocorticoid", may be employed in the context of the present invention as well. Such future glucocorticoids include compounds which specifically bind to and activate the glucocorticoid receptor. The term "specifically binds to the GC receptor" means in accordance with the present invention that the GC (or a compound which is assumed to act like a GC) associates with (e.g., interacts with) the GC receptor (also known as NR3C1 , nuclear receptor subfamily 3, group C, member 1 ) to a statistically significant degree as compared to association with proteins/receptors generally (i.e., non-specific binding). When the GC receptor binds to glucocorticoids, its primary mechanism of action is the regulation of gene transcription. In the absence of GC, the glucocorticoid receptor (GR) resides in the cytosol complexed with a variety of proteins including heat shock protein 90 (hsp90), heat shock protein 70 (hsp70) and the protein FKBP52 (FK506-binding protein 52). The binding of the GC to the glucocorticoid receptor results in release of the heat shock proteins. It is thus envisaged that a future GC, or a pharmaceutically acceptable derivative or salt of a GC is preferably able to bind to the GC receptor and to release the above mentioned heat shock proteins. The activated GR complex up-regulates the expression of anti-inflammatory proteins in the nucleus or represses the expression of pro-inflammatory proteins in the cytosol (by preventing the translocation of other transcription factors from the cytosol into the nucleus).

In a preferred embodiment, said GC is selected from the most clinical used and relevant GCs like dexamethasone, prednisone, prednisolone, methylprednisolone, budesonide, and combinations thereof. In the context of the embodiments of the present invention, all of the above mentioned compounds may be used alone or in combination.

In a preferred embodiment, said GC is dexamethasone. Dexamethasone has the highest glucocorticoid potency of the most commonly used steroids and also has the longest half-life (see Table 1 below). Furthermore dexamethasone has a better bioavailability than other steroids. But a person skilled in the field can select one of the other known glucocorticoids, some of which are disclosed herein, and select an appropriate effective dose to ameliorate or prevent hepatic and/or gastroenterological adverse events that may result from the treatment of a patient in need thereof with an EpCAMxCD3 bispecific antibody, such as patients with advanced adenocarcinoma of the lung, small cell lung cancer, gastric cancer including adenocarcinoma of gastroesophageal junction, colorectal cancer, metastatic breast cancer, hormone-refractory prostate cancer, ovarian and endometrial carcinomas.

Table 1 : Comparison of the biological activity and half-life of different glucocorticoids

Agent Approx, Relative Relatim Biologic eq fv. dose antiinflammatory mimratacorticofd half-life (mg) (glucocorticoid) (Na* retaining) (Iws)

potency potency

Cortisone 5.1 5,1 g¾

Hydrocortisone 20 1 1 8-12

Prednisone 5 4 0J 18-36

Prednisolone 5 4 0.8 18-38

Methylprednl&olone 5 5 0J 18-38

Dexamethasone 0.75 25 0 3S-54

In another preferred embodiment, the GC - preferably the dexamethasone - is administered in combination with another GC.

The term "in combination with" as used herein refers to the combined use according to the invention of two or more substances, e.g. the combined use of dexamethasone and one or more additional GCs. The combined use can be simultaneous/concurrent, overlapping, or sequential, these three terms being generally interpreted in the light of the prescription made by the physician.

The term "simultaneous" refers to circumstances under which the GCs are active at the same time, for example when they are administered at the same time as one or more separate pharmaceutical products, or if they are administered in one and the same pharmaceutical composition.

The term "sequential" refers to such instances where one of the GCs is acting first, and the second GC acts subsequently. A sequential action can be obtained by administering the GCs in question as separate pharmaceutical compositions with desired intervals, or as one pharmaceutical composition in which the GCs in question are differently formulated (compartmentalized), for example with a view to obtaining a different release time, providing an improved product stability, or to optimizing the GC dosage. The term "overlapping" refers to such instances where the GC activity periods are neither completely simultaneous nor completely sequential, i.e. there is a certain period in which the GCs are both active. Accordingly, in a preferred embodiment of the present invention, the GC - preferably the dexamethasone - is administered in combination with a locally acting GC, more preferably with budesonide.

Usually, if budesonide is administered in combination with dexamethasone, the administration of budesonide can be started either concomitantly with the beginning of the dexamethasone administration (i.e. both administrations coincide in their beginning), or at a later time point, e.g. 1 , 2, 3, 4, 5, 6, or 7 days after the beginning of the dexamethasone administration, or even later. It is hence envisaged that dexamethasone and budesonide are preferably administered either in a simultaneous or in an overlapping manner.

In another preferred embodiment of the present invention, two or more GCs are administered in a sequential manner. In other words, the administration of the first/initial GC (preferably dexamethasone) is replaced/substituted by the administration of another (second/following) GC, preferably of a systemically acting GC, more preferably of prednisone, prednisolone or methylprednisolone. This replacement can occur at any time after the administration of the first dose of the initial GC (preferably dexamethasone). Preferably, the substitution of the initial GC (e.g. dexamethasone) by the following GC (e.g. prednisone, prednisolone or methylprednisolone) occurs at the earliest on the first day of the EpCAMxCD3 bispecific antibody administration, more preferably at the earliest on the second day of the antibody administration, and most preferably at the earliest on the third day of the antibody administration. However, any later time point is also encompassed within the scope of the present invention. Hence, in another preferred embodiment of the present invention, the GC - preferably the dexamethasone - is administered in combination with prednisone, prednisolone and/or methylprednisolone. The hepatic and/or gastroenterological side effects are "caused by" the administration of an EpCAMxCD3 bispecific antibody to a patient. The term "caused by" means that the EpCAMxCD3 bispecific antibody is causative for the hepatic and/or gastroenterological side effects. The skilled person can easily evaluate whether the administration an EpCAMxCD3 bispecific antibody is causative for a hepatic and/or gastroenterological effect or not. To this end, it is just required to closely monitor the patient during the course of the administration and to detect, thereby, that the administration of the EpCAMxCD3 bispecific antibody was causative for the hepatic and/or gastroenterological side effects. Likewise, it is envisaged to discontinue the administration of the EpCAMxCD3 bispecific antibody and to evaluate whether the hepatic and/or gastroenterological side effects are thereby ameliorated or even fade away, which also indicates that the hepatic and/or gastroenterological side effects were caused by said EpCAMxCD3 bispecific antibody (see also Example 1 ). According to the present invention, the administration of the GC is started prior to the administration of the EpCAMxCD3 bispecific antibody. "Prior to" means that the beginning of the GC therapy precedes the beginning of the antibody therapy. Preferably, the GC administration begins in the range of between 1 hour and 4 days or between 3 hours and 48 hours before the beginning of the EpCAMxCD3 bispecific antibody administration, more preferably between 3 hours and 36 hours or between 3 hours and 24 hours, especially preferably between 4 hours and 18 hours or between 5 hours and 15 hours, and most preferably between 6 hours and 12 hours, for example about 8 hours, prior to the beginning of the antibody administration. Hence, in a very preferred embodiment of the present invention, the administration of the GC is started between 3 and 24 hours, preferably between 6 and 12 hours prior to the administration of the EpCAMxCD3 bispecific antibody.

According to the present invention, the administration of the GC is started prior to the administration of the first dose or dose step and/or prior to the administration of any subsequent dose or dose step of the EpCAMxCD3 bispecific antibody.

In general, one treatment cycle of a pharmaceutical agent or substance (e.g. a glucocorticoid or an EpCAMxCD3 bispecific antibody) can consist of one, two, three or even more "dose steps". Each dose step is characterized by at least two parameters: the amount of the agent to be administered (the dose), and the time period of the administration. This period of time can vary between the different dose steps, and it can last e.g. one day or longer, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 days, 2 weeks, 3 weeks, 4 weeks, or even longer, if needed.

As used herein, the term "dose" refers to the amount of a pharmaceutical agent or substance (e.g. a glucocorticoid or an EpCAMxCD3 bispecific antibody) which is administered to a patient. Preferably, the term "dose" refers to a "daily dose", i.e. to the total amount of a specific substance which is administered to a patient in one day [24 hours].

In the context of the present invention, the administration of GC starts "prior to" the administration of the EpCAMxCD3 bispecific antibody, wherein this time point of the beginning of the antibody administration refers to each individual dose or dose step of the antibody administration. For example, one treatment cycle of the EpCAMxCD3 bispecific antibody can consist of two dose steps: A first (daily) dose of the EpCAMxCD3 bispecific antibody is administered for a first period of time (= first dose step), and consecutively a second (daily) dose of the EpCAMxCD3 bispecific antibody is administered for a second period of time (= second dose step). According to the present invention, the administration of the GC is started either prior to the administration of the first dose (or first dose step) of the EpCAMxCD3 bispecific antibody, or it is started prior to the administration of the second dose (or second dose step) of the EpCAMxCD3 bispecific antibody, or both. The same applies if the antibody treatment cycle consists of three or even more dose steps.

If a patient has never been treated with an EpCAMxCD3 bispecific antibody, or if a previously administered EpCAMxCD3 bispecific antibody was already cleared so that no serum levels of the antibody can be detected in the patient, then the administration of the GC beginning prior to the administration of the EpCAMxCD3 bispecific antibody serves the purpose of preventing the occurrence of hepatic and/or gastroenterological adverse events, or alleviating the expression grade of these prospective adverse events. Alternatively, a patient can be in the course of an EpCAMxCD3 bispecific antibody treatment cycle, i.e. the patient is being submitted to a specific antibody dose or dose step, resulting in a detectable or non-detectable EpCAMxCD3 bispecific antibody serum level. This specific dose or dose step can be low enough to not evoke any hepatic and/or gastroenterological side effects, or to cause only low grade or medium grade adverse events. If the dosage regimen now schedules a dose escalation, i.e. if a higher dose of the EpCAMxCD3 bispecific antibody is to be administered, it can be assumed that hepatic and/or gastroenterological side effects occur for the first time, or existing side effects worsen. Hence, the administration of the GC should be started before the higher dose of the EpCAMxCD3 bispecific antibody is administered, thereby preventing the occurrence of side effects, or alleviating and/or treating existing side effects.

In a preferred embodiment of the present invention, a first dose of the EpCAMxCD3 bispecific antibody is administered for a first period of time and optionally consecutively a second dose of the EpCAMxCD3 bispecific antibody is administered for a second period of time, wherein the second dose exceeds the first dose.

In this context, the term "dose" preferably refers to a "daily dose." The term "exceeds" hence means that the amount of EpCAMxCD3 bispecific antibody that is administered to a patient by day during the second dose step is higher than the amount of EpCAMxCD3 bispecific antibody that is administered by day during the first dose step. Preferably, the second dose exceeds the first dose by a factor of about 1.5 or 2, more preferably by a factor of about 2.5 or 3, and most preferably by a factor of about 3.5 or 4. Other factors e.g. in the range between 5 and 10 (such as a factor of 8) or even higher (such as a factor of 12 or 15) are also encompassed within the scope of the present invention.

The exact dose of the EpCAMxCD3 bispecific antibody will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for age, body weight, general health, sex, diet, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art.

In one aspect of the methods/dosage regimens of the present invention, said first dose of the EpCAMxCD3 bispecific antibody is from 1 to 6 μg/d, i.e. 1 , 2, 3, 4, 5 or 6 μg/d, 1 to 3 μg/d, i.e. 1 , 2, or 3μg/d being preferred, and 3 μg/d being most preferred. In another aspect, said first dose is from 3 to 24 μg/d or from 6 to 24 μg/d, preferably from 6 to 18 μg/d, i.e. 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17 or 18 μg/d, 9 to 15 μg/d being more preferred, and 12 μg/d being most preferred.

"d" denotes one day. A dose of, for example, 1 μg/d means that ' g of the EpCAMxCD3 bispecific antibody is preferably administered evenly or continuously across one day. "Continuously across one day" refers to an infusion which is allowed to proceed permanently without interruption.

In one aspect of the methods/dosage regimens of the present invention, said second dose of the EpCAMxCD3 bispecific antibody is from 5 to 25 μg/d, i.e. 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, or 25 μg/d, 10 to 15 μg/d, i.e. 10, 1 1 , 12, 13, 14 or 15 μg/d being preferred, and 12 μg/d being most preferred. In another aspect, said second dose is from 24 to 120 μg/d or from 24 to 72 μg/d, preferably from 30 to 70 μg/d or from 36 to 60 μg/d, with 40 to 50 μg or 42 to 54 μg/d being more preferred, and 48 μg/d being most preferred. It is also envisaged that said second dose is from 70 to 180 μg/d or from 70 to 150 μg7d, preferably from 72 to 144 μg/d or from 80 to 120 μg/d, more preferably from 90 to 110 μg/d or from 95 to 100 μg/d, most preferably around 96 μg/d. As outlined herein above, it is preferred that the second dose of the EpCAMxCD3 bispecific antibody exceeds the first dose.

The term "μς" includes '^g of the EpCAMxCD3 bispecific antibody preparation". It is preferred that not more than 10% of said EpCAMxCD3 bispecific antibody preparation is incorrectly folded. It follows that in a preferred embodiment, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or even 100% of the EpCAMxCD3 bispecific antibody is correctly folded. It is also conceivable that the antibody preparation may optionally comprise further ingredients, for example a lyoprotectant, a surfactant, a filler, a binder, and/or bulking agent etc. The amount of such further ingredients is, preferably, not included in the term '^g" as used in the context of the "dose" and or methods of the present invention.

It must be understood that some ranges given herein are illustrated by increments, such as increments of ten or five. These ranges, however, also encompass smaller increments, for example those exemplified by increments of one (10 to 30 includes for example 10, 1 1 , 12, 13, 13 etc. up to 30), or still smaller increments, for example values after the decimal point. The duration of the first period of time and of the second period of time (and of any subsequent period of time, see hereinafter) may be variable in view of, for example, the age, sex, body weight, etc. of the human patient. The exact administration time of the EpCAMxCD3 bispecific antibody will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques.

It is envisaged that said first period of time of the EpCAMxCD3 bispecific antibody administration is at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 days long, whereby even longer periods of time of e.g. up to three weeks (e.g. 15, 16, 17, 18, 19, 20 or 21 days) or up to four weeks (e.g. 22, 23, 24, 25, 26, 27 or 28 days) or even longer are also included. The first period of time is preferably at least 3 days, ideally between 7 and 14 days, more preferably between 7 and 10 days, most preferably 7 or 8 days. In another embodiment, the first period of time is between 1 and 3 weeks, preferably, between 10 and 18 days, e.g. 10, 11 , 12, 13, 14, 15, 16, 17 or 18 days, more preferably between 12 and 16 days, most preferably around 14 days.

It is envisaged that said second period of time of the EpCAMxCD3 bispecific antibody administration is at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 days long, whereby even longer periods of time of e.g. up to three weeks (e.g. 15, 16, 17, 18, 19, 20 or 21 days) or up to four weeks (e.g. 22, 23, 24, 25, 26, 27, or 28 days) or even longer such as up to five weeks (e.g. 29, 30, 31 , 32, 33, 34 or 35 days) or up to six weeks (e.g. 36, 37, 38, 39, 40, 41 or 42 days) or longer are also included. The second period of time is ideally between 7 and 14 days, more preferably between 7 and 10 days. In another embodiment, the second period of time is ideally between 2 weeks and 5 weeks, more preferably between 3 weeks and 4 weeks, most preferably around 3 weeks.

It will be understood that the term "one week" means seven full days. It will furthermore be understood that "at least two weeks" also includes two weeks plus 1 , 2, 3, 4, 5 or 6 days. The term "longer" (periods of time) is thereby not limited to a (one) complete day as the lowest time unit, i.e. ½ days, or full hours are also conceivable. It is however preferred that the smallest time unit is one full day [24 hours], particularly in the context of the administration of the EpCAMxCD3 bispecific antibody.

As used herein, an interval (such as a time or a dose interval) which is defined as "X to Y" equates with an interval which is defined as "between X and Y". Both intervals specifically include the upper limit and also the lower limit. This means that for example a time interval of "1 to 4 days" or "between 1 and 4 days" includes a period of time of one, two, three and/or four days. Further, this time interval also encompasses intermediate periods such as 2.5 days or 3 days plus 6 hours etc. A dose interval of "1 to 3 mg" or "between 1 and 3 mg" includes doses of 1 , 2 and 3 mg. Further, this dose range also encompasses smaller increments, for example values after the decimal point.

In another preferred embodiment of the present invention, after administering the second dose of the EpCAMxCD3 bispecific antibody, a third dose of the EpCAMxCD3 bispecific antibody is administered for a third period of time, wherein the third dose exceeds the second dose. Accordingly, the present invention provides a three-stage (three-step) administration scheme (dosage regimen) to be applied in the uses and methods described herein. Again, in this context, the term "dose" preferably refers to a "daily dose." The term "exceeds" hence means that the amount of EpCAMxCD3 bispecific antibody that is administered to a patient by day during the third dose step is higher than the amount of EpCAMxCD3 bispecific antibody that is administered by day during the second dose step. Preferably, the third dose exceeds the second dose by a factor of about 1.5 or 2, more preferably by a factor of about 2.5 or 3, and most preferably by a factor of about 3.5 or 4. Other factors e.g. in the range between 5 and 10 (such as a factor of 8) or even higher (such as a factor of 12 or 15) are also encompassed within the scope of the present invention. In one further aspect of the methods/dosage regimen of the present invention, said third dose is 10 to 120 pg/d, i.e. 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10 or 120 pg/d, or even higher, such as up to 130 or up to 140 or up to 150 or up to 200 μg/d. Between 40 and 60 μg/d (i.e. 40, 50 or 60 [ug/d) are preferred, and most preferred are 48 μg/d. Alternatively, between 60 and 90 μg/d are preferred, such as 60, 70, 80 or 90 μg/d, with 72 μg/d being most preferred. Alternatively, between 90 and 110 μg/d (i.e. 90, 100 or 1 10 μg/d) are preferred, and most preferred are 96 μg/d. Alternatively, between 70 and 150 μg/d or between 1 10 and 150 μg/d (e.g. 1 10, 120, 130, 140 or 150 μg/d) are preferred, and most preferred are 120 or 144 μg/d. Alternatively, between 150 and 200 μg/d are preferred, e.g. 160, 170, 180, 190 or 200 μg/d. As outlined herein above, it is preferred that the third dose of the EpCAMxCD3 bispecific antibody exceeds the second dose.

It is further envisaged that said third period of time of the EpCAMxCD3 bispecific antibody administration is at least 1 , 2, 3, 4, 5, 6, 7, 8 or even more weeks long, between 1 and 4 weeks being preferred, and most preferred between 3 and 4 weeks. Again, the term "at least x weeks" also includes x weeks plus 1 , 2, 3, 4, 5 or 6 days.

It is also envisaged that a treatment cycle of the EpCAMxCD3 bispecific antibody can encompass more than three dose steps. In this case, and in conformity with the above, it is preferred that after administering the third dose of the EpCAMxCD3 bispecific antibody, a fourth dose of the EpCAMxCD3 bispecific antibody is administered for a fourth period of time, wherein the fourth dose exceeds the third dose. In one further aspect of the methods/dosage regimen of the present invention, said fourth dose is 10 to 120 Mg/d, i.e. 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10 or 120 pg/d, or even higher, such as 130, 140, 150, 160, 170, 180, 190, 200 μg/d or higher. Between 80 and 120 μg/d (i.e. 80, 90, 100, 1 10 and 120 μg/d) are preferred, and most preferred are about 96 μg/d. Alternatively, between 120 and 180 μg/d are preferred, and most preferred are about 120 or about 144 μg/d.

It is further envisaged that said fourth period of time of the EpCAMxCD3 bispecific antibody administration is at least 1 , 2, 3, 4, 5, 6, 7, 8 or even more weeks long, between 1 and 4 weeks being preferred, and most preferred between 3 and 4 weeks. The term "at least x weeks" also includes x weeks plus 1 , 2, 3, 4, 5 or 6 days.

When the administration scheme of the EpCAMxCD3 bispecific antibody has reached the target dose, this target dose is preferably administered for a period of time of about 2 to 5 weeks, preferably 2 to 4 weeks, more preferably 3 to 4 weeks and most preferably about 3 weeks or about 4 weeks. Within a dose escalation scheme, the term "target dose" refers to the final and preferably highest dose of the EpCAMxCD3 bispecific antibody that is to be administered to the patient. This target dose is preferably effective in eliminating tumor cells. The above described administration scheme of two or more dose steps is also called "dose escalation", referring to a treatment cycle which comprises two or more dose steps, each dose exceeding the previous one. "Dose escalation" hence means sequentially administering increasing doses of a pharmaceutical substance or compound or agent, e.g. in order to reach a stepwise adaptation of the patient to the treatment.

In a further preferred embodiment, the present invention encompasses the continuous administration of a flat dose of the EpCAMxCD3 bispecific antibody without escalation to a subsequent higher dose. For example, the present invention includes the administration of about

24μg/d, 48μg/d, 72 μg/d, 96 μg/d, 120 Mg/d, 144 g/d, 150 pg/d, 160 pg/d, 170 pg/d, 180 pg/d, 190 pg/d, 200 μg/d or even more of an EpCAMxCD3 bispecific antibody, until the conclusion of a course of the treatment up to 8 weeks [56 days], and even longer, if determined to be safe and effective. It will be understood that interim or intermediate values are also encompassed by the present invention, such as any dose from 1 to 3μg/d, from 3 to 12μg/d, from 12 to 24μg/d, from 24 to 48μg/d, from 48 to 72 μg/d, from 48 to 96μg/d, from 72 to 96 μg/d, from 96 to 120μg/d, from 120 to 144 μg/d, from 120 to 150 μg/d, from 150 to 200 μg/d or even more of an EpCAMxCD3 bispecific antibody.

Furthermore, it is within the scope of the present invention that one or more of the dose steps of the EpCAMxCD3 bispecific antibody as defined hereinbefore is / are omitted within one treatment cycle. For example, it is possible to start a cycle with a preferred first dose step of e.g. 12 μg/d (denoted as "second dose step") instead of e.g. 3 μg/d (denoted as "first dose step"). Alternatively, it is e.g. possible that the dose step which is denoted as "second dose step" is immediately followed by the dose step denoted as "fourth dose step".

The EpCAMxCD3 bispecific antibody doses as disclosed herein are indicated as "flat doses" (i.e. in '^g/day"), which means that they refer to daily doses and are not related to the body weight or body surface of a patient. However, it is alternatively in line with the present invention that each of the doses disclosed herein can be converted from an amount in "[\g per day" into ' g/m² (body surface) per day" by dividing the respective dose with the divisor 1.9, or vice versa, i.e. converting a dose from an amount (in μg)/m²/d into μg/d by multiplying the respective dose with the factor 1.9. Accordingly, each of the doses disclosed herein can be applied in the methods and uses by dividing it by the divisor 1 .9. For example, a dose of 5 μg/m²/d is converted into 9.5 μg/d, a dose of 15 μg/m² is converted into 28.5 μg/m²/ and a dose of 60 μg/m²/ is converted into 1 14 μg/m², and vice versa. It is preferred that a decimal digit that results from the multiplication or division is either rounded up or rounded down, respectively, to a whole number. For example, a dose of 9.5 μg/d can be rounded down to 9 μg/d and a dose of 28.5 μg/m² can be rounded down to 28 μg/ m². Likewise, a dose of 9.5 μg/d can be rounded up to 10 μg/d and a dose of 28.5 μg/m² can be rounded up to 29 μg/ m². It is also alternatively envisaged that each dose disclosed herein can be converted from an amount in "[\g per day" into '^g/kg (body weight) per day". A person skilled in the art will be able to convert these dose indications. Generally, it is assumed that the average body weight is about 73-74 kg. A daily dose of e.g. 10 μg/day would be converted into about 8.2 μg per day for a patient having a body weight of 60 kg and into about 10.9 μg per day for a patient having a body weight of 80 kg. Usually an upper weight limit of about 90 kg body weight is not exceeded in this calculation. In other words, even if a patient's body weight exceeds 90 kg, the daily antibody dose will be calculated on the base of 90 kg. According to another preferred embodiment of the present invention, the first dose, the second dose, the third dose and/or any subsequent dose of the EpCAMxCD3 bispecific antibody are administered continually.

The administration of an EpCAMxCD3 bispecific antibody (for example in the form of a pharmaceutical composition) is preferably continually or as also used herein "continuously". A continual or continuous administration refers to an administration which is essentially without interruption. "Essentially without interruption" includes a continual administration usually without an interrupted flow or spatial extension. The treatment regimen of an EpCAMxCD3 bispecific antibody can also encompass more than one cycle, e.g. two, three, four or more cycles. It is envisaged that two consecutive cycles of time (i.e. cycles of administration) are interrupted by an intermediate period of time (i.e. a break between the previous cycle and the subsequent / following cycle). Said intermediate period of time is preferably as short as possible (as the EpCAM-positive epithelial cancer might grow in the meantime) but may last for one or more days or even one or two or even more weeks such as 3 weeks or 4 weeks or longer, depending on the circumstances. The aim of this interruption has to be seen as a recreational phase allowing the patient to recover from any adverse effects or other symptoms, provided that this is necessary. In a preferred embodiment said intermediate period of time (which is between the previous and the subsequent cycle) is two weeks or less, more preferably it is one week or less. In an alternative embodiment, said intermediate period of time is preferably at least one week, more preferably at least 2 weeks, such as between 2 and 3 weeks. The methods/dosage regimen of the present invention as described herein, whether supra or infra, can refer to the first cycle of EpCAMxCD3 bispecific antibody administration and/or to any subsequent cycle.

By way of example, WO 201 1/033105 discloses a treatment regimen which is specifically included herein by way of reference thereto.

In a preferred embodiment, the administration of the GC is started prior to the administration of the first dose of the EpCAMxCD3 bispecific antibody and/or prior to the administration of the second dose of the EpCAMxCD3 bispecific antibody and/or prior to the administration of the third dose of the EpCAMxCD3 bispecific antibody and/or prior to the administration of any subsequent dose of the EpCAMxCD3 bispecific antibody. The GC can be administered during the first cycle, the second cycle, the third cycle and/or any subsequent cycle of the administration of the EpCAMxCD3 bispecific antibody.

The GC can be administered for various periods of time, and those skilled in the art will be able to determine, using no more than routine experimentation, an appropriate administration period which will be effective to ameliorate or prevent hepatic and/or gastroenterological adverse events caused by the EpCAMxCD3 bispecific antibody. The GC is administered at least once. As mentioned hereinbefore, the GC administration preferably begins in the range of between 3 hours and 48 hours before the beginning of the EpCAMxCD3 bispecific antibody administration, most preferably between 6 hours and 12 hours (e.g. about 8 hours) prior to the beginning of the antibody administration. According to a preferred embodiment, the GC administration is continued after the beginning of the EpCAMxCD3 bispecific antibody administration.

The administration scheme according to the present invention hence encompasses an overlapping administration of the GC and the EpCAMxCD3 bispecific antibody, and it includes the possibility that the administration of the GC is continued - if required - after the administration of the EpCAMxCD3 bispecific antibody (i.e. the respective dose step) has ended.

Preferably, the total period of GC administration is at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 days, or at least 3, 4, 5, 6, 7 or 8 weeks or even longer. More preferably, once the administration of the EpCAmxCD3 bispecific antibody has started, the GC administration is continued for at least one day, more preferably for at least two days, and even more preferably for at least three days. In a preferred embodiment, the GC is administered in an initial dose and subsequently tapered off in one or more dose steps.

The term "initial dose" or "starting dose" refers to the first dose that is given at the beginning of the treatment, usually with the objective of getting the patient under the influence of the pharmaceutical substance or agent, e.g. the GC. If the treatment cycle of the EpCAMxCD3 bispecific antibody consists of two or more dose steps (preferably escalating dose steps), then the term "initial dose" or "starting dose" of the GC preferably refers to each individual dose or dose step of the antibody administration. In other words, the administration of each dose or dose step of the EpCAMxCD3 bispecific antibody is preceded by the beginning of the GC administration characterized by a specific initial GC dose.

Furthermore, it is envisaged that the term "dose" preferably refers to a "daily dose". This definition also encompasses the following scenario: If the daily dose of a substance (i.e. the dose that is administered within 24 hours) is "x", and the substance is only administered for a fraction of a day, e.g. for half a day (12 hours), then the total amount of the administered substance corresponds to the respective fraction of the daily dose, e.g. "½ x", thereby still complying with "x" as being the daily dose.

The initial GC dose encompasses at least the GC dose that is administered before the administration of the EpCAMxCD3 bispecific antibody is started. Optionally, the initial GC dose can furthermore encompass the GC dose that is administered once the antibody administration has started.

The term "to taper off or "tapering off" means fading out a medication or discontinuing a medication gradually. This gradual/successive diminution of the initial GC dose is carried out in either one or more (e.g. two, three, four, five or more) dose steps. It is also possible to stop the GC administration without tapering off of the initial dose. Furthermore, it is envisaged that the GC administration can be restarted again in the course of the ongoing administration of the EpCAMxCD3 bispecific antibody, if required.

In a preferred embodiment, the initial dose of the GC is administered for a period of at least 2 days, more preferably at least 2.5 days. In an even more preferred embodiment, the initial dose of the GC is administered (i.e. its administration is continued) for a period of at least 2 days as from the beginning of the EpCAMxCD3 bispecific antibody administration. In a preferred embodiment, the initial dose of the GC is tapered off by sequentially administering a halving dose, wherein each dose step is administered for a period of at least one day.

It is hence envisaged that each GC dose step is characterized by a GC dose which corresponds to half the previous GC dose. If the initial GC dose is for example 24 mg/day (administered e.g. in three single doses of 8 mg each), the following GC dose would be 12 mg/day (administered e.g. in three single doses of 4 mg each), and the next GC dose 6 mg/day (administered in e.g. in three single doses of 2 mg each or in two single doses of 3 mg each), and so on. Each one of these doses or dose steps, preferably each dose or dose step that follows the initial dose or dose step, is administered for a period of at least one day. Longer periods such as at least 2, 3, 4, 5, 6 or 7 days or even more are also encompassed. A "halving dose" can be administered in different ways. For example, an initial GC dose of 24 mg/day can be administered in four single doses of 6 mg each. A corresponding halving dose of 12 mg/day could be administered e.g. in two single doses of 6 mg each or in four single doses of 3 mg each or even in one single dose of 12 mg. The GC is preferably administered in an amount which is sufficient to ameliorate, treat and/or prevent said hepatic and/or gastroenterological adverse effects caused by an EpCAMxCD3 bispecific antibody.

The dose of the GC that is to be used in accordance with the embodiments of the present invention is not limited, i.e. it will depend on the circumstances of the individual patient. GC can be administered intravenously or orally. Said dosage can be administered all at once or subdivided into smaller "single" dosages (see the appended examples). In a preferred embodiment, the initial dose of dexamethasone is in the range of 8 to 56 mg/day, more preferably of 8 to 48 or 8 to 40 mg/day, even more preferably in the range of 12 to 36 mg/day or 12 to 32 mg/day, especially preferably in the range of 12 to 24 mg/day or 16 to 24 mg/day, with 24 mg/day being the most preferred (administered e.g. in three single doses of 8 mg each).

The initial dose of budesonide is preferably in the range of 1 to 20 mg/day, more preferably of 1 to 18 or 1 to 15 mg/day, even more preferably in the range of 3 to 15 mg/day or 3 to 12 mg/day, especially preferably in the range of 6 to 12 mg/day or 6 to 9 mg/day, with 9 mg/day (administered e.g. in 3 single doses of 3 mg each) being the most preferred.

While dexamethasone administration is preferably discontinued by tapering off the initial dose, the budesonide treatment can be discontinued without gradual or successive diminution of the initial dose. The initial dose of prednisolone is preferably in the range of 50 to 600 mg/day, more preferably of 50 to 500 or 100 to 500 mg/day, even more preferably in the range of 150 to 500 mg/day or 150 to 400 mg/day, especially preferably in the range of 200 to 400 mg/day or 200 to 300 mg/day, with 200 mg/day (administered e.g. in 2 single doses of 100 mg each) being the most preferred.

In another preferred embodiment, the daily dose (including the initial dose and any possible subsequent dose steps) of GC, preferably of dexamethasone, is administered in one to six single doses, more preferably in two to four single doses, most preferably in three single doses.

In this context, the term" single dose" refers to the number of administration time points in the course of one day (24 hours). As discussed hereinbefore, a daily GC dose of "x" mg can be administered in different manners: one single dose of x mg, two single doses of ½ x mg, three single doses of ½ x mg, four single doses of ¼ x mg, and so on. Also combinations are envisaged, such as one single dose of ½ x mg plus two single doses of ¼ x mg.

In a very preferred administration scheme, dexamethasone is administered in the range of between 6 and 48 hours before the administration of the first dose of the EpCAMxCD3 bispecific antibody, more preferably between 6 and 12 hours, and even more preferably about 8 hours prior to the first dose antibody administration. It is preferred that this GC administration consists of one single dose of between 4 and 16 mg, preferably of 8 mg dexamethasone. Then approximately 1 hour (range from 15min up to 2 hours including 30min, 45min, 60min, 75min and 90min) before the first dose of the EpCAMxCD3 bispecific antibody is administered, a dose of dexamethasone is again administered to the patient. Alternatively, approximately 1 hour (range from 15min up to 2 hours including 30min, 45min, 60min, 75min and 90min) after the first dose of the EpCAMxCD3 bispecific antibody is administered, a (single) dose of dexamethasone is again administered to the patient. This single dose is preferably between 4 and 16 mg, more preferably of about 8 mg dexamethasone. Then the administration of dexamethasone is continued for one or more days, preferably two to three days, after the first dose of the EpCAMxCD3 bispecific antibody, preferably on the two days after the first antibody administration. This administration scheme is preferably characterized by a daily dexamethasone dose of between 16 and 32 mg/day, more preferably of about 24 mg by day. This dose can be applied e.g. in single steps of 2x8 mg or 3x8 mg or 4x8 mg dexamethasone, 3x8 mg being preferred. The time range between 6 and 48 hours includes the administration of the GC dose, preferably the dexamethasone dose, and means that the times prior to the first administration of the EpCAMxCD3 bispecific antibody are 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47 and 48 hours. Similarly, the preferred time range between 6 and 12 hours includes the administration of the GC dose, preferably the dexamethasone dose, prior to the first administration of the EpCAMxCD3 bispecific antibody and includes 6, 7, 8, 9, 10, 1 1 and 12 hours.

An "adverse effect", which is sometimes also denoted as "side effect" or "adverse event" (in clinical studies), "adverse reaction", "side action" or "secondary effect" is a harmful and undesired effect resulting from medication in the treatment of a patient with an EpCAMxCD3 bispecific antibody.

A "hepatic adverse effect" which is sometimes also denoted as "hepatic symptom" includes conditions of a human patient such as all forms of increased serum level of liver enzymes. The standard panel of liver enzymes comprises albumin (alb), alanine transaminase (ALT, also called alanine aminotransferase = ALAT or serum glutamic pyruvic transaminase = SGPT), aspartate transaminase (AST, also called aspartate aminotransferase = ASAT or serum glutamic oxaloacetic transaminase = SGOT), alkaline phosphatase (also called AP or ALP), total bilirubin (TBIL), direct bilirubin (conjugated bilirubin), gamma glutamyl transpeptidase (GGT), 5' nucleotidase and others.

According to a preferred embodiment, said hepatic adverse event is an increase of the serum level of at least one liver enzyme, preferably an increased serum level of one or more of aspartate transaminase (AST), alanine transaminase (ALT), bilirubin (preferably total bilirubin), and alkaline phosphatase (AP). The increase of the serum level of said at least one liver enzyme is at its maximum up to grade 4 in accordance with the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) which is further described herein below. Accordingly, the increase of the serum level of said at least one liver enzyme may also be up to grade 1 , 2 or 3, while grade 4 is the maximum.

The increase is preferably a transient one. "Transient" when used in the context of an increase of the serum level of said at least one liver enzyme means that the increase is not permanent, but disappears after treatment stop or during continued further infusion. It is also envisaged that the transient increase in the serum level of liver enzymes is not necessarily accompanied by pathological findings in imaging, substantial tissue damage or impaired synthesis parameters of the liver.

Generally spoken, the activity of a liver enzyme is commonly used as a "window" to the liver, since it provides guidance about the condition/state of the liver. For example, if the liver is damaged by, for example, alcohol or other medicaments, or has an abnormal function for any other reason, liver enzymes leak into the blood where they are normally not present. Accordingly, the serum level of a liver enzyme can be measured by way of the activity of the liver enzyme. An activity of a liver enzyme that is above (i.e. increased or elevated) a commonly accepted reference value is usually indicative of a potential abnormal function and/or damage of the liver. An activity of a liver enzyme is thus measurable by liver function tests (LFTs or LFs), i.e., clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. For liver enzymes, reference values (normal values) are known and commonly accepted. A reference value is a set of values used by a health professional to interpret a set of medical test results. The reference value is usually defined as the set of values 95 percent of the normal population falls within, or two standard deviations from the mean. It is determined by collecting data from vast numbers of laboratory tests. In case of liver enzymes the reference value is given as international units (IU). International units are based on measured biological activity or effect.

An increase (preferably transient) of the serum level of a liver enzyme is measured in multiples of the upper limit of normal (ULN). In accordance with the NCI Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (Publish Date: December 12, 2003) the multiples of the ULN are categorized in grades. A grade refers to the severity of the adverse effects. The CTCAE v3.0 displays grades 1 through 5 with unique clinical descriptions of severity for each adverse effects:

Grade 1 : mild adverse effects

Grade 2: Moderate adverse effects

Grade 3: Severe adverse effects

Grade 4: Life-threatening or disabling adverse effects.

Grade 5: Death of the patient

Liver transaminases such as aspartate transaminase (AST) and alanine transaminase (ALT) provide for the state of cellular integrity of the liver, since in case of a liver damage or malfunction these enzymes leak from damaged or malfunctioning liver cells into the blood.

Accordingly, in the context of the methods of the present invention, AST and/or ALT are the preferred liver enzymes (liver markers). In some preferred embodiments said at least one liver enzyme comprises AST and/or ALT and optionally also bilirubin and/or alkaline phosphatase.

Aspartate transaminase (AST) also called Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartate aminotransferase (ASAT) is similar to Alanine transaminase (ALT) in that it is another enzyme associated with liver parenchymal cells. It is raised in acute liver damage, but is also present in red blood cells, and cardiac and skeletal muscle and is therefore not specific to the liver. The ratio of AST to ALT is sometimes useful in differentiating between causes of liver damage. Elevated AST levels are not specific for liver damage. A usual reference value for AST is 10 to 50 IU/I. In accordance with the Common Terminology Criteria for Adverse Events v3.0 the grading for AST is as follows:

Grade 1 : >ULN - 2.5 x ULN

Grade 2: >2.5 - 5.0 x ULN

Grade 3: 5.0 - 20.0 x ULN

Grade 4: >20.0 x ULN

Grade 5: -/-

Alanine transaminase (ALT), also called Serum Glutamic Pyruvate Transaminase (SGPT) or Alanine aminotransferase (ALAT) is an enzyme present in hepatocytes (liver cells). When a cell is damaged, it leaks this enzyme into the blood, where it is measured. ALT rises dramatically in acute liver damage, such as viral hepatitis or paracetamol (acetaminophen) overdose. A usual reference value for ALT is 5 to 50 IU/1. In accordance with the Common Terminology Criteria for Adverse Events v3.0 the grading for ALT is as follows:

Grade 1 : >ULN - 2.5 x ULN

Grade 2: >2.5 - 5.0 x ULN

Grade 3: >5.0 - 20.0 x ULN

Grade 4: >20.0 x ULN

Grade 5: -/-

Other liver enzymes such as alkaline phosphatase (AP) provide for conditions linked to the biliary tract.

Accordingly, it is also envisaged that as a further liver enzyme alkaline phosphatase (AP or ALP) the increase or decrease, respectively, could be measured in the context of the present invention. AP is an enzyme in the cells lining the biliary ducts of the liver. AP levels in plasma will rise with large bile duct obstruction, intrahepatic cholestasis or infiltrative diseases of the liver. AP is also present in bone and placental tissue, so it is higher in growing children (as their bones are being remodeled) and elderly patients with Paget's disease. A usual reference value for AP is 30 to 120 IU/I. In accordance with the Common Terminology Criteria for Adverse Events v3.0 the grading for AP is as follows:

Grade 1 : >ULN - 2.5 x ULN

Grade 2: >2.5 - 5.0 x ULN

Grade 3: >5.0 - 20.0 x ULN

Grade 4: >20.0 x ULN

Grade 5: -/-

Another liver enzyme the increase or decrease, respectively, could be measured in the context of the present invention is bilirubin. Bilirubin (formerly referred to as hematoidin) is the yellow breakdown product of normal heme catabolism. A usual reference value for bilirubin is 1 -1.2 mg/dl as an upper limit. A value indicated in the unit "mg/dl" can be converted into the international unit of "μηιοΙ/Γ' by multiplying the respective value with the factor 17.1 .

In accordance with the Common Terminology Criteria for Adverse Events v3.0 the grading for bilirubin is as follows:

Grade 1 : >ULN - 1 .5 x ULN

Grade 2: >1 .5 - 3.0 x ULN

Grade 3: >3.0 - 10.0 x ULN

Grade 4: >10.0 x ULN

Grade 5: -/-

A "gastroenterological adverse effect" which is sometimes also denoted as "gastroenterological symptom" as used herein includes conditions of a human patient such as all forms of diarrhea, exudative enteropathy, enteritis, colitis, nausea, vomiting, abdominal pain and others.

"Diarrhea" is the condition of having excessively liquid or excessively frequent stools, e.g. three or more loose or liquid bowel movements / stools per day, or more stools than is normal for that person. In accordance with the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0, publish date August 09, 2006), the grading for diarrhea is as follows: Grade 1 : Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline

Grade 2: Increase of 4 - 6 stools per day over baseline; intravenous (IV) fluids indicated <24 hours; moderate increase in ostomy output compared to baseline; not interfering with ADL (activities of daily living)

Grade 3: Increase of >7 stools per day over baseline; incontinence; IV fluids >24 hours; hospitalization; severe increase in ostomy output compared to baseline; interfering with ADL

Grade 4: Life-threatening consequences (e.g., hemodynamic collapse)

Grade 5: Death

"Exudative enteropathy" refers to a series of gastrointestinal disorders which share in common an abnormal permeability of the gastrointestinal tract. More specifically, they can be characterized by the excessive loss of plasma protein, mainly albumin, into the gastrointestinal tract, usually in the absence of actual bleeding. They occur in the stomach as well as the small bowel.

"Enteritis" refers to an inflammation of the intestine, especially the small intestine / small bowel. Symptoms include abdominal pain, cramping, diarrhea, dehydration and fever. In accordance with the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0, publish date August 09, 2006), the grading for enteritis is as follows:

Grade 1 : Asymptomatic, pathologic or radiographic findings only

Grade 2: Abdominal pain; mucus or blood in stool

Grade 3: Abdominal pain, fever, change in bowel habits with ileus; peritoneal signs Grade 4: Life-threatening consequences (e.g., perforation, bleeding, ischemia, necrosis) Grade 5: Death

"Colitis" refers to an Inflammation of the colon and is often used to describe an inflammation of the large intestine (colon, caecum, and rectum). The signs and symptoms of colitides are quite variable and dependent on the etiology or cause of the given colitis and factors that modify its course and severity. Symptoms of colitis may include: abdominal pain, loss of appetite, fatigue, diarrhea, cramping, urgency and bloating. Signs may include: abdominal tenderness, weight loss, changes in bowel habits (increased frequency), fever, bleeding (overt or occult)/bloody stools, diarrhea and distension. Signs seen on colonoscopy include: colonic mucosal erythema (redness of the inner surface of the colon), ulcers, bleeding. Symptoms suggestive of colitis are worked-up by obtaining the medical history, a physical examination and laboratory tests (complete blood count, electrolytes, stool culture and sensitivity, stool ova and parasites et cetera). Additional tests may include medical imaging (e.g. abdominal computed tomography, abdominal X-rays) and an examination with a camera inserted into the rectum (sigmoidoscopy, colonoscopy).

In accordance with the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0, publish date August 09, 2006), the grading for colitis is as follows:

Grade 1 : Asymptomatic, pathologic or radiographic findings only

Grade 2: Abdominal pain; mucus or blood in stool

Grade 3: Abdominal pain, fever, change in bowel habits with ileus; peritoneal signs Grade 4: Life-threatening consequences (e.g., perforation, bleeding, ischemia, necrosis, toxic megacolon)

Grade 5: Death

"Nausea" is an unpleasant sensation of unease and discomfort vaguely referred to the epigastrium and abdomen or more precisely to the stomach, usually accompanied by the urge (but not always leading) to vomit. In accordance with the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0, publish date August 09, 2006), the grading for nausea is as follows:

Grade 1 : Loss of appetite without alteration in eating habits

Grade 2: Oral intake decreased without significant weight loss, dehydration or malnutrition; intravenous (IV) fluids indicated <24 hours

Grade 3: Inadequate oral caloric or fluid intake; IV fluids, tube feedings, or TPN (total parenteral nutrition) indicated >24 hours

Grade 4: Life-threatening consequences

Grade 5: Death

"Vomiting" (known medically as emesis) refers to the forceful expulsion of the contents of one's stomach through the mouth and sometimes through the nose. In accordance with the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0, publish date August 09, 2006), the grading for vomiting is as follows: Grade 1 : one episode in 24 hours

Grade 2: two to five episodes in 24 hours; intravenous (IV) fluids indicated <24 hours Grade 3: > six episodes in 24 hours; IV fluids, or TPN (total parenteral nutrition) indicated for >24 hours

Grade 4: Life-threatening consequences

Grade 5: Death

The abdomen constitutes the part of the body between the thorax (chest) and pelvis.

The region enclosed by the abdomen is termed the "abdominal cavity". The abdominal organs encompass the digestive tract (stomach, small intestine, large intestine with cecum and appendix), accessory organs of the digestive tract (liver, gallbladder and pancreas), the urinary system (kidneys and ureters) and the spleen. "Abdominal pain" is graded as "pain" in the Terminology Criteria for Adverse Events (CTCAE, version 3.0, publish date August 09, 2006), with the following grading:

Grade 1 : mild pain not interfering with function

Grade 2: moderate pain; pain or analgesics interfering with function, but not interfering with ADL

Grade 3: severe pain; pain or analgesics severely interfering with ADL

Grade 4: disabling

Grade 5: -/-

Hence, according to one embodiment, the gastroenterological adverse event is one or more of diarrhea, exudative enteropathy, enteritis, colitis, nausea, abdominal pain and vomiting.

In the context of the present invention, the herein mentioned "patient" is a mammal, preferably a human, who will be or (already) is treated with an EpCAMxCD3 bispecific antibody. In a preferred embodiment, said patient or more preferably said human patient is assumed / suspected to comprise EpCAM positive epithelial cancer cells or comprises EpCAM positive epithelial cancer cells. In the latter case, said patient has already been diagnosed to comprise such cells. These malignant EpCAM positive epithelial cancer cells are present in a patient developing and/or suffering from e.g. adenocarcinoma, including cancers of gastrointestinal, lung, breast, ovarian, urological (bladder, prostate), and pancreatic origin. Said gastrointestinal cancer is for example gastric cancer, colorectal cancer, upper gastrointestinal cancer, gastro-esophageal carcinoma, or metastatic variants thereof, and said lung cancer is for example small-cell lung carcinoma (SCLC), non-small-cell lung carcinoma (NSCLC) (e.g. adenocarcinoma of the lung, large cell lung carcinoma, squamous cell lung carcinoma), or metastatic variants thereof.

In the context of the present invention, an EpCAMxCD3 bispecific antibody comprises a first binding domain capable of binding to CD3, preferably to human CD3, and even more preferably to an epitope of the CD3 epsilon chain, and a second binding domain capable of binding to EpCAM, preferably to human EpCAM. Examples for bispecific molecules according to the methods of the invention are described in great detail in WO2005/040220 (PCT/EP2004/01 1646), which is incorporated herein by reference in its entirety. All the specific EpCAMxCD3 bispecific antibodies disclosed therein, including their variants, fragments, equivalents etc. are particularly preferred EpCAMxCD3 bispecific antibodies of the present invention.

As used herein, an "EpCAMxCD3 bispecific single chain antibody" denotes a single polypeptide chain comprising at least two binding domains. Such single chain antibodies are preferred in the context of the methods/dosage regimen of the present invention. Each binding domain comprises at least one variable region from an antibody heavy chain ("VH or H region"), wherein the VH region of the first binding domain specifically binds to the CD3 molecule, more preferably to the CD3 epsilon molecule, and the VH region of the second binding domain specifically binds to EpCAM. The two binding domains are optionally linked to one another by a short polypeptide spacer. A non- limiting example for a polypeptide spacer is Gly-Gly-Gly-Gly-Ser (G-G-G-G-S) and repeats thereof. Each binding domain may additionally comprise one variable region from an antibody light chain ("VL or L region"), the VH region and VL region within each of the first and second binding domains being linked to one another via a polypeptide linker, for example of the type disclosed and claimed in EP 623679 B1 , but in any case long enough to allow the VH region and VL region of the first binding domain and the VH region and VL region of the second binding domain to pair with one another such that, together, they are able to specifically bind to the respective first and second binding domains. Such EpCAMxCD3 bispecific single chain antibodies are described in great detail in WO2005/040220 (PCT/EP2004/01 1646), which is incorporated herein by reference in its entirety. The term "binding domain" characterizes in connection with the present invention a domain of a polypeptide which specifically binds to/interacts with a given target structure/antigen/epitope. Thus, the binding domain is an "antigen-interaction-site". The term "antigen-interaction-site" defines, in accordance with the present invention, a motif of a polypeptide, which is able to specifically interact with a specific antigen or a specific group of antigens, e.g. the identical antigen in different species. Said binding/interaction is also understood to define a "specific recognition". The term "specifically recognizing" means in accordance with this invention that the antibody molecule is capable of specifically interacting with and/or binding to at least two, preferably at least three, more preferably at least four amino acids of an antigen, e.g. the human CD3 antigen as defined herein. Such binding may be exemplified by the specificity of a "lock-and-key- principle". Thus, specific motifs in the amino acid sequence of the binding domain and the antigen bind to each other as a result of their primary, secondary or tertiary structure as well as the result of secondary modifications of said structure. The specific interaction of the antigen-interaction-site with its specific antigen may result as well in a simple binding of said site to the antigen. Moreover, the specific interaction of the binding domain/antigen-interaction-site with its specific antigen may alternatively result in the initiation of a signal, e.g. due to the induction of a change of the conformation of the antigen, an oligomerization of the antigen, etc. A preferred example of a binding domain in line with the present invention is an antibody. The binding domain may be a monoclonal or polyclonal antibody or derived from a monoclonal or polyclonal antibody.

The definition of the term "antibody" includes embodiments such as monoclonal, chimeric, single chain, de-immunized, humanized and human antibodies. In addition to full-length antibodies, the definition also includes antibody derivatives and antibody fragments, like, inter alia, Fab fragments. Antibody fragments or derivatives further comprise F(ab')₂, Fv, scFv fragments or single domain antibodies such as domain antibodies or nanobodies, single variable domain antibodies or immunoglobulin single variable domain comprising merely one variable domain, which might be VHH, VH or VL, that specifically bind an antigen or epitope independently of other V regions or domains; see, for example, Harlow E. and Lane D. (1988) and (1999), (Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, eds. Harlow et al.); Kontermann and Dubel, Antibody Engineering, Springer, 2nd ed. 2010 and Little, Recombinant Antibodies for Immunotherapy, Cambridge University Press 2009. Said term also includes diabodies or Dual-Affinity Re-Targeting (DART) antibodies. Further envisaged are (bispecific) single chain diabodies, tandem diabodies (Tandab), „minibodies" exemplified by a structure which is as follows: (VH-VL-CH3)₂, (scFv-CH3)₂ or (scFv-CH3-scFv)₂, „Fc DART" and „lgG DART", and multibodies such as triabodies. Immunoglobulin single variable domains encompass not only an isolated antibody single variable domain polypeptide, but also larger polypeptides that comprise one or more monomers of an antibody single variable domain polypeptide sequence.

Various procedures are known in the art and may be used for the production of such antibodies and/or fragments. Thus, (antibody) derivatives can be produced by peptidomimetics. Further, techniques described for the production of single chain antibodies (see, inter alia, US Patent 4,946,778, Kontermann and Dubel (2010), loc. cit. and Little (2009), loc. cit.) can be adapted to produce single chain antibodies specific for elected polypeptide(s). Also, transgenic animals may be used to express humanized antibodies specific for polypeptides and fusion proteins of this invention. For the preparation of monoclonal antibodies, any technique, providing antibodies produced by continuous cell line cultures can be used. Examples for such techniques include the hybridoma technique (Kohler and Milstein Nature 256 (1975), 495-497), the trioma technique, the human B cell hybridoma technique (Kozbor, Immunology Today 4 (1983), 72) and the EBV hybridoma technique to produce human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985), 77-96). Surface plasmon resonance as employed in the BIAcore system can be used to increase the efficiency of phage antibodies which bind to an epitope of a target polypeptide, such as CD3 epsilon (Schier, Human Antibodies Hybridomas 7 (1996), 97-105; Malmborg, J. Immunol. Methods 183 (1995), 7-13). It is also envisaged in the context of this invention that the term "antibody" comprises antibody constructs, which may be expressed in a host as described herein below, e.g. antibody constructs which may be transfected and/or transduced via, inter alia, viruses or plasmid vectors. Furthermore, the term "antibody" as employed herein also relates to functional derivatives, fragments or variants of the antibodies described herein which display the same specificity as the described antibodies. Examples of "antibody variants" include humanized variants of non-human antibodies, "affinity matured" antibodies (see, e.g. Hawkins et al. J. Mol. Biol. 254, 889-896 (1992) and Lowman et a/., Biochemistry 30, 10832- 10837 (1991 )) and antibody mutants with altered effector function(s) (see, e.g., US Patent 5, 648, 260, Kontermann and Dubel (2010), loc. cit. and Little(2009), loc. cit.).

Bispecific antibody formats are preferred; however other multispecific antibody formats (trispecifc, tetrabodies etc.) are not excluded. It is also envisaged that the binding molecule of the invention has, in addition to its function to bind to the target molecules EpCAM and CD3, a further function. In this format, the binding molecule is a tri- or multifunctional binding molecule by targeting plasma cells through binding to EpCAM, mediating cytotoxic T cell activity through CD3 binding and providing a further function such as a fully functional Fc constant domain mediating antibody-dependent cellular cytotoxicity through recruitment of effector cells like NK cells, a label (fluorescent etc.), a therapeutic agent such as, e.g. a toxin or radionuclide, and/or means to enhance serum half-life, etc. As used herein, "CD3" denotes a molecule expressed as part of the T cell receptor and has the meaning as typically ascribed to it in the prior art. In human, it encompasses in individual or independently combined form all known CD3 subunits, for example CD3 epsilon, CD3 delta, CD3 gamma, CD3 zeta, CD3 alpha and CD3 beta. The human CD3 epsilon is indicated in GenBank Accession No.NM_000733.

A bispecific antibody which binds to the human CD3 epsilon is preferred. The CD3 epsilon epitope disclosed in great detail in WO 2008/1 19567 or in WO 2008/1 19566 is even more preferred.

In a preferred embodiment of the present invention, the EpCAMxCD3 bispecific antibody comprises one or more amino acid sequences selected from the group consisting of the following sequences depicted in WO 2008/1 19567:

• A VH region of the CD3 binding part comprising: (a) CDR-H1 as depicted in SEQ ID NO: 12, CDR-H2 as depicted in SEQ ID NO: 13 and CDR-H3 as depicted in SEQ ID NO: 14;

(b) CDR-H1 as depicted in SEQ ID NO: 30, CDR-H2 as depicted in SEQ ID NO: 31 and CDR-H3 as depicted in SEQ ID NO: 32;

(c) CDR-H1 as depicted in SEQ ID NO: 48, CDR-H2 as depicted in SEQ ID NO: 49 and CDR-H3 as depicted in SEQ ID NO: 50;

(d) CDR-H1 as depicted in SEQ ID NO: 66, CDR-H2 as depicted in SEQ ID NO: 67 and CDR-H3 as depicted in SEQ ID NO: 68;

(e) CDR-H1 as depicted in SEQ ID NO: 84, CDR-H2 as depicted in SEQ ID NO: 85 and CDR-H3 as depicted in SEQ ID NO: 86;

(f) CDR-H 1 as depicted in SEQ ID NO: 102, CDR-H2 as depicted in SEQ ID NO: 103 and CDR-H3 as depicted in SEQ ID NO: 104;

(g) CDR-H1 as depicted in SEQ ID NO: 120, CDR-H2 as depicted in SEQ ID NO: 121 and CDR-H3 as depicted in SEQ ID NO: 122;

(h) CDR-H1 as depicted in SEQ ID NO: 138, CDR-H2 as depicted in SEQ ID NO: 139 and CDR-H3 as depicted in SEQ ID NO: 140;

(i) CDR-H 1 as depicted in SEQ ID NO: 156, CDR-H2 as depicted in SEQ ID NO: 157 and CDR-H3 as depicted in SEQ ID NO: 158; and

G) CDR-H 1 as depicted in SEQ ID NO: 174, CDR-H2 as depicted in SEQ ID NO: 175 and CDR-H3 as depicted in SEQ ID NO: 176

• A VL region of the CD3 binding part comprising:

a) CDR-L1 as depicted in SEQ ID NO: 27, CDR-L2 as depicted in SEQ ID NO: 28 and CDR-L3 as depicted in SEQ ID NO: 29;

(b) CDR-L1 as depicted in SEQ ID NO: 1 17, CDR-L2 as depicted in SEQ ID NO: 1 18 and CDR-L3 as depicted in SEQ ID NO: 1 19; and

(c) CDR-L1 as depicted in SEQ ID NO: 153, CDR-L2 as depicted in SEQ ID NO: 154 and CDR-L3 as depicted in SEQ ID NO: 155

• SEQ ID NO: 35, 39, 125, 129, 161 or 165 (VL region of the CD3 binding domain)

• SEQ ID NO: 15, 19, 33, 37, 51 , 55, 69, 73, 87, 91 , 105, 109, 123, 127, 141 , 145, 159, 163, 177 (VH region of the CD3 binding domain)

• A VH and VL region of the CD3 binding part comprising:

(a) a VL region as depicted in SEQ ID NO: 17 or 21 and a VH region as depicted in SEQ ID NO: 15 or 19; (b) a VL region as depicted in SEQ ID NO: 35 or 39 and a VH region as depicted in SEQ ID NO: 33 or 37;

(c) a VL region as depicted in SEQ ID NO: 53 or 57 and a VH region as depicted in SEQ ID NO: 51 or 55;

(d) a VL region as depicted in SEQ ID NO: 71 or 75 and a VH region as depicted in SEQ ID NO: 69 or 73;

(e) a VL region as depicted in SEQ ID NO: 89 or 93 and a VH region as depicted in SEQ ID NO: 87 or 91 ;

(f) a VL region as depicted in SEQ ID NO: 107 or 1 1 1 and a VH region as depicted in SEQ ID NO: 105 or 109;

(g) a VL region as depicted in SEQ ID NO: 125 or 129 and a VH region as depicted in SEQ ID NO: 123 or 127;

(h) a VL region as depicted in SEQ ID NO: 143 or 147 and a VH region as depicted in SEQ ID NO: 141 or 145;

(i) a VL region as depicted in SEQ ID NO: 161 or 165 and a VH region as depicted in SEQ ID NO: 159 or 163; and

(j) a VL region as depicted in SEQ ID NO: 179 or 183 and a VH region as depicted in SEQ ID NO: 177 or 181

• SEQ ID NOs: 23, 25, 41 , 43, 59, 61 , 77, 79, 95, 97, 1 13, 1 15, 131 , 133, 149, 151 , 167, 169, 185 or 187 (VH and VL region of the CD3 binding part)

• as well as any other sequence disclosed in WO 2008/1 19567 which is comprised within a CD3 binding domain or within an EpCAM binding domain of an antibody.

The human EpCAM protein is indicated in GenBank Accession No. NM_002354.

In a preferred embodiment of the methods/dosage regimens of the present invention, the bispecific single chain antibody construct is a VL (EpCAM) - VH (EpCAM) - VH (CD3) - VL (CD3) bispecific single chain antibody construct. It is, however, also envisaged that the methods of the invention can be carried out with EpCAMxCD3 bispecific single chain antibodies of other domain arrangements, such as: VH( EpCAM)-VL( EpCAM)-VH(CD3)-VL(CD3),

VL( EpCAM)-VH( EpCAM)-VL(CD3)-VH(CD3),

VH( EpCAM)-VL( EpCAM)-VL(CD3)-VH(CD3), VL(CD3)-VH(CD3)-VH( EpCAM)-VL( EpCAM),

VH(CD3)-VL(CD3)-VH( EpCAM)-VL( EpCAM),

VL(CD3)-VH(CD3)-VL( EpCAM)-VH( EpCAM), or

VH(CD3)-VL(CD3)-VL( EpCAM)-VH( EpCAM).

The EpCAMxCD3 bispecific single chain antibodies which are disclosed in WO 2004/106383 and WO 2010/037835 are preferred antibodies to be used in the context of the present invention. More specifically, an EpCAMxCD3 bispecific antibody comprising a sequence as depicted in any one of SEQ ID NOs: 2, 4, 8, 10, 12, 14, 16, 18, 20, 30, 36, 39, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60 of WO 2004/106383 is a preferred antibody to be used in the present invention. Furthermore, an EpCAMxCD3 bispecific antibody with an EpCAM binding domain comprising a variable heavy chain amino acid sequence as depicted in any one of SEQ ID NOs: 80, 84, 88, 92 and 96 of WO 2004/106383 and/or comprising a variable light chain amino acid sequence as depicted in any one of SEQ ID NOs: 82, 86, 90, 94 and 98 of WO 2004/106383 is also encompassed by the present invention. Furthermore, an EpCAMxCD3 bispecific antibody with a CD3 binding domain comprising a variable heavy chain amino acid sequence as depicted in SEQ ID NO: 72 or 77 of WO 2004/106383 and/or comprising a variable light chain sequence as depicted in SEQ ID NO: 74 of WO 2004/106383 is also a preferred embodiment of the present invention. Those skilled in the art can easily identify, within the above sequences, the heavy and light chain CDRs. For example, SEQ ID NO: 75 of WO 2004/106383 represents the VH-CDR1 of the anti-CD3 binding domain, and SEQ ID NO: 78 of WO 2004/106383 represents the VH-CDR3 of the anti-CD3 binding domain. Further VH- CDR3 sequences of the EpCAM binding domain are depicted in Figure 1 1A of WO 2004/106383. Further VH-CDR3 sequences are depicted in SEQ ID NOs: 61-69 of WO 2004/106383. An EpCAMxCD3 bispecific antibody comprising one or more of the above CDR sequences is also a preferred embodiment of the present invention.

In another preferred embodiment of the methods/dosage regimen of the present invention, the EpCAMxCD3 bispecific antibody comprises an amino acid sequence as depicted in one or more of SEQ ID NOs: 934-1 127 of WO 2010/037835. In a more preferred embodiment of the methods/dosage regimen of the present invention, the bispecific single chain antibody construct comprises CDR H1-3 as disclosed in SEQ ID NO: 88 (CDRH1 ), SEQ ID NO: 92 (CDRH2), and SEQ ID NO: 96 (CDRH3) disclosed in WO2005/040220 (PCT/EP2004/01 1646), and CDR L1-3 as disclosed in SEQ ID NO: 100 (CDRL1 ), SEQ ID NO: 102 (CDRL2), and SEQ ID NO: 104 (CDRL3) as disclosed in WO2005/040220 (PCT/EP2004/011646), i.e. the CDRs which characterize MT1 10. Said sequence numbers are also depicted in the Table 2 below.

Table 2: SEQ ID NOs for preferred CDRs of the CD3 binding domain

The CDRs referred to herein are in accordance with the Kabat numbering system. The Kabat numbering scheme is a widely adopted standard for numbering the residues in an antibody in a consistent manner (Kabat et al., Sequences of Proteins of Immunological Interest, 1991 ).

In another preferred embodiment of the present invention, the EpCAMxCD3 bispecific antibody comprises one or more amino acid sequences selected from the group consisting of the following sequences depicted in WO 2005/040220:

· SEQ ID NO: 88 (CDR-H1 of the CD3 binding domain)

• SEQ ID NO: 90 or 92 (CDR-H2 of the CD3 binding domain) SEQ ID NO: 96, 108, 1 19-127 (CDR-H3 of the CD3 binding domain)

SEQ ID NO: 98 or 100 (CDR-L1 of the CD3 binding domain)

SEQ ID NO: 102 (CDR-L2 of the CD3 binding domain)

SEQ ID NO: 104 (CDR-L3 of the CD3 binding domain)

SEQ ID NO: 74 or 76 (VH of the CD3 binding domain)

SEQ ID NO: 78, 80, 82 or 1 12 (VL of the CD3 binding domain)

SEQ ID NO: 137, 141 , 145, 149, 133 (VH of the EpCAM binding domain)

SEQ ID NO: 139, 143, 147, 151 , 135 (VL of the EpCAM binding domain)

SEQ ID NO: 31 , 33, 35, 37, 39, 49, 55, 58, 61 , 63, 65, 67, 237, 239, 241 , 243,

245, 247, 249, 251 , 253, 255, 257, 259, 261 , 263, 265, 267, 269, 271 , 273, 275,

277, 279, 281 , 283, 285, 287, 289, 291 , 293, 295, 297, 299, 301 , 303, 305, 307,

309, 31 1 , 313, 315, 317, 319, 321 , 323 and 325 (comprising VH and VL of both the CD3 binding domain and the EpCAM binding domain)

amino acid sequences depicted in Tables 1A, 2A, 3A, 4A, and 5A

as well as any other sequence disclosed in WO 2005/040220 which is comprised within a CD3 binding domain or within an EpCAM binding domain of an antibody.

In an even more preferred embodiment of the method of the invention, the EpCAMxCD3 bispecific single chain antibody construct comprises (or consists of) an amino acid sequence as set forth in SEQ ID NO: 63 as disclosed in WO2005/040220 (PCT/EP2004/01 1646) and depicted below and referred to as SEQ ID NO: 7, or an amino acid sequence at least 90%, preferably 95% identical / homologous to said SEQ ID NO: 63 (which is also disclosed herein below). The EpCAMxCD3 bispecific single chain antibody construct which is characterized by that sequence is MT1 10.

Amino acid sequence of MT1 10: SEQ ID NO: 7 = SEQ ID NO: 63 of WO 2005/040220

VL (EpCAM) - VH (EpCAM) - VH (CD3) - VL (CD3):

Met Gly Trp Ser Cys lie lie Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser Glu Leu Val Met Thr Gin Ser Pro Ser Ser Leu Thr Val

20 25 30

Thr Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gin Ser Leu

35 40 45 Leu Asn Ser Gly Asn Gin Lys Asn Leu Thr Trp Tyr Gin Gin Lys 50 55 60

Pro Gly Gin Pro Pro Lys Leu Leu lie Trp Ala Ser Thr Arg Glu 65 70 75 80

Gly Val Pro Asp Arg Phe Thr Gly Gly Ser Gly Thr Asp Phe

85 95

Thr Leu Thr lie Ser Ser Val Gin Ala Glu Asp Leu Ala Val Tyr Tyr

100 105 110

Cys Gin Asn Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys

115 120 125

Leu Glu lie Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 130 135 140

Gly Gly Ser Glu Val Gin Leu Leu Glu Gin Ser Gly Ala Glu Leu Val 145 150 155 160

Arg Pro Gly Thr Ser Val Lys lie Ser Cys Lys Ala Ser Gly Tyr Ala

165 170 175

Phe Thr Asn Tyr Trp Leu Gly Trp Val Lys Gin Arg Pro Gly His Gly

180 185 190

Leu Glu Trp lie Gly Asp lie Phe Pro Gly Ser Gly Asn lie His

195 200 205

Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser 210 215 220

Ser Thr Ala Tyr Met Gin Leu Ser Ser Leu Thr Phe Glu Asp Ser Ala 225 230 235 240

Val Tyr Phe Cys Ala Arg Leu Arg Asn Trp Asp Glu Pro Met Asp Tyr

245 250 255

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser

260 265 270

Asp Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

275 280 285

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg 290 295 300

Thr Met His Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp lie 305 310 315 320

Gly Tyr lie Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Ala Asp Ser Val

325 330 335

Lys Gly Arg Phe Thr lie Thr Thr Asp Lys Ser Thr Ser Thr Ala Tyr

340 345 350 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys

355 360 365

Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gin Gly

370 375 380

Thr Thr Val Thr Val Ser Ser Gly Glu Gly Thr Ser Thr Gly Ser Gly

385 390 395 400

Gly Ser Gly Gly Ser Gly Gly Ala Asp Asp lie Val Leu Thr Gin Ser

405 410 415

Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys

420 425 430

Arg Ala Ser Gin Ser Val Ser Tyr Met Asn Trp Tyr Gin Gin Lys Pro

435 440 445

Gly Lys Ala Pro Lys Arg Trp lie Tyr Asp Thr Ser Lys Val Ala Ser

450 455 460

Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser

465 470 475 480

Leu Thr lie Asn Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys

485 490 495

Gin Gin Trp Ser Ser Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val

500 505 510

Glu lie Lys

515

Thus, in a most preferred embodiment of the methods/dosage regimen of the present invention said EpCAMxCD3 bispecific single chain antibody is MT110 as characterized by the above indicated amino acid sequence.

The methods/dosage regimen of the present invention include an EpCAMxCD3 bispecific single chain antibody molecule comprising an amino acid sequence as depicted in SEQ ID NO: 63 above (or in WO2005/040220 (PCT/EP2004/01 1646)), as well as an amino acid sequence at least 90 % or preferably 95 % identical / homologous, most preferred at least 96, 97, 98, or 99 % identical / homologous to said amino acid sequence. It is to be understood that the sequence identity / homology is determined over the entire amino acid sequence. For sequence alignments, for example, the programs Gap or BestFit can be used (Needleman and Wunsch J. Mol. Biol. 48 (1970), 443-453; Smith and Waterman, Adv. Appl. Math 2 (1981 ), 482^189), which is contained in the GCG software package (Genetics Computer Group, 575 Science Drive, Madison, Wisconsin, USA 5371 1 (1991 ). It is a routine method for those skilled in the art to determine and identify an amino acid sequence having e.g. 90%, 95%, 96%, 97%, 98% or 99% sequence identity / homology to the amino acid sequences of the EpCAMxCD3 bispecific single chain antibody described herein (preferably MT1 10). For example, according to Crick's Wobble hypothesis, the 5' base on the anti-codon is not as spatially confined as the other two bases, and could thus have non-standard base pairing. Put in other words: the third position in a codon triplet may vary so that two triplets which differ in this third position may encode the same amino acid residue. Said hypothesis is well known to the person skilled in the art (see e.g. http://en.wikipedia.org/wiki/Wobble_Hypothesis; Crick, J Mol Biol 19 (1966): 548-55). It is furthermore a routine procedure for those skilled in the art to determine cytotoxic activity of such an amino acid sequence having e.g. 90%, 95%, 96%, 97%, 98% or 99% sequence identity / homology to the nucleotide or amino acid sequences of the EpCAMxCD3 bispecific single chain antibody described herein. Cytotoxic activity of the EpCAMxCD3 bispecific single chain antibody or an antibody construct having e.g. 90%, 95%, 96%, 97%, 98% or 99% sequence identity / homology to the amino acid sequences of the EpCAMxCD3 bispecific single chain antibody can be detected by methods as illustrated e.g. in WO2005/040220 (PCT/EP2004/01 1646).

The methods/dosage regimen of the present invention further include an EpCAMxCD3 bispecific antibody comprising an amino acid sequence as depicted in any one (or more) of the above amino acid sequences (e.g. representing CDR, VH, VL, VH+VL or scFv sequences) and which is at least 90% or preferably 95% identical / homologous, most preferably at least 96, 97, 98, or 99% identical / homologous to said amino acid sequences.

Preferably, the homology is over the entire amino acid sequence, e.g. the variable heavy chain and/or variable light chain sequence. More preferably, the homology is within the CDRs or the homology is within the framework regions (FRs or non-CDRs) e.g of such a variable heavy and/or light chain. Accordingly, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acids may be substituted within each of the FRs. Such a FR substitution variant is still capable of binding to CD3 or to EpCAM, respectively, as described herein. The skilled person can easily identify the FRs (or non-CDRs). For example, SEQ ID NOs: 1-6 show CDR sequences comprised in one or more of SEQ ID NOs: 63, 74 and/or 80 of WO 2005/040220.

Alternatively, in any one of the CDRs set out in the sequences above (e.g. SEQ ID NOs: 1-6, or any other), one, two, three four, five, six, seven, eight, nine, or ten amino acids may be substituted. Preferably, such a CDR having substitutions is still capable of binding to CD3 or to EpCAM, respectively, as described herein.

The present invention also relates to a (pharmaceutical) kit or package comprising a GC and/or an EpCAMxCD3 bispecific antibody and instructions for use and/or an imprint indicating that the GC is to be employed for the treatment, amelioration and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by said an EpCAMxCD3 bispecific antibody in a patient. Preferably, the instructions for use and/or the imprint indicate that the administration of the GC is started prior to the administration of (the first dose or any subsequent dose of) the EpCAMxCD3 bispecific antibody. Said GC and EpCAMxCD3 bispecific antibody are preferably packaged together in one sealed package or kit. It is also envisaged that the package or kit of the present invention further comprises means to administer the GC and/or the EpCAMxCD3 bispecific antibody to a patient and/or means for reconstituting the GC and/or the EpCAMxCD3 bispecific antibody and/or means for diluting the GC and/or the EpCAMxCD3 bispecific antibody, and/or buffers, vials, teflon bags or infusion bags which are normally used for the infusion of therapeutic agents. "Means" thereby includes one or more article(s) selected from the group consisting of a syringe, a hypodermic needle, a cannula, a catheter, an infusion bag for intravenous administration, intravenous vehicles, vials, buffers, stabilizers, written instructions which aid the skilled person in the preparation of the respective doses and infusions of the invention etc. By "complete response" is intended an absence of clinically detectable disease or adverse effect with normalization of any previously abnormal imaging studies such as e.g. radiography, magnetic resonance imaging (MRI), fiduciary markers, nuclear diagnostic imaging (e.g. scintigraphy, SPECT and PET), photoacoustic imaging, digital infrared imaging thermography, ultrasound and tomography (such as linear tomography, poly tomography, zonography, orthopantomography and computed tomography). Such a response preferably persists for at least 4 to 8 weeks, sometimes 6 to 8 weeks or more than 8, 10, 12, 14, 16, 18 or 20 weeks or longer, following treatment according to the invention. Alternatively, an improvement in the disease or adverse effect may be categorized as being a partial response.

By "partial response" is intended at least about a 50% decrease in all measurable tumor burden (i.e., the number of malignant cells present in the patient, or the measured bulk of tumor masses) in the absence of new lesions and persisting for 4 to 8 weeks or more than 8, 10, 12, 14, 16, 18 or 20 weeks or longer. A "complete response" does, however, not necessarily indicate that a disease has been cured, since a patient may relapse. However, if so, the patient can again be treated with a composition comprising an EpCAMxCD3 bispecific antibody as described herein.

The Figures show:

Figure 1 : Liver parameters (GOT AST, GPT ALT, AP and bilirubin) of a patient treated with schema 2 (see Examples) and MT1 10 in two dose steps.

Figure 2: Liver parameters (GOT AST, GPT ALT, AP and bilirubin) of a patient treated with schema 2 (see Examples) and MT1 10 in three dose steps.

Figure 3: Liver parameters (GOT AST, GPT ALT, AP and bilirubin) of a patient treated with schema 3 (see Examples) and MT1 10 in two dose steps.

Figure 4: Liver parameters (GOT AST, GPT ALT, AP and bilirubin) of a patient treated with schema 3 (see Examples) and MT1 10 in three dose steps. Figure 5: Liver parameters in a patient with ovarian carcinoma treated at an MT1 10 dose of 96 (see Example 2).

EXAMPLES

The following examples illustrate the invention. These examples should not be construed as to limit the scope of this invention. The examples are included for purposes of illustration, and the present invention is limited only by the claims.

Patients with adenocarcinoma of the lung, small cell lung cancer, gastric cancer, colorectal, hormone-refractory prostate cancer have been treated with MT1 10, and the administration of the dexamethasone which was started prior to the administration of MT1 10 worked as amelioration, treatment or prophylaxis of hepatic and/or gastroenterological adverse events.

The administration of therapeutic dexamethasone was beneficial in that hepatic and/or gastroenterological symptoms diminished or disappeared without the necessity to stop MT1 10 treatment.

Example 1 : MT110 treatment

MT110 treatment consists of a continuous intravenous infusion in repeated cycles (2 to 4 weeks treatment break) until disease progression or unacceptable side effects. During first cycle MT1 10 dose is incrementally escalated by weekly dose escalation steps until treatment at target dose for 3-4 weeks immediately in cycle 1 or with start of treatment at target dose in cycle 2. Number of dose escalation steps may increase with increasing target dose. Current dose escalation steps in the run-in phase are 3 and 12 μg/d. Target dose can be 24 or 48 μg/d or higher (e.g., 96 μg/d) or also intermediate dose levels are possible.

Table 3: Incidence of adverse drug reactions in connection with MT1 10 treatment (dosage between 1 and 24 μg/d; N=36)

Number and pei centage

of patien ts

MedDRA System Organ Class and Preferred Term N %

Lymphopenia / Lymphocyte count decreased 31 (86.1 %)

Transaminase increased 28 (77.8%)

Lipase increased 16 (44.4%)

Blood bilirubin increased 12 (33.3%)

Glutamate dehydrogenase increased 10 (27.8%)

Blood alkaline phosphatase increased 9 (25%)

Blood amylase increased 8 (22.2%)

Blood lactate dehydrogenase increased 9 (25.0%)

C-reactive protein increased 6 (16.7%)

Protein total decreased 6 (16.7%)

Blood albumin decreased 5 (13.9%)

White blood cell count increased 4 (11 .1 %)

Fibrin D dimer increased 4 (11 .1 %)

General disorders and administration site conditions 17 (47.2%)

Pyrexia 1 1 (30.6)%

Oedema peripheral 4 (11 .1 %)

Fatigue 3 (8.3%)

Gastrointestinal disorders 12 (33.3%)

Nausea 7 (19.4%)

Vomiting 6 (16.7%)

Diarrhea 6 (16.7%)

Table 4: Treatment emergent Adverse Events (TEAES) of MT1 10 treated patients

(MT1 10 doses of 1 μg/d until 48 μg/d; N = 49)

Preferred Term Events Pat n Pat (%)

Investigations

Gamma-glutamyltransferase increased 54 41 (83.7%)

Alanine aminotransferase increased 57 37 (75.5%)

Aspartate aminotransferase increased 64 33 (67.3%)

Blood bilirubin increased 20 17 (34.7%)

Blood alkaline phosphatase increased 23 16 (32.7%)

Glutamate dehydrogenase increased 26 15 (30.6%)

Hepatic enzyme increased 1 1 (2.0%)

Liver function test abnormal 1 1 (2.0%) Gastrointestinal disorders

Diarrhea 25 13 (26.5%)

Nausea 15 12 (24.5%)

Vomiting 13 10 (20.4%)

Abdominal pain 9 9 (18.4%)

Start of MT110 infusion and each dose escalation step should be administered with concomitant corticosteroid treatment to mitigate side effects of MT1 10 treatment that are associated with start of infusion and dose escalation steps; these are specifically alterations in liver parameters (aminotransferases AST and ALT, AP and bilirubin). With the course of the study the corticosteroid treatment was refined to achieve a better mitigation of liver enzyme alterations.

Example 2: Corticosteroid Treatment and Liver Parameters

Schema 1 : The initial concomitant corticosteroid schema for treatments at lowest MT1 10 dose (1 μg/d) consisted of methylprednisolone (100 mg i.v. or equivalent corticosteroid) to be administered once on day 0, one hour prior to the start of the MT1 10 infusion. Despite the prednisolone treatment, 2 out of 3 patients developed a grade 3 or 4 increase of aminotransferases. Therefore, the corticosteroid schema was adapted with regard to dose and length of concomitant treatment. Schema 2: Additional 3 patients were treated with 1 μg/d MT1 10 and concomitantly 100 mg prednisolone (or equivalent corticosteroid) twice daily (approx. every 12 hours) for the first 3 days of MT1 10 infusion. First dose of corticosteroid was administered approx. one hour prior to the start of the MT1 10 infusion. Treatment for more than 3 days was possible and also increase of prednisolone dose up to 4x 100mg per day (approx. every 6 hours) was allowed. Since none of the 3 patients showed an increase of aminotransferases of grade 2 or higher this schema was also used for a MT1 10 start dose of 3 μg/d.

Meanwhile, 27 patients were treated at a start dose of 3 μg/d, and the following aminotransferase increases were observed, see Table 5. Table 5: Occurrence of increased liver parameters in patients subjected to different MT1 10 dosages and prednisolone treatment

With this concomitant corticosteroid treatment escalation of MT1 10 doses of up to 24 μg/d was possible. Figure 1 shows a patient treated with schema 2 and MT1 10 in two dose steps. Figure 2 shows a patient treated with schema 2 and MT1 10 in three dose steps. Nevertheless, even with highest corticosteroid dose occurrence of grade 3 bilirubin and grade 4 aminotransferases could not completely be avoided. Consequently, corticosteroid treatment was extended to start already approx. 6-12 hours prior to the start of the MT1 10 infusion and to use dexamethasone in the new schema 3. Schema 3: The current concomitant corticosteroid treatment consists of one dexamethasone dose on day -1 , 6-12 hours prior to start of MT1 10 infusion, followed by 3x8 mg dexamethasone (approx. every 8 hours) for days 0 to 2 or longer, if needed, preferably for the first 3 days of any new dose step. This new schema was already administered in 7 patients with the following observations, see Table 6.

Table 6: Occurrence of increased liver parameters in patients subjected to different MT1 10 dosages and dexamethasone treatment

Figure 3 shows a patient treated with new schema 3 and MT1 10 in two dose steps. Figure 4 shows a patient treated with new schema 3 and MT1 10 in three dose steps.

With the new schema 3 an additional mitigation of initial liver parameter alterations is obvious with regard to bilirubin elevation as well as aminotransferase elevations: During the first week at the respective MT1 10 dose step a grade 3 increase in bilirubin was completely avoided and aminotransferase increases were significantly reduced comparing occurrences of grade 3/4 elevations with the new corticosteroid schema versus the old one. With the new dexamethasone coverage a dose level of 48 μg/d could be assessed as tolerable and it is now possible to investigate higher MT110 doses (e.g. 48 μg/d or 96 μg/d and higher doses) in the ongoing clinical trial (Figure 5: example of liver parameters in a patient with ovarian carcinoma treated at 96 μg/d).

Example 3: Diarrhea

Observation: Patients with occurrence of diarrhea within the first 14 days of MT110 treatment.

Worst CTCAE grade per patient (n and percentage) and per administered MT1 10 dose, see Table 7.

Table 7: CTCAE grades for diarrhea in patients subjected to different dosages of MT110

Summary of patients with diarrhea occurring within the first 2 weeks of a dose step:

1. More patients develop diarrhea with higher MT1 10 doses.

2. Grade 3 diarrhea in 17% of the patients at 24 μg MT1 10 per day and in 60% of the patients at 48 μg MT1 10 per day.

Performed intervention in patients with diarrhea or signs of enteritis treated in MT1 10 clinical trial:

• Continuation of dexamethasone treatment and addition of other known antidiarrheal agents (e.g. loperamide, Tannacomp®).

· Addition of budesonide (Entocort) to concomitant dexamethasone treatment.

• Continuation of corticosteroid treatment with prednisolone.

Claims

1. Glucocorticoid (GC) for use in the amelioration, treatment and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by (the administration of) an EpCAMxCD3 bispecific antibody in a patient, wherein the administration of the GC is started prior to the administration of the EpCAMxCD3 bispecific antibody.

2. The use of claim 1 , wherein said GC is dexamethasone.

3. The use of claim 2, wherein said dexamethasone is administered in combination with another GC selected from the group consisting of budesonide, prednisone, prednisolone and methylprednisolone.

4. The use of any one of the preceding claims, wherein a first dose of the EpCAMxCD3 bispecific antibody is administered for a first period of time and consecutively a second dose of the EpCAMxCD3 bispecific antibody is administered for a second period of time, wherein the second dose exceeds the first dose.

5. The use of claim 4, wherein after administering the second dose of the EpCAMxCD3 bispecific antibody, a third dose of the EpCAMxCD3 bispecific antibody is administered for a third period of time, wherein the third dose exceeds the second dose.

6. The use of claim 4 or 5, wherein the first dose, the second dose and/or the third dose of the EpCAMxCD3 bispecific antibody are administered continually.

7. The use of any one of claims 4 to 6, wherein said first dose of the EpCAMxCD3 bispecific antibody is between 3 and 24 μg/day.

8. The use of any one of claims 4 to 7, wherein said second dose of the EpCAMxCD3 bispecific antibody is between 24 and 120 μg/day.

9. The use of any one of claims 5 to 8, wherein said third dose of the EpCAMxCD3 bispecific antibody is between 70 and 150 μg/day.

10. The use of any one of the preceding claims, wherein the administration of the GC is started prior to the administration of the first dose of the EpCAMxCD3 bispecific antibody and/or prior to the administration of the second dose of the EpCAMxCD3 bispecific antibody and/or prior to the administration of the third dose of the EpCAMxCD3 bispecific antibody.

1 1 . The use of any one of the preceding claims, wherein the administration of the GC is started between 3 and 24 hours, preferably between 6 and 12 hours prior to the administration of the EpCAMxCD3 bispecific antibody.

12. The use of any one of the preceding claims, wherein the GC is administered in an initial dose and subsequently tapered off in one or more dose steps.

13. The use of any one of the preceding claims, wherein the initial dose of the GC is administered for a period of at least two days.

14. The use of claim 12 or 13, wherein the initial dose of the GC is tapered off by sequentially administering a halving dose, wherein each dose step is administered for a period of at least one day.

15. The use of any one of claims 2 to 14, wherein the initial dose of dexamethasone is in the range of 8 to 40 mg/day.

16. The use ofany one of claims 2 to 15, wherein the daily dose of dexamethasone is administered in one to six single doses.

17. The use of any one of the preceding claims, wherein the GC is administered intravenously or orally.

18. The use of any one of the preceding claims, wherein said EpCAMxCD3 bispecific antibody is a single chain antibody, preferably MT1 10.

19. The use of any one of the preceding claims, wherein said hepatic adverse event is an increased serum level of one or more of aspartate transaminase (AST), alanine transaminase (ALT), bilirubin and alkaline phosphatase (AP).

20. The use of any one of the preceding claims, wherein said gastroenterological adverse event is one or more of diarrhea, exudative enteropathy, enteritis, colitis, vomiting, abdominal pain and nausea.

21 . The use of any one of the preceding claims, wherein said patient is a human.

22. The use of claim 21 , wherein said human patient comprises or is assumed to comprise EpCAM positive epithelial cancer cells.

23. Kit comprising a GC and an EpCAMxCD3 bispecific antibody and instructions for use and/or an imprint indicating that the GC is to be employed for the treatment, amelioration and/or prophylaxis of hepatic and/or gastroenterological adverse events caused by (the administration of) an EpCAMxCD3 bispecific antibody in a patient.