Clinical Trials Register

Summary
EudraCT Number:	2008-001557-17
Sponsor's Protocol Code Number:	IP-CAT-AC-03
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-08-04
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2008-001557-17

A.3

Full title of the trial

Two-arm, randomized, open-label, phase IIIb study investigating the safety of a 3 hour i.p. infusion of catumaxomab with and without prednisolone premedication in patients with malignant ascites due to epithelial cancer

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to investigate the safety of a treatment with catumaxomab given as 3 hour infusions into the peritoneal cavity in patients with an accumulation of fluid in the peritoneal cavity, which can develop due to various cancer types. Half of the patients receive prednisolone as premedication and the other half does not.

A.3.2

Name or abbreviated title of the trial where available

CASIMAS

A.4.1

Sponsor's protocol code number

IP-CAT-AC-03

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00822809

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Fresenius Biotech GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fresenius Biotech GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fresenius Biotech GmbH
B.5.2	Functional name of contact point	Medical Information
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Ring 193a
B.5.3.2	Town/ city	Munich
B.5.3.3	Post code	80807
B.5.3.4	Country	Germany
B.5.4	Telephone number	+498930659311
B.5.6	E-mail	med.info@fresenius-biotech.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Removab 10 microgram
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Biotech GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	catumaxomab
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CATUMAXOMAB
D.3.9.1	CAS number	509077-98-9
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Antibody developed by hybridoma method
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Removab 50 microgram
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Biotech GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	catumaxomab
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraperitoneal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CATUMAXOMAB
D.3.9.1	CAS number	509077-98-9
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Antibody developed by hybridoma method
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Solu-Decortin H
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck KGaA
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	prednisolone
D.3.2	Product code	prednisolone
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	1715-33-9
D.3.9.3	Other descriptive name	PREDNISOLONE SODIUM SUCCINATE
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	glucocorticoid

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Malignant Ascites

E.1.1.1

Medical condition in easily understood language

Accumulation of fluid in the peritoneal cavity due to various cancer types

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	PT
E.1.2	Classification code	10025538
E.1.2	Term	Malignant ascites
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to compare the 3 hour i.p. infusion of catumaxomab with prednisolone to catumaxomab without prednisolone by demonstrating superiority for safety and non inferiority for efficacy.

E.2.2

Secondary objectives of the trial

The secondary objectives of the study are to determine additional efficacy, additional safety, Quality of Life, human anti mouse antibodies (HAMAs), and ascites-related symptom score following a 3 hour i.p. infusion of catumaxomab with and without prednisolone. Immunomonitoring and pharmacokinetics (PK) will be assessed at selected sites.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients will be enrolled in this study only if they meet all of the following criteria:
• Signed and dated informed consent,
• Age: ≥18 years,
• Karnofsky index ≥60%,
• Histological confirmed diagnosis of epithelial cancer,
• Patients with malignant ascites requiring therapeutic ascites paracentesis,
• Patients where standard therapy is not available or no longer feasible,
• Life expectancy >12 weeks,
• BMI between 17 and 40kg/m2; prior to calculation of BMI reduce "body weight" by weight of current estimated ascites volume (exploratory value is sufficient)

E.4

Principal exclusion criteria

Patients will not be enrolled in this study if they meet any of the following criteria:
• Documented acute or chronic infection,
• Concomitant treatment with other investigational product, cancer chemo-, or radiotherapy,
• In cases of previous exposure to investigational product, cancer, chemo- or radiotherapy (except for local radiation therapy for bone marrow metastasis) patients must be excluded if not sufficiently recovered from previous treatment (toxicity present) based on adequate laboratory values and general status according to other in/exclusion criteria (i.e. this might be less than 1 or 2 weeks after a weekly or bi-weekly scheduled previous therapy regimen). Patients must not have been exposed to nitrosoureas or mitomycin C within 6 weeks prior to the first infusion of catumaxomab.
• Previous treatment with entirely murine monoclonal antibodies
• Known or suspected hypersensitivity to catumaxomab or similar antibodies,
• Long-lasting steroid treatment (≥ 7 days), Patients should only be included after stepwise discontinuation and free of steroids for a minimum of 5 days
• Inadequate respiratory function, including symptomatic pleural effusion,
• Inadequate renal function (creatinine >1.5 x upper limit of normal [ULN],
• Inadequate hepatic function (aspartate aminotransferase, (AST), alanine aminotransferase (ALT) >5x ULN; bilirubin >1.5ULN)
• Platelets <80000 cells/mm3; absolute neutrophil count (ANC) <1500 cells/mm3,
• Albumin: lower than 3 g/dL or total protein < 6 g/dL
• Partial thromboplastin time (PTT) >2 x ULN
• Hemoglobin <8g/dL,
• Patients requiring entirely parenteral nutrition,
• Patients with ileus or with symptomatic subileus within the last 30 days,
• Signs or symptoms of relevant cardiovascular disease, congestive heart failure or cardiac arrhythmias (New York Heart Association [NYHA] class >II),
• Liver metastases with volume >70% of liver metastasized tissue,
• Known portal vein obstruction,
• Known brain metastases,
• Pregnant (as evidenced by positive pregnancy test at screening), or nursing women or women of childbearing potential and men who are not using an effective contraceptive method during the study and at least 3 months after the last infusion,
• Unable or unwilling to comply fully with the protocol,
• Patients with any other severe disease that would render a participation in the study an undue risk according to judgment of investigator.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint consists of 2 parts analyzed in a hierarchical manner:
1. Safety:
Composite safety score of 3 hours i.p. infusion of catumaxomab with and without prednisolone. The composite safety score is calculated from the frequency and intensity of the main known adverse events (AEs) caused by catumaxomab: fever, nausea, vomiting, and abdominal pain. The CTC-grade of these AEs will be summarized using an AE-score. The composite safety score will be compared between the 2 treatment groups.
2. Efficacy
A co-primary endpoint is puncture-free survival (PuFS) defined as the time from clock start to first need for therapeutic ascites puncture or death, whichever occurs first. The clock starts after the last infusion of catumaxomab.
In order to objectify the need for a therapeutic puncture, an ascites puncture will only be performed if there is a medical need according to predefined criteria.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoint safety: Up to and including safety visit.
Primary efficacy endpoint: first need for therapeutic ascites puncture or death, whichever occurs first

E.5.2

Secondary end point(s)

Efficacy endpoints:
• Time to next ascites puncture,
• Number of ascites punctures until end of life time,
• Overall survival,
• Anti-cancer treatment (Type, No. of treatments).
Safety endpoints:
• Incidence and severity of all AEs, No. of patients with AE
• Incidence of cytokine release related symptoms
• Hospitalization
• Changes in clinically relevant laboratory values hematology, clinical chemistry, coagulation, and urinalysis),
• Physical examination,
• Vital signs.
Additional parameters:
• EpCAM evaluation (retrospective) of ascites cells at screening,
• Quality of Life (EQ-5D),
• Ascites-related symptoms (FACIT-AI),
• Human anti-mouse antibody (HAMA)
• PK (at selected sites only),
• Immunomonitoring (at selected sites).

E.5.2.1

Timepoint(s) of evaluation of this end point

Time to ascites puncture, number of ascites punctures, anti-cancer treatment and OS until death or 6 months after the last patient is randomized.
Incidence and severity AEs, Number of patients with AE, Incidence of cytokine release related symptoms, Changes in clinically relevant laboratory values, physical examination and vital signs until Safety Visit; Hospitalization until End of Study:
EpCam at Screening or day 0 (before first treatment);
QOL + Ascites related symptoms until End of Study; Human anti-mouse antibody (HAMA) during treatment until first puncture after end of treatment; PK before and during treatment period, until day 28 after last infusion and on day of first puncture after treatment;
Immunomonitoring until Safety Visit.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

parallel groups: catumaxomab with and without prednisolone

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

110

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Ukraine

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

please see protocol

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1