Clinical Trials Register

Summary
EudraCT Number:	2011-003201-14
Sponsor's Protocol Code Number:	ERTUSO
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-10-26
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

Germany - PEI

A.2

EudraCT number

2011-003201-14

A.3

Full title of the trial

Phase I/II, Open Label, Dose Escalating Study To Investigate Safety, Tolerability, And Preliminary Efficacy Of The Trifunctional Anti-HER-2/neu x Anti-CD3 Antibody Ertumaxomab In Patients With HER-2/neu Expressing (1+/SISH positive, 2+ and 3+) Solid Tumors Progressing After Standard Therapy

A.3.1

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

Study To Investigate Safety, Tolerability, And Preliminary Efficacy Of The Trifunctional Anti-HER-2/neu x Anti-CD3 Antibody Ertumaxomab In Patients With HER-2/neu Expressing Solid Tumors Progressing After Standard Therapy

A.3.2

Name or abbreviated title of the trial where available

S497

A.4.1

Sponsor's protocol code number

ERTUSO

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	Krankenhaus Nordwest GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	TRION Pharma
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
B.5.2	Functional name of contact point

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	No
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	ertumaxomab
D.3.2	Product code	rexomun
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ERTUMAXOMAB
D.3.9.1	CAS number	509077-99-0
D.3.9.3	Other descriptive name	rexomun
D.3.9.4	EV Substance Code	SUB25396
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	100
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	No

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

Patients with HER2/neu (1+/SISH positive, 2+ and 3+) expressing solid tumors that are progressing after standard therapy

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10049280
E.1.2	Term	Solid tumour
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objectives of the study is to assess the safety and tolerability of ertumaxomab in order to determine the maximum tolerated dose (MTD) and to establish a recommended dose (RD) for further development

E.2.2

Secondary objectives of the trial

The secondary objectives of the study are:
•To assess pharmacodynamic data (HAMA, serum levels of cytokines, blood cell count, cellular and humoral immune response, tumor cell depletion from peripheral blood)
•To assess the pharmacokinetics (PK) of ertumaxomab
•To assess the incidence and intensity of adverse events (AEs)
•To evaluate the response to ertumaxomab treatment in terms of clinical efficacy after the first and after the second treatment cycle and at follow-up visits, assessed by established screening methods and evaluated based on immune related response criteria (irRC)
•To evaluate whether the application of a second treatment cycle can boost the active immunization (determined by measurement of cellular and humoral immune response)
•To evaluate potential prognostic and predictive biomarkers (circulating tumor cells, lymphocyte count, HER2/neu mRNA levels, mRNA based subtyping of tumor-infiltrating lymphocytes)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Signed and dated informed consent form.
• Male or female* patients aged ≥ 18 years and with a life expectancy of at least 4 months.
• Negative pregnancy test at screening (and not more than 72 hours prior to the first ertumaxomab infusion) for women of childbearing potential. Patients must agree to use adequate contraception during the study. Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap).
• Measurable disease, defined as at least one lesion that is measurable in one dimension.
• Solid HER2/neu positive tumors (1+/SISH positive, 2+, and 3+), histologically confirmed.
• Patients must have disease progression during or after standard therapy and/or are no longer feasible for approved therapies.
• Previous therapies must be discontinued at least 2 weeks (6 weeks in case mitomycin C) prior to administration of ertumaxomab and all treatment related toxicities must have resolved or decreased to CTC grade 1 (with the exception of alopecia and peripheral neuropathy).
• If patients have received HER2-targeting therapies, all HER2-targeting therapies must have been discontinued before study entry.
• Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
• Adequate hematological, liver and kidney function:
o Thrombocytes > 100000 / mm³ (= 100 x 109/L)
o Neutrophil count > 1500/mm³ (= 1.5 x 109/L)
o Serum glutamic oxaloacetic transaminase (SGOT / aspartate aminotransferase (AST)) and serum glutamic pyruvate transaminase (SGPT / alanine aminotransferase (ALT)) within limits of normal; in patients with liver metastases ≤ 2.5 x upper limit of normal (ULN)
o Serum bilirubin ≤ 1.5 x ULN
o Creatinine ≤ 1.5 x ULN or clearance ≥ 60 mL/min
o Partial thromboplastin time (PTT) within limits of normal

• Adequate recovery from prior systemic therapy.
• Patients capable to understand the purposes and risks of the study, and who are willing and able to participate in the study
• Left ventricular ejection fraction must be > 50% at echocardiography

E.4

Principal exclusion criteria

• Patients currently being treated with medication or anticonvulsants for brain or central nervous system metastases or patients that have documented radiologic evidence of active brain or central nervous system metastases within 12 weeks of study entry.
• Patients with a prior diagnosis of any other malignancy (unless cured by surgery or other appropriate treatments greater than 2 years before study entry), Patients with in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin may be included at any time.
• ≥ 5 preceding chemotherapies.
• Documented acute or chronic infection or other concurrent non-malignant co morbidities that are uncontrolled, such as unstable or uncontrolled pectorial angina, myocardial infarction during the last 6 months, valvular heart disease that requires treatment, acute myocarditis or congestive heart failure (CHF, NYHA III or IV).
• Patients with a human immunodeficiency virus, hepatitis B or hepatitis C positive status are excluded from participation in the study.
• Any concurrent chemotherapy, radiotherapy (except for local radiation therapy for bone marrow metastasis), hormonal therapy, immunotherapy or corticoid therapy.
• Treatment with any investigational product within 2 weeks prior to first administration of ertumaxomab.
• Patients with documented autoimmune diseases.
• Known hypersensitivity to murine proteins and any other component of the drug.
• Abnormal organ or bone marrow function as defined below (any single parameter to fulfill condition):
o ANC < 1.5 Gpt/l (1.5x109/L, 1500/mm3)
o Hemoglobin <9.0 g/dl
o Platelet count < 75Gpt/l (75x109/L, 75,000/mm³)
o AST(SGOT)/ALT(SGPT) > 3 x upper limit of normal (ULN);
or: in case of metastatic liver disease
AST(SGOT)/ALT(SGPT) > 5 x ULN
o Alkaline Phophatase > 2.5 x ULN
o Serum (total) bilirubin > 1,5 x ULN for the institution;
or in case of metastatic liver disease:
o Serum (total) bilirubin > 3 x ULN for the institution;
o Serum creatinine > 1.5 x ULN

• Any other concurrent disease or medical conditions that are deemed to interfere with the conduct of the study as judged by the investigator.
• Known hypersensitivity to ertumaxomab and its analogues in general, or to any other component of the study drug formulation.
• Pregnant women, nursing mothers, lactating women, and women of child-bearing potential who are unwilling to use effective contraception.
• Use of immune-suppressive agents for the past 4 weeks prior to first administration of ertumaxomab. For regular use of systemic corticosteroids, patients should only be included after stepwise discontinuation to be free of steroids for a minimum of 7 days prior to first treatment.
• Unwilling or unable to follow protocol requirements.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the incidence rate of dose limiting toxicities (DLTs) at each dose level during the first treatment cycle in order to define the MTD

E.5.1.1

Timepoint(s) of evaluation of this end point

continously during and after first treatment cycle

E.5.2

Secondary end point(s)

Secondary endpoints of this phase I/II clinical study are:

Safety and tolerability endpoint
•Overall frequency and intensity of AEs
Pharmacodynamic endpoints
•Evaluation of anti-drug antibodies (HAMA) by ELISA technique
•Evaluation of serum levels of cytokines and immune cell count
•Blood cell count (immune status)
•Tumor cell depletion from peripheral blood (PCR / IHC)
•Cellular immune responses: HER2/neu and EpCAM specific T cells
•Humoral immune responses: autologous anti-EpCAM / anti-Her2neu antibodies

Basic pharmacokinetics data
•Free ertumaxomab in peripheral blood

Efficacy endpoints are:
•Determination whether lymphocyte count before first cycle and before second cycle can be correlated with outcome
•To evaluate the efficacy of ertumaxomab treatment after the first and after the second treatment cycle and at follow-up visits in terms of clinical activity by established screening methods based on irRC criteria
•Evaluation whether the application of a second treatment cycle can boost the active immunization as determined by measurement of cellular and humoral immune response
•Identification and quantification of circulating tumor cells prior to the study and in the course of the study

Further efficacy endpoints are
•Antitumor activity (ORR) and clinical benefit (PR, CR, SD, TTP, PFS, OS) according irRC
•Delta TTP (TTP study – TTP pretreatment)
•Prediction of treatment outcome by molecular markers, testing the hypothesis that high mRNA levels of HER2, HER3, HER4, CXCL9 and/or B-Cell markers are indicative for ertumaxomab efficacy

E.5.2.1

Timepoint(s) of evaluation of this end point

continously during and after first and second treatment cycle

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Safety, Tolerability, And Preliminary Efficacy

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

last visit of the last subject undergoing the trial

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	30
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	30
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	30

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-03-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-12-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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