Clinical Trials Register

Summary
EudraCT Number:	2009-016584-10
Sponsor's Protocol Code Number:	SAKK75/08
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-11-09
Trial results	View 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

Austria - BASG

A.2

EudraCT number

2009-016584-10

A.3

Full title of the trial

Multimodal therapy with and without cetuximab in patients with locally advanced esophageal carcinoma. An open-label phase III trial

A.3.1

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

Multimodal therapy (chemotherapy, radiation, surgery) with and without cetuximab, an additional anti-tumor agent, in patients with locally advanced esophageal carcinoma.

A.4.1

Sponsor's protocol code number

SAKK75/08

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01107639

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	Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung SAKK
B.1.3.4	Country	Switzerland
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	SAKK
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	Merck KGaA, 64293 Darmstadt
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	Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung SAKK
B.5.2	Functional name of contact point	Trial Coordinator
B.5.3	Address:
B.5.3.1	Street Address	Effingerstrasse 40
B.5.3.2	Town/ city	Bern
B.5.3.3	Post code	3008
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+4131389 91 91
B.5.5	Fax number	+4131389 92 00
B.5.6	E-mail	sakkcc@sakk.ch

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.2.1.2	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.3.4	Pharmaceutical form	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	CETUXIMAB
D.3.9.1	CAS number	205923564
D.3.9.4	EV Substance Code	SUB01178MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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	Yes
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.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.2.1.2	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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
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	CISPLATIN
D.3.9.1	CAS number	15663-27-1
D.3.9.4	EV Substance Code	SUB07483MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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	No
D.IMP: 3
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.2.1.2	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.3.4	Pharmaceutical form	Concentrate 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.3.8	INN - Proposed INN	Docetaxel
D.3.9.1	CAS number	114977-28-5
D.3.9.4	EV Substance Code	SUB12492MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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	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

Locally advanced esophageal carcinoma.

E.1.1.1

Medical condition in easily understood language

Advanced esophagus cancer.

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10056092
E.1.2	Term	Adenocarcinoma of oesophagus
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10041824
E.1.2	Term	Squamous cell carcinoma of esophagus
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine the efficacy of neoadjuvant radiochemotherapy (RCT) combined with immunotherapy followed by adjuvant immunotherapy compared with the same schedule without immunotherapy (neoadjuvant and adjuvant).

E.2.2

Secondary objectives of the trial

Compare the toxicity of the two therapy arms and determine patterns of failure overall and with regard to histology; further to evaluate economic aspects in a subproject and to perform a radiotherapy quality assurance program.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Translational research: Biobanking of tissue samples from initial biopsy and from surgical specimen (applicable for patients who gave consent for biobanking only).

E.3

Principal inclusion criteria

Histologically confirmed squamous cell carcinoma (including basaloid-squamous cell and adenosquamous carcinoma) or adenocarcinoma of the thoracic esophagus or the esophagogastric junction (from 5 cm below the entrance of the esophagus into the thorax to the gastric cardia (=esophagogastric junction), types I and II according to the Siewert staging system).
Resectable, locally advanced disease (the stage is determined by the combination of CT scan, EUS and PET and by a multidisciplinary team discussion)
Age: 18-75 years
Health status: WHO performance status (PS) ≤ 1
Patient is considered operable (appropriate organ functions)
Adequate renal function: creatinine clearance > 60 mL/min, calculated according to the formula of Cockroft-Gault
Adequate pulmonary function: FEV1 > 1.5L or, if < 1.5L at least 75% of the reference value
Adequate hepatic function: bilirubin ≤ 1.0 x ULN, AP ≤ 2.5 x ULN, AST ≤ 1.5 x ULN
Adequate hematologic values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
Normal coagulation according to local standard
Patient compliance and geographic proximity allow proper staging and follow-up.
Women are not breastfeeding, are using effective contraception if sexually active, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter.
Men agree not to father a child during participation in the trial and during the twelve months thereafter.

E.4

Principal exclusion criteria

Stage T1 Nany M0
Stage T2 N0 M0
Stage T4a due to infiltration of the tracheo-bronchial tree or organ involvement which cannot be operated on with curative intent (R0) as decided by a multidisciplinary team discussion
Stage T4b
Distant metastasis (M1)
Cervical esophageal carcinoma and tumors involving the first 5 cm of the thoracic esophagus
Airway infiltration in case of tumors at or above the tracheal bifurcation
Peritoneal carcinomatosis in case of adenocarcinomas infiltrating the gastric cardia (i.e. esophagogastric junction carcinoma Siewert type I or II)
Previous malignancies within five years or concomitant malignancies, except: nonmelanomatous skin cancer or adequately treated in situ cervical cancer
Prior chemotherapy in oncological indication within the last 5 years or prior RT to the chest
Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last twelve months, significant arrhythmias)
Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent and answering the questions of the EQ-5D questionnaire and HEA forms (EQ-5D questionnaire and HEA forms applicable for Swiss centers and for patients who gave consent for the HEA only)
Active uncontrolled infection
Serious underlying medical condition (judged by the investigator) which could impair the ability of the patient to participate in the trial (e.g. uncontrolled diabetes mellitus, active autoimmune disease)
Pre-existing peripheral neuropathy (> grade 1) or pre-existing hardness of hearing
Concurrent treatment with other experimental drugs or other anti-cancer therapy; treatment in a clinical trial within 30 days prior to trial entry
Definite contraindications for the use of corticosteroids and antihistamines as premedication
Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs
Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Time from randomization to one of the following events, whichever comes first:
· Tumor progression at any time
· Recurrence at local, regional or distant site after surgery
· Death from any cause

E.5.2

Secondary end point(s)

· Progression-free survival after surgery (PFS-OP)
· Adverse events according to CTCAE version 4.0 and major postoperative complications
. Time to progression
· Pathological remission (=TRG 1+2)
· R0-resection
· Overall survival
· Time to loco-regional failure after R0-resection
· Time to systemic failure after R0-resection
· Feasibility of the therapy: Completion of therapy
· In-hospital mortality
· Compliance with radiotherapy standards

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to protocol section 13.

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

E.6.7

Pharmacodynamic

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)

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)

Yes

E.7.4

Therapeutic use (Phase IV)

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

Standard therapy w/o IMP

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

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

Switzerland

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

The inclusion of patients is planned to start in Q2 2010 and will stop after the inclusion of 300 patients, which is expected in Q3 2013. Trial termination (last follow-up visit of the last patient) is expected to be in Q2 2019.
All patients will be followed up for five years after the inclusion of the last patient, or less than five years if the trial team decides to stop collecting further follow-up data.

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.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

180

F.4.2.2

In the whole clinical trial

300

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

No. Patients will be followed-up for 5 years (or until trial team decides to stop collecting further follow-up data).

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

2010-12-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-03-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-12-09

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