Clinical Trials Register

Summary
EudraCT Number:	2020-002909-25
Sponsor's Protocol Code Number:	74310
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-10-07
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

Netherlands - Competent Authority

A.2

EudraCT number

2020-002909-25

A.3

Full title of the trial

Blood-borne assessment of stromal activation in esophageal adenocarcinoma to guide tocilizumab therapy: a randomized phase II proof-of-concept study

Behandeling van patiënten met resectabel oesofagaal adenocarcinoom met chemoradiatie gevolgd door resectie en tocilizumab op basis van bloedonderzoek naar de activiteit van steuncellen: een gerandomiseerde, fase II studie

A.3.1

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

A phase II trial of the efficacy of tocilizumab in patients with resectable esophageal adenocarcinoma grouped for stromal activation

Onderzoek naar de behandeling van patiënten met slokdarmkanker met chemotherapie, bestraling en tocilizumab op basis van bloedonderzoek naar de activiteit van steuncellen.

A.3.2

Name or abbreviated title of the trial where available

BASALT

A.4.1

Sponsor's protocol code number

74310

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	Amsterdam University Medical Centers
B.1.3.4	Country	Netherlands
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	Oncode Institute
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amsterdam UMC - location VUmc
B.5.2	Functional name of contact point	Trialbureau Medical Oncology
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081HV
B.5.3.4	Country	Netherlands
B.5.6	E-mail	trialmedonc@amc.uva.nl

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	RoActemra
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration 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	tocilizumab
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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.IMP: 2
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	Paclitaxel
D.2.1.1.2	Name of the Marketing Authorisation holder	Fresenius Kabi Nederland BV
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Paclitaxel
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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.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	Carboplatin
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Carboplatin
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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

oesophageal adenocarcinoma

oesofagaal adenocarcinoom

E.1.1.1

Medical condition in easily understood language

oesophageal cancer

slokdarmkanker

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 objective of this study is to demonstrate that stroma-targeting by tocilizumab in esophageal adenocarcinoma patients with highly activated stroma increases efficacy of chemoradiotherapy measured by pathological response according to the Mandard criteria. Patients will be stratified for ADAM12, a non-invasive blood-borne marker of stromal activation.

Het primaire doel van deze studie is om aan te tonen dat de onderdrukking van stroma-activiteit door tocilizumab in oesofagaal adenocarcinoom de effectiviteit van chemoradiatie vergroot zoals gemeten door de Mandard score. Patienten zullen gestratificeerd worden op basis van ADAM12, een marker voor stroma activiteit

E.2.2

Secondary objectives of the trial

•Efficacy and mechanism of action of tocilizumab with neoadjuvant chemoration against esophagastric cancer by:
oR0 resection rate
oProgression free survival
oOverall survival
oIL6-STAT3 pathway inhibition measured by gene expression analysis
oLevels of IL-6 in serum.
oPhosphorylated STAT3 and stromal abundance measured by immunohistochemistry in formalin-fixed paraffin-embedded tumor tissue
•Levels of ADAM12 in tumor biopsies and serum
•Incidence and severity of toxicity defined according to CTCAE v5.0 and Radiation Oncology Group (RTOG) criteria
•Incidence and severity of post-operative complications according to the Clavien - Dindo classification
•Percentage completion of chemotherapy and radiation treatment
•Percentage withdrawal rate from surgery due to tocilizumab related complications
•Percentage delay of surgery due to tocilizumab related complications
Exploratory objectives are to identify additional predictive biomarkers based on tumor, fecal and blood samples.

1. effectiviteit en werkingsmechanisme van tocilizumab met neoadjuvante chemoradiatie tegen slokdarmkanker door:
-R0 resectie
-Progressievrije overleving
-Totale overleving
-IL6-STAT3 inhibitie door gen expressie analyse
-IL6 in het serum
-gefosforyleerd STAT3 en stromale overvloed bij immunohistochemie
2. ADAM12 in serum en tumorbiopten
3. Incidentie en ernst van toxiciteit op basis van de CTCAE v5.0 en RTOG criteria
4. Incidentie en ernst van post-operatieve complicaties op basis van de Clavien-Dindo classificatie
5. Percentage voltooiing van chemoradiatie
6. Percentage afblazen van operatie door bijwerkingen van tocilizumab
7. Percentage uitstel van operatie door bijwerkingen van tocilizumab
Exploratieve doelen zijn het identificeren van additionele predictieve biomarkers op basis van tumor- en bloedmonsters en uitwerpselen

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically proven adenocarcinoma of the esophagus or gastroesophageal junction.
- Surgically resectable (<T4b, N0 or N+, M0)
- Patient is fit for surgery

- Histologisch bewezen adenocarcinoom van de oesofagus of de gastro-oesofagale junctie
- de tumor is chirurgisch te verwijderen (<T4b, N0 of N+, M0)
- Patient is fit genoeg om de operatie te ondergaan.

E.4

Principal exclusion criteria

- Past (within 5 years) or current history of malignancy other than entry diagnosis interfering with prognosis of esophageal cancer, not including superficial and adequately treated skin and cervical malignancies.

- Een andere maligniteit die interfereert met de prognose van slokdarmkanker

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is pathological response to chemoradiotherapy according to the Mandard criteria.

Het primaire eindpunt is pathologische response op chemoradiatie op basis van de Mandard score

E.5.1.1

Timepoint(s) of evaluation of this end point

At surgery

Bij de operatie

E.5.2

Secondary end point(s)

Secondary endpoints:
•Efficacy and mechanism of action of tocilizumab with neoadjuvant chemoration against esophagastric cancer by:
oR0 resection rate
oProgression free survival
oOverall survival
oIL6-STAT3 pathway inhibition measured by gene expression analysis
oLevels of IL-6 in serum.
oPhosphorylated STAT3 and stromal abundance measured by immunohistochemistry in formalin-fixed paraffin-embedded tumor tissue
•Levels of ADAM12 in tumor biopsies and serum
•Incidence and severity of toxicity defined according to CTCAE v5.0 and Radiation Oncology Group (RTOG) criteria
•Incidence and severity of post-operative complications according to the Clavien - Dindo classification
•Percentage completion of chemotherapy and radiation treatment
•Percentage withdrawal rate from surgery due to tocilizumab related complications
•Percentage delay of surgery due to tocilizumab related complications
Exploratory objectives are to identify additional predictive biomarkers based on tumor, fecal and blood samples.

Secundaire eindpunten:
1. effectiviteit en werkingsmechanisme van tocilizumab met neoadjuvante chemoradiatie tegen slokdarmkanker door:
-R0 resectie
-Progressievrije overleving
-Totale overleving
-IL6-STAT3 inhibitie door gen expressie analyse
-IL6 in het serum
-gefosforyleerd STAT3 en stromale overvloed bij immunohistochemie
2. ADAM12 in serum en tumorbiopten
3. Incidentie en ernst van toxiciteit op basis van de CTCAE v5.0 en RTOG criteria
4. Incidentie en ernst van post-operatieve complicaties op basis van de Clavien-Dindo classificatie
5. Percentage voltooiing van chemoradiatie
6. Percentage afblazen van operatie door bijwerkingen van tocilizumab
7. Percentage uitstel van operatie door bijwerkingen van tocilizumab
Exploratieve eindpunten zijn additionele predictieve biomarkers op basis van tumor- en bloedmonsters en uitwerpselen

E.5.2.1

Timepoint(s) of evaluation of this end point

At surgery and during follow-up

bij de operatie en gedurende follow-up

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)

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

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

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

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

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

LVLS

Laatste studiebezoek van laatst geincludeerde patient

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

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:

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.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)

None

Geen

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

2020-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-21

P. End of Trial
P.	End of Trial Status	Ongoing

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