Clinical Trials Register

Summary
EudraCT Number:	2018-004798-29
Sponsor's Protocol Code Number:	M18TAT
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-07-25
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

2018-004798-29

A.3

Full title of the trial

Track and treat in NSCLC (TATIN) – ctDNA guided treatment of early resistance to targeted treatment in patients with EGFR positive NSCLC

Monitoren en behandelen van vroege resistentie tijdens osimertinib behandeling door middel van circulerend tumor DNA in het bloed bij patiënten met EGFR positief longkanker – de TATIN studie.

A.3.1

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

ctDNA guided treatment of early resistance to targeted treatment

behandelen van vroege resistentie tijdens osimertinib behandeling door middel van circulerend tumor DNA in het bloed

A.3.2

Name or abbreviated title of the trial where available

TATIN

A.4.1

Sponsor's protocol code number

M18TAT

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	Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
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	Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
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	Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis
B.5.2	Functional name of contact point	Dr. A.J. de Langen
B.5.3	Address:
B.5.3.1	Street Address	Plesmanlaan 121
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1066 CX
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00310205122958
B.5.6	E-mail	j.d.langen@nki.nl

D. IMP Identification
D.IMP: 1
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	Tagrisso
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca
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	osimertinib
D.3.2	Product code	1421373-65-0
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	osimertinib
D.3.9.1	CAS number	L01Xe
D.3.9.2	Current sponsor code	EMEA/H/C/004124
D.3.9.3	Other descriptive name	OSIMERTINIB
D.3.9.4	EV Substance Code	SUB176340
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	80
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: 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	Xalkori
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
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	crizotinib
D.3.2	Product code	877399-52-5
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Crizotinib
D.3.9.1	CAS number	877399-52-5
D.3.9.3	Other descriptive name	CRIZOTINIB
D.3.9.4	EV Substance Code	SUB32267
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	250
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

Patients with histologically confirmed metastatic NSCLC, characterized by a sensitizing exon 19 deletion or exon 21 L858R EGFR mutation that are eligible for osimertinib treatment.

Patiënten met gemetastaseerd histologisch bevestigede NSCLC, EGFR positief

E.1.1.1

Medical condition in easily understood language

non small cell lung cancer

niet-kleincellig longkanker

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	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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

• To identify the percentage of patients in which a drug resistant clone can be detected with ctDNA before the emergence of radiological progression.
• To determine the success rate of crizotinib and osimertinib combination treatment to eliminate MET amplification, defined by disappearance of the MET amplification clone in a subsequent ctDNA sample.

• Het identificeren van het percentage patiënten waarbij een resistente kloon kan worden gedetecteerd met ctDNA voor radiologische progressie.
• Bepalen van de slagingskans van crizotinib en osimertinib om MET-amplificatie te elimineren, door in een volgende ctDNA analyse aan te kunnen tonen dat de MET amplificatie verdwenen is.

E.2.2

Secondary objectives of the trial

• Lag time between ctDNA based detection of a resistant clone and radiological progression.
• Correlation of ctDNA results with that of the tumor biopsy upon radiological progression.
• The time to disappearance of the MET amplification clone after crizotinib initiation as detected by ctDNA.
• The time to re-appearance of MET amplification as detected by ctDNA or tumor biopsy in case of radiological progression after successful elimination with crizotinib treatment.

• De tijd tussen op ctDNA gebaseerde detectie van een resistente kloon en de radiologische progressie.
• Correlatie van ctDNA resultaten met die van de tumorbiopsie na radiologische progressie.
• De tijd tot verdwijning van de MET amplificatie na toedienen van crizotinib zoals gedetecteerd door ctDNA.
• De tijd tot het opnieuw verschijnen van MET-amplificatie zoals gedetecteerd door ctDNA of tumorbiopsie in het geval van radiologische progressie na succesvolle eliminatie met crizotinib-behandeling.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically confirmed metastatic NSCLC, characterized by a sensitizing exon 19 deletion or exon 21 L858R EGFR mutation.
2. WHO performance status 0-2.
3. Eligible for osimertinib treatment according to the label and according to the treating physician.
4. Patients must be ≥18 years of age.

1. Gemetastaseerd histologisch bevestigde NSCLC, gekenmerkt door een sensibiliserende exon 19 deletie of exon 21 L858R EGFR-mutatie.
2. WHO performance status 0-2.
3. In aanmerking komen voor osimertinib-behandeling volgens het label en volgens de behandelend arts
4. Patiënten moeten 18 jaar o ouder zijn.

E.4

Principal exclusion criteria

1. Patients with symptomatic central nervous system metastases who are neurologically unstable. Unstable brain metastases except for those who have completed definitive therapy and have had a stable neurological status for 2 weeks after completion of definitive therapy. Patients may be on corticosteroids to control brain metastases if they have been on a stable dose for 2 weeks prior to the start of study treatment and are clinically asymptomatic.

1. Patiënten met symptomatische uitzaaiingen in het centrale zenuwstelsel die neurologisch onstabiel zijn. Onstabiele hersenmetastasen met uitzondering van degenen die de hele behandeling hebben voltooid en een stabiele neurologische status hebben 2 weken na voltooiing van de therapie. Patiënten mogen corticosteroïden gebruiken om hersenmetastasen te beheersen als ze 2 weken voorafgaand aan de start van de studie een stabiele dosis hebben en klinisch asymptomatisch zijn.

E.5 End points

E.5.1

Primary end point(s)

1. The percentage of patients in which a drug resistant clone can be detected with ctDNA before the emergence of radiological progression.
2. When crizotinib treatment results in elimination of the MET amplification positive clone in 4/7 (57%) of patients.

1. Het percentage patiënten waarbij een resistente kloon kan worden gedetecteerd met ctDNA voor radiologische progressie.
2. Wanneer behandeling met crizotinib resulteert in de eliminatie van de MET-amplificatie-positieve kloon bij 4/7 (57%) van de patiënten.

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months after start treatment

3 maanden na start van de behandeling

E.5.2

Secondary end point(s)

1. Lag time between ctDNA based detection of a resistant clone and radiological progression.
2. Correlation of ctDNA results with that of the tumor biopsy upon radiological progression.
3. The time to disappearance of the MET amplification clone after crizotinib initiation as detected by ctDNA.
4. The time to re-appearance of MET amplification as detected by ctDNA or tumor biopsy in case of radiological progression after successful elimination with crizotinib treatment.

1. De tijd tussen op ctDNA gebaseerde detectie van een resistente kloon en de radiologische progressie.
2. Correlatie van ctDNA resultaten met die van de tumorbiopsie na radiologische progressie.
3. De tijd tot verdwijning van de MET amplificatie na toedienen van crizotinib zoals gedetecteerd door ctDNA.
4. De tijd tot het opnieuw verschijnen van MET-amplificatie zoals gedetecteerd door ctDNA of tumorbiopsie in het geval van radiologische progressie na succesvolle eliminatie met crizotinib-behandeling.

E.5.2.1

Timepoint(s) of evaluation of this end point

at time of radiological progression during osimertinib treatment

op het moment van radiologische progressie tijdens osimertinib behandeling

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

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.8.2.4

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

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

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

100

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

2019-01-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-12-09

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