Clinical Trials Register

Summary
EudraCT Number:	2020-000177-25
Sponsor's Protocol Code Number:	ATA129-EBV-205
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-03-04
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2020-000177-25

A.3

Full title of the trial

An Open-label, Single-arm, Multicohort, Phase 2 Study to Assess the Efficacy and Safety of Tabelecleucel in Subjects with Epstein-Barr Virus-associated Diseases (EBVision)

A.3.1

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

A study for subjects with Epstein-Barr Virus-associated Diseases

A.4.1

Sponsor's protocol code number

ATA129-EBV-205

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/490/2020

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Atara Biotherapeutics, Inc.
B.1.3.4	Country	United States
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	Atara Biotherapeutics, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Atara Biotherapeutics, Inc.
B.5.2	Functional name of contact point	Carter Hultman
B.5.3	Address:
B.5.3.1	Street Address	2380 Conejo Spectrum Street, Suite 200
B.5.3.2	Town/ city	Thousands Oaks
B.5.3.3	Post code	91320
B.5.3.4	Country	United States
B.5.6	E-mail	chultman@atarabio.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.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/16/1627
D.3 Description of the IMP
D.3.1	Product name	tabelecleucel
D.3.2	Product code	ATA129
D.3.4	Pharmaceutical form	Suspension 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	TABELECLEUCEL
D.3.9.2	Current sponsor code	ATA129
D.3.9.4	EV Substance Code	SUB194902
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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	Yes
D.3.11.3.5.1	CAT classification and reference number	Somatic cell therapy medicinal product, 30 May 2016 Doc. Ref. EMA/CAT/327742/2016
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	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	Ebvallo
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Medicament
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/16/1627
D.3 Description of the IMP
D.3.1	Product name	tabelecleucel
D.3.2	Product code	ATA129
D.3.4	Pharmaceutical form	Suspension 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	TABELECLEUCEL
D.3.9.2	Current sponsor code	ATA129
D.3.9.4	EV Substance Code	SUB194902
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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	Yes
D.3.11.3.5.1	CAT classification and reference number	Somatic cell therapy medicinal product, 30 May 2016 Doc. Ref. EMA/CAT/327742/2016
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

• EBV+ primary imunodeficiency lymphoproliferative disease (LPD)
• EBV+ associated lymphoproliferative disease in the setting of acquired (non-congenital) immunodeficiency (EBV+ AID LPD)
• EBV+ associated post-transplant LPD involving the central nervous system (EBV+ CNS PTLD)
• EBV+ post-transplant LPD where standard first line therapy (rituximab or chemotherapy) is inappropriate, including CD20-negative disease
• EBV+ sarcomas, including leiomyosarcoma, or smooth muscle tumors

E.1.1.1

Medical condition in easily understood language

Epstein-Barr Virus-associated Diseases

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	27.0
E.1.2	Level	PT
E.1.2	Classification code	10068349
E.1.2	Term	Epstein-Barr virus associated lymphoproliferative disorder
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

To determine the clinical benefit of tabelecleucel (allogeneic Epstein-Barr virus-specific cytotoxic T lymphocytes [EBV-CTLs]) in subjects with EBV-associated diseases as measured by the objective response rate (ORR)

E.2.2

Secondary objectives of the trial

To evaluate additional clinically relevant outcomes in EBV-associated diseases treated with tabelecleucel

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. ECOG performance status ≤3 for subjects aged ≥16 years; Lansky score ≥20 for subjects from ≥1 year to <16 years
2. Adequate organ function, unless organ dysfunction is considered to be due to the underlying EBV-associated disease
3. Males and females of any age
For subjects with PID LPD
4. Provided written informed consent and assent, if required by law for pediatric subjects in accordance with the requirements
5.Relapsed and/or refractory (R/R) or newly diagnosed PID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator
LPD confirmed by at least 1 of the following:
a. Biopsy-proven EBV+ LPD
b. Positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF
Subjects with R/R disease must have had at least one prior line of systemic therapy and one of the following:
a.Radiographic disease progression per Lugano Classification during or after treatment
b.Failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
6.Subjects may have systemic disease only, systemic and CNS disease or CNS disease only, meeting one of the following criteria:
a.Systemic disease measurable per Lugano Classification criteria, by PET-CT as evidenced by 18F-deoxyglucose avidity, except when contraindicated or mandated by local practice, then MRI may be used.
b.CNS only disease measurable by MRI, CT, or by cytology and flow cytometry with EBV detected in CSF
For subjects with AID LPD
7.R/R or newly diagnosed AID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator, confirmed by at least 1 of the following criteria:
a.Biopsy-proven EBV+ LPD
b.Positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF
Subjects with R/R disease must have had at least one prior line of systemic therapy and one of the following:
a.Radiographic disease progression per Lugano Classification during or after treatment
b.Failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
8.Subjects may have systemic disease only, systemic and CNS disease or CNS disease only, meeting one of the following criteria:
a. Systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18F-deoxyglucose avidity
b. CNS only disease measurable by MRI, CT, or by cytology and flow cytometry with EBV detected in CSF
9. For subjects with AID of idiopathic etiology or AID attributable to immunosenescence, objective laboratory evidence of immunodeficiency (e.g., lymphopenia, hypogammaglobulinemia).
For subjects with CNS PTLD
10.R/R or newly diagnosed CNS PTLD for whom the standard first line therapy is inappropriate, as determined by the investigator, confirmed by at least 1 of the following:
a.Biopsy-proven EBV+ CNS PTLD
b.Positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF
Subjects with R/R disease must have had at least one prior line of systemic therapy and one of the following:
a.Radiographic disease progression per Lugano Classification during or after treatment
b.Failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
11.Subjects may have systemic and CNS disease, or CNS disease only meeting the following criteria:
a.When present, systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18F-deoxyglucose avidity, except when contraindicated or mandated by local practice, then MRI may be used.
b.CNS only disease must be measurable by MRI, CT, or by cytology and flow cytometry with EBV detected in CSF. Contrast-enhanced CT scans may be substituted in patients in whom MRI is medically contraindicated (e.g., cardiac pacemaker) or unavailable
For subjects with EBV+ PTLD, where standard first line therapy (rituximab and/or chemotherapy) is inappropriate, including CD20-negative disease
12.Biopsy-proven EBV+ PTLD for whom standard first-line therapy is inappropriate
13.Subjects must have systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18F-deoxyglucose avidity
For subjects with Sarcoma, Including LMS, or smooth muscle tumors
14.EBV+ sarcoma or smooth muscle tumor with rapidly progressive disease defined as progressive disease per RECIST 1.1 criteria as documented radiographically within a 6-month interval prior to enrollment.
Subjects with newly diagnosed EBV+ sarcoma for whom the standard first-line therapy is inappropriate
15.Biopsy-proven EBV+ sarcoma meeting one of the following criteria:
a.Pathologically confirmed EBV+ Leiomyosarcoma
b.EBV+ Sarcoma or smooth muscle tumor
16.Measurable disease using CT, and/or MRI following RECIST 1.1 criteria

E.4

Principal exclusion criteria

1. Currently active Burkitt, T cell, NK/T-cell lymphoma/LPD, Hodgkin, plasmablastic, transformed lymphoma, active hemophagocytic lymphohistiocytosis, or other malignancies requiring systemic therapy
2. Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment, or known history of HIV infection
3. Suspected or confirmed grade ≥ 2 acute (GvHD) per the CIBMTR consensus grading system or moderate/severe chronic GvHD per NIH consensus criteria at the time of the enrollment
4. Need for vasopressor or ventilatory support at the time of enrollment
5. Prior therapy (in order of increasing washout period) prior to enrollment, as follows:
a. Within 4 weeks or 5 half-lives (whichever is shorter):
i. Any investigational product (co-enrollment in a non-interventional study or a study for sample collection only is permitted)
ii. Any chemotherapy (systemic or intrathecal), targeted small molecule therapy, or antibody/biologic therapy. Note: prior anti-CD20 antibody use is permitted within the washout period if a subsequent disease response assessment indicates disease
progression.
b. Within 8 weeks:
i. Prior tabelecleucel (>8 weeks prior to enrollment) is permitted (in consultation with the Medical Monitor) if response was obtained or if usual protocol-directed therapeutic options were not exhausted (e.g., restriction switch options)
ii. Cellular therapies: chimeric antigen receptor (CAR) therapies directed at T cells or T cell subsets, donor lymphocyte infusion, other CTLs, or virus-specific T cells
iii. Therapies which could impact tabelecleucel function: Anti-thymocyte globulin, alemtuzumab
c. any prior treatment with EBV-CTLs with the exception of tabelecleucel as above
6.Female who is breastfeeding or pregnant
7.Any of the following while undergoing treatment with tabelecleucel
and for 90 days after the last dose (details are specified in the body of
the protocol):
For females of childbearing potential: 1) unwilling to use a highly effective method of contraception (i.e., one that can achieve a failure rate of less than 1% per year when used consistently and correctly) or 2) unwilling to refrain from donating eggs
For males: 1) unwilling to use a condom during sexual intercourse or 2) unwilling to refrain from donating sperm or 3) has a female partner of childbearing potential who is unwilling to use a highly effective method of contraception (refer to protocol Section 5.6.4)
8. Inability or unwillingness to comply with all study procedures
9. Ongoing need for daily steroids of >0.5 mg/kg prednisone or glucocorticoid equivalent ongoing methotrexate, or extracorporeal photopheresis. For subjects with CNS disease, protocol specified dexamethasone is permitted
10.Any conditions that may put the study outcomes at undue risk:
a.Life expectancy < 60 days
b.Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk
11. History of prior allogeneic HCT or SOT
12. Prior systemic therapy for PTLD

E.5 End points

E.5.1

Primary end point(s)

The ORR obtained following administration of tabelecleucel with the first two different human leukocyte antigen (HLA) restrictions

E.5.1.1

Timepoint(s) of evaluation of this end point

Monitored throughout the study

E.5.2

Secondary end point(s)

• Overall survival (OS)
• Duration of response (DOR)
• Progression-free survival (PFS)
• For EBV-associated lymphoproliferative disease in the setting of primary imunodeficiency (EBV+ PID LPD) cohort:
o Number of subjects who reach definitive therapy (i.e., allogeneic HCT) for the underlying disease
o Time to definitive therapy
• For EBV+ sarcoma cohort, including leiomyosarcoma (LMS), or smooth muscle tumors
o Clinical benefit rate
o ORR by immune response evaluation criteria in solid tumors (iRECIST) criteria [Seymour 2017]

E.5.2.1

Timepoint(s) of evaluation of this end point

Monitored throughout the study

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

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.8.3

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

United Kingdom

United States

Austria

Belgium

France

Italy

Spain

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

End of study visit is at 24 ± 1 months after cycle 1 day 1 for each subject

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

Yes

F.1.1