Clinical Trials Register

Summary
EudraCT Number:	2017-002949-30
Sponsor's Protocol Code Number:	ATA129-EBV-302
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-12-02
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

2017-002949-30

A.3

Full title of the trial

Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Subjects with Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease after Failure of Rituximab or Rituximab and Chemotherapy (ALLELE Study)

A.3.1

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

A study for subjects after organ or cell transplantation after failure of prior treatment

A.3.2

Name or abbreviated title of the trial where available

ALLELE study

A.4.1

Sponsor's protocol code number

ATA129-EBV-302

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	Cherilyn L. Rohr
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.5.4	Telephone number	1805330 6458
B.5.6	E-mail	crohr@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	No
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	5×10E7 cells/ml
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

Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease

E.1.1.1

Medical condition in easily understood language

Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease after failure of prior treatment

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	21.1
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.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10075146
E.1.2	Term	Post transplant 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 (ATA129; allogeneic Epstein-Barr virus specific cytotoxic T lymphocytes [EBV-CTLs]) in subjects with EBV-associated post-transplant
lymphoproliferative disease (EBV+ PTLD) following (1) solid organ transplant (SOT) and after failure of rituximab (Subgroup A) and rituximab plus chemotherapy (Subgroup B) or (2) allogeneic hematopoietic cell transplant (HCT) after failure of rituximab, as measured by the objective response rate (ORR).

E.2.2

Secondary objectives of the trial

- To evaluate duration of response (DOR) in the SOT and HCT cohorts separately
- To evaluate ORR and DOR in the SOT and HCT cohorts combined
- To evaluate rates of complete response (CR) and partial response (PR)
- To evaluate time to response and time to best response
- To evaluate overall survival (OS)
- To evaluate graft status (SOT subjects only)
- To characterize the safety profile of tabelecleucel in this subject population

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Prior SOT of kidney, liver, heart, lung, pancreas, small bowel, or any combination of these (SOT cohort);
or prior allogeneic HCT (HCT cohort).
2. A diagnosis of locally-assessed, biopsy-proven EBV+ PTLD.
3. Availability of appropriate partially HLA-matched and restricted tabelecleucel has been confirmed by the sponsor.
4. Measurable, 18F-deoxyglucose (FDG)-avid (Deauville score ≥ 3) systemic disease using Lugano
Classification response criteria by positron emission tomography (PET)-diagnostic computed tomography (CT), except when contraindicated or mandated by local practice, then magnetic resonance imaging (MRI) may be used. For subjects with treated central nervous system (CNS) disease, head diagnostic CT
and/or brain/spinal MRI as clinically appropriate will be required to follow CNS disease response per Lugano Classification response criteria.
5. Treatment failure of rituximab or interchangeable commercially available biosimilar monotherapy
(SOT subgroup A or HCT cohort) or rituximab plus any concurrent or sequentially administered
chemotherapy regimen (SOT subgroup B) for treatment of PTLD. Treatment failure is defined based on rituximab response as follows:
a.Radiographic disease progression per Lugano Classification following a minimum cumulative dose
of 1125 mg/m2 rituximab (typically, 3 weekly doses of 375 mg/m2), or
b. Failure to achieve CR or PR, defined by Lugano radiographic criteria, after a minimum cumulative dose of 1500 mg/m2 rituximab (typically, 4 weekly doses of 375 mg/m2), or
c. Relapse/progression of PTLD after a response to rituximab (SOT subgroup A or HCT cohort) or
rituximab plus chemotherapy (SOT subgroup B), defined as radiographic and/or biopsy evidence of relapse/progression consistent with PTLD; if the underlying disease for which the subject underwent allogeneic HCT (HCT cohort) was lymphoma, biopsy confirmation of relapsed EBV+ PTLD is required.
6. Males and females of any age.
7. Eastern Cooperative Oncology Group performance status ≤ 3 for subjects aged > 16 years; Lansky score ≥ 20 for subjects from birth to 16 years.
8. For HCT cohort only: If allogeneic HCT was performed as treatment for an acute lymphoid or myeloid malignancy, the underlying primary disease for which the subject underwent transplant must be in morphologic remission.
9. Adequate organ function:
a. Absolute neutrophil count ≥ 1000/μL (SOT cohort) or ≥ 500/μL (HCT cohort), with or without
cytokine support
b. Platelet count ≥ 50,000/μL, with or without transfusion or cytokine support. For HCT cohort, platelet count < 50,000/μL but ≥ 20,000/μL, with or without transfusion support, is permissible if the subject has not had grade ≥ 2 bleeding in the prior 4 weeks (where grading of the bleeding is determined per the National Cancer Institute’s Common Terminology Criteria for Adverse Events [CTCAE], version 5.0)
c. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBILI)
each < 5 × the upper limit of normal (ULN); however, ALT, AST, and TBILI each ≤ 10 × ULN is
acceptable if the elevation is considered by the investigator to be due to EBV and/or PTLD
involvement of the liver as long as there is no known evidence of significant liver dysfunction (eg,
elevated prothrombin time due to liver dysfunction, signs/symptoms of liver dysfunction such as
asterixis, or similar).
10. Subject or subject’s representative is willing and able to provide written informed consent.

E.4

Principal exclusion criteria

1. Burkitt lymphoma, classical Hodgkin lymphoma, or any T-cell lymphoma.
2. Daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or
extracorporeal photopheresis.
3. Untreated CNS PTLD or CNS PTLD for which the subject is actively receiving CNS-directed
chemotherapy (systemic or intrathecal) or radiotherapy at enrollment. NOTE: Subjects with previously treated CNS PTLD may enroll if CNS-directed therapy is complete.
4. Suspected or confirmed grade ≥ 2 graft-versus-host disease per the Center for International Blood and Marrow Transplant Research (CIBMTR) consensus grading system at enrollment.
5. Ongoing or recent use of a checkpoint inhibitor agent (eg, ipilimumab, pembrolizumab, nivolumab) within 3 drug half-lives from the most recent dose to enrollment.
6. For HCT cohort only: Active adenovirus viremia.
7. Need for vasopressor or ventilatory support.
8. Antithymocyte globulin or similar anti-T-cell antibody therapy ≤ 4 weeks prior to enrollment.
9. Treatment with EBV-CTLs or chimeric antigen receptor (CAR) T cells directed against B cells within 8 weeks of enrollment (SOT or HCT cohorts); or unselected donor lymphocyte infusion within 8 weeks of enrollment (HCT cohort only).
10. Female who is breastfeeding or pregnant or female of childbearing potential or male with a female partner of childbearing potential unwilling to use a highly effective method of contraception.
11. Inability to comply with study-related procedures
12. Subjects with PTLD following SOT who are eligible for rituximab plus chemotherapy regimen, or any other established, recommended treatment option

E.5 End points

E.5.1

Primary end point(s)

The ORR (CR or PR) obtained following administration of tabelecleucel with up to 2 different HLA
restrictions in the SOT or HCT cohort

E.5.1.1

Timepoint(s) of evaluation of this end point

Monitored throughout the study

E.5.2

Secondary end point(s)

- DOR in SOT and HCT cohorts separately.
- ORR and DOR in SOT and HCT cohorts combined.
- Rates of CR and PR
- Time to response and time to best response
- OS
- Rates of allograft loss/rejection episodes (for SOT cohort only): loss is defined as allograft removal, resumption of renal replacement therapy (kidney), initiation of a ventricular assist device (heart), need for mechanical ventilation or extracorporeal membrane oxygenation (lung), re-transplant (any), or placement on a SOT list (any); rejection episodes will be defined according to appropriate criteria for the particular organ transplant.

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

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)

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

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

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

Australia

Canada

United States

Austria

Belgium

France

Germany

Italy

Spain

United Kingdom

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

After treatment is completed or discontinued, subjects will be assessed for disease response every 3 months, up to 24 months from cycle 1 day 1, and every 6 months thereafter up to 5 years from cycle 1 day 1 for survival status.

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