A Study to Evaluate Tabelecleucel in Participants With Epstein-barr Virus-associated Diseases

Sponsor

Atara Biotherapeutics (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04554914

Collaborator

(none)

228

Enrollment

Locations

Arms

93.6

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy and safety of tabelecleucel in participants with Epstein-Barr virus (EBV) associated diseases.

Condition or Disease	Intervention/Treatment	Phase
Epstein-Barr Virus (EBV)-Associated Diseases EBV+ Lymphoproliferative Disease With Primary Immunodeficiency (PID LPD) EBV+ Lymphoproliferative Disease With Acquired (Non-congenital) Immunodeficiency (AID LPD) EBV+ Posttransplant Lymphoproliferative Disease in Central Nervous System (CNS PTLD) EBV+ Post-transplant Lymphoproliferative Disease (EBV+ PTLD) Solid Organ Transplant Complications Lymphoproliferative Disorders Allogeneic Hematopoietic Cell Transplant Stem Cell Transplant Complications EBV+ Sarcomas Leiomyosarcoma Chronic Active Epstein-Barr Virus (CAEBV) Chronic Active Epstein-Barr Virus With Hemophagocytic Lymphohistiocytosis (HLH) Lymphohistiocytosis, Hemophagocytic	Biological: Tabelecleucel	Phase 2

Detailed Description

This is a multicenter, multicohort, open label, single-arm, Phase 2 study to assess the efficacy and safety of tabelecleucel for the treatment of EBV-associated diseases in participants who are newly diagnosed or relapsed/refractory to prior treatment. Newly diagnosed or relapsed/refractory participants will be enrolled in one of the following cohorts:

EBV+ lymphoproliferative disease (LPD) in the setting of primary immunodeficiency (PID) (PID LPD)
EBV+ LPD in the setting of acquired (non-congenital) immunodeficiency (AID) (AID LPD)
EBV+ posttransplant lymphoproliferative disorder involving the central nervous system (CNS PTLD)
EBV+ PTLD where standard first line therapy (rituximab or chemotherapy) is not appropriate, including CD20 negative disease
EBV+ sarcomas, including leiomyosarcoma (LMS)
Chronic active EBV (CAEBV) and EBV+ hemophagocytic lymphohistiocytosis (HLH) (CAEBV/HLH cohort)

Tabelecleucel will be administered in cycles lasting for 35 days. During each cycle, participants will receive tabelecleucel at a dose of 2 x 10^6 cells/kg intravenously (IV) weekly for 3 weeks, followed by observation through Day 35. Treatment will continue until maximal disease progression, unacceptable toxicity, or initiation of nonprotocol therapy for the underlying disease. For EBV+ sarcoma cohort, treatment will continue until disease progression, unacceptable toxicity, or up to 24 months from first dose. Participants who fail to respond to initial tabelecleucel treatment may continue tabelecleucel with a different human leukocyte antigen (HLA) restriction (termed a Restriction Switch), if available; administration of tabelecleucel with up to 4 different HLA restrictions is allowed for any participant.

Participants will complete a safety follow-up visit at 30 days after the last dose. Participants without documented disease progression will be assessed every 3 months after the safety follow-up visit for continued evaluation of disease response until the end of study (EOS) visit at 24-month after first dose. Participants with disease progression any time prior to the EOS visit will continue to be followed every 3 months for survival status until the EOS visit.

An adaptive 2-stage design will be used for each cohort in this study. For each cohort, approximately 8 participants will be enrolled in Stage 1. The decision to move to Stage 2 enrollment will be based on an interim analysis of the first 8 evaluable participants in the cohort using investigator's assessment (per defined radiologic, clinical, and/or laboratory response criteria). The number of participants enrolled in Stage 2 for each cohort will depend on the number of observed responders in Stage 1.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

228 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 14, 2021

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

May 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EBV+ PID LPD Participants with newly diagnosed or relapsed/refractory EBV+ PID LPD will receive IV tabelecleucel.	Biological: Tabelecleucel Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases. Other Names: tab-cel® ATA129 EBV-CTLs
Experimental: EBV+ AID LPD Participants with newly diagnosed or relapsed/refractory EBV+ AID LPD will receive IV tabelecleucel.	Biological: Tabelecleucel Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases. Other Names: tab-cel® ATA129 EBV-CTLs
Experimental: EBV+ PTLD CNS Participants with newly diagnosed or relapsed/refractory EBV+ PTLD CNS will receive IV tabelecleucel.	Biological: Tabelecleucel Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases. Other Names: tab-cel® ATA129 EBV-CTLs
Experimental: EBV+ PTLD (ineligible for first-line therapy or CD20 negative) Participants with EBV+ PTLD where standard first line therapy (rituximab or chemotherapy) is not appropriate, including CD20 negative disease will receive IV tabelecleucel.	Biological: Tabelecleucel Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases. Other Names: tab-cel® ATA129 EBV-CTLs
Experimental: EBV+ sarcoma, including LMS Participants with newly diagnosed or failed systemic first-line therapy for EBV+ sarcoma will receive IV tabelecleucel.	Biological: Tabelecleucel Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases. Other Names: tab-cel® ATA129 EBV-CTLs
Experimental: CAEBV/ HLH Participants with newly diagnosed or previously treated CAEBV or EBV viremia with HLH will receive IV tabelecleucel.	Biological: Tabelecleucel Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases. Other Names: tab-cel® ATA129 EBV-CTLs

Outcome Measures

Primary Outcome Measures

Objective response rate (ORR) [Up to 2 years]

Secondary Outcome Measures

Overall survival (OS) [Up to 2 years]
Duration of response (DOR) [Up to 2 years]
Progression-free survival (PFS) [Up to 2 years]
For EBV+ PID LPD and CAEBV/HLH cohorts who are eligible for allogeneic HCT: Number of participants who reach definitive therapy (ie, allogeneic HCT) for the underlying disease [Up to 2 years]
For EBV+ PID LPD and CAEBV/HLH cohorts who are eligible for allogeneic HCT: Time to allogeneic HCT [Up to 2 years]
For EBV+ sarcomas, including LMS: Clinical benefit rate [Up to 2 years]
For EBV+ sarcomas, including LMS: ORR by immune response evaluation criteria in solid tumors (iRECIST) criteria [Up to 2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of EBV+ disorder
Eastern Cooperative Oncology Group performance status <= 3 for participants aged >= 16 years; Lansky score >= 20 for participants from 1 year to < 16 years
Adequate organ function test results, unless organ dysfunction is considered to be due to the underlying EBV-associated disease by the investigator

Cohort-specific Inclusion Criteria:

For participants with PID LPD:
Newly diagnosed or relapsed/refractory LPD confirmed by biopsy-proven EBV+ LPD or positive cerebrospinal fluid (CSF) cytology with or without radiographically measurable intracranial disease with EBV detected in CSF
Participant must have systemic measurable disease and/ or CNS measurable disease
Definitive therapy (eg, allogeneic HCT, gene therapy) for the underlying PID is planned
Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
For participants with AID LPD:
Newly diagnosed or relapsed/refractory LPD confirmed by biopsy-proven EBV+ LPD or positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF
Participant must have systemic measurable disease and/ or CNS measurable disease
Participants who are human immunodeficiency virus positive (HIV+) must meet both of the following criteria: Have an HIV viral load assessed by reverse transcription-polymerase chain reaction (RT-PCR) below the lower limit of detection and CD4 >= 50 cells/μL within 6 months prior to the first dose of tabelecleucel
Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
For participants with CNS PTLD:
Newly diagnosed or relapsed/refractory EBV+ CNS PTLD histologically confirmed by biopsy-proven EBV+ CNS PTLD or positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF
Participant may have systemic and CNS disease or CNS disease only
Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
For participants with EBV+ PTLD, where standard first line therapy (rituximab and/or chemotherapy) is not appropriate, including CD20-negative disease:
Newly diagnosed, biopsy-proven EBV+ PTLD
Ineligible for standard first-line therapy for EBV+ PTLD, as determined by the investigator
Participants must have systemic disease measurable per Lugano Classification criteria, except when contraindicated or mandated by local practice, then MRI may be used.
For participants with sarcoma, including LMS:
Newly diagnosed or failed systemic first-line therapy for EBV+ sarcoma. Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ sarcoma, as determined by the investigator.
Biopsy-proven EBV+ sarcoma
Measurable disease using diagnostic PET/CT and/or MRI following RECIST 1.1 criteria
For participants with CAEBV:
Newly diagnosed or previously treated CAEBV
Detectable EBV viremia on at least 2 occasions at a minimum of 90 days apart
At least 3 active clinical findings (per Kimura H, et al. Front Immunol. 2017;8:1867) as: Fever >= 38.5°C; splenomegaly, lymphadenopathy, and/or hepatomegaly; cytopenia affecting at least 2 or 3 lineages in the peripheral blood (hemoglobin < 9 g/dL, platelets < 100 × 10^{3/mL, neutrophils < 1 ×
10}3/mL); hypogammaglobulinemia; hemophagocytosis; hepatitis; neuropathy; rash; and hydroa vacciniforme
For participants with EBV+ viremia with HLH:
Newly diagnosed or previously treated EBV+ viremia with HLH
A molecular diagnosis consistent with HLH-2004 trial (per Henter JI, et al. Pediatr Blood Cancer. 2007;48:124-31) OR 5 or more of the clinical symptoms (per Jordan MB, et al. Blood. 2011;118:4041-4052): Fever >= 38.5°C; splenomegaly; cytopenia affecting at least 2 or 3 lineages in the peripheral blood (hemoglobin < 9 g/dL, platelets < 100 × 10^{3/mL, neutrophils < 1 × 10}3/mL); hypertriglyceridemia (fasting >= 265 mg/dL) and/or hypofibrinogenemia (<= 150 mg/dL); hemophagocytosis in bone marrow, spleen, lymph nodes, or liver; low or absent natural killer cell (NK-cell) activity; ferritin >= 500 ng/mL; and elevated soluble CD25

Exclusion Criteria:

Burkitt, T-cell (except in the setting of HLH), natural killer/T-cell lymphoma/LPD, Hodgkin, or transformed lymphoma
Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment
Suspected or confirmed Grade >= 2 acute graft-versus-host disease (GvHD) per the Center for International Blood and Marrow Transplant Research (CIBMTR) consensus grading system or extensive chronic GvHD per National Institutes of Health (NIH) consensus criteria at the time of the enrollment
Need for vasopressor or ventilatory support
Prior therapy (in order of increasing washout period) prior to enrollment as:
Within 4 weeks or 5 half-lives (whichever is shorter) for any investigational product and/ or 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
Within <= 8 weeks for cellular therapies (EBV-CTLs, chimeric antigen receptor therapies directed at T cells or T-cell subsets, donor lymphocyte infusion, other CTLs); and/or therapies which could impact tabelecleucel function (anti-thymocyte globulin, alemtuzumab)
Unwilling to use protocol specified contraceptive methods
Women who are pregnant or breastfeeding
Ongoing need for daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis (protocol-specified dexamethasone is permitted and concludes by the time of enrollment)
For participants with PID LPD or AID LPD: history of prior allogeneic HCT or solid organ transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Orange County (Pediatrics [up to 25 years old])	Orange	California	United States	92868
2	University of California Davis Comprehensive Cancer Center (Adults and Pediatrics)	Sacramento	California	United States	95817
3	Sylvester Comprehensive Cancer Center/ University of Miami	Miami	Florida	United States	33136
4	Moffit Cancer Center (Adults only)	Tampa	Florida	United States	33612
5	Children's Healthcare of Atlanta (Pediatrics only [up to 25 years old])	Atlanta	Georgia	United States	30322
6	Emory University/Winship Cancer Institute (Adults [>= 16 years])	Atlanta	Georgia	United States	30322
7	Ann & Robert H. Lurie Children's Hospital of Chicago (Pediatrics only)	Chicago	Illinois	United States	60611
8	University of Maryland Medical Center (Adults only)	Baltimore	Maryland	United States	21201
9	Dana Farber Cancer Institute (DFCI) (Adults and Pediatrics)	Boston	Massachusetts	United States	02215
10	University of Michigan Rogel Cancer Center (Adults and Pediatrics)	Ann Arbor	Michigan	United States	48109
11	University of Minnesota (Adults only)	Minneapolis	Minnesota	United States	55455
12	Washington University in St. Louis (Adults only)	Saint Louis	Missouri	United States	63110
13	The Children's Hospital at Montefiore (Adults and Pediatrics)	Bronx	New York	United States	10467
14	Columbia University Irving Medical Center (Adults only)	New York	New York	United States	10032
15	Memorial Sloan-Kettering Cancer Center (Adults and Pediatrics)	New York	New York	United States	10065
16	Cleveland Clinic Taussig Cancer Center (Adults and Pediatrics)	Cleveland	Ohio	United States	44195
17	The Ohio State University - The James Cancer Hospital and Solove Research Institute (Adults only)	Columbus	Ohio	United States	43210
18	Oregon Health and Science University (Adults and Pediatrics)	Portland	Oregon	United States	97239
19	Medical University of South Carolina (Adults and Pediatrics)	Charleston	South Carolina	United States	29425
20	University of Texas Southwestern Medical Center (Pediatrics only)	Dallas	Texas	United States	75390
21	MD Anderson (Adults and Pediatrics)	Houston	Texas	United States	77030
22	Medizinische Universität Graz (Adults only)	Graz	Styria	Austria	8036
23	Uniklinikum Salzburg Landeskrankenhaus (Adults only)	Salzburg		Austria	5020
24	Medizinische Universität Wien (Adults only)	Wien		Austria	1090
25	Hôpital Universitaire des Enfants Reine Fabiola (Pediatrics only)	Bruxelles	Brussles	Belgium	1020
26	Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan (Adults only)	Brugge	West-Vlaanderen	Belgium	8000
27	Algemeen Ziekenhuis Delta - Campus Rumbeke (Adults only)	Roeselare	West-Vlaanderen	Belgium	8800
28	Hôpital Saint-Eloi (Adults and Pediatrics)	Montpellier Cedex 5		France	34295
29	Hôpital Universitaire Pitié Salpêtrière (Adults only)	Paris		France	75013
30	Hôpital Necker-Enfants Malades (Adults and Pediatrics)	Paris		France	75015
31	Azienda Ospedaliero-Universitaria Pisana (Adults only)	Pisa		Italy	56126
32	Ospedale Pediatrico Bambino Gesù (Adults and Pediatrics)	Roma		Italy	00165
33	Ospedale Infantile Regina Margherita (Pediatrics only)	Torino		Italy	10126
34	Hospital Universitari Vall d'Hebrón (Adults and Pediatrics)	Barcelona		Spain	08035
35	Hospital Universitario Ramón y Cajal (Adults only)	Madrid		Spain	28034
36	Hospital Universitario Viegen del Rocio (Adults and Pediatrics)	Sevilla		Spain	41013
37	University Hospital Birmingham NHS Foundation Trust (Adults only)	Birmingham	England	United Kingdom	B15 2TH
38	Great Ormond Street Hospital (Pediatrics only)	London	England	United Kingdom	WC1N 3JH