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

Stem Cell Transplant Complications Clinical Trial

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 (EBVision)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04554914
• Other study ID #: ATA129-EBV-205
• Secondary ID: 2020-000177-25
• Status: Recruiting
• Phase: Phase 2
• Start date: July 14, 2021
• Est. completion date: May 2029

Study information

• Verified date: October 2023
• Source: Atara Biotherapeutics
• Contact: Study Director
• Phone: 650-278-8930
• Email: clinicalstudies[@]atarabio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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. Participants will be enrolled in one of the following cohorts:

• EBV+ lymphoproliferative disease (LPD) in the setting of primary immunodeficiency (PID) (EBV+ PID LPD) that is relapsed and/or refractory (R/R) or newly diagnosed where standard first-line therapy is inappropriate

• EBV+ LPD in the setting of acquired (non-congenital) immunodeficiency (AID) (EBV+ AID LPD) that is R/R or newly diagnosed where standard first-line therapy is inappropriate

• EBV+ posttransplant lymphoproliferative disease (PTLD) involving the central nervous system (CNS) (EBV+ CNS PTLD) that is R/R or newly diagnosed where standard first-line therapy is inappropriate

• EBV+ PTLD where standard first-line therapy (rituximab or chemotherapy) is inappropriate, including cluster of differentiation antigen 20 (CD20)-negative disease

• EBV+ sarcomas, including leiomyosarcoma (LMS), or smooth muscle tumors that is rapidly progressive where standard first-line therapy is inappropriate

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 response, 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, two consecutive complete responses (CRs), or up to 12 months from the 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 four different HLA restrictions is allowed for any participant.

After treatment is completed or discontinued, participants will complete a safety follow-up visit at 30 days after the last dose and then will enter a quarterly follow-up period. 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, 8 evaluable 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) who receive tabelecleucel and have at least 1 valid postbaseline disease response assessment. The number of participants enrolled in Stage 2 for each cohort will depend on the number of observed responders in Stage 1. Sponsor may decide not to move forward to Stage 2 in any cohort even if the criteria to move forward for that cohort are met. The decision not to move forward may also be based on data from one or other cohorts.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 190
• Est. completion date: May 2029
• Est. primary completion date: June 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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:

• R/R or newly diagnosed PID LPD for whom the standard first-line therapy is inappropriate, as determined by investigator. The LPD is confirmed by at least biopsy-proven EBV+ LPD or positive cerebrospinal fluid (CSF) cytology with or without radiographically measurable intracranial disease with EBV detected in CSF.

• Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification (Cheson BD, et al. J Clin Oncol. 2014;27:3059) during or after treatment or failure to achieve a CR or partial response (PR) (defined by Lugano radiographic criteria) after standard first-line therapy

• Participant may have systemic disease only, systemic and CNS disease, or CNS disease only

• For participants with AID LPD:

• R/R or newly diagnosed AID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator. The LPD is confirmed by at least biopsy-proven EBV+ LPD or positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF.

• Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification during or after treatment or failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy

• Participant may have systemic disease only, systemic and CNS disease, or CNS disease only

• For participants with AID etiology or AID attributable to immunosenescence, objective laboratory evidence of immunodeficiency

• For participants with CNS PTLD:

• R/R or newly diagnosed EBV+ CNS PTLD for whom the standard first-line therapy is inappropriate, as determined by the investigator. The CNS PTLD is histologically confirmed by at least biopsy-proven EBV+ CNS PTLD or positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF.

• Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification during or after treatment or failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy

• Participant may have systemic and CNS disease or CNS disease only

• For participants with EBV+ PTLD, including CD20-negative disease:

• Biopsy-proven EBV+ PTLD for whom standard first-line therapy (rituximab and/or chemotherapy) is inappropriate, 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, or smooth muscle tumors:

• 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

• Participants with newly diagnosed EBV+ sarcoma for whom the standard first-line therapy is inappropriate, as determined by the investigator

• Biopsy-proven EBV+ sarcoma meeting one of the criteria's of pathologically confirmed EBV+ Leiomyosarcoma or EBV+ sarcoma or smooth muscle tumor

• Measurable disease using diagnostic CT and/or MRI following RECIST 1.1 criteria (Eisenhauer et al. 2009. Eur J Cancer 45[2]:228-247)

Exclusion Criteria:

• Currently active Burkitt, T-cell, natural killer/T-cell lymphoma/LPD, Hodgkin, plasmablastic, transformed lymphoma, active hemophagocytic lymphohistiocytosis, or other malignancies requiring systemic therapy

• Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment, or known history of human immunodeficiency virus (HIV) infection

• 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 at the time of enrollment

• Prior therapy (in order of increasing washout period) prior to enrollment as follows:

• 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: prior tabelecleucel (>8 weeks prior to enrollment) is permitted if response was obtained or if usual protocol-directed therapeutic options were not exhausted, for cellular therapies (chimeric antigen receptor therapies directed at T-cells or T-cell subsets, donor lymphocyte infusion, other CTLs or virus-specific T-cells); and/or therapies which could impact tabelecleucel function (anti-thymocyte globulin, alemtuzumab)

• Any prior treatment with EBV-CTLs with the exception of tabelecleucel as above

• Women who are breastfeeding or pregnant

• Unwilling to comply with protocol specified contraceptive/reproductive restrictions from enrollment through 90 days after the last treatment

• Ongoing need for daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis (for participants with CNS disease, protocol-specified dexamethasone is permitted and concludes by the time of enrollment)

• Any conditions that may put the study outcomes at undue risk (life expectancy < 60 days or any life-threatening illness, medical condition, or organ system dysfunction)

• For participants with PID LPD or AID LPD: history of prior allogeneic HCT or solid organ transplant

• For participants with EBV+ PTLD: prior systemic therapy for PTLD

Related Conditions & MeSH terms

• Allogeneic Hematopoietic Cell Transplant
• EBV+ Post-transplant Lymphoproliferative Disease (EBV+ PTLD)
• EBV+ Sarcomas
• Epstein-Barr Virus (EBV)-Associated Diseases
• Epstein-Barr Virus Infections
• Immunologic Deficiency Syndromes
• Leiomyosarcoma
• Lymphoproliferative Disorders
• Primary Immunodeficiency Diseases
• Solid Organ Transplant Complications
• Stem Cell Transplant Complications

Intervention

Biological:
• Tabelecleucel
Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.

Locations

Country	Name	City	State
Austria	Medizinische Universität Graz (Adults only)	Graz	Styria
Austria	Uniklinikum Salzburg Landeskrankenhaus (Adults only)	Salzburg
Austria	Medizinische Universität Wien (Adults only)	Wien
Belgium	Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan (Adults only)	Brugge	West-Vlaanderen
Belgium	Hôpital Universitaire des Enfants Reine Fabiola (Pediatrics only)	Bruxelles	Brussles
Belgium	Algemeen Ziekenhuis Delta - Campus Rumbeke (Adults only)	Roeselare	West-Vlaanderen
France	Hôpital Saint-Eloi (Adults and Pediatrics)	Montpellier Cedex 5
France	Hôpital Necker-Enfants Malades (Adults and Pediatrics)	Paris
France	Hôpital Universitaire Pitié Salpêtrière (Adults only)	Paris
Italy	Azienda Ospedaliero-Universitaria Pisana (Adults only)	Pisa
Italy	Ospedale Pediatrico Bambino Gesù (Adults and Pediatrics)	Roma
Italy	Ospedale Infantile Regina Margherita (Pediatrics only)	Torino
Spain	Hospital Universitari Vall d'Hebrón (Adults and Pediatrics)	Barcelona
Spain	Hospital Universitario Ramón y Cajal (Adults only)	Madrid
Spain	Hospital Universitario Viegen del Rocio (Adults and Pediatrics)	Sevilla
United Kingdom	University Hospital Birmingham NHS Foundation Trust (Adults only)	Birmingham	England
United Kingdom	Great Ormond Street Hospital (Pediatrics only)	London	England
United States	University of Michigan Rogel Cancer Center (Adults and Pediatrics)	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta (Pediatrics only [up to 25 years old])	Atlanta	Georgia
United States	Emory University/Winship Cancer Institute (Adults [>= 16 years])	Atlanta	Georgia
United States	University of Maryland Medical Center (Adults only)	Baltimore	Maryland
United States	Dana Farber Cancer Institute (DFCI) (Adults and Pediatrics)	Boston	Massachusetts
United States	The Children's Hospital at Montefiore (Adults and Pediatrics)	Bronx	New York
United States	Medical University of South Carolina (Adults and Pediatrics)	Charleston	South Carolina
United States	Ann & Robert H. Lurie Children's Hospital of Chicago (Pediatrics only)	Chicago	Illinois
United States	Cleveland Clinic Taussig Cancer Center (Adults and Pediatrics)	Cleveland	Ohio
United States	The Ohio State University - The James Cancer Hospital and Solove Research Institute (Adults only)	Columbus	Ohio
United States	University of Texas Southwestern Medical Center (Pediatrics only)	Dallas	Texas
United States	MD Anderson (Adults and Pediatrics)	Houston	Texas
United States	University of California Los Angeles (UCLA) (Adults and Pediatrics)	Los Angeles	California
United States	Sylvester Comprehensive Cancer Center/ University of Miami	Miami	Florida
United States	University of Minnesota (Adults only)	Minneapolis	Minnesota
United States	Columbia University Irving Medical Center (Adults only)	New York	New York
United States	Memorial Sloan-Kettering Cancer Center (Adults and Pediatrics)	New York	New York
United States	Children's Hospital of Orange County (Pediatrics [up to 25 years old])	Orange	California
United States	Lucile Packard Children's Hospital Stanford (Pediatrics only)	Palo Alto	California
United States	Oregon Health and Science University (Adults and Pediatrics)	Portland	Oregon
United States	University of California Davis Comprehensive Cancer Center (Adults and Pediatrics)	Sacramento	California
United States	Washington University in St. Louis (Adults only)	Saint Louis	Missouri
United States	Moffit Cancer Center (Adults only)	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Atara Biotherapeutics

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  France,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response rate (ORR)		Up to 2 years
Secondary	Overall survival (OS)		Up to 2 years
Secondary	Duration of response (DOR)		Up to 2 years
Secondary	Progression-free survival (PFS)		Up to 2 years
Secondary	For EBV+ PID LPD cohort: Number of participants who reach definitive therapy (ie, allogeneic HCT) for the underlying disease		Up to 2 years
Secondary	For EBV+ PID LPD cohort: Time to definitive therapy		Up to 2 years
Secondary	For EBV+ sarcoma cohort, including LMS or smooth muscle tumors: Clinical benefit rate		Up to 2 years
Secondary	For EBV+ sarcoma cohort, including LMS or smooth muscle tumors: ORR by immune Response Evaluation Criteria in Solid Tumors (iRECIST) criteria		Up to 2 years