Clinical trial NCT04554914: A Study to Evaluate Tabelecleucel in Participants With Epstein-barr Virus-associated Diseases
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Epstein-Barr Virus (EBV)-Associated Diseases
EBV+ Lymphoproliferative Disease With Primary Immunodeficiency (EBV+ PID LPD)
EBV+ Lymphoproliferative Disease With Acquired (Non-congenital) Immunodeficiency (EBV+ AID LPD)
EBV+ Posttransplant Lymphoproliferative Disease in Central Nervous System (EBV+ 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
Keywords: Allogeneic, Off-The-Shelf T-cell Immunotherapy
Epstein-Barr Virus (EBV)
Epstein-Barr Virus-specific Cytotoxic T lymphocyte (EBV-CTL)
Solid Organ Transplant (SOT)
Hematopoietic Cell Transplant (HCT)
EBVision
Lead sponsor: Atara Biotherapeutics
Sponsor class: INDUSTRY
First posted: 2020-09-18
Enrollment: 190
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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. 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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective response rate (ORR)
timeFrame: Up to 2 years
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Up to 2 years
measure: Duration of response (DOR)
timeFrame: Up to 2 years
measure: Progression-free survival (PFS)
timeFrame: Up to 2 years
measure: For EBV+ PID LPD cohort: Number of participants who reach definitive therapy (ie, allogeneic HCT) for the underlying disease
timeFrame: Up to 2 years
measure: For EBV+ PID LPD cohort: Time to definitive therapy
timeFrame: Up to 2 years
measure: For EBV+ sarcoma cohort, including LMS or smooth muscle tumors: Clinical benefit rate
timeFrame: Up to 2 years
measure: For EBV+ sarcoma cohort, including LMS or smooth muscle tumors: ORR by immune Response Evaluation Criteria in Solid Tumors (iRECIST) criteria
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: LOS Angeles
country: United States
facility: University of California Los Angeles (UCLA) (Adults and Pediatrics)
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County (Pediatrics [up to 25 years old])
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford (Pediatrics only)
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center (Adults and Pediatrics)
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center/ University of Miami
state: Florida
city: Tampa
country: United States
facility: Moffit Cancer Center (Adults only)
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta (Pediatrics only [up to 25 years old])
state: Georgia
city: Atlanta
country: United States
facility: Emory University/Winship Cancer Institute (Adults [>= 16 years])
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago (Pediatrics only)
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center (Adults only)
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute (DFCI) (Adults and Pediatrics)
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Rogel Cancer Center (Adults and Pediatrics)
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota (Adults only)
state: Minnesota
city: St. Louis
country: United States
facility: Washington University in St. Louis (Adults only)
state: Missouri
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore (Adults and Pediatrics)
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center (Adults only)
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center (Adults and Pediatrics)
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center (Adults and Pediatrics)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University - The James Cancer Hospital and Solove Research Institute (Adults only)
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University (Adults and Pediatrics)
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina (Adults and Pediatrics)
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center (Pediatrics only)
state: Texas
city: Houston
country: United States
facility: MD Anderson (Adults and Pediatrics)
state: Texas
city: Graz
country: Austria
facility: Medizinische Universität Graz (Adults only)
state: Styria
city: Salzburg
country: Austria
facility: Uniklinikum Salzburg Landeskrankenhaus (Adults only)
city: Wien
country: Austria
facility: Medizinische Universität Wien (Adults only)
city: Bruxelles
country: Belgium
facility: Hôpital Universitaire des Enfants Reine Fabiola (Pediatrics only)
state: Brussles
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan (Adults only)
state: West-Vlaanderen
city: Roeselare
country: Belgium
facility: Algemeen Ziekenhuis Delta - Campus Rumbeke (Adults only)
state: West-Vlaanderen
city: Montpellier Cedex 5
country: France
facility: Hôpital Saint-Eloi (Adults and Pediatrics)
state: Montpellier
city: Paris
country: France
facility: Hôpital Universitaire Pitié Salpêtrière (Adults only)
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades (Adults and Pediatrics)
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Universitaria Pisana (Adults only)
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù (Adults and Pediatrics)
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita (Pediatrics only)
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón (Adults and Pediatrics)
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal (Adults only)
city: Sevilla
country: Spain
facility: Hospital Universitario Viegen del Rocio (Adults and Pediatrics)
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham NHS Foundation Trust (Adults only)
state: England
city: London
country: United Kingdom
facility: Great Ormond Street Hospital (Pediatrics only)
state: England
Study officials:
affiliation: Atara Biotherapeutics
name: Justin Wahlstrom, MD
role: STUDY_DIRECTOR
References: