Clinical trial NCT03394365: Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Participants With Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease (EBV+ PTLD) After Failure of Rituximab or Rituximab and Chemotherapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Epstein-Barr Virus+ Associated Post-transplant Lymphoproliferative Disease (EBV+ PTLD)
Solid Organ Transplant Complications
Lymphoproliferative Disorders
Allogeneic Hematopoietic Cell Transplant
Stem Cell Transplant Complications
Keywords: Epstein-Barr Virus (EBV)-associated Lymphoproliferative Disease (LPD)
Epstein-Barr Virus (EBV)
Cytotoxic T lymphocyte (CTL)
Cancer After Transplant
Kidney transplant
Renal transplant
Liver transplant
Heart transplant
Lung transplant
Intestinal transplant
Pancreas transplant
Post-transplant Lymphoma
Solid Organ Transplant (SOT)
Bone Marrow Transplant Complications
Epstein-Barr Virus-specific Cytotoxic T Lymphocytes (EBV-CTL)
Hematopoietic Cell Transplant (HCT)
Hematopoietic Stem Cell Transplantation (HSCT)
Allogeneic Hematopoietic Cell Transplant
Allogeneic, Off-The-Shelf T-cell Immunotherapy
Lead sponsor: Atara Biotherapeutics
Sponsor class: INDUSTRY
First posted: 2018-01-09
Enrollment: 66
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 determine the clinical benefit and characterize the safety profile of tabelecleucel for the treatment of Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV+ PTLD) in the setting of (1) solid organ transplant (SOT) after failure of rituximab (SOT-R) and rituximab plus chemotherapy (SOT-R+C) or (2) allogeneic hematopoietic cell transplant (HCT) after failure of rituximab.

Detailed description: This is a multicenter, open-label, phase 3 study to assess the efficacy and safety of tabelecleucel for the treatment of EBV+ PTLD in the setting of SOT-R and SOT-R+C (Cohort \[C\]-SOT) or HCT after failure of rituximab (C-HCT).

SOT-R further included participants:

1. who did not receive chemotherapy and did not have a documented medical reason not to receive chemotherapy (SOT-Ro) or
2. who were considered chemotherapy ineligible/inappropriate (SOT-R-Ci)

Combined population (SOT-R-Ci, SOT-R+C, and HCT) and (SOT-R-Ci and SOT-R+C) who received commercial product, or a product manufactured using a comparable process version (PV) were also used for analysis of outcomes.

Enrollment will be preceded by confirmation of availability of partially human leukocyte antigen (HLA) matched and restricted tabelecleucel for the participant.

Study procedures and product administration will be the same for each cohort. Tabelecleucel will be administered in cycles lasting 5 weeks (35 days). During each cycle, participants will receive intravenous tabelecleucel at a dose of 2 × 10\^6 cells/kg on Days 1, 8, and 15, followed by observation through Day 35. Treatment will continue until maximal response, unacceptable toxicity, initiation of non protocol therapy, or failure of tabelecleucel with up to 2 different HLA restrictions (C-SOT) or up to 4 different HLA restrictions (C-HCT). The study includes a total of 5 years of follow-up for disease and survival status.

Eligibility criteria: Inclusion Criteria:

1. Prior SOT of kidney, liver, heart, lung, pancreas, small bowel, or any combination of these (C-SOT); or prior allogeneic HCT (C-HCT)
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, a head 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 (C-SOT-R or C-HCT) or rituximab plus any concurrent or sequentially administered chemotherapy regimen (C-SOT-R+C) for treatment of PTLD.
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 \&amp;lt; 16 years
8. For C-HCT 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

   1. Absolute neutrophil count ≥ 1000/μL, (C-SOT) or ≥ 500/μL (C-HCT), with or without cytokine support
   2. Platelet count ≥ 50,000/μL, with or without transfusion or cytokine support. For C-HCT, platelet count \&amp;lt; 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)
   3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin each \&amp;lt; 5 × the upper limit of normal; however, ALT, AST, and total bilirubin each ≤ 10 × upper limit of normal 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
10. Subject or subject's representative is willing and able to provide written informed consent

Exclusion Criteria:

1. Burkitt lymphoma, classical Hodgkin lymphoma, or any T cell lymphoma
2. Daily steroids of \&amp;gt; 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 (GvHD) per the Center for International Blood and Marrow Transplant Research 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 C-HCT: 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 Epstein-Barr virus cytotoxic T lymphocytes or chimeric antigen receptor T cells directed against B cells within 8 weeks of enrollment (C-SOT or C-HCT), or unselected donor lymphocyte infusion within 8 weeks of enrollment (C-HCT 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. Any medical condition or organ system dysfunction that in the investigator\&amp;#39;s opinion, could compromise the participant\&amp;#39;s safety or ability to complete the study

Primary outcomes:
measure: Objective response rate (ORR) in the Analysis Cohorts C-SOT, C-HCT, and Combined Population (C-SOT-R+C, C-SOT-R-Ci, and C-HCT) Who Received Commercial Product, or a Product Manufactured Using a Comparable PV
timeFrame: 2 years
Secondary outcomes:
measure: Duration of response (DOR) in the Analysis Cohorts C-SOT and C-HCT Separately
timeFrame: 2 years
measure: ORR and DOR in the Analysis Cohorts C-SOT and C-HCT Combined
timeFrame: 2 years
measure: ORR and DOR in Participants who Received Commercial Product or a Product Manufactured Using a Comparable PV in the Analysis Cohorts C-SOT-R-Ci and C-SOT-R+C Separately and Combined, and in the Analysis Cohort C-HCT
timeFrame: 2 years
measure: DOR in the Analysis Cohort of the Combined Population (C-SOT-R+C, C-SOT-R-Ci, and C-HCT) who Received Commercial Product or a Product Manufactured Using a Comparable PV
timeFrame: 2 years
measure: Rates of Complete Response (CR) and Partial Response (PR)
timeFrame: 2 years
measure: Time to Response
timeFrame: 2 years
measure: Time to Best Response
timeFrame: 2 years
measure: Overall Survival (OS)
timeFrame: 2 years
measure: Rates of Allograft Loss or Rejection Episodes (Analysis Cohort C-SOT)
timeFrame: 2 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope (Adults and Pediatrics)
state: California
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center (Adults only)
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center (Adults only)
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles, Div. of Research Immunology/BMT (Adults and Pediatrics)
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center (Adults and Pediatrics)
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center (Adults only)
state: California
city: New Haven
country: United States
facility: Yale University (Adults and Pediatrics)
state: Connecticut
city: Washington
country: United States
facility: MedStar Georgetown University Hospital (Adults and Pediatrics)
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida (Adults and Pediatrics)
state: Florida
city: Miami
country: United States
facility: University of Miami/Jackson Memorial Hospital (Adults only)
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute (Adults only)
state: Georgia
city: Atlanta
country: United States
facility: Arthur M. Blank Hospital (Pediatrics)
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago (Adults and Pediatrics)
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center - Duchossois Center for Advanced Medicine (Adults only)
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center (Adults and Pediatrics)
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland School of Medicine (Adults only)
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute, Brigham and Women's Hospital (Adults and Pediatrics)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine (Adults only)
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center (Adults only)
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center (Pediatrics only)
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine (Adults only)
state: New York
city: New York
country: United States
facility: Columbia University Medical Center (Adults and Pediatrics)
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center (Adults and Pediatrics)
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center (Adults and Pediatrics)
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Children's Hospital (Adults and Pediatrics)
state: North Carolina
city: Durham
country: United States
facility: Duke Cancer Institute (Adults only)
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation (Adults and Pediatrics)
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital (Pediatrics only)
state: Ohio
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (Adults and Pediatrics)
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University Physicians Pavilion (Adults and Pediatrics)
state: Oregon
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania (Adults only)
state: Pennsylvania
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia Oncology Division, Blood & Marrow Transplant Section (Pediatrics)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center (Adults only)
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina (Adults and Pediatrics)
state: South Carolina
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital (Pediatrics only)
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center Henry-Joyce Cancer Clinic (Adults and Pediatrics)
state: Tennessee
city: Dallas
country: United States
facility: Baylor Scott and White Research Institute (Adults only)
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center - Children's Medical Center (Pediatrics only)
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center (Pediatrics and Adult)
state: Texas
city: Milwaukee
country: United States
facility: Froedtert and Medical College of Wisconsin - Clinical Cancer Center (Adults only)
state: Wisconsin
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead (Pediatrics only)
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital (Adults only)
state: New South Wales
city: Chermside
country: Australia
facility: The Prince Charles Hospital (Adults only)
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital (Adults only)
state: South Australia
city: Melbourne
country: Australia
facility: The Royal Children's Hospital Melbourne (Pediatrics only)
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital (Adults only)
state: Western Australia
city: Wien
country: Austria
facility: Medizinische Universitat Wien (Adults only)
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège Site Sart Tilman (Adults and Pediatrics)
state: Brussels
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven (Adults and Pediatrics)
state: Flemish Brabant
city: Calgary
country: Canada
facility: Alberta Children's Hospital (Adults and Pediatrics)
state: Alberta
city: Toronto
country: Canada
facility: Sick Kids (Pediatrics only)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre (Adults only)
state: Ontario
city: Pessac
country: France
facility: Centre Hospitalier Universitaire de Bordeaux (Adults only)
state: Aquitaine
city: Paris
country: France
facility: Hôpital Saint Antoine (Adults only)
state: Ile-de-France
city: Lille cedex
country: France
facility: Centre Hospitalier Régional Universitaire de Lille (Adults and Pediatrics)
state: Nord-Pas-de-Calais
city: Paris 15
country: France
facility: Hôpital Necker-Enfants Malades (Pediatrics only)
state: Île-de-France
city: Paris Cedex 13
country: France
facility: Hôpital Universitaire Pitié Salpêtrière (Adults only)
state: Île-de-France
city: Milano
country: Italy
facility: Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (Adults only)
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo (Adults and Pediatrics)
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli (Adults only)
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesu (Pediatrics only)
city: Torino
country: Italy
facility: Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino (Adults only)
city: Badalona
country: Spain
facility: Hospital Duran i Reynals (Adults and Pediatrics)
state: Barcelona
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla (Adults and Pediatrics)
state: Cantabria
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón - Institut de Recerca (Adults and Pediatrics)
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón (Adults and Pediatrics)
city: Sevilla
country: Spain
facility: University Hospital Virgen del Rocio (Adults and Pediatrics)
city: Valencia
country: Spain
facility: Hospital Universitario La Fe (Adults and Pediatrics)
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust (Adults only)
state: England
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust (Adults only)
state: England
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust (Adults only)
state: England
Study officials:
affiliation: Atara Biotherapeutics
name: Aditi Mehta, DO
role: STUDY_DIRECTOR
References: