A study for subjects with Epstein-Barr Virus-associated Diseases

Phase 1

Conditions: • EBV+ primary imunodeficiency lymphoproliferative disease (LPD)• EBV+ associated lymphoproliferative disease in the setting of acquired (non-congenital) immunodeficiency (EBV+ AID LPD)• EBV+ associated post-transplant LPD involving the central nervous system (EBV+ CNS PTLD)• EBV+ post-transplant LPD where standard first line therapy (rituximab or chemotherapy) is inappropriate, including CD20-negative disease• EBV+ sarcomas, including leiomyosarcoma, or smooth muscle tumors
MedDRA version: 27.0Level: PTClassification code 10068349Term: Epstein-Barr virus associated lymphoproliferative disorderSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Registration Number: EUCTR2020-000177-25-BE

Lead Sponsor: Atara Biotherapeutics, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 190

Inclusion Criteria

1. ECOG performance status =3 for subjects aged =16 years; Lansky score =20 for subjects from =1 year to <16 years
2. Adequate organ function, unless organ dysfunction is considered to be due to the underlying EBV-associated disease
3. Males and females of any age
For subjects with PID LPD
4. Provided written informed consent and assent, if required by law for pediatric subjects in accordance with the requirements
5.Relapsed and/or refractory (R/R) or newly diagnosed PID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator
LPD confirmed by at least 1 of the following:
a. Biopsy-proven EBV+ LPD
b. Positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF
Subjects with R/R disease must have had at least one prior line of systemic therapy and one of the following:
a.Radiographic disease progression per Lugano Classification during or after treatment
b.Failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
6.Subjects may have systemic disease only, systemic and CNS disease or CNS disease only, meeting one of the following criteria:
a.Systemic disease measurable per Lugano Classification criteria, by PET-CT as evidenced by 18F-deoxyglucose avidity, except when contraindicated or mandated by local practice, then MRI may be used.
b.CNS only disease measurable by MRI, CT, or by cytology and flow cytometry with EBV detected in CSF
For subjects with AID LPD
7.R/R or newly diagnosed AID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator, confirmed by at least 1 of the following criteria:
a.Biopsy-proven EBV+ LPD
b.Positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF
Subjects with R/R disease must have had at least one prior line of systemic therapy and one of the following:
a.Radiographic disease progression per Lugano Classification during or after treatment
b.Failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
8.Subjects may have systemic disease only, systemic and CNS disease or CNS disease only, meeting one of the following criteria:
a. Systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18F-deoxyglucose avidity
b. CNS only disease measurable by MRI, CT, or by cytology and flow cytometry with EBV detected in CSF
9. For subjects with AID of idiopathic etiology or AID attributable to immunosenescence, objective laboratory evidence of immunodeficiency (e.g., lymphopenia, hypogammaglobulinemia).
For subjects with CNS PTLD
10.R/R or newly diagnosed CNS PTLD for whom the standard first line therapy is inappropriate, as determined by the investigator, confirmed by at least 1 of the following:
a.Biopsy-proven EBV+ CNS PTLD
b.Positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF
Subjects with R/R disease must have had at least one prior line of systemic therapy and one of the following:
a.Radiographic disease progression per Lugano Classification during or after treatment
b.Failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
11.Subjects may have systemic and CNS disease, or CNS disease only meeting the following criteria:
a.When present, systemic disease measurable per Lugano Clas

Exclusion Criteria

1. Currently active Burkitt, T cell, NK/T-cell lymphoma/LPD, Hodgkin, plasmablastic, transformed lymphoma, active hemophagocytic lymphohistiocytosis, or other malignancies requiring systemic therapy
2. Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment, or known history of HIV infection
3. Suspected or confirmed grade = 2 acute (GvHD) per the CIBMTR consensus grading system or moderate/severe chronic GvHD per NIH consensus criteria at the time of the enrollment
4. Need for vasopressor or ventilatory support at the time of enrollment
5. Prior therapy (in order of increasing washout period) prior to enrollment, as follows:
a. Within 4 weeks or 5 half-lives (whichever is shorter):
i. Any investigational product (co-enrollment in a non-interventional study or a study for sample collection only is permitted)
ii. 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.
b. Within 8 weeks:
i. Prior tabelecleucel (>8 weeks prior to enrollment) is permitted (in consultation with the Medical Monitor) if response was obtained or if usual protocol-directed therapeutic options were not exhausted (e.g., restriction switch options)
ii. Cellular therapies: chimeric antigen receptor (CAR) therapies directed at T cells or T cell subsets, donor lymphocyte infusion, other CTLs, or virus-specific T cells
iii. Therapies which could impact tabelecleucel function: Anti-thymocyte globulin, alemtuzumab
c. any prior treatment with EBV-CTLs with the exception of tabelecleucel as above
6.Female who is breastfeeding or pregnant
7.Any of the following while undergoing treatment with tabelecleucel
and for 90 days after the last dose (details are specified in the body of
the protocol):
For females of childbearing potential: 1) unwilling to use a highly effective method of contraception (i.e., one that can achieve a failure rate of less than 1% per year when used consistently and correctly) or 2) unwilling to refrain from donating eggs
For males: 1) unwilling to use a condom during sexual intercourse or 2) unwilling to refrain from donating sperm or 3) has a female partner of childbearing potential who is unwilling to use a highly effective method of contraception (refer to protocol Section 5.6.4)
8. Inability or unwillingness to comply with all study procedures
9. Ongoing need for daily steroids of >0.5 mg/kg prednisone or glucocorticoid equivalent ongoing methotrexate, or extracorporeal photopheresis. For subjects with CNS disease, protocol specified dexamethasone is permitted
10.Any conditions that may put the study outcomes at undue risk:
a.Life expectancy < 60 days
b.Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk
11. History of prior allogeneic HCT or SOT
12. Prior systemic therapy for PTLD

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine the clinical benefit of tabelecleucel (allogeneic Epstein-Barr virus-specific cytotoxic T lymphocytes [EBV-CTLs]) in subjects with EBV-associated diseases as measured by the objective response rate (ORR);Secondary Objective: To evaluate additional clinically relevant outcomes in EBV-associated diseases treated with tabelecleucel;Primary end point(s): The ORR obtained following administration of tabelecleucel with the first two different human leukocyte antigen (HLA) restrictions;Timepoint(s) of evaluation of this end point: Monitored throughout the study

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Overall survival (OS)<br>• Duration of response (DOR)<br>• Progression-free survival (PFS)<br>• For EBV-associated lymphoproliferative disease in the setting of primary imunodeficiency (EBV+ PID LPD) cohort:<br>o Number of subjects who reach definitive therapy (i.e., allogeneic HCT) for the underlying disease<br>o Time to definitive therapy<br>• For EBV+ sarcoma cohort, including leiomyosarcoma (LMS), or smooth muscle tumors<br>o Clinical benefit rate<br>o ORR by immune response evaluation criteria in solid tumors (iRECIST) criteria [Seymour 2017];Timepoint(s) of evaluation of this end point: Monitored throughout the study