E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
• EBV+ primary imunodeficiency lymphoproliferative disease (LPD)
• EBV+ LPD in the setting of acquired (non-congenital) immunodeficiency
• EBV+ post-transplant LPD involving the central nervous system
• EBV+ post-transplant LPD where standard first line therapy (rituximab or chemotherapy) is not appropriate, including
CD20-negative disease
• EBV+ sarcomas, including leiomyosarcoma
• Chronic active Epstein-Barr virus and EBV+ hemophagocytic lymphohistiocytosis |
|
E.1.1.1 | Medical condition in easily understood language |
Epstein-Barr Virus-associated Diseases |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068349 |
E.1.2 | Term | Epstein-Barr virus associated lymphoproliferative disorder |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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) |
|
E.2.2 | Secondary objectives of the trial |
To evaluate additional clinically relevant outcomes in EBV-associated diseases treated with tabelecleucel |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. Newly diagnosed or relapsed/refractory 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
6. Systemic and/or CNS disease must be measurable by the at least 1 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 disease measurable by MRI, CT, or by positive cytology with EBV detected in CSF
7. Definitive therapy for the underlying PID is planned
8. Subjects with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD
For Subjects with AID LPD
9. Newly diagnosed or relapsed/refractory LPD 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
10. Systemic and/or CNS disease must be measurable by at least 1 of the following criteria:
a. Systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18F-deoxyglucose avidity
b. CNS disease measurable by MRI, CT, or by positive cytology with EBV detected in CSF
11. Subjects who are HIV+ must meet both of the following criteria:
a. An HIV viral load assessed by RT-PCR below the lower limit of detection, according to the institutional standard, within 6 months of the first dose of tabelecleucel
b. CD4 ≥ 50 cells/μL within 6 months prior to the first dose of tabelecleucel
12. Subjects with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD
For Subjects with CNS PTLD
13. Newly diagnosed or relapsed/refractory EBV+ CNS PTLD 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
14. Subject may have systemic and CNS disease, or CNS disease only meeting the following criteria:
a. When present, systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18F-deoxyglucose avidity, except when contraindicated or mandated by local practice, then MRI may be used.
b. CNS disease must be measurable by MRI, CT, or by positive cytology with EBV detected in CSF
15. Subjects with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD
For subjects with EBV+ PTLD, where standard first line therapy (rituximab and/or chemotherapy) is not appropriate, including CD20-negative disease
16. Newly diagnosed, biopsy-proven EBV+ PTLD
17. Ineligible for standard first-line therapy for EBV+ PTLD
18. Subjects must have systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18F-deoxyglucose avidity
For Subjects with Sarcoma, Including LMS
19. Newly diagnosed or failed systemic first-line therapy for EBV+ sarcoma. Subjects with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ sarcoma
20. Biopsy-proven EBV+ sarcoma
21. Measurable disease using PET-CT, CT, and/or MRI following RECIST 1.1 criteria
For Subjects with CAEBV
22. Newly diagnosed or previously treated CAEBV
23. Detectable EBV viremia on at least 2 occasions at a minimum of 90 days apart
24. At least 3 active clinical findings from the following list:
a. Fever ≥38.5°C
b. Splenomegaly, lymphadenopathy, and/or hepatomegaly
c. 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
d. Hypogammaglobulinemia
e. Hemophagocytosis
f. Hepatitis
g. Neuropathy
h. Rash
i. Hydroa vacciniforme
For Subjects with EBV+ viremia with HLH
25. Newly diagnosed or previously treated EBV+ viremia with HLH
26. A molecular diagnosis consistent with HLH-2004 trial
OR
Five or more of the following clinical symptoms:
a. Fever ≥38.5°C
b. Splenomegaly
c. 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
d. Hypertriglyceridemia (fasting ≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
e. Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver
f. Low or absent (NK-cell) activity
g. Ferritin ≥500 ng/mL
h. Elevated soluble CD25 |
|
E.4 | Principal exclusion criteria |
1. Burkitt, T cell (except in the setting of HLH), NK/T-cell lymphoma/LPD, Hodgkin, or transformed lymphoma
2. Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment
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. ≤8 weeks:
i. Cellular therapies: EBV-CTLs, chimeric antigen receptor (CAR) therapies directed at T cells or T cell subsets, donor lymphocyte infusion, other CTLs
ii. Therapies which could impact tabelecleucel function: Anti-thymocyte globulin, alemtuzumab
6. 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
7. Inability or unwillingness to comply with all study procedures
8. 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
9 History of prior allogeneic HCT or SOT |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The ORR obtained following administration of tabelecleucel with up to 4 different human leukocyte antigen (HLA) restrictions |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Monitored throughout the study |
|
E.5.2 | Secondary end point(s) |
• Overall survival (OS)
• Duration of response (DOR)
• Progression-free survival (PFS)
• For EBV-associated lymphoproliferative disease in the setting of primary imunodeficiency (EBV+ PID LPD) and chronic active EBV/hemophagocytic lymphohistiocytosis (CAEBV/HLH) cohorts who are eligible for allogeneic hematopoietic cell
transplant (HCT):
o Number of subjects who reach definitive therapy (ie, allogeneic HCT) for the underlying disease
o Time to allogeneic HCT
• For EBV+ sarcoma cohort, including leiomyosarcoma (LMS)
o Clinical benefit rate
o ORR by immune response evaluation criteria in solid tumors (iRECIST) criteria |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Monitored throughout the study |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
France |
Spain |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study visit is at 24 ± 1 months after cycle 1 day 1 for each subject |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 25 |