A Phase II Study of Epstein-Barr Virus-Specific Immunotherapy for Nasopharyngeal Carcinoma

Study Overview
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Brief Summary
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The purpose of this research study is to determine how effective and how safe it is to give an Epstein-Barr Virus (EBV) immunotherapy product to participants with nasopharyngeal carcinoma (NPC) associated with EBV that has come back or spread to other parts of the participant's body. This is phase II study with the aim of establishing a baseline of efficacy.

Detailed Description
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The study follows a pilot study optimizing and refining the manufacturing process, streamlining logistics (eg infusion protocol, enrolling out-of-town patients), increasing the cell dose, defining optimal patient eligibility, and improving monitoring for patients. Eligible participants will undergo a blood draw to obtain peripheral blood mononuclear cells (PBMCs) used for preparation of the immunotherapy product [estimated time 14-16 weeks]. Participants' PBMCs will be isolated by density centrifugation from peripheral blood and then infected with EBV to generate EBV-transformed B-lymphoblastoid cell lines (LCLs). LCLs will be irradiated and then used to stimulate autologous T cells, yielding an EBV-specific, autologous T cell product.

Official Title
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A Phase II Study of Epstein-Barr Virus-Specific Immunotherapy for Nasopharyngeal Carcinoma

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Biological: Epstein-Barr Virus Specific Immunotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven NPC of an WHO grade, associated with EBV infection documented by the presence of EBER expression by in situ hybridization in the tumor. Positive EBER staining from another institution must be confirmed by pathology review at Brigham and Women's Hospital. Other confirmation of EBV-associated disease is acceptable, such as EBV DNA in situ hybridization, if EBER analysis is not adequate Incurable NPC Recovery from toxicity from any prior NPC therapy to grade 1 or better 18 years of age or older Evaluable or measurable disease, according to modified RECIST ECOG Performance Status of 0 or 1 Adequate bone marrow, liver and renal function as outlined in protocol Exclusion Criteria: Radiotherapy for primary NPC within 8 weeks of enrollment, or radiotherapy for any other reason within 6 weeks Chemotherapy for NPC within 2 weeks of enrollment Other cancer in the past 5 years, except for carcinoma in situ of the cervix or bladder, or non-melanomatous skin cancer Uncontrolled central nervous system metastases Active hepatitis, known HIV, or other condition that requires immunosuppressive therapy, including current use of high dose systemic corticosteroids Autoimmune disease, such as systemic lupus erythematosis or rheumatoid arthritis, that is active and requires current immunosuppressive therapy Active uncontrolled serious infection Women of child-bearing potential who have a positive pregnancy test or are breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EBV-stimulated cytotoxic T-lymphocyte (EBV-CTL) Immunotherapy<br>Eligible participants underwent a blood draw to obtain peripheral blood mononuclear cells (PBMCs) used for preparation of the immunotherapy product [estimated preparation time 14-16 weeks]. Participants received palliative chemotherapy for NPC as standard of care during the period required for T-cell production. Participants who achieved a partial response or better while receiving palliative chemotherapy continued to receive chemotherapy for 3 to 6 cycles and were only eligible for immunotherapy when progressive disease (PD) was confirmed. Each participant received a minimum of 2 EBV-CTL infusions, given 2 weeks apart, at doses of 1x108 cells/m2. A 3rd infusion was offered to participants 8-12 weeks after the 2nd infusion based on response, tolerability and sufficient immunotherapy product reserves. | Biological: Epstein-Barr Virus Specific Immunotherapy<br> <br> * Other names: Cell based vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate (ORR) | ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. | Restaging scans were performed every 8 weeks on treatment up to 20 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | TTP estimated using the Kaplan-Meier method is defined as the duration of time from registration to documented first observation of progressive disease (PD), or censored at date last known progression-free. Based on RECIST 1.1, radiographic PD is defined as at least a 20% increase in the sum of the longest diameter (LD) for all target lesions (up to 10), taking as reference the smallest sum LD since beginning treatment or the appearance of one or more new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing lesions. | Restaging scans were performed every 8 weeks until PD. Follow-up duration was up to 92 months. | 
| Number of Participants With Grade 1-2 Fatigue Adverse Events, as Accurate and Appropriate | All grade 1-2 fatigue adverse events (AE) with any treatment attribution as reported on case report forms were counted. The number of participants experiencing at least one grade 1-2 fatigue AE during the time of observation. | Adverse events were assessed after each infusion treatment. Treatment duration was up to 66 months. | 
| Overall Survival (OS) | OS estimated using the Kaplan-Meier (KM) method is defined as the time from registration to death, or censored at the date last known alive. | Participants were followed for survival per institutional practice until death or lost-to-follow-up. Follow-up duration was up to 92 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epstein-Barr Virus, NPC, EBV, immunotherapy