A Phase III Trial Evaluating Chemotherapy and Immunotherapy for Advanced Nasopharyngeal Carcinoma (NPC) Patients

Study Overview
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Brief Summary
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This study is a multi-center, randomized, open label, Phase III clinical trial for advanced Nasopharyngeal Carcinoma(NPC) Patients. Drugs used in chemotherapy, such as gemcitabine and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving an infusion of a person's cytotoxic T cells (CTL) that have been treated in the laboratory may help the body build an effective immune response to kill tumor cells. Giving combination chemotherapy together with laboratory-treated T cells may kill more tumor cells. This Phase III trial is to assess if combined gemcitabine-carboplatin (GC) followed by adoptive T-cell therapy would improve clinical outcome for patients with advanced nasopharyngeal carcinoma (NPC). It is also the world's first, and largest, Phase 3 T-cell therapy cancer trial ever conducted, and enrollment is ongoing for 330 patients from 30 hospital centers across Asia and the United States. This clinical trial is conducted on the back of a successful Phase 2 NPC trial involving 38 patients at the National Cancer Centre, Singapore. This trial produced the best published 2-year (62.9%), and median overall survival (OS) data (29.9 months) in 35 patients with advanced NPC who received autologous EBV-specific CTL. Kindly see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978790/ for the Phase 2 publication titled Adoptive T-cell Transfer and Chemotherapy in the First line treatment of Metastatic and/or Locally Recurrent Nasopharyngeal Carcinoma.

Detailed Description
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330 patients will be randomized after their eligibility status has been fully determined and informed consent has been obtained. Patients will be randomly allocated to receive either Arm A (Gemcitabine and Carboplatin (GC) x 4* cycles and EBV-specific CTL) or Arm B (GC x 6 cycles alone) in a 1:1 ratio using a stratified block randomization scheme. The stratification variables are country and disease stage (metastatic vs locally recurrent). *Additional 1-2 chemotherapy cycles (up to total 6 chemo cycles) might be given upon discretion of Investigator, if EBV-specific CTL infusions are not available in time for the 1st scheduled infusion. After randomization, patients in Arm A will have their peripheral blood taken for the establishment of cytotoxic T cell line and EBV transformed lymphoblastoid cell line (CTL). Within two weeks of enrollment, patients will commence combination GC chemotherapy for a total of 4 cycles. Patients in Stage 2 of study will receive the EBV-specific CTL immunotherapy. As of 1 May 2020, patients who have not received the first infusion of EBV-specific CTLs, will instead continue to receive a total of 6 cycles combination of Gemcitabine (1000 mg/m2) and carboplatin (AUC2) on Days 1, 8, 15 every 28 days

Official Title
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A Multicentre, Randomized, Open-Label, Phase III Clinical Trial Of Gemcitabine And Carboplatin Followed By Epstein-Barr Virus-Specific Autologous Cytotoxic T Lymphocytes Versus Gemcitabine And Carboplatin As First Line Treatment For Advanced Nasopharyngeal Carcinoma(NPC) Patients

Conditions
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Nasopharyngeal Carcinoma

Intervention / Treatment
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* Biological: autologous EBV specific Cytotoxic T cells
* Drug: combination IV gemcitabine and IV carboplatin (AUC2)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Metastatic or locally recurrent EBV-positive, non-keratinizing and/ or undifferentiated NPC* who do not have curative options such as chemo-radiation or surgery *Subjects will be enrolled based on confirmed histology diagnosis of the NPC Radiologically measurable disease as per RECIST 1.1 Human Immunodeficiency Virus (HIV) negative* * Status of HIV must be confirmed via a HIV antibody test or other confirmatory tests available within 4 weeks of screening Bilirubin <2 x upper limit of normal (ULN) and aspartate aminotransferase (AST), alanine aminotransferase (ALT) <3 x ULN Calculated creatinine clearance (CRCL) ≥40 mL/min. Glomerular Filtration Rate (GFR) is calculated based on Cockcroft-Gault method. Normal corrected calcium levels Absolute neutrophil count >1200/mm3, hemoglobin (Hb) ≥10 g/dL and platelets ≥100,000/mm3 Male or female Age ≥ 18 years or according to local legal age of consent Eastern Cooperative Oncology Group Performance Scale (ECOG-PS) ≤2 Written informed consent Life expectancy >6 months Key Exclusion Criteria Severe concomitant illness i.e. chronic obstructive pulmonary disease (COPD), ischemic heart disease (IHD), active congestive cardiac failure (CCF), active angina pectoris, uncontrolled arrhythmia, uncontrolled hypertension HIV Positive* * Status of HIV must be confirmed via a HIV antibody test or other confirmatory tests available within 4 weeks of screening Pregnant or lactating females Refuse of use of contraception during trial (both male and female patients) Investigational therapy less than one month prior to study entry Pre-existing peripheral neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] ≥2) Central nervous system metastasis Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis and T1] or any cancer curatively treated >3 years prior to study entry Positive hepatitis B surface antigen (HBsAg) results Known history of hepatitis C and recovery status has not been determined at time of screening Prior anti-cancer treatment for metastatic or locally recurrent disease, EXCEPT: For metastatic or locally recurrent disease, localised palliative radiotherapy is allowed. For locally recurrent disease, the following treatment is allowed Prior radiotherapy with curative intent Prior chemo-radiotherapy with curative intent Adjuvant chemotherapy Localised palliative radiotherapy Prior chemotherapy must be > 6 months before screening Severe intercurrent infections Prior immunotherapy for metastatic or locally recurrent disease The following is allowable: • Adjuvant immunotherapy/ biologics Prior adjuvant immunotherapy/ biologics must be > 6 months before screening

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>4 cycles* of combination IV Gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days, followed sequentially by T-cell immunotherapy (2 cycles) of autologous EBV specific Cytotoxic T cells every 2 weeks, followed by EBV-specific CTL immunotherapy (4 cycles) every 8 weeks after 6 weeks from the second cycle. *Additional 1-2 chemotherapy cycles (up to total 6 chemo cycles) might be given upon discretion of Investigator, if EBV-specific CTL infusions are not available in time for the 1st scheduled infusion. As of 1 May 2020, patients who have not received the first infusion of EBV-specific CTLs, will instead continue to receive a total of 6 cycles combination of Gemcitabine (1000 mg/m2) and carboplatin (AUC2) on Days 1, 8, 15 every 28 days | Biological: autologous EBV specific Cytotoxic T cells<br>* The CTL line will be prepared by co-cultivation of the irradiated EBV-LCL with patient PBMC. A proportion of peripheral blood will be used to generate EBV specific CTLs.<br>Drug: combination IV gemcitabine and IV carboplatin (AUC2)<br>* 4 cycles for Arm A and 6 cycles for Arm B<br>|
| Active Comparator: Arm B<br>6 cycles of combination IV gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days. | Drug: combination IV gemcitabine and IV carboplatin (AUC2)<br>* 4 cycles for Arm A and 6 cycles for Arm B<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) of Subjects With Advanced Nasopharyngeal Carcinoma. | Efficacy of EBV-CTL following first line chemotherapy was compared to chemotherapy alone in terms of OS of subjects with advanced nasopharyngeal carcinoma. Overall survival was defined as the duration in months from the day of randomization until death from any cause for a subject known to be deceased, or censored at the last contact date that a subject was known to be alive or lost to follow-up. | From randomization until death, assessed up to 7 years. Survivors and lost to follow-up subjects were censored at the date of last contact. Survival follow-up was done every 12 weeks from end of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) of Subjects With Advanced Nasopharyngeal Carcinoma. | Progression-free survival was defined as the duration from randomization to the first occurrence of documented disease progression [based on imaging results] or death from any cause, whichever occurred first. | From randomization until first occurrence of disease progression or death of any cause, whichever occurred first, assessed up to 7 years. Subjects who received subsequent anti-cancer therapy were censored at the date of last tumor assessment. | 
| Overall Response Rate (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Overall response rate was assessed by sites using computed tomography/magnetic resonance imaging based on RECIST version 1.1, which defined Complete Response (CR) as disappearance of all lesions and pathologic lymph nodes; Partial Response (PR) as >=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; Stable disease (SD) as no PR and no progressive disease (PD); PD as >=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. The ORR for each treatment arm was comprised of the proportion of subjects who achieved a best overall response of CR or PR while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. Subjects who achieved CR or PR are responders, otherwise are non-responders. | From randomization until End of Treatment, an average of 13 months for the gemcitabine+carboplatin and EBVCTL arm and 6 months for the gemcitabine+carboplatin only arm. | 
| Clinical Benefit Rate (CBR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Clinical benefit rate (CBR) was assessed using computed tomography/magnetic resonance imaging based on RECIST version 1.1., which defined CR as disappearance of all lesions and pathologic lymph nodes; PR as >=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; SD as no PR and no PD; PD as >=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. CBR was defined as the proportion of subjects who achieved CR, PR, or SD while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. | From randomization until End of Treatment, an average of 13 months for the gemcitabine+carboplatin and EBVCTL arm and 6 months for the gemcitabine+carboplatin only arm. | 
| Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Best overall response (BOR) was assessed using computed tomography/magnetic resonance imaging based on RECIST version 1.1., which defined CR as disappearance of all lesions and pathologic lymph nodes; PR as >=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; SD as no PR and no PD; PD as >=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. The BOR of each treatment arm consisted of CR, PR, SD, PD, NE, and NA while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. The ORR was comprised of the proportion of subjects who achieved a BOR of CR or PR. | From randomization until End of Treatment, an average of 13 months for the gemcitabine+carboplatin and EBVCTL arm and 6 months for the gemcitabine+carboplatin only arm. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cell therapy, Nasopharyngeal Carcinoma (NPC), NPC, immunotherapy, Nasopharyngeal Cancer, Nose Cancer, Head and Neck Cancer, Cytotoxic T cells, chemotherapy, Epstein-Barr Virus