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

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".

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

Eligibility Criteria:
Key Inclusion Criteria

1. 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
2. Radiologically measurable disease as per RECIST 1.1
3. 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
4. Bilirubin \<2 x upper limit of normal (ULN) and aspartate aminotransferase (AST), alanine aminotransferase (ALT) \<3 x ULN
5. Calculated creatinine clearance (CRCL) ≥40 mL/min. Glomerular Filtration Rate (GFR) is calculated based on Cockcroft-Gault method.
6. Normal corrected calcium levels
7. Absolute neutrophil count \>1200/mm3, hemoglobin (Hb) ≥10 g/dL and platelets ≥100,000/mm3
8. Male or female
9. Age ≥ 18 years or according to local legal age of consent
10. Eastern Cooperative Oncology Group Performance Scale (ECOG-PS) ≤2
11. Written informed consent
12. Life expectancy \>6 months

Key Exclusion Criteria

1. 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
2. HIV Positive\*

   \* Status of HIV must be confirmed via a HIV antibody test or other confirmatory tests available within 4 weeks of screening
3. Pregnant or lactating females
4. Refuse of use of contraception during trial (both male and female patients)
5. Investigational therapy less than one month prior to study entry
6. Pre-existing peripheral neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] ≥2)
7. Central nervous system metastasis
8. 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
9. Positive hepatitis B surface antigen (HBsAg) results
10. Known history of hepatitis C and recovery status has not been determined at time of screening
11. 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
12. Severe intercurrent infections
13. 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