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Carboplatin

Gemcitabine

Immunomodulating Agents

Antimetabolites

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

6 cycles of combination IV gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days.

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.

autologous EBV specific Cytotoxic T cells

4 cycles for Arm A and 6 cycles for Arm B

combination IV gemcitabine and IV carboplatin (AUC2)

Han Chong TOH

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

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

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

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.

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.

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.

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.

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.

Tessa Therapeutics

Safety analyses are based on the Safety Analysis Set, defined as all randomized subjects who received at least one dose of study treatment. Subjects were analyzed according to the treatment actually received.

Chemo + EBV-CTL

Chemo Only

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Singapore

United States

Taiwan

Malaysia

Thailand

Region of Enrollment

NPC staging by Investigator per 7th American Joint Committee on Cancer (AJCC); Tumor (T)1 Nasopharynx, oropharynx, nasal cavity without extension, T2 Parapharyngeal extension, T3 Skull base, paranasal sinuses, T4 Intracranial, cranial, hypopharynx, orbit, infratemporal fossa/masticator; Nodes (N)0 No lymph node metastasis, N1 Cervical, retropharyngeal nodes, ≤6 cm, N2 Bilateral metastasis, ≤6cm, N3 \>6 cm, supraclavicular fossa, Metastasis (M)0 No metastasis, M1 metastasis. Stage II:T2 N0-1 M0, T1 N1 M0; Stage III:T1-3 N2 M0, T3 N0-1 M0; Stage IVA:T4 N0-2 M0; Stage IVB:T N3 M0; Stage IVC:T N M1

Nasopharyngeal Cancer (NPC) stage at time of study entry

Disease Status per Randomization Stratification

ECOG PS Scale, as assessed by Investigator - Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

Intent-to-treat Analysis Set - all subjects randomized to treatment.

Khong-Bee Kang, Senior Manager Clinical Development

Overall Survival (OS) of Subjects With Advanced Nasopharyngeal Carcinoma.

Progression-free Survival (PFS) of Subjects With Advanced Nasopharyngeal Carcinoma.

Overall Response Rate (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma.

Clinical Benefit Rate (CBR) of Subjects With Advanced Nasopharyngeal Carcinoma.

Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma.

Two consecutive stages:

* 4 cycles of combination IV gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days. Option to add 1 to 2 cycles (i.e., up to 6 cycles total)
* 6 cycles of immunotherapy with EBV-specific CTL (1 x 10\^8 cells/m2) starting 2 to 4 weeks after last chemotherapy treatment. Subsequent chemotherapy cycles occurred 2 weeks after the first immunotherapy dose, 6 weeks after the second immunotherapy dose, and every 8 weeks thereafter

Spots Global Cancer Trial Database for autologous ebv specific cytotoxic t cells