Nasopharyngeal Carcinoma
Conditions
Keywords
Nasopharyngeal Carcinoma (NPC), NPC, immunotherapy, Nasopharyngeal Cancer, Nose Cancer, Cell therapy, Head and Neck Cancer, Cytotoxic T cells, chemotherapy, Epstein-Barr Virus
Brief summary
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
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
Interventions
BIOLOGICALautologous EBV specific Cytotoxic T cells
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.
DRUGcombination IV gemcitabine and IV carboplatin (AUC2)
4 cycles for Arm A and 6 cycles for Arm B
Sponsors
Tessa Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) of Subjects With Advanced Nasopharyngeal Carcinoma. | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) of Subjects With Advanced Nasopharyngeal Carcinoma. | 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. | 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 (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma. | 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. | 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) of Subjects With Advanced Nasopharyngeal Carcinoma. | 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) 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) of Subjects With Advanced Nasopharyngeal Carcinoma. | 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) 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. |
Countries
Malaysia, Singapore, Taiwan, Thailand, United States
Participant flow
Recruitment details
This study randomized 330 subjects at 23 sites in Asia and 7 sites in the United States from 17 Jul 2014 to 28 Feb 2022.
Pre-assignment details
Subjects were randomized in a 1:1 ratio to receive open-label Gemcitabine and Carpoblatin followed by Autologus Epstein-Barr Virus-specific Cytotoxic T Cells (Chemo + EBV-CTL) versus Gemcitabine and Carboplatin alone (Chemo Only).
Participants by arm
| Arm | Count |
|---|---|
| Chemo + EBV-CTL gemcitabine/carboplatin and EBV-CTL | 164 |
| Chemo Only gemcitabine/carboplatin | 166 |
| Total | 330 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 15 |
| Overall Study | Death | 16 | 8 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance with Study Schedule | 1 | 0 |
| Overall Study | No Study Drug | 2 | 0 |
| Overall Study | Not treated | 1 | 4 |
| Overall Study | Other | 1 | 10 |
| Overall Study | Progressive Disease | 69 | 21 |
| Overall Study | Randomized by Mistake with Study Treatment | 0 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 7 |
Baseline characteristics
| Characteristic | Chemo Only | Total | Chemo + EBV-CTL |
|---|---|---|---|
| Age, Continuous | 55 years | 54 years | 53 years |
| Disease Status per Randomization Stratification Locally recurrent | 50 Participants | 99 Participants | 49 Participants |
| Disease Status per Randomization Stratification Metastatic | 116 Participants | 231 Participants | 115 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 0 | 99 Participants | 186 Participants | 87 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 1 | 65 Participants | 138 Participants | 73 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 2 | 2 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 157 Participants | 313 Participants | 156 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 16 Participants | 7 Participants |
| Nasopharyngeal Cancer (NPC) stage at time of study entry Others | 3 Participants | 6 Participants | 3 Participants |
| Nasopharyngeal Cancer (NPC) stage at time of study entry Stage II | 5 Participants | 20 Participants | 15 Participants |
| Nasopharyngeal Cancer (NPC) stage at time of study entry Stage III | 16 Participants | 31 Participants | 15 Participants |
| Nasopharyngeal Cancer (NPC) stage at time of study entry Stage IVA | 24 Participants | 38 Participants | 14 Participants |
| Nasopharyngeal Cancer (NPC) stage at time of study entry Stage IVB | 34 Participants | 57 Participants | 23 Participants |
| Nasopharyngeal Cancer (NPC) stage at time of study entry Stage IVC | 84 Participants | 178 Participants | 94 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 160 Participants | 320 Participants | 160 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 7 Participants | 2 Participants |
| Region of Enrollment Malaysia | 53 Participants | 106 Participants | 53 Participants |
| Region of Enrollment Singapore | 17 Participants | 34 Participants | 17 Participants |
| Region of Enrollment Taiwan | 34 Participants | 68 Participants | 34 Participants |
| Region of Enrollment Thailand | 47 Participants | 93 Participants | 46 Participants |
| Region of Enrollment United States | 15 Participants | 29 Participants | 14 Participants |
| Sex: Female, Male Female | 40 Participants | 82 Participants | 42 Participants |
| Sex: Female, Male Male | 126 Participants | 248 Participants | 122 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 163 | 8 / 162 |
| other Total, other adverse events | 163 / 163 | 162 / 162 |
| serious Total, serious adverse events | 68 / 163 | 46 / 162 |
Outcome results
Primary
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.
Time frame: 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.
Population: Intent-to-Treat Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemo + EBV-CTL | Overall Survival (OS) of Subjects With Advanced Nasopharyngeal Carcinoma. | 25 Months |
| Chemo Only | Overall Survival (OS) of Subjects With Advanced Nasopharyngeal Carcinoma. | 24.9 Months |
p-value: 0.194295% CI: [0.91, 1.56]Log Rank
Secondary
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.
Time frame: 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.
Population: Intent-to-Treat Analysis Set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Chemo + EBV-CTL | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Complete Response (CR) | 6 Participants |
| Chemo + EBV-CTL | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Partial Response (PR) | 94 Participants |
| Chemo + EBV-CTL | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Stable Disease (SD) | 45 Participants |
| Chemo + EBV-CTL | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Progressive Disease (PD) | 9 Participants |
| Chemo + EBV-CTL | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | NE (Not evaluable) | 1 Participants |
| Chemo + EBV-CTL | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | NA (Not applicable) | 9 Participants |
| Chemo Only | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | NE (Not evaluable) | 0 Participants |
| Chemo Only | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Complete Response (CR) | 14 Participants |
| Chemo Only | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Progressive Disease (PD) | 10 Participants |
| Chemo Only | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Partial Response (PR) | 91 Participants |
| Chemo Only | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | NA (Not applicable) | 10 Participants |
| Chemo Only | Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Stable Disease (SD) | 41 Participants |
Secondary
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.
Time frame: 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.
Population: Intent-to-Treat Analysis Set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Chemo + EBV-CTL | Clinical Benefit Rate (CBR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Clinical Benefit (CR/PR/2 consecutive SD) | 139 Participants |
| Chemo + EBV-CTL | Clinical Benefit Rate (CBR) of Subjects With Advanced Nasopharyngeal Carcinoma. | No Clinical Benefit (Otherwise) | 25 Participants |
| Chemo Only | Clinical Benefit Rate (CBR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Clinical Benefit (CR/PR/2 consecutive SD) | 136 Participants |
| Chemo Only | Clinical Benefit Rate (CBR) of Subjects With Advanced Nasopharyngeal Carcinoma. | No Clinical Benefit (Otherwise) | 30 Participants |
Secondary
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.
Time frame: 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.
Population: Intent-to-Treat Analysis Set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Chemo + EBV-CTL | Overall Response Rate (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Responders (CR/PR) | 100 Participants |
| Chemo + EBV-CTL | Overall Response Rate (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Non-Responders (SD/PD/NA/NE) | 64 Participants |
| Chemo Only | Overall Response Rate (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Responders (CR/PR) | 105 Participants |
| Chemo Only | Overall Response Rate (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma. | Non-Responders (SD/PD/NA/NE) | 61 Participants |
Secondary
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.
Time frame: 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.
Population: Intent-to-Treat Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemo + EBV-CTL | Progression-free Survival (PFS) of Subjects With Advanced Nasopharyngeal Carcinoma. | 7.9 Months |
| Chemo Only | Progression-free Survival (PFS) of Subjects With Advanced Nasopharyngeal Carcinoma. | 8.5 Months |