Clinical Trials List
Protocol NumberT1317
NCT Number(ClinicalTrials.gov Identfier)NCT03544099
2018-10-01 - 2022-12-31
Phase II
Recruiting5
Terminated3
ICD-10C11.9
Malignant neoplasm of nasopharynx, unspecified
ICD-10C11
Malignant neoplasm of nasopharynx
Pembrolizumab for Nasopharyngeal Carcinoma Patients With Detectable Plasma Epstein-Barr Virus DNA But Without Clinically Detectable Residual Diseases and/or Metastases After Curative Chemoradiation - A Single Arm Phase II Trial
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Trial Applicant
National Health Research Institutes
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Sponsor
National Health Research Institutes, Taiwan
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Trial scale
Taiwan Multiple Center
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Update
2025/08/20
Investigators and Locations
The Actual Total Number of Participants Enrolled
0 Recruiting
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Ming-Yu Lien Division of Hematology & Oncology
- Yu-Min Liao Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Kwang-Yu Chang Division of Hematology & Oncology
- 劉奕廷 Division of Hematology & Oncology
- Shang-Yin Wu Division of Hematology & Oncology
- Nai-Jung Chiang Division of Hematology & Oncology
- Hui-Jen Tsai Division of Hematology & Oncology
- Shang-Hung Chen Division of Hematology & Oncology
- 姜乃榕 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Audit
None
Co-Principal Investigator
- 廖斌志 Division of Hematology & Oncology
- Hsiang-Fong Kao Division of Hematology & Oncology
- HUAI-CHENG HUANG Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- 曾雁明 Division of Radiation Therapy
- Chi-Ting Liau Division of Radiation Therapy
- Tzu-Chen Yen Division of Nuclear Medicine
- 黃炳勝 Division of Radiation Therapy
- Shu-Hang Ag Division of Radiology
- Tung-Chieh Chang Division of Radiation Therapy
- Cheng-Lung Hsu Division of Radiation Therapy
- 范綱行 Division of Radiation Therapy
- Chia-Hsun Hsieh Division of Radiation Therapy
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- Ming-Ying Lan Division of Otolaryngology
- Sheng-Yu Chen Division of Hematology & Oncology
- Mu-Hsin Chang Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Condition/Disease
Nasopharyngeal Carcinoma
Objectives
This phase II study is aimed to prove the efficacy of adjuvant therapy with pembrolizumab for nasopharyngeal carcinoma patients with detectable plasma EBV DNA after curative chemoradiation.
Nasopharyngeal cancer was a malignancy related to Epstein-Barr virus infection. It was a malignancy endemic in Southeast Asia, Taiwan, and China. The primary treatment was chemoradiation. The three-year disease free survival was around 50-60% for locally-advanced (stage IVA, IVB) NPC. Adjuvant chemotherapy after curative chemoradiation is a strategy to improve disease control rate for advanced NPC. However, two phase III trials in Taiwan (TCOG 1394) and China failed to prove its efficacy on improving disease control and overall survival. How to identify patients who are truly at risk is an important question for the therapy of advanced NPC.
Plasma EBV DNA copy number is a biomarker predicting the recurrent risk of nasopharyngeal cancer. A higher level of plasma EBV DNA before chemoradiation is related to a poorer prognosis. A detectable EBV DNA after chemoradiation, which is a hint for occult residual or metastatic disease, is a strong predictor for early recurrence. The relapse free survival at two years for patients with detectable plasma EBV DNA (> 0 copies/mL) was around 20%. The results of other similar trials are summarized on table 1.
Cancer cells escaped from the immune surveillance by several mechanisms. One of them is activating immune inhibitory pathway by "immune checkpoints" . Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1) is one immune checkpoint axis to regulate immune response against cancer. Pembrolizumab (MK-3475), an anti-PD-1 antibody, had a good activity against melanoma and other types of cancers. The toxicity profiles were tolerable. In the Keynote-028 phase Ib trial, pembrolizumab showed good clinical activity against recurrent or metastatic NPC. The overall response rate is 22%, and the disease control rate is 77.8%. This data is encouraging for further clinical trials of pembrolizumab for NPC.
PD-1/PD-L1 axis has an important role for the resistance of chemoradiation[18]. In patients refractory to chemoradiation, the expression of PD-1 and PD-L1 increased in the tumor. In animal model, sequential administration of anti-PD-1 after radiation significantly improved the progression free survival in mice with tumors [19]. This concept supports the investigator's sequential design for high-risk NPC patients.
Test Drug
Pembrolizumab (MK3475)
Active Ingredient
Pembrolizumab
Dosage Form
Injection
Dosage
100mg/4ml
Endpoints
Primary
-One-year disease free survival (DFS-1y)
One-year disease free survival (DFS-1y) is defined as the time from entry to the first documented recurrent or metastatic lesion per RECIST 1.1 based on site investigator review or death due to any cause, whichever occurs first.
Secondary
-Overall survival
Overall Survival (OS) is defined as the time from entry to death due to any cause. Subjects without documented death at the time of the final analysis will be censored at the date of the last follow-up.
-Disease Free Survival (DFS)
Disease Free Survival (DFS) is defined as the time from entry to the first documented recurrent or metastatic lesion per RECIST 1.1 based on site investigator review or death due to any cause, whichever occurs first.
-Time to Local Recurrence
Time to local recurrence is defined as the time from entry to the first documented local recurrence per RECIST 1.1 based on site investigator review, whichever occurs first.
-Time to Distant Metastases
Time to local recurrence is defined as the time from entry to the first distant metastases per RECIST 1.1 based on site investigator review, whichever occurs first.
-DFS – irRECIST by site investigator review
DFS per irRECIST are defined as specified for the respective endpoints using RECIST 1.1 above, with the exception that a confirmation assessment of PD (at least 4 weeks after the initial PD assessment) is required for subjects who remain on treatment following a documented PD per RECIST 1.1. Subjects who discontinue treatment following a documented PD assessment per RECIST 1.1 will be counted as having disease progression on the date of the documented PD assessment.
-One-year disease free survival (DFS-1y)
One-year disease free survival (DFS-1y) is defined as the time from entry to the first documented recurrent or metastatic lesion per RECIST 1.1 based on site investigator review or death due to any cause, whichever occurs first.
Secondary
-Overall survival
Overall Survival (OS) is defined as the time from entry to death due to any cause. Subjects without documented death at the time of the final analysis will be censored at the date of the last follow-up.
-Disease Free Survival (DFS)
Disease Free Survival (DFS) is defined as the time from entry to the first documented recurrent or metastatic lesion per RECIST 1.1 based on site investigator review or death due to any cause, whichever occurs first.
-Time to Local Recurrence
Time to local recurrence is defined as the time from entry to the first documented local recurrence per RECIST 1.1 based on site investigator review, whichever occurs first.
-Time to Distant Metastases
Time to local recurrence is defined as the time from entry to the first distant metastases per RECIST 1.1 based on site investigator review, whichever occurs first.
-DFS – irRECIST by site investigator review
DFS per irRECIST are defined as specified for the respective endpoints using RECIST 1.1 above, with the exception that a confirmation assessment of PD (at least 4 weeks after the initial PD assessment) is required for subjects who remain on treatment following a documented PD per RECIST 1.1. Subjects who discontinue treatment following a documented PD assessment per RECIST 1.1 will be counted as having disease progression on the date of the documented PD assessment.
Inclution Criteria
nclusion criteria
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be more than 20 years of age on day of signing informed consent.
3. Have a performance status of 0 or 1 on the ECOG Performance Scale
4. Demonstrate adequate organ function as defined in Table 2
5. Histology proven nasopharyngeal carcinoma. Biopsy at nasopharynx is mandatory.
6. Completing radiotherapy more than 66Gy (curative intent radiotherapy)
7. Detectable plasma EBV DNA: it is defined by the following criteria:
a. The first test of plasma EBV DNA: 6-8 weeks after the last dose of radiotherapy.
b. If the first test of plasma EBV DNA is detectable:
- Within the “linear dynamic range”: eligible by one single EBV DNA testing
- Lower than the “linear dynamic range”: it should be repeated within 2-4 weeks after the report day of first test of plasma EBV DNA. If both results are detectable, the patient is eligible
- *The “linear dynamic range” is defined as the highest to the lowest quantifiable copy number established by means of a calibration curve (MIQE guidelines, 7.4.2 section, Clin Chem. 2009;55(4):611-22)
8. No detectable residual disease or distant metastases after imaging studies:
The following examinations should be completed within 28 days after the report day of detectable plasma EBV DNA. If a repeated test of plasma EBV DNA is necessary by criteria 7, the following examination should be completed within 28 days after the report day of the repeated plasma EBV DNA test.
a. For locally residual disease, head and neck MRI should be completed. For patients who cannot take MRI, CT scan with and without contrast should be completed.
b. For distant metastases, one of the following studies should be completed.
- Whole body PET-CT scan (if the modality is available)
- CT scan with and without contrast of chest and abdomen, and bone scan
9. Female subject of childbearing potential should have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential (Section 5.5.2) must be willing to use an adequate method of contraception as outlined in Section 5.5.2 – Contraception, for the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. Male subjects of childbearing potential (Section 5.5.2) must agree to use an adequate method of contraception as outlined in Section 5.5.2- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be more than 20 years of age on day of signing informed consent.
3. Have a performance status of 0 or 1 on the ECOG Performance Scale
4. Demonstrate adequate organ function as defined in Table 2
5. Histology proven nasopharyngeal carcinoma. Biopsy at nasopharynx is mandatory.
6. Completing radiotherapy more than 66Gy (curative intent radiotherapy)
7. Detectable plasma EBV DNA: it is defined by the following criteria:
a. The first test of plasma EBV DNA: 6-8 weeks after the last dose of radiotherapy.
b. If the first test of plasma EBV DNA is detectable:
- Within the “linear dynamic range”: eligible by one single EBV DNA testing
- Lower than the “linear dynamic range”: it should be repeated within 2-4 weeks after the report day of first test of plasma EBV DNA. If both results are detectable, the patient is eligible
- *The “linear dynamic range” is defined as the highest to the lowest quantifiable copy number established by means of a calibration curve (MIQE guidelines, 7.4.2 section, Clin Chem. 2009;55(4):611-22)
8. No detectable residual disease or distant metastases after imaging studies:
The following examinations should be completed within 28 days after the report day of detectable plasma EBV DNA. If a repeated test of plasma EBV DNA is necessary by criteria 7, the following examination should be completed within 28 days after the report day of the repeated plasma EBV DNA test.
a. For locally residual disease, head and neck MRI should be completed. For patients who cannot take MRI, CT scan with and without contrast should be completed.
b. For distant metastases, one of the following studies should be completed.
- Whole body PET-CT scan (if the modality is available)
- CT scan with and without contrast of chest and abdomen, and bone scan
9. Female subject of childbearing potential should have a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential (Section 5.5.2) must be willing to use an adequate method of contraception as outlined in Section 5.5.2 – Contraception, for the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. Male subjects of childbearing potential (Section 5.5.2) must agree to use an adequate method of contraception as outlined in Section 5.5.2- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Exclusion Criteria
5.1.2 Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Other malignancies diagnosed before or concurrently with the diagnosis of NPC.
2. Take chemotherapy or other anti-cancer agents after curative chemoradiation.
3. Documented residual / recurrent local disease or distant metastases after completing chemoradiation.
4. Plasma EBV DNA is un-detectable.
5. Unresolved grade 2 or more acute toxicities related to chemoradiation
6. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
7. Hypersensitivity to pembrolizumab or any of its excipients.
8. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Topical or inhaled steroids is not considered as systemic treatment.
9. Has known history of pneumonitis requiring steroids, or any evidence of active, non-infectious pneumonitis
10. Has an active infection requiring systemic therapy 14 days before signing informed consent.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
17. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
The subject must be excluded from participating in the trial if the subject:
1. Other malignancies diagnosed before or concurrently with the diagnosis of NPC.
2. Take chemotherapy or other anti-cancer agents after curative chemoradiation.
3. Documented residual / recurrent local disease or distant metastases after completing chemoradiation.
4. Plasma EBV DNA is un-detectable.
5. Unresolved grade 2 or more acute toxicities related to chemoradiation
6. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
7. Hypersensitivity to pembrolizumab or any of its excipients.
8. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Topical or inhaled steroids is not considered as systemic treatment.
9. Has known history of pneumonitis requiring steroids, or any evidence of active, non-infectious pneumonitis
10. Has an active infection requiring systemic therapy 14 days before signing informed consent.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
17. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
The Estimated Number of Participants
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Taiwan
63 participants
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Global
0 participants
