Nasopharyngeal Carcinoma (NPC)
Conditions
Keywords
Nasopharyngeal Carcinoma, Anti-PD-1 therapy, induction chemotherapy
Brief summary
The main questions it aims to answer are: 1. Does the combination of GP induction chemotherapy and toripalimab improve the 3-year progression-free survival (PFS) compared to GP induction chemotherapy with placebo? 2. What are the differences in CR after induction therapy, 3-year overall survival (OS), locoregional progression, and distant progression between the two groups? 3. What are the differences in safety between the two groups? 4. Are there predictive biomarkers of therapeutic efficacy, such as changes in EBV DNA or immune parameters, that correlate with treatment outcomes? Researchers will compare the GP + toripalimab group with the GP + placebo group to see if the toripalimab combination shows superior efficacy. Participants will: Receive either GP chemotherapy with toripalimab or GP chemotherapy with placebo as induction therapy. Undergo concurrent chemoradiotherapy ± adjuvant metronomic capecitabine following induction therapy. Be monitored closely for safety and efficacy outcomes.
Detailed description
Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Gemcitabine plus cisplatin (GP) has been demonstrated an effective chemotherapy regimen for NPC patients in previous studies. The results of GP combined with concurrent chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma showed 10% of locoregionally advanced NPC patients had complete response after three cycles of GP induction chemotherapy, and GP induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival (85.3% vs 76.5%) and overall survival (94.6% vs 90.3%) among locoregionally advanced NPC patients , as compared with chemoradiotherapy alone. Therefore, GP regimen has been established as the highest level of evidence-based induction chemotherapy in the 2020 National Comprehensive Cancer Network (NCCN) guidelines. Despite this intensified treatment approach, 20-30% of patients still have disease recurrences, highlighting the need for novel treatments in this population. Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma. So we hypothesize that GP induction chemotherapy combined with toripalimab could further improve survival of patients with locoregionally advanced NPC. The goal of this randomized, double-blind, controlled phase III clinical trial is to evaluate the efficacy and safety of the GP induction chemotherapy combined with toripalimab or placebo , followed by concurrent chemoradiotherapy ± adjuvant metronomic capecitabine in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.
Interventions
DRUGTORIPALIMAB INJECTION (JS001 ) combine with GP chemotherapy
Drug: Toripalimab 240mg will be given every 3 weeks for 3 cycles, started on day 1 of induction chemotherapy. Other Names: JS001 PD-1 antibody Drug: Gemcitabine 1000mg/m2, d1 \& 8 of every cycle, every 3 weeks for 3 cycles before radiation. Drug: Cisplatin Induction cisplatin 80mg/m2, every 3 weeks for 3 cycles before radiation; Concurrent cisplatin 100mg/m2, every 3 weeks for 3 cycles during radiation Other Names: DDP Radiation: intensity-modulated radiotherapy Definitive intensity-modulated radiotherapy (IMRT) of 70 Gy will be given in 33 fractions. Other Names: IMRT
DRUGGP plus placebo induction therapy
Drug: Placebo 240mg will be given every 3 weeks for 3 cycles, started on day 1 of induction chemotherapy. Drug: Gemcitabine 1000mg/m2, d1 \& 8 of every cycle, every 3 weeks for 3 cycles before radiation. Drug: Cisplatin Induction cisplatin 80mg/m2, every 3 weeks for 3 cycles before radiation; Concurrent cisplatin 100mg/m2, every 3 weeks for 3 cycles during radiation Other Names: DDP Radiation: intensity-modulated radiotherapy Definitive intensity-modulated radiotherapy (IMRT) of 70 Gy will be given in 33 fractions. Other Names: IMRT
Sponsors
Sun Yat-sen University
First Affiliated Hospital of Guangxi Medical University
Guangxi Medical University Cancer Center
Affiliated Hospital of Guangdong Medical University
Cancer Hospital Chinese Academy of Medical Science, Shenzhen Center
The University of Hong Kong-Shenzhen Hospital
Hunan Cancer Hospital
Affiliated Cancer Hospital of Guizhou Medical University
Sichuan Cancer Hospital and Research Institute
Fujian Cancer Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntarily participates and signs an informed consent form. 2. Aged 18-70 years, male or non-pregnant female. 3. Pathologically confirmed nasopharyngeal non-keratinizing carcinoma (differentiated or undifferentiated, i.e., WHO Type II or III). 4. Staging of any T, N2-3 or T4N1 (9th AJCC/UICC staging), with no distant metastasis. 5. ECOG performance status score of 0-1. 6. Hemoglobin (HGB) ≥90 g/L, neutrocyte count≥1.5×10⁹/L, platelets (PLT) ≥100×10⁹ /L. 7. Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5×upper limit of normal (ULN), and bilirubin ≤ 1.5×ULN. 8. Adequate renal function: creatinine clearance rate ≥ 60 ml/min (Cockcroft-Gault formula). 9. Women of childbearing potential (WOCBP) who are sexually active must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of the study drug. Men who are sexually active with WOCBP must be willing to adhere to effective contraception during treatment and for 1 year after the last dose of the study drug.
Exclusion criteria
1. Age \> 70 years or \< 18 years. 2. Patients with recurrence or distant metastases. 3. Pathologically confirmed nasopharyngeal keratinizing squamous cell carcinoma (WHO Type I). 4. Patients who have previously undergone radiotherapy or systemic chemotherapy. 5. Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus DNA \>1000 copies/ml or 200IU/ml. 6. Hepatitis C virus (HCV) antibody positive. 7. Has active autoimmune disease, except type I diabetes, hypothyroidism treated with replacement therapy, and skin disease that doesn't require systemic treatment (e.g., vitiligo, psoriasis, or alopecia). 8. Has any condition that required systemic corticosteroid (equivalent to prednisone \>10mg/d) or other immunosuppressive therapy within 28 days before informed consent. Patients who received systemic corticosteroid equivalent to prednisone ≤10mg/d, inhale or topical corticosteroids will be allowed. 9. Has a known history of active bacillus tuberculosis within 1 year; patients with adequately treated active bacillus tuberculosis over 1 year ago will be allowed. 10. Has a known history of interstitial lung disease. 11. Has received a live vaccine within 30 days before informed consent or will receive a live vaccine in the near future. 12. Is pregnant or breastfeeding. 13. Prior malignancy within 5 years, except in situ cancer, adequately treated non-melanoma skin cancer and papillary thyroid carcinoma. 14. Has known allergy to large molecule protein products or any compound of toripalimab. 15. Has a known history of human immunodeficiency virus infection. 16. Any other condition, including symptomatic heart failure, unstable angina, myocardial infarction, active infection requiring systemic therapy, mental illness, or domestic/social factors, deemed by the investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study or interferes with the interpretation of the results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 3 years | Defined as the time from randomisation to first progression (locoregional or distant) or death, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | 9 weeks | CR assessed by investigator, according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1) from the National Cancer Institute (NCI). Disease response evaluated after the completion of the induction therapy. Complete response defined as the complete disappearance of the target and non-target lesion(s) identified at baseline after radiological evaluation by Magnetic Resonance Imaging (MRI) . |
| Incidence of Acute and Late Toxicity | 3 years | Incidence of acute toxicity is calculated for each adverse event respectively and severity is evaluated on basis of Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria. Late radiation toxicities were assessed using the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme. |
| Overall Survival | 3 years | Defined as the time from randomization to death from any cause. |
| Locoregional Progression | 3 years | Defined as the time from randomization to the occurrence of a locoregional progression. Cumulative incidence of locoregional progression will be calculated within a competing risk framework (Fine and Gray 1999). |
| Distant Progression | 3 years | Defined as the time from randomization to the occurrence of a distant progression. Cumulative incidence of distant progression will be calculated within a competing risk framework (Fine and Gray 1999). |
Countries
China
Outcome results
None listed