A Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Tislelizumab + Chemotherapy Followed by Adjuvant Tislelizumab for the Treatment of Patients With Locoregionally Advanced Nasopharyngeal Carcinoma
Overview
- Phase
- Phase 3
- Intervention
- Tislelizumab
- Conditions
- Nasopharyngeal Carcinoma
- Sponsor
- Sun Yat-sen University
- Enrollment
- 450
- Locations
- 4
- Primary Endpoint
- Complete Response
- Status
- Active, Not Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this study is to explore the efficacy and safety of a combination of GP chemotherapy and tislelizumab in neoadjuvant therapy combined with tislelizumab in adjuvant therapy of locoregionally advanced nasopharyngeal carcinoma patients.
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 neoadjuvant chemotherapy, and GP neoadjuvant 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 neoadjuvant chemotherapy in the 2020 National Comprehensive Cancer Network (NCCN) guidelines. Recently, immune checkpoint inhibitors, such as anti-programmed cell death-1 (PD-1)monoclonal antibody has shown promising efficacy in the treatment of tumor patients. Clinical trials have shown objective response rates of 20.5%-34% in patients with recurrent or metastatic NPC patients receiving anti PD-1 monoclonal antibody immunotherapy including pembrolizumab, nivolumab, camrelizumab, and toripalimab. The current NCCN guidelines recommend anti PD-1 monoclonal antibody as a second-line treatment for recurrent or metastatic NPC. More and more evidence show that immunotherapy combined with chemotherapy has a synergistic effect in treating tumors. GP chemotherapy combined with anti PD-1 antibody has achieved the initial effect in NPC. Phase 1 trials have shown the combination of camrelizumab plus GP chemotherapy in recurrent or metastatic NPC led to a proportion of 91% patients achieving an objective response. In addition, previous studeis showed that PD-1 antibody adjuvant therapy had good feasibility and effectiveness in the treatment of nasopharyngeal carcinoma. Tislelizumab, approved by the National Medical Products Administration in China, is an anti-PD-1 monoclonal IgG4 antibody with higher affinity to PD-1 than pembrolizumab and nivolumab and was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Multiple clinical trials have shown strong anti-neoplastic activity of tislelizumab in various tumors including NPC. Clinical trial has shown an objective response rates of 43% in patients with recurrent metastatic nasopharyngeal carcinoma treated with tirelizumab, which is superior to other anti PD-1 monoclonal antibodys. So we hypothesize that GP neoadjuvant chemotherapy combined with tislelizumab and tislelizumab adjuvant therapy could further improve survival of patients with locaregionally advanced NPC. Based on this, this study aims to evaluate the efficacy and safety of gemcitabine plus cisplatin chemotherapy combined with tislelizumab neoadjuvant therapy, followed by cisplatin based concurrent chemoradiotherapy, then followed by tislelizumab adjuvant therapy in the patients with locoregionally advanced nasopharyngeal carcinoma, to provide new evidence for individualized comprehensive treatment in NPC.
Investigators
Hai-Qiang Mai,MD,PhD
MD
Sun Yat-sen University
Eligibility Criteria
Inclusion Criteria
- •Patients must be informed of the investigational nature of this study and give written informed consent.
- •Age ≥ 18 years and ≤70 years,men or non-pregnant women.
- •Patients with histologically confirmed Nonkeratinizing carcinoma of the nasopharynx (differentiated or undifferentiated type, WHO II or III).
- •Tumor staged as III-IVA (AJCC 8th, except T3N0，T3N1(Only retropharyngeal lymph nodes metastasized).
- •No previous anti-tumor treatment.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or
- •Adequate marrow function:White blood cell count (WBC)≥4.0×109 /L, Hemoglobin ≥ 90g/L, Platelet count ≥100×109/L.
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2×upper limit of normal (ULN),serum total bilirubin (TBIL) ≤2.0 times the upper limit of normal (ULN) .Adequate renal function: creatinine clearance rate≥60 ml/min or Creatinine ≤1.5× upper limit of normal value.
Exclusion Criteria
- •Patients with recurrent or metastatic nasopharyngeal carcinoma.
- •Histologically confirmed with keratinizing squamous cell carcinoma of the nasopharynx.
- •Prior therapy with radiation or systemic chemotherapy.
- •Women in the period of pregnancy, lactation, or reproductive without effective contraceptive measures.
- •Seropositivity for human immunodeficiency virus (HIV).
- •Known history of other malignancies (except cured basal cell carcinoma or carcinoma in situ of the cervix).
- •Prior exposure to immune checkpoint inhibitors,including anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies.
- •Patients with immunodeficiency disease or a history of organ transplantation.
- •Received large doses of glucocorticoids, anticancer monoclonal antibodies, or other immunosuppressants within 4 weeks.
- •Patients with severe dysfunction of heart, liver, lung, kidney or marrow.
Arms & Interventions
GP combined with Tislelizumab neoadjuvant therapy+CCRT+Tislelizumab adjuvant therapy
Patients receive neoadjuvant therapy with gemcitabine(1000mg per square meter on day 1,8) , cisplatin (80mg per square meter on day 1) and tislelizumab(200mg) every three weeks for three cycles before radiotherapy, then followed by concurrent IMRT and cisplatin (100mg per square meter) concurrent every three weeks during radiotherapy (D1,D22,D43 of RT) ,then followed by adjuvant therapy with tislelizumab(200mg) every three weeks for eight cycles after radiotherapy
Intervention: Tislelizumab
GP combine with Placebo neoadjuvant therapy+CCRT+Placebo adjuvant therapy
Patients receive neoadjuvant therapy with gemcitabine(1000mg per square meter on day 1,8) , cisplatin (80mg per square meter on day 1) and Placebo(200mg) every three weeks for three cycles before radiotherapy, then followed by concurrent IMRT and cisplatin (100mg per square meter) concurrent every three weeks during radiotherapy (D1,D22,D43 of RT) ,then followed by adjuvant therapy with Placebo(200mg) every three weeks for eight cycles after radiotherapy
Intervention: Placebo
Outcomes
Primary Outcomes
Complete Response
Time Frame: 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 neoadjuvant 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) .
Progression-free Survival (PFS)
Time Frame: 3 years
defined as the time from random assignment to documented local or regional relapse, distant metastasis, or death from any cause, whichever occurred first.
Secondary Outcomes
- Overall Survival(OS)(3 years)
- Locoregional failure-free survival(LRRFS)(3 years)
- Distant metastasis-free survival(DMFS)(3 years)
- Number of participants with adverse events(up to 3 years)