Toripalimab Vs. Placebo Wtih GP Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma (Navigation)

Toripalimab Versus Placebo Combined with Induction Chemotherapy Followed by Concurrent Chemoradiotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma: a Multicenter, Randomized, Placebo-controlled, Double-blind, Phase 3 Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Nasopharyngeal Carcinoma (NPC)
• Intervention / Treatment: Drug: GP plus placebo induction therapy; Drug: TORIPALIMAB INJECTION (JS001 ) combine with GP chemotherapy

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.

• Study Type: Interventional
• Enrollment (Estimated): 466
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hai-Qiang Mai, Ph. D.; Phone Number: +86-020-87343643; Email: maihq@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun Yat-sen University Cancer Center
      • Contact: Hai-Qiang Mai, MD,PhD; Phone Number: 00862087343643; Email: maihq@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Induction GP+placebo group; GP + Placebo Induction Therapy: Gemcitabine: 1000 mg/m² on days 1 and 8 DDP (cisplatin): 80 mg/m² on day 1 Placebo: 240 mg on day 1 Total of 3 cycles. Concurrent Chemoradiotherapy (CCRT): DDP (cisplatin): 100 mg/m² on day 1 of radiation, then every 3 weeks during radiotherapy. Total of 3 cycles (administered on D1, D22, and D43). Adjuvant Metronomic Capecitabine Therapy: Starts 4-6 weeks after the completion of radiotherapy and continues for up to 1 year. Adjuvant metronomi capecitabine is administered at the physician's discretion: Capecitabine: 650 mg/m², administered BID (twice daily).	Drug: GP 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
Experimental: Induction GP+toripalimab group; Induction GP + Toripalimab Therapy: Gemcitabine: 1000 mg/m² on days 1 and 8 DDP (cisplatin): 80 mg/m² on day 1 Toripalimab: 240 mg on day 1 Total of 3 cycles. Concurrent Chemoradiotherapy (CCRT): DDP (cisplatin): 100 mg/m² on day 1 of radiation, then every 3 weeks during radiotherapy. Total of 3 cycles (administered on D1, D22, and D43). Adjuvant Metronomic Capecitabine Therapy: Starts 4-6 weeks after the completion of radiotherapy and continues for up to 1 year. Adjuvant metronomic capecitabine therapy is administered at the physician's discretion: Capecitabine: 650 mg/m², administered BID (twice daily).	Drug: TORIPALIMAB 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Defined as the time from randomisation to first progression (locoregional or distant) or death, whichever occurred first.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Defined as the time from randomization to death from any cause.	3 years
Locoregional Progression	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).	3 years
Distant Progression	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).	3 years
Complete Response Rate	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) .	9 weeks
Incidence of Acute and Late Toxicity	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.	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The correlation of pre-treatement plasma EBV DNA and dynamic change after induction therapy between with the PFS	Plasma EBV DNA testing will be conducted before treatment and after induction therapy	3 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Fujian Cancer Hospital; Hunan Cancer Hospital; The University of Hong Kong-Shenzhen Hospital; Sichuan Cancer Hospital and Research Institute; First Affiliated Hospital of Guangxi Medical University; Guangxi Medical University Cancer Center; Affiliated Hospital of Guangdong Medical University; Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center; The Affiliated Cancer Hosipital of Guizhou Meidical University

Publications and helpful links

General Publications

• Zhang Y, Chen L, Hu GQ, Zhang N, Zhu XD, Yang KY, Jin F, Shi M, Chen YP, Hu WH, Cheng ZB, Wang SY, Tian Y, Wang XC, Sun Y, Li JG, Li WF, Li YH, Tang LL, Mao YP, Zhou GQ, Sun R, Liu X, Guo R, Long GX, Liang SQ, Li L, Huang J, Long JH, Zang J, Liu QD, Zou L, Su QF, Zheng BM, Xiao Y, Guo Y, Han F, Mo HY, Lv JW, Du XJ, Xu C, Liu N, Li YQ, Chua MLK, Xie FY, Sun Y, Ma J. Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma. N Engl J Med. 2019 Sep 19;381(12):1124-1135. doi: 10.1056/NEJMoa1905287. Epub 2019 May 31.
• Chen YP, Liu X, Zhou Q, Yang KY, Jin F, Zhu XD, Shi M, Hu GQ, Hu WH, Sun Y, Wu HF, Wu H, Lin Q, Wang H, Tian Y, Zhang N, Wang XC, Shen LF, Liu ZZ, Huang J, Luo XL, Li L, Zang J, Mei Q, Zheng BM, Yue D, Xu J, Wu SG, Shi YX, Mao YP, Chen L, Li WF, Zhou GQ, Sun R, Guo R, Zhang Y, Xu C, Lv JW, Guo Y, Feng HX, Tang LL, Xie FY, Sun Y, Ma J. Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial. Lancet. 2021 Jul 24;398(10297):303-313. doi: 10.1016/S0140-6736(21)01123-5. Epub 2021 Jun 7.
• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. Erratum In: CA Cancer J Clin. 2020 Jul;70(4):313. doi: 10.3322/caac.21609.
• Mai HQ, Chen QY, Chen D, Hu C, Yang K, Wen J, Li J, Shi YR, Jin F, Xu R, Pan J, Qu S, Li P, Hu C, Liu YC, Jiang Y, He X, Wang HM, Lim WT, Liao W, He X, Chen X, Liu Z, Yuan X, Li Q, Lin X, Jing S, Chen Y, Lu Y, Hsieh CY, Yang MH, Yen CJ, Samol J, Feng H, Yao S, Keegan P, Xu RH. Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial. Nat Med. 2021 Sep;27(9):1536-1543. doi: 10.1038/s41591-021-01444-0. Epub 2021 Aug 2. Erratum In: Nat Med. 2022 Jan;28(1):214. doi: 10.1038/s41591-021-01673-3.

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2025
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2032

Study Registration Dates

• First Submitted: November 25, 2024
• First Submitted That Met QC Criteria: November 27, 2024
• First Posted (Actual): December 2, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 17, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: induction chemotherapy; Nasopharyngeal Carcinoma; Anti-PD-1 therapy
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Nasopharyngeal Neoplasms; Nasopharyngeal Carcinoma; Carcinoma
• Other Study ID Numbers: 2024-FXY-323

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No