PD-1 Blockade Combined With De-intensified Chemoradiotherapy Sparing Concurrent Cisplatin in Nasopharyngeal Carcinoma

NCT ID: NCT04907370

Last Updated: 2025-07-16

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 532 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-01
• Study Completion Date: 2027-03-01

Brief Summary

This is a phase 3, multi-center, randomized controlled trial, with the purpose to evaluate the therapeutic efficacy and safety of PD-1 blockade (toripalimab) combined with the de-intensified chemoradiotherapy sparing concurrent cisplatin (i.e., toripalimab incorporated into induction chemotherapy and radiotherapy) in high-risk locoregionally advanced nasopharyngeal carcinoma.

Detailed Description

This phase 3, multi-center, randomized controlled trial plans to enroll 532 patients with newly-diagnosed, pathologically-proven, untreated locoregionally advanced nasopharyngeal carcinoma (LANPC) at high-risk of distant metastasis (T4N1 and T1-4N2-3, according to American Joint Committee on Cancer [AJCC]/Union for International Cancer Control [UICC] 8th edition clinical staging system). Patients will receive 3 cycles of induction chemotherapy (IC; gemcitabine-cisplatin regimen) followed by 1) experimental arm (de-intensification group): intensity-modulated radiotherapy (IMRT) alone or 2) control arm (standard group): 2 cycles of concurrent cisplatin plus IMRT (CCRT). For both of the two arms, toripalimab will be adopted on day 1 of the first cycle IC and continue every 3 weeks for 6 cycles till the end of IMRT, with the first and last 3 cycles of toripalimab administrated along with IC and CCRT/IMRT, respectively. After three weeks of the completion of IMRT, adjuvant toripalimab will be used every 3 weeks for 11 cycles, and therefore the entire treatment process is expected to last for one year.

Conditions

Nasopharyngeal Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Toripalimab Combined with Induction Chemotherapy Followed by Radiotherapy Alone

All participants will receive induction chemotherapy (IC; every 3 weeks × 3 cycles; gemcitabine 1000 mg/m2 day 1, 8 + cisplatin 80 mg/m2 day 1) followed by intensity-modulated radiotherapy (IMRT; 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day) alone. PD-1 blockade toripalimab (240 mg per cycle) will start on day 1 of the first cycle IC and continue every 3 weeks for 6 cycles till the end of IMRT, involving the whole-course of IC + IMRT alone. The first and last 3 cycles of toripalimab are administrated concurrently with IC and IMRT, respectively. After 3 weeks of the completion of IMRT, adjuvant toripalimab (240 mg per cycle) will begin every 3 weeks for 11 cycles.

Group Type: EXPERIMENTAL

PD-1 blocking antibody

Intervention Type: DRUG

1. IC phase of PD-1 blocking antibody: every 3 weeks × 3 cycles; 240 mg, day 1; start on day 1 of the first cycle IC and continue every 3 weeks for 3 cycles till the end of IC.

2. IMRT phase of PD-1 blocking antibody: every 3 weeks × 3 cycles; 240 mg, day 1; start on day 1 of IMRT or CCRT and continue every 3 weeks for 3 cycles till the end of IMRT.

3. Adjuvant PD-1 blocking antibody: every 3 weeks × 11 cycles; 240 mg, day 1

Gemcitabine

Intervention Type: DRUG

Gemcitabine as induction chemotherapy, 1000 mg/m2 day 1, 8 per cycle, every 3 weeks for 3 cycles

Cisplatin (80mg/m2)

Intervention Type: DRUG

Cisplatin as induction chemotherapy, 80 mg/m2 day 1 per cycle, every 3 weeks for 3 cycles

Intensity-modulated radiotherapy

Intervention Type: RADIATION

Definitive IMRT of 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day

Toripalimab Combined with Induction Chemotherapy Followed by Concurrent Chemoradiotherapy

All participants will receive induction chemotherapy (IC; every 3 weeks × 3 cycles of gemcitabine 1000 mg/m2 day 1, 8 + cisplatin 80 mg/m2 day 1) followed by concurrent chemoradiotherapy (CCRT; every 3 weeks × 2 cycles of cisplatin + IMRT 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day). PD-1 blockade toripalimab (240 mg per cycle) will start on day 1 of the first cycle IC and continue every 3 weeks for 6 cycles till the end of CCRT, involving the whole-course of IC + CCRT. The first and last 3 cycles of toripalimab are administrated concurrently with IC and CCRT, respectively. After 3 weeks of the completion of CCRT, adjuvant toripalimab (240 mg per cycle) will begin every 3 weeks for 11 cycles.

Group Type: ACTIVE_COMPARATOR

PD-1 blocking antibody

Intervention Type: DRUG

1. IC phase of PD-1 blocking antibody: every 3 weeks × 3 cycles; 240 mg, day 1; start on day 1 of the first cycle IC and continue every 3 weeks for 3 cycles till the end of IC.

2. IMRT phase of PD-1 blocking antibody: every 3 weeks × 3 cycles; 240 mg, day 1; start on day 1 of IMRT or CCRT and continue every 3 weeks for 3 cycles till the end of IMRT.

3. Adjuvant PD-1 blocking antibody: every 3 weeks × 11 cycles; 240 mg, day 1

Gemcitabine

Intervention Type: DRUG

Gemcitabine as induction chemotherapy, 1000 mg/m2 day 1, 8 per cycle, every 3 weeks for 3 cycles

Cisplatin (80mg/m2)

Intervention Type: DRUG

Cisplatin as induction chemotherapy, 80 mg/m2 day 1 per cycle, every 3 weeks for 3 cycles

Cisplatin (100mg/m2)

Intervention Type: DRUG

Cisplatin as concurrent chemotherapy, 100 mg/m2 day 1 per cycle, every 3 weeks for 2 cycles

Intensity-modulated radiotherapy

Intervention Type: RADIATION

Definitive IMRT of 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day

Interventions

PD-1 blocking antibody

1. IC phase of PD-1 blocking antibody: every 3 weeks × 3 cycles; 240 mg, day 1; start on day 1 of the first cycle IC and continue every 3 weeks for 3 cycles till the end of IC.

2. IMRT phase of PD-1 blocking antibody: every 3 weeks × 3 cycles; 240 mg, day 1; start on day 1 of IMRT or CCRT and continue every 3 weeks for 3 cycles till the end of IMRT.

3. Adjuvant PD-1 blocking antibody: every 3 weeks × 11 cycles; 240 mg, day 1

Intervention Type: DRUG

Gemcitabine

Gemcitabine as induction chemotherapy, 1000 mg/m2 day 1, 8 per cycle, every 3 weeks for 3 cycles

Intervention Type: DRUG

Cisplatin (80mg/m2)

Cisplatin as induction chemotherapy, 80 mg/m2 day 1 per cycle, every 3 weeks for 3 cycles

Intervention Type: DRUG

Cisplatin (100mg/m2)

Cisplatin as concurrent chemotherapy, 100 mg/m2 day 1 per cycle, every 3 weeks for 2 cycles

Intervention Type: DRUG

Intensity-modulated radiotherapy

Definitive IMRT of 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day

Intervention Type: RADIATION

Other Intervention Names

PD-1 Blockade; GEM; DDP; DDP; IMRT

Eligibility Criteria

Inclusion Criteria

1. Age: 18 to 65;

2. Pathological type: non-keratinizing carcinoma (World Health Organization criteria);

3. Diagnosed with LANPC (T4N1, T1-4N2-3) according to the 8th edition clinical staging system of the American Joint Committee on Cancer [AJCC]/Union for International Cancer Control [UICC];

4. ECOG performance score: 0 to 1;

5. Normal bone marrow function: white blood cell count > 4×109/L, hemoglobin > 90g/L, platelet count > 100×109/L;

Exclusion Criteria

7. Normal liver and kidney function: total bilirubin ≤ 1.5 × upper limit of normal (ULN); alanine transaminase and aspartate transaminase ≤ 2.5 × ULN; alkaline phosphatase ≤ 2.5 × ULN; creatinine clearance rate ≥ 60 ml/min;

8. Patients must sign informed consent and be willing and able to comply with the requirements of visits, treatment, laboratory tests and other research requirements stipulated in the research schedule;

9. Subjects with pregnancy ability must agree to use reliable contraceptive measures from screening to 1 year after treatment.

1. Hepatitis B virus surface antigen (HBsAg) positive and HBV DNA > 1×10E3 copies/ml; anti-hepatitis C virus positive;

2. Anti-human immunodeficiency virus (HIV) positive or diagnosed with acquired immune deficiency syndrome (AIDS);

3. Active tuberculosis: active tuberculosis in the past 1 year should be excluded regardless with treatment; history of active tuberculosis over 1 year should be excluded except that previous regulatory anti-tuberculosis treatment is proved;

4. Active, known or suspected autoimmune disease (including but not limited to uveitis, enteritis, hepatitis, pituitary, nephritis, vasculitis, hyperthyroidism, hypothyroidism and asthma requiring bronchiectasis). Exceptions are type I diabetes mellitus, hypothyroidism requiring hormone replacement therapy, skin disorders requiring no systemic treatment (such as vitiligo, psoriasis or alopecia);

5. Previous interstitial lung disease or pneumonia requiring oral or intravenous steroid therapy;

6. Chronic treatment with systemic glucocorticoid (dose equivalent to or over 10 mg prednisone per day) or any other form of immunosuppressive therapy. Subjects who used inhaled or topical corticosteroids were eligible;

7. Uncontrolled heart disease, for example: 1) heart failure (NYHA level ≥ 2); 2) unstable angina; 3) myocardial infarction in past 1 year; 4) supraventricular or ventricular arrhythmia requiring treatment or intervention;

8. Pregnant or lactating women (pregnancy test should be considered for women with sexual life and fertility);

9. Previous or concurrent with other malignant tumors, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ and thyroid papillary cancer;

10. Allergy to macromolecular protein preparations, or any component of nivolumab;

11. Active infection requiring systemic treatment;

12. Receiving live vaccine within 30 days of the initial nivolumab;

13. History of organ transplantation;

14. History of psychotropic disease, alcoholism or drug abuse; other situation assessed by the investigators that may compromise the safety or compliance of patients, such as serious disease requiring timely treatment (including mental illness), severe laboratory abnormalities, or family-social risk factors.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shanghai Junshi Bioscience Co., Ltd.

OTHER

Sponsor Role: collaborator

Sun Yat-sen University

OTHER

Sponsor Role: lead

Responsible Party

Jun Ma, MD

Vice President of SYSUCC

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jun Ma, M.D.

Role: PRINCIPAL_INVESTIGATOR

Sun Yat-sen University

Locations

Beijing Cancer Hospital

Beijing, Beijing Municipality, China

Chongqing Cancer Hospital

Chongqing, Chongqing Municipality, China

First People's Hospital of Foshan

Foshan, Guangdong, China

Panyu central hospital

Guangzhou, Guangdong, China

Cancer Hospital of Guangxi Medical University

Nanning, Guangxi, China

Cancer Hospital of Guizhou Medical University

Guiyang, Guizhou, China

Hubei Province Cancer Hosiptal

Wuhan, Hubei, China

Tongji Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology

Wuhan, Hubei, China

Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology

Wuhan, Hubei, China

Xiangya Hospital Central South University

Changsha, Hunan, China

Jiangxi Province Cancer Hospital

Nanchang, Jiangxi, China

Zhejiang Province Cancer Hospital

Hangzhou, Zhejiang, China

Countries

China

References

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.

Reference Type: RESULT

PMID: 31150573 (View on PubMed)

Ma BBY, Lim WT, Goh BC, Hui EP, Lo KW, Pettinger A, Foster NR, Riess JW, Agulnik M, Chang AYC, Chopra A, Kish JA, Chung CH, Adkins DR, Cullen KJ, Gitlitz BJ, Lim DW, To KF, Chan KCA, Lo YMD, King AD, Erlichman C, Yin J, Costello BA, Chan ATC. Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol. 2018 May 10;36(14):1412-1418. doi: 10.1200/JCO.2017.77.0388. Epub 2018 Mar 27.

Reference Type: RESULT

PMID: 29584545 (View on PubMed)

Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, Mehnert JM, Algazi A, van Brummelen EMJ, Saraf S, Thanigaimani P, Cheng JD, Hansen AR. Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol. 2017 Dec 20;35(36):4050-4056. doi: 10.1200/JCO.2017.73.3675. Epub 2017 Aug 24.

Reference Type: RESULT

PMID: 28837405 (View on PubMed)

Fang W, Yang Y, Ma Y, Hong S, Lin L, He X, Xiong J, Li P, Zhao H, Huang Y, Zhang Y, Chen L, Zhou N, Zhao Y, Hou X, Yang Q, Zhang L. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 2018 Oct;19(10):1338-1350. doi: 10.1016/S1470-2045(18)30495-9. Epub 2018 Sep 10.

Reference Type: RESULT

PMID: 30213452 (View on PubMed)

Wang FH, Wei XL, Feng J, Li Q, Xu N, Hu XC, Liao W, Jiang Y, Lin XY, Zhang QY, Yuan XL, Huang HX, Chen Y, Dai GH, Shi JH, Shen L, Yang SJ, Shu YQ, Liu YP, Wang W, Wu H, Feng H, Yao S, Xu RH. Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02). J Clin Oncol. 2021 Mar 1;39(7):704-712. doi: 10.1200/JCO.20.02712. Epub 2021 Jan 25.

Reference Type: RESULT

PMID: 33492986 (View on PubMed)

DIAMOND Study Group; Xu C, Liang XY, Huang XQ, Jin F, Yang KY, Hu GY, Zhu XD, Wang Y, Huang Y, Zhang N, Hu DS, Guo L, Zou GR, Chen XZ, Xiao SW, Li JG, Shen LF, Li YY, Huang J, Long GX, Li L, Huang L, She LJ, Wu Y, Zeng WH, Qiang MY, Liu WX, Su Y, Tang LL, Xie FY, Han F, Lu LX, Xiang YQ, Mao YP, Li WF, Liu X, Yang Q, Zhou GQ, Guo R, Ouyang PY, Wang XH, Chen L, Liu LT, Lin L, Li JB, Lin AH, Zhao HY, Hong SB, Jie YS, Huang HL, Tang XH, Zeng YC, Yun JP, Zang SB, Du ZM, Ye ZL, Liu LZ, Tian L, Li HJ, Peng YL, Liu N, Li YQ, Liang YL, Wei HM, Chen YP, Zhang Y, Du XJ, Lv JW, Sun Y, Ma J. Toripalimab Combination Therapy Without Concurrent Cisplatin for Nasopharyngeal Carcinoma: The DIAMOND Randomized Clinical Trial. JAMA. 2025 Sep 16;334(11):973-983. doi: 10.1001/jama.2025.13205.

Reference Type: DERIVED

PMID: 40839372 (View on PubMed)

Other Identifiers

JS001-ISS-CO291

Identifier Type: -

Identifier Source: org_study_id