PD-1 Blockade Combined With De-intensification Radical Chemoradiotherapy in Nasopharyngeal Carcinoma

Nasopharyngeal Carcinoma Clinical Trial

— DIAMOND  

Official title:

Toripalimab Combined With Induction Chemotherapy Followed by Radiotherapy Alone or Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A Phase 3, Multi-center, Randomized Controlled Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04907370
• Other study ID #: JS001-ISS-CO291
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: August 1, 2021
• Est. completion date: May 1, 2027

Study information

• Verified date: February 2024
• Source: Sun Yat-sen University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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-intensification radical chemoradiotherapy sparing concurrent cisplatin (i.e., toripalimab plus induction chemotherapy followed by radiotherapy alone) in high-risk locoregionally advanced nasopharyngeal carcinoma.

Description:

This phase 3, multi-center, randomized controlled trial plans to enroll 520 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 540
• Est. completion date: May 1, 2027
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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;

6. Normal values of thyroid function, amylase and lipase examination, pituitary function, inflammation and infection indicators, myocardial enzymes, and ECG results. For patients older than 50 years with a smoking history, normal lung function are required. Patients with abnormal ECG and/or a history of vascular disease (but not meeting the exclusion criteria listed in the exclusion criteria 7) need further testing and require normal results of myocardial function and color Doppler ultrasound.

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.

Exclusion Criteria:

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.

Related Conditions & MeSH terms

• Carcinoma
• Nasopharyngeal Carcinoma

Intervention

Drug:
• PD-1 blocking antibody
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. 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. Adjuvant PD-1 blocking antibody: every 3 weeks × 11 cycles; 240 mg, day 1
• Gemcitabine
Gemcitabine as induction chemotherapy, 1000 mg/m2 day 1, 8 per cycle, every 3 weeks for 3 cycles
• Cisplatin (80mg/m2)
Cisplatin as induction chemotherapy, 80 mg/m2 day 1 per cycle, every 3 weeks for 3 cycles
• Cisplatin (100mg/m2)
Cisplatin as concurrent chemotherapy, 100 mg/m2 day 1 per cycle, every 3 weeks for 2 cycles

Radiation:
• Intensity-modulated radiotherapy
Definitive IMRT of 70 Gy, 33 fractions, 5 fractions/week, 1 fraction/day

Locations

Country	Name	City	State
China	Beijing Cancer Hospital	Beijing	Beijing
China	Xiangya Hospital Central South University	Changsha	Hunan
China	Chongqing Cancer Hospital	Chongqing	Chongqing
China	First People's Hospital of Foshan	Foshan	Guangdong
China	Panyu central hospital	Guangzhou	Guangdong
China	Cancer Hospital of Guizhou Medical University	Guiyang	Guizhou
China	Zhejiang Province Cancer Hospital	Hangzhou	Zhejiang
China	Jiangxi Province Cancer Hospital	Nanchang	Jiangxi
China	Cancer Hospital of Guangxi Medical University	Nanning	Guangxi
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

Sponsors (2)

Lead Sponsor	Collaborator
Sun Yat-sen University	Shanghai Junshi Bioscience Co., Ltd.

Country where clinical trial is conducted

China, 

References & Publications (5)

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 — View Citation

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 Nasopharynge — View Citation

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 Ac — View Citation

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 P — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Correlation between pre-treatment PD-L1 expression level and FFS	Pre-treatment PD-L1 expression level of tumor cell is evaluated centrally by means of immunohistochemical testing. This is a single assessment with only one unit of measure, since the correlation is aimed to be roughly categorized into positive and negative.	3-year
Other	Correlation between pre-treatment PD-L1 expression level and OS	Pre-treatment PD-L1 expression level of tumor cell is evaluated centrally by means of immunohistochemical testing. This is a single assessment with only one unit of measure, since the correlation is aimed to be roughly categorized into positive and negative.	3-year
Other	Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and PFS	TILs are lymphoid cells (T cells) that infiltrate solid tumors (intra-tumoral TILs) and stroma (stromal TILs), which play an important role in the tumor microenvironment. This is a single assessment with only one unit of measure, since the correlation is aimed to be roughly categorized into positive and negative.	3-year
Other	Correlation between the percentage of tumor-infiltrating lymphocytes (TILs) and OS	TILs are lymphoid cells (T cells) that infiltrate solid tumors (intra-tumoral TILs) and stroma (stromal TILs), which play an important role in the tumor microenvironment. This is a single assessment with only one unit of measure, since the correlation is aimed to be roughly categorized into positive and negative.	3-year
Other	Evaluate failure-free survival in the subgroup of age at diagnosis (year)	Subgroup analysis	3-year
Other	Evaluate failure-free survival in the subgroup of gender (male and female)	Subgroup analysis	3-year
Other	Evaluate failure-free survival in the subgroup of plasma Epstein-Barr virus DNA level	Subgroup analysis	3-year
Other	Evaluate failure-free survival in the subgroup of clinical stage	Subgroup analysis	3-year
Other	Evaluate the regression of tumor and parotid glands during radiotherapy	Evaluate the anatomical (size, volume, and 3-dimensional axis) and dosimetric changes of primary tumor, lymph node, and parotid glands during 33-fractionation radiotherapy by using cone beam computed tomography	From the first fraction of radiotherapy to the end of treatment
Primary	Failure-free survival (FFS)	Failure-free survival is measured from day of diagnosis until treatment failure, death from any cause, or last follow-up visit, whichever occurred first	3-year
Secondary	Overall survival (OS)	Overall survival is measured from day of diagnosis until death due to any cause or the latest known date alive	3-year
Secondary	Locoregional failure-free survival (LRFFS)	Locoregional failure-free survival is measured from day of diagnosis until local or regional recurrence	3-year
Secondary	Distant failure-free survival (DFFS)	Distant failure-free survival is measured from day of diagnosis until distant metastasis	3-year
Secondary	Incidence rate of investigator-reported adverse events (AEs)	Analysis of investigator-reported adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by investigators according to the Common Terminology Criteria for Adverse Events, version 5.0	3-year
Secondary	Incidence rate of patient-reported adverse events (AEs)	Analysis of patient-reported adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by patients themselves	3-year
Secondary	Quality of life (QoL): questionnaire	Changes in QoL of participants from initial treatment to 6 months after the completion of 6 cycles adjuvant PD-1 blocking antibody. QoL is evaluated with the use of (1) the head-and-neck-specific module (H&N35) of the Quality of Life Questionnaire-Core 30 module (QLQ-C30), which is established by European Organization for Research and Treatment of Cancer (EORTC) and (2) the general and head-and-neck-specific module of the evaluation tool developed by the Functional Assessment of Cancer Therapy (FACT). Scores for the module range of H&N35 QLQ-C30 from 0 to 100, with higher scores indicating better functioning or well-being or higher symptom burden (scales measuring symptom burden were reverse-scored to facilitate presentation)	week 1, 20, 40, 64