Sintilimab (PD-1 Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma (CONTINUUM)

Sintilimab (PD-1 Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma: a Randomized, Multicenter, Phase 3 Trial

The CONTINUUM trial plans to enroll patients with stage III-IVA (AJCC 8th, except T3N0-1 or T4N0) locoregionally-advanced nasopharyngeal carcinoma (LANPC). Patients will be randomized in a 1:1 ratio to receive 3 cycles of induction chemotherapy with gemcitabine and cisplatin and concurrent cisplatin-radiation or the same regimen plus Sintilimab. All patients will receive intensity-modulated radiotherapy (IMRT). Sintilimab will begin on day 1 of induction chemotherapy and continue every 3 weeks for 12 cycles.

Study Overview

• Status: Active, not recruiting
• Conditions: Nasopharyngeal Neoplasms
• Intervention / Treatment: Radiation: intensity-modulated radiotherapy; Drug: Gemcitabine; Drug: Cisplatin; Drug: Sintilimab

• Study Type: Interventional
• Enrollment (Actual): 425
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Foshan, Guangdong, China
      • First People's Hospital of Foshan
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-sen University Cancer Center
    • Guangzhou, Guangdong, China, 510060
      • Panyu Central Hospital
  • Guangxi
    • Nanning, Guangxi, China
      • Cancer Hospital of Guangxi Medical University
  • Guizhou
    • Guiyang, Guizhou, China
      • Cancer Hospital of Guizhou Medical University
  • Hubei
    • Wuhan, Hubei, China
      • Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology
  • Hunan
    • Changsha, Hunan, China
      • Xiangya Hospital Central South University
  • Shanxi
    • Xi'an, Shanxi, China
      • Xijing Hospital, Fourth Military Medical University
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital, Sichuan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with histologically confirmed nasopharyngeal carcinoma.
2. Tumor staged as III-IVA (AJCC 8th, except T3N0-1 or T4N0).
3. Eastern Cooperative Oncology Group performance status ≤1.
4. Adequate marrow function: neutrocyte count≥1.5×10e9/L, hemoglobin ≥90g/L and platelet count ≥100×10e9/L.
5. Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) ≤2.5×upper limit of normal (ULN), and bilirubin ≤ 1.5×ULN.
6. Adequate renal function: creatinine clearance rate ≥ 60 ml/min (Cockcroft-Gault formula).
7. Patients must be informed of the investigational nature of this study and give written informed consent.
8. 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 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 > 65 or < 18.
2. Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus DNA >1×10e3 copies/ml or 200IU/ml
3. Hepatitis C virus (HCV) antibody positive
4. 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).
5. Has any condition that required systemic corticosteroid (equivalent to prednisone >10mg/d) or other immunosuppressive therapy within 28 days before informed consent. Patients received systemic corticosteroid equivalent to prednisone ≤10mg/d, inhale or topical corticosteroid will be allowed.
6. Has a known history of active TB (bacillus tuberculosis) within 1 year; patients with adequately treated active TB over 1 year ago will be allowed.
7. Has a known history of interstitial lung disease.
8. Has received a live vaccine within 30 days before informed consent or will receive a live vaccine in the near future.
9. Is pregnant or breastfeeding.
10. Prior malignancy within 5 years, except in situ cancer, adequately treated non-melanoma skin cancer, and papillary thyroid carcinoma.
11. Has known allergy to large molecule protein products or any compound of sintilimab.
12. Has a known history of human immunodeficiency virus (HIV) infection.
13. 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: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Chemoradiation arm; Patients will receive induction chemotherapy with gemcitabine (1g/m2, d1 & 8 of every cycle) and cisplatin (80mg/m2, d1 of every cycle), every 3 weeks for 3 cycles before radiation. Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy in 33 fractions will be given. Concurrent cisplatin of 100mg/m2 will be administered every 3 weeks for 2 cycles during IMRT.	Radiation: intensity-modulated radiotherapy; Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy will be given in 33 fractions.; Other Names: IMRT; Drug: Gemcitabine; Gemcitabine 1g/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 2 cycles during radiation; Other Names: DDP
Experimental: Sintilimab arm; Patients will receive induction chemotherapy with gemcitabine (1g/m2, d1 & 8 of every cycle) and cisplatin (80mg/m2, d1 of every cycle), every 3 weeks for 3 cycles before radiation. Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy in 33 fractions will be given. Concurrent cisplatin of 100mg/m2 will be administered every 3 weeks for 2 cycles during IMRT. Sintilimab 200mg will be given every 3 weeks for 12 cycles, started on day 1 of induction chemotherapy.	Radiation: intensity-modulated radiotherapy; Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy will be given in 33 fractions.; Other Names: IMRT; Drug: Gemcitabine; Gemcitabine 1g/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 2 cycles during radiation; Other Names: DDP; Drug: Sintilimab; Sintilimab 200mg will be given every 3 weeks for 12 cycles, started on day 1 of induction chemotherapy.; Other Names: IBI308; PD-1 antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	calculated from randomization to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events (AEs) and serious adverse events (SAEs)	Graded according to CTCAE V5.0.	3 years
Overall survival (OS)	calculated from randomization to the date of death from any cause.	3 years
Distant metastasis-free survival (DMFS)	calculated from randomization to the date of first distant metastasis, or death from any cause, whichever occurred first.	3 years
Locoregional recurrence-free survival (LRFS)	calculated from randomization to the date of locoregional persistence, 1st locoregional recurrence, or death from any cause, whichever occurred first.	3 years
Quality of life (QoL)	The change of QoL from randomization to the start of radiotherapy, the end of radiotherapy, 34 weeks (at the end of sintilimab treatment in the sintilimab arm and the corresponding timepoint in the chemoradiation arm), 2 years and 3 years after randomization. The EORTC QoL questionnaire-C30 (EORTC QLQ-C30）version 3.0 will be used. This questionnaire comprises 30 questions, 24 of which are aggregated into nine multi-question scales, that is, five functioning scales (e.g., physical), three symptom scales (e.g., fatigue) and one global health status scale. The remaining six single-question (e.g., dyspnoea) scales assess symptoms. These 15 scales will be scored according to the official Scoring Manual.	3 years
Event-free survival (EFS) within different subgroups	analyses for EFS will be performed within the following subgroups: Epstein-Barr virus (EBV) DNA (<4000copies/ml vs. ≥4000copies/ml), different PD-L1 expression levels (<1% vs. ≥1%), tertiary lymphoid structure (+ vs. -), age, gender, performance status, T category, N category, and stage (III vs. IVA).	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The association of circulation autoimmune antibodies with immune-related adverse events		1 year
The association of circulation cytokines, chemokines, and growth factors/regulators with immune-related adverse events		1 year
The association of gene expression with the efficacy of sintilimab	RNA sequencing will be conducted using baseline tumor samples.	3 years
The association of cell populations with the efficacy of sintilimab	Multiplex Immunofluorescence will be conducted to assess tumor and immune-related markers in baseline tumor samples.	3 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Innovent Biologics (Suzhou) Co. Ltd.
• Investigators: Principal Investigator: Jun Ma, MD, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2018
• Primary Completion (Actual): February 28, 2023
• Study Completion (Anticipated): January 1, 2025

Study Registration Dates

• First Submitted: October 3, 2018
• First Submitted That Met QC Criteria: October 6, 2018
• First Posted (Actual): October 9, 2018

Study Record Updates

• Last Update Posted (Actual): March 28, 2023
• Last Update Submitted That Met QC Criteria: March 24, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine
• Other Study ID Numbers: 2018-FXY-135-FLK

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Complete de-identified patient data set
• IPD Sharing Time Frame: For 2 years started from 12 months after publication of the primary trial report.
• IPD Sharing Access Criteria: Authoritative researchers who provide a methodologically sound proposal for individual participant data meta-analysis.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No