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

• ClinicalTrials.gov Identifier: NCT03700476
• Recruitment Status: Active, not recruiting
• First Posted: October 9, 2018
• Last Update Posted: March 28, 2023
• Sponsor: Sun Yat-sen University
• Collaborator: Innovent Biologics (Suzhou) Co. Ltd.
• Information provided by (Responsible Party): Jun Ma, MD, Sun Yat-sen University

Tracking Information

• First Submitted Date: October 3, 2018
• First Posted Date: October 9, 2018
• Last Update Posted Date: March 28, 2023
• Actual Study Start Date: December 21, 2018
• Actual Primary Completion Date: February 28, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 6, 2022)

Event-free survival (EFS) [ Time Frame: 3 years ]

calculated from randomization to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first.

Original Primary Outcome Measures (submitted: October 6, 2018)

Failure-free survival (FFS) [ Time Frame: 3 years ]

calculated from randomization to the date of locoregional failure, distant failure, or death from any cause, whichever occurred first.

Current Secondary Outcome Measures (submitted: March 24, 2023)

• Overall survival (OS) [ Time Frame: 3 years ]
  calculated from randomization to the date of death from any cause.
• Distant metastasis-free survival (DMFS) [ Time Frame: 3 years ]
  calculated from randomization to the date of first distant metastasis, or death from any cause, whichever occurred first.
• Locoregional recurrence-free survival (LRFS) [ Time Frame: 3 years ]
  calculated from randomization to the date of locoregional persistence, 1st locoregional recurrence, or death from any cause, whichever occurred first.
• Adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 3 years ]
  Graded according to CTCAE V5.0.
• Quality of life (QoL) [ Time Frame: 3 years ]
  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.
• Event-free survival (EFS) within different subgroups [ Time Frame: 3 years ]
  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).

Original Secondary Outcome Measures (submitted: October 6, 2018)

• Overall survival (OS) [ Time Frame: 3 years ]
  calculated from randomization to the date of death from any cause.
• Distant failure-free survival (DFFS) [ Time Frame: 3 years ]
  calculated from randomization to the date of first distant metastasis.
• Locoregional failure-free survival (LRFFS) [ Time Frame: 3 years ]
  calculated from randomization to the date of locoregional persistence or 1st locoregional recurrence.
• Adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 3 years ]
  Graded according to CTCAE V5.0.
• Quality of life (QoL) [ Time Frame: 16 months ]
  The change of QoL from randomization to 12 months after chemoradiation. The European Organization for Research and Treatment of Cancer quality of life 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: 1. Estimate the average of the questions that contribute to the scale; this is the raw score. 2. Use a linear transformation to standardise the raw score, so that scores range from 0 to 100. Thus, a high score for a functional scale represents a high level of functioning, a high score for the global health status represents a high QoL, but a high score for a symptom scale represents a high level of problems.
• Failure-free survival (FFS) within different subgroups [ Time Frame: 3 years ]
  analyses for FFS will be performed within the following subgroups: Epstein-Barr virus (EBV) DNA (≤2000copies/ml vs. >2000copies/ml), different PD-L1 expression levels, and stage (III vs. IVA).
• Overall survival (OS) within different subgroups [ Time Frame: 3 years ]
  analyses for OS will be performed within the following subgroups: EBV DNA (≤2000copies/ml vs. >2000copies/ml), different PD-L1 expression levels, and stage (III vs. IVA).
• Distant failure-free survival (DFFS) within different subgroups [ Time Frame: 3 years ]
  analyses for DFFS will be performed within the following subgroups: EBV DNA (≤2000copies/ml vs. >2000copies/ml), different PD-L1 expression levels, and stage (III vs. IVA).
• Locoregional failure-free survival (LRFFS) within different subgroups [ Time Frame: 3 years ]
  analyses for LRFFS will be performed within the following subgroups: EBV DNA (≤2000copies/ml vs. >2000copies/ml), different PD-L1 expression levels, and stage (III vs. IVA).

Current Other Pre-specified Outcome Measures (submitted: March 24, 2023)

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

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Sintilimab (PD-1 Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma
• Official Title: Sintilimab (PD-1 Antibody) and Chemoradiotherapy in Locoregionally-advanced Nasopharyngeal Carcinoma: a Randomized, Multicenter, Phase 3 Trial
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Nasopharyngeal Neoplasms

Intervention

• 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
• 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 Name: DDP
• Radiation: intensity-modulated radiotherapy
  Definitive intensity-modulated radiotherapy (IMRT) of 6996cGy will be given in 33 fractions.
  Other Name: IMRT

Study Arms

• 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.
  Interventions:

  • Drug: Sintilimab
  • Drug: Gemcitabine
  • Drug: Cisplatin
  • Radiation: intensity-modulated radiotherapy
• 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.
  Interventions:

  • Drug: Gemcitabine
  • Drug: Cisplatin
  • Radiation: intensity-modulated radiotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 3, 2022): 425
• Original Estimated Enrollment (submitted: October 6, 2018): 420
• Estimated Study Completion Date: January 2025
• Actual Primary Completion Date: February 28, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT03700476
• Other Study ID Numbers: 2018-FXY-135-FLK
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Complete de-identified patient data set
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Analytic Code
• Time Frame: For 2 years started from 12 months after publication of the primary trial report.
• Access Criteria: Authoritative researchers who provide a methodologically sound proposal for individual participant data meta-analysis.

• Current Responsible Party: Jun Ma, MD, Sun Yat-sen University
• Original Responsible Party: Same as current
• Current Study Sponsor: Sun Yat-sen University
• Original Study Sponsor: Same as current
• Collaborators: Innovent Biologics (Suzhou) Co. Ltd.

Investigators

• Principal Investigator: Jun Ma, MD; Sun Yat-sen University

• PRS Account: Sun Yat-sen University
• Verification Date: March 2023