Induction PD-1 Inhibitor and Chemotherapy Followed by Chemoradiotherapy in Unresectable or Inoperable HPV-negative LA-HNSCC

Induction Chemoimmunotherapy Followed by Concurrent Chemoradiotherapy and Adjuvant Immunotherapy Versus Concurrent Chemoradiotherapy Alone in Unresectable or Inoperable Locoregionally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma: A Randomized, Controlled, Phase 2 Study

The goal of this clinical trial is to evaluate if adding chemotherapy and immunotherapy as induction treatment prior to definitive chemoradiotherapy could improve the outcomes of locally advanced HPV-negative head and neck squamous cell that are not amenable to surgery. The study aims to answer:

1. Does this treatment improve the survival outcomes of participants?
2. How do the tumors of participants response to the treatment?
3. How is the safety of this treatment? Researchers will compare this treatment (induction chemoimmunotherapy, followed by concurrent chemoradiotherapy, and then immunotherapy as maintenance therapy) to concurrent chemoradiotherapy to see whether it provides additional clinical benefits.

Study Overview

• Status: Not yet recruiting
• Conditions: HPV-unrelated Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Biological: Tislelizumab; Drug: Paclitaxel; Drug: Cisplatin (75 mg/m2); Radiation: Intensity-Modulated Radiotherapy; Drug: Cisplatin (80 mg/m2)

Detailed Description

This multicenter, prospective, open-label, phase II randomized controlled clinical trial plans to enroll 104 treatment naïve participants with locally advanced (III-IVB by UICC/AJCC 8th), unresectable or inoperable HPV-negative head and neck squamous cell carcinoma (HNSCC). Patients will be stratified by primary tumor site (oropharynx vs. non-oropharynx) and randomly assigned (1:1) to one of two treatment arms: (1) Arm A (Experimental): Induction phase, three cycles of tislelizumab plus paclitaxel and cisplatin; Concurrent chemoradiotherapy (CCRT) phase, definitive radiotherapy concurrent with two cycles of cisplatin; Adjuvant phase, 13 cycles of tislelizumab. (2) Arm B (Comparator): CCRT, definitive radiotherapy concurrent with two cycles of cisplatin. The primary hypothesis is that the addition of induction chemoimmunotherapy and adjuvant immunotherapy improves event-free survival compared to chemoradiotherapy alone.

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xin Zhou, M.D.; Phone Number: +8618017863989; Email: zhoux1013@shca.org.cn
• Study Contact Backup: Name: Xueguan Lu, M.D.; Phone Number: +8618121299382; Email: luxueguan@shca.org.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200032
      • Fudan Universtiy Shanghai Cancer Center
      • Contact: Xin Zhou, M.D.; Phone Number: +86 18017863989; Email: zhoux1013@shca.org.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Pathologically confirmed HPV-negative head and neck squamous cell carcinoma (including laryngeal, hypopharyngeal, or oropharyngeal cancer).
• Loco-regionally advanced (Stage III-IVB) disease according to the 8th edition clinical staging system of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC).
• Confirmed by a multidisciplinary team (MDT) as not amenable to curative surgery and deemed suitable for definitive concurrent chemoradiotherapy.

"Not amenable to curative surgery" includes unresectable disease (anatomic impossibility of resection) or inoperable disease (patient medically unable to tolerate or declining surgical resection).

• ECOG performance status of 0-1.
• Pre-treatment neutrophils ≥ 1.5 × 10⁹/L, hemoglobin ≥ 90 g/L, platelets ≥ 100 × 10⁹/L; total bilirubin ≤ 1.5 × upper limit of normal (ULN), ALT ≤ 1.5 × ULN, AST ≤ 1.5 × ULN, ALP ≤ 2.5 × ULN; creatinine ≤ 1.5 × ULN.
• Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN (patients on a stable dose of anticoagulant therapy, such as low molecular weight heparin or warfarin, with an INR within the therapeutic range for the anticoagulant, are eligible for screening).
• Normal pulmonary and cardiac function.
• Normal myocardial enzyme profile.
• No prior radiotherapy, chemotherapy, immunotherapy, or biological targeted therapy, or any other antitumor treatment for the current tumor lesion(s).
• Women of childbearing potential must have a negative pregnancy test (serum) within 7 days before enrollment and must voluntarily use appropriate contraception during the observation period and for 8 weeks after the last treatment; for men, they must be surgically sterile or agree to use appropriate contraception during the observation period and for 8 weeks after the last treatment.
• Participants 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.

Exclusion Criteria:

• Has a history or presence of other malignancies, except for those that have been cured and with no evidence of disease for over 5 years (such as basal cell carcinoma of the skin, carcinoma in situ of the cervix, and papillary thyroid carcinoma, etc.).
• Has active autoimmune diseases or a history of autoimmune diseases (e.g., interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes); excluding autoimmune-mediated hypothyroidism stabilized with thyroid hormone replacement therapy; type I diabetes mellitus stabilized on insulin regimen; vitiligo or childhood asthma/allergies that have resolved and require no intervention in adulthood.
• Has uncontrolled cardiac clinical symptoms or diseases, such as: (a) NYHA Class II or above heart failure; (b) unstable angina; (c) myocardial infarction within the past year; (d) clinically significant supraventricular or ventricular arrhythmias requiring clinical intervention.
• Has severe infection (CTCAE > Grade 2) within 4 weeks prior to the first dose of the study drug, active infection during screening, or unexplained fever > 38.5°C before administration (tumor-related fever may be considered for inclusion).
• Has a history of allergy to any component of anti-PD-1 antibodies, paclitaxel-based drugs, or cisplatin.
• Prior radiotherapy, chemotherapy, immunotherapy (including PD-1, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, cancer vaccines, etc.), or biological targeted therapy for the current hypopharyngeal/laryngeal/oropharyngeal cancer.
• Concurrent participation in another clinical study, unless it is an observational (non-interventional) study or the follow-up phase of an interventional study.
• Requirement for systemic treatment with corticosteroids (prednisone equivalent dose > 10 mg/day) or other immunosuppressive agents within 2 weeks prior to the first dose of the study drug, except for topical use to manage local inflammation, prevent allergies, or manage nausea and vomiting. Other special cases should be discussed with the investigator. Inhaled or topical steroids and physiological doses of corticosteroid replacement for adrenal insufficiency (≤ 10 mg/day prednisone equivalent) are permitted in the absence of active autoimmune disease.
• Major surgery or severe trauma within 4 weeks prior to the first dose of the study drug.
• Has a history of immunodeficiency, including positive HIV test, other acquired or congenital immunodeficiency diseases, or history of organ transplantation or allogeneic bone marrow transplantation.
• Has a history of interstitial lung disease (excluding radiation pneumonitis not treated with steroids) or non-infectious pneumonitis.
• Has a history or CT evidence of active tuberculosis infection, or history of active tuberculosis infection within 1 year prior to enrollment, or history of active tuberculosis infection more than 1 year ago without formal treatment.
• Active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10⁴ copies/mL) or hepatitis C (positive HCV antibody with HCV-RNA above the lower limit of detection of the assay).
• Known history of drug abuse, alcohol abuse, or substance addiction
• Pregnant or lactating women.
• Other factors considered by the investigator that may lead to premature termination of the study, such as other severe diseases (including psychiatric disorders) requiring combined treatment, severely abnormal laboratory test values, family or social factors, or any other circumstances that may compromise subject safety or integrity of the study data.

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
Experimental: Induction tislelizumab/chemotherapy + CCRT + adjuvant tislelizumab; Participants receive three cycles of induction chemoimmunotherapy (tislelizumab + paclitaxel-cisplatin) before initiation of CCRT. During CCRT, participants receive two cycles of concurrent cisplatin. After completion of radiotherapy, participants receive additional 13 cycles of adjuvant tislelizumab.	Biological: Tislelizumab; As induction immunotherapy, 200 mg administered IV infusion on Day 1 of each 21-day cycle, for 3 cycles.; As adjuvant immunotherapy, 200 mg administered IV infusion on Day 1 of each 21-day cycle, for 13 cycles.; Other Names: Tevimbra; Drug: Paclitaxel; - As induction chemotherapy, 175 mg/m2 administered IV infusion on Day 2 of each 21-day cycle, for 3 cycles.; Drug: Cisplatin (75 mg/m2); - As induction chemotherapy, 75 mg/m2 administered IV infusion on Day 2-4 of each 21-day cycle, for three cycles.; Radiation: Intensity-Modulated Radiotherapy; - Definitive IMRT: 70Gy given in 35 fractions over 7 weeks; Other Names: IMRT; Drug: Cisplatin (80 mg/m2); - As concurrent chemotherapy, 80 mg/m2 administered IV infusion on Day 1-3 of each 21-day cycle, for two cycles.
Active Comparator: Concurrent Chemoradiotherapy; Participants receive standard-of-care CCRT, consisting of IMRT with a total dose of 70Gy and two cycles of concurrent cisplatin.	Radiation: Intensity-Modulated Radiotherapy; - Definitive IMRT: 70Gy given in 35 fractions over 7 weeks; Other Names: IMRT; Drug: Cisplatin (80 mg/m2); - As concurrent chemotherapy, 80 mg/m2 administered IV infusion on Day 1-3 of each 21-day cycle, for two cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free Survival (EFS)	Defined as the time to the earliest occurrence of progressive disease that precluded chemoradiotherapy or prevented completion of chemoradiotherapy, disease recurrence, or death from any cause.	2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the time from randomization to death due to any cause.	2 year
Locoregional Recurrence-Free Survival (LRFS)	Defined as the time from randomization to the first documented event of local or regional recurrence.	2 year
Distant Metastasis-free survival (DMFS)	Defined as the time from randomization to the first documented event of distant metastasis.	2 year
Objective Response Rate (ORR)	Defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST). ORR will be evaluated after induction treatment, CCRT, and adjuvant immunotherapy, respectively.	Through study completion, an average of 1 year
Incidence of Adverse Events	All adverse events will be documented, including treatment-emergent AEs (TEAEs) and immune-related AEs (irAEs), in the form of all-grade AEs and grade 3-4 AEs. AEs will be evaluated by investigators according to the Common Terminology Criteria for Adverse Events, version 5.0.	2 year
Quality of Life (QoL) (EORTC QLQ-H&N35)	Changes in QoL of participants from baseline to up to 6 months after the completion of adjuvant immunotherapy. QoL will be evaluated with the questionnaires of the head-and-neck-specific module (H&N35) of the Quality of Life Questionnaire-Core 30 module (QLQ-C30).	Baseline and up to 6 months
Quality of life (Qol) (FACT-HN)	Changes in QoL of participants from baseline to up to 6 months after the completion of adjuvant immunotherapy. QoL will be evaluated with the questionnaires of the general and head-and-neck-specific (HN) module of the evaluation tool developed by the Functional Assessment of Cancer Therapy (FACT).	Baseline and up to 6 months

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): March 1, 2030

Study Registration Dates

• First Submitted: August 16, 2026
• First Submitted That Met QC Criteria: August 19, 2026
• First Posted (Actual): August 20, 2026

Study Record Updates

• Last Update Posted (Actual): August 20, 2026
• Last Update Submitted That Met QC Criteria: August 19, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Chemotherapy; Head and Neck Squamous Cell Carcinoma; Chemoradiotherapy; Programmed Cell Death Receptor 1 (PD-1); Induction Treatment
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Parkinson Disease 4, Autosomal Dominant Lewy Body; Organic Chemicals; Therapeutics; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Taxoids; Cyclodecanes; Diterpenes; Platinum Compounds; Radiotherapy; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Paclitaxel; Cisplatin; Radiotherapy, Intensity-Modulated; tislelizumab
• Other Study ID Numbers: NACI-HN-FD

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