Rimegepant-Sensitized Neoadjuvant Chemoimmunotherapy for Oral or Oropharyngeal Squamous Cell Carcinoma

A Phase II Randomized Controlled Clinical Trial of Rimegepant-Sensitized Neoadjuvant Chemoimmunotherapy in Patients With Oral/Oropharyngeal Squamous Cell Carcinoma

This study will evaluate whether adding rimegepant to standard neoadjuvant chemoimmunotherapy can improve treatment response in patients with primary or recurrent oral or oropharyngeal squamous cell carcinoma who are planned to undergo surgery.

Rimegepant blocks the receptor for calcitonin gene-related peptide, also known as CGRP. CGRP signaling may affect the tumor immune environment and the response of tumors to anticancer treatment.

The study includes an initial safety run-in stage involving 20 participants, followed by a randomized controlled stage involving 200 participants. During the randomized stage, participants will be assigned in a 1:1 ratio to receive standard neoadjuvant chemoimmunotherapy either with or without rimegepant. All participants will receive two cycles of neoadjuvant treatment followed by definitive or intended curative surgery.

The main outcome is the major pathological response rate, defined as 10% or less residual viable tumor in the surgical specimen. Other outcomes include pathological complete response, objective response, event-free survival, overall survival, changes in pain and quality of life, and treatment safety.

Study Overview

• Status: Not yet recruiting
• Conditions: Oral Squamous Cell Carcinoma (OSCC); Oropharyngeal Squamous Cell Carcinoma (OPSCC)
• Intervention / Treatment: Drug: Rimegepant; Drug: Tislelizumab; Drug: Nab-paclitaxel; Drug: Cisplatin

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yu Zhang; Phone Number: +86-13818927554; Email: zhang.yu4@zs-hospital.sh.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200032
      • Zhongshan hospital, Fudan university
      • Contact: Yu Zhang; Phone Number: +86-13818927554; Email: zhang.yu4@zs-hospital.sh.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18 to 75 years, regardless of sex.
• Histologically or cytologically confirmed oral or oropharyngeal squamous cell carcinoma, including primary disease or recurrent disease after previous treatment that is considered amenable to repeat curative-intent resection.
• Planned to receive neoadjuvant chemoimmunotherapy followed by surgery after multidisciplinary evaluation.
• At least one evaluable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Adequate major organ function.
• Voluntary participation and provision of written informed consent.

Exclusion Criteria:

• Severe cardiac, hepatic, or renal dysfunction.
• Active autoimmune disease.
• Pregnancy or breastfeeding.
• Known allergy or hypersensitivity to rimegepant or any component of the planned neoadjuvant treatment.
• Any condition that, in the investigator's judgment, makes the participant unsuitable for enrollment.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety Run-In Combination Arm; Twenty participants will receive rimegepant plus standard neoadjuvant chemoimmunotherapy for two 3-week cycles, followed by definitive or intended curative surgery. Safety and tolerability will be evaluated before initiation of the randomized stage.	Drug: Rimegepant; Rimegepant 75 mg will be administered orally every other day from the initiation until the completion of neoadjuvant chemoimmunotherapy.; Drug: Tislelizumab; Tislelizumab 200 mg will be administered by intravenous infusion on Day 1 of each 3-week treatment cycle for two cycles.; Drug: Nab-paclitaxel; Nab-paclitaxel 260 mg/m² will be administered by intravenous infusion on Day 2 of each 3-week treatment cycle for two cycles.; Drug: Cisplatin; A total dose of cisplatin 75 mg/m² will be administered intravenously over Days 2 and 3 of each 3-week treatment cycle for two cycles.
Experimental: Randomized Combination Arm; Participants randomized to this arm will receive rimegepant plus standard neoadjuvant chemoimmunotherapy for two 3-week cycles, followed by definitive or intended curative surgery.	Drug: Rimegepant; Rimegepant 75 mg will be administered orally every other day from the initiation until the completion of neoadjuvant chemoimmunotherapy.; Drug: Tislelizumab; Tislelizumab 200 mg will be administered by intravenous infusion on Day 1 of each 3-week treatment cycle for two cycles.; Drug: Nab-paclitaxel; Nab-paclitaxel 260 mg/m² will be administered by intravenous infusion on Day 2 of each 3-week treatment cycle for two cycles.; Drug: Cisplatin; A total dose of cisplatin 75 mg/m² will be administered intravenously over Days 2 and 3 of each 3-week treatment cycle for two cycles.
Active Comparator: Randomized Control Arm; Participants randomized to this arm will receive standard neoadjuvant chemoimmunotherapy alone for two 3-week cycles, followed by definitive or intended curative surgery.	Drug: Tislelizumab; Tislelizumab 200 mg will be administered by intravenous infusion on Day 1 of each 3-week treatment cycle for two cycles.; Drug: Nab-paclitaxel; Nab-paclitaxel 260 mg/m² will be administered by intravenous infusion on Day 2 of each 3-week treatment cycle for two cycles.; Drug: Cisplatin; A total dose of cisplatin 75 mg/m² will be administered intravenously over Days 2 and 3 of each 3-week treatment cycle for two cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response Rate	Percentage of participants with 10% or less residual viable tumor cells in the resected primary or recurrent tumor specimen after neoadjuvant treatment. For the randomized efficacy analysis, participants who do not undergo surgery or whose surgical specimens are not evaluable for pathological response will be considered not to have achieved major pathological response. Results will also be reported separately for participants with primary and recurrent disease.	At pathological assessment of the definitive surgical specimen after completion of two 3-week cycles of neoadjuvant treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response Rate	Percentage of participants with no residual viable tumor cells in the resected primary or recurrent tumor specimen after neoadjuvant treatment, using the same pathological assessment scope as that used for major pathological response. Participants who do not undergo surgery or whose surgical specimens are not evaluable for pathological response will be considered not to have achieved pathological complete response in the randomized efficacy analysis.	At pathological assessment of the definitive surgical specimen after completion of two 3-week cycles of neoadjuvant treatment
Objective Response Rate	Percentage of participants with a complete response or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1.	From baseline to preoperative radiographic assessment after completion of two 3-week cycles of neoadjuvant treatment
Event-Free Survival	Event-free survival is defined as the time from randomization to the first occurrence of any of the following: disease progression during neoadjuvant treatment that precludes the planned definitive or intended curative surgery; locoregional recurrence or progression after surgery; distant metastasis or distant disease progression; or death from any cause. Participants without an event will be censored at the date of the last assessment confirming that they remained event-free.	From randomization to the first event or censoring, assessed up to 5 years
Overall Survival	Overall survival is defined as the time from randomization to death from any cause. Participants who are alive at the time of analysis will be censored at the date they were last known to be alive.	From randomization until death or censoring, assessed up to 5 years
Change From Baseline in Pain Score	Change from baseline in pain severity as assessed using the McGill Pain Questionnaire. Changes in pain scores will be compared between treatment groups at protocol-specified assessment time points.	At baseline, at the end of each neoadjuvant treatment cycle, and at the preoperative assessment
Change From Baseline in Quality of Life	Change from baseline in quality-of-life scores assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.	At baseline, at the end of each neoadjuvant treatment cycle, and at the preoperative assessment
Incidence of Treatment-Emergent Adverse Events	Incidence, type, and severity of treatment-emergent adverse events and serious adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.	From signing informed consent through 90 days after the last dose of study treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Peripheral Blood Immune Cell Subset Proportions Assessed by Multiparameter Flow Cytometry	Multiparameter flow cytometry will be used to quantify major immune cell subsets in peripheral blood mononuclear cells, including CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and monocytes. Each immune cell subset will be reported as a percentage of total viable peripheral blood mononuclear cells. Changes from baseline will be reported in percentage points at each post-baseline assessment.	At baseline; at the end of Cycle 1 (Day 21); at the end of Cycle 2 (Day 42); and on the day of definitive surgery before anesthesia
Change From Baseline in Tumor-Infiltrating Immune Cell Subset Proportions Assessed by Single-Cell RNA Sequencing	Single-cell RNA sequencing will be used to quantify tumor-infiltrating immune cell subsets in paired pretreatment biopsy and definitive surgical specimens, including T cells, B cells, natural killer cells, macrophages, and other myeloid cells. Each immune cell subset will be reported as a percentage of all viable cells captured in the corresponding specimen. Changes from baseline will be reported in percentage points.	At baseline, using the pretreatment biopsy obtained before Cycle 1, and at definitive surgery after completion of two 21-day cycles of neoadjuvant treatment
CGRP Pathway Biomarkers	Changes in the expression of biomarkers related to the calcitonin gene-related peptide signaling pathway in tumor tissue and/or peripheral blood.	At baseline, using peripheral blood and the pretreatment tumor biopsy obtained before Cycle 1, and at definitive surgery after completion of two 21-day cycles of neoadjuvant treatment

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital
• Collaborators: Pfizer

Publications and helpful links

General Publications

• Zhang Y, Guo Y, Liu Z, Sun Y, Yang X, Chen M, Feng G, Lin C, Wang Y, Zhang Z, Zhu Y, Ye J, Liu J, Shi J, Zhou X, Han Q, Liu Y, Jiang Q, Yu Y, Wang X, Zhang C, Sun Y, Zhou J, Fan J, Ji T. Cancer cells co-opt an inter-organ neuroimmune circuit to escape immune surveillance. Cell. 2025 Nov 26;188(24):6754-6773.e29. doi: 10.1016/j.cell.2025.09.029. Epub 2025 Oct 24.
• Zhang Y, Lin C, Liu Z, Sun Y, Chen M, Guo Y, Liu W, Zhang C, Chen W, Sun J, Xia R, Hu Y, Yang X, Li J, Zhang Z, Cao W, Sun S, Wang X, Ji T. Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies. Cell Metab. 2022 Dec 6;34(12):1999-2017.e10. doi: 10.1016/j.cmet.2022.10.012. Epub 2022 Nov 16.
• Balood M, Ahmadi M, Eichwald T, Ahmadi A, Majdoubi A, Roversi K, Roversi K, Lucido CT, Restaino AC, Huang S, Ji L, Huang KC, Semerena E, Thomas SC, Trevino AE, Merrison H, Parrin A, Doyle B, Vermeer DW, Spanos WC, Williamson CS, Seehus CR, Foster SL, Dai H, Shu CJ, Rangachari M, Thibodeau J, V Del Rincon S, Drapkin R, Rafei M, Ghasemlou N, Vermeer PD, Woolf CJ, Talbot S. Nociceptor neurons affect cancer immunosurveillance. Nature. 2022 Nov;611(7935):405-412. doi: 10.1038/s41586-022-05374-w. Epub 2022 Nov 2.

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 31, 2028
• Study Completion (Estimated): October 31, 2033

Study Registration Dates

• First Submitted: July 19, 2026
• First Submitted That Met QC Criteria: September 9, 2026
• First Posted (Actual): September 10, 2026

Study Record Updates

• Last Update Posted (Actual): September 10, 2026
• Last Update Submitted That Met QC Criteria: September 9, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Cisplatin; Tislelizumab; CGRP Receptor Antagonist; Nab-Paclitaxel; Neoadjuvant Chemoimmunotherapy; Calcitonin Gene-Related Peptide; Rimegepant; Major Pathological Response
• 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; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Platinum Compounds; Cisplatin; 130-nm albumin-bound paclitaxel; tislelizumab; rimegepant sulfate
• Other Study ID Numbers: B2026-377R

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data are not currently planned to be shared. The study involves sensitive clinical, pathological, and human genetic resource data. Any future sharing of de-identified participant-level data would require additional institutional ethics review, compliance with applicable Chinese regulations on human genetic resources and data security, and appropriate data use agreements. The registry record will be updated if the sharing plan changes.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No