H&N NEO-COMBAT XL: Neoadjuvant XL-092 (Zanzalintinib) and Pembrolizumab (Keytruda) in Surgically Resectable, HPV Negative Oral Cavity Squamous Cell Carcinoma (OCSCC) (NEO COMBAT XL)

This is a multicenter, single arm Phase 2B study in subjects with locally advanced oral cavity squamous cell carcinoma (OCSCC) with surgically resectable disease. The study will assess the combination of neoadjuvant XL092 and pembrolizumab for safety and improvement of pathologic response rates compared to historical standard of care with perioperative pembrolizumab. The primary objective is to estimate the pathologic response rate defined as either pathological complete response (pCR), which is the absence of residual viable tumor, or major pathologic response (MPR), which is <10% of residual tumor following the completion of neoadjuvant therapy and surgery. The study will be conducted in two stages. Per Simon's Stage 1, 11 patients will be enrolled. Simon Stage 2 will be gated on multiple factors. If ≥2 pathologic response is observed (pCR or MPR), the trial will proceed with cohort expansion and enroll an additional 15 patients for a total of 26 patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Cancer; Oral Cavity Squamous Cell Carcinoma
• Intervention / Treatment: Drug: XL092; Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rose Hall; Phone Number: 919-984-0000; Email: rose_hall@med.unc.edu
• Study Contact Backup: Name: Shamina Williams; Phone Number: 919-984-0000; Email: shamina_williams@med.unc.edu

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
      • Contact: Nikki C Schmitt; Email: Nicole.cherie.schmitt@emory.edu
      • Principal Investigator: Nikki C Schmitt, MD
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
      • Contact: Siddharth Sheth, MD; Email: siddharth.sheth@unchealth.unc.edu
      • Contact: Rose Hall, MSW; Phone Number: 984-974-8440; Email: rose_hall@med.unc.edu
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.
• Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee.
• Age ≥ 18 years at the time of consent.
• Tumors must have PD-L1 Combined Positive Score (CPS) ≥ 1.
• ECOG or Karnofsky Performance Status of 0-1
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) within 30 days prior to treatment .

Exclusion Criteria:

• Known HPV-positive cancer
• Active infection requiring systemic therapy.
• Prior treatment with XL-092
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Locally advanced oral cavity squamous cell carcinoma; Locally advanced oral cavity squamous cell carcinoma (OCSCC) with surgically resectable disease.	Drug: XL092; 60 mg oral once a day; Drug: Pembrolizumab; 200 mg intravenous for 30 minutes in every 21 days for

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of pathologic response	Rate of pathologic response, assessed following surgery, will be defined as either pathological complete response (pCR), which is the absence of residual viable tumor or major pathological response (MPR), which is <10% residual tumor.	Up to 66 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neoadjuvant Adverse Events	Safety will be defined as the rate of treatment emergent adverse events with neoadjuvant XL-092 and pembrolizumab (CTCAE v5.0).	Up to 66 days
Events Free Survival (EFS)	EFS will be defined as the time from first treatment to an event which may include disease progression, discontinuation of the treatment for any reason, or death from any cause, where disease progression will be determined based on Radiographic response will be measured according to Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST 1.1). RECIST indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	Up to 15 months
Objective response rate (ORR)	ORR following neoadjuvant therapy: an objective response will be classified per the Radiographic response will be measured according to Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST 1.1) if a partial or complete response is observed. RECIST indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	Up to 15 months
Time to surgery	Time to surgery: defined as the time from completion of neoadjuvant therapy to date of surgery. Individuals who do not receive surgery due to progressive disease, non-TEAE death or individuals who experience surgery delays due to toxicity will not be counted.	Up to 66 days
Overall survival (OS)	OS is defined as the time from time of first treatment to death due to any cause.	Up to 15 months

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: Exelixis
• Investigators: Principal Investigator: Siddharth Sheth, MD, UNC Lineberger Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 6, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: neoadjuvant treatment; pembrolizumab; surgically resectable; HPV negative; pathologic response; XL092
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; pembrolizumab
• Other Study ID Numbers: LCCC2517

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