Pembrolizumab, INCB081776, and Radiation Therapy for Head and Neck Squamous Cell Carcinoma

Pilot Study of INCB081776 Together With Palliative Radiation and Anti-PD-1 Checkpoint Blockade With Pembrolizumab in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)

This study is evaluating INCB081776 when given in combination with the checkpoint inhibitor pembrolizumab and palliative radiation therapy in patients with metastatic or recurrent metastatic or recurrent head and neck squamous cell carcinoma (HNSCC). 12 participants will be enrolled and can expect to be on study for up to 12 months.

Study Overview

• Status: Active, not recruiting
• Conditions: Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Drug: INCB081776; Drug: Pembrolizumab; Radiation: Palliative RT

Detailed Description

Primary Objective

• To evaluate the safety and tolerability of INCB081776 in combination with pembrolizumab and standard palliative radiation therapy in subjects with recurrent/metastatic squamous cell carcinoma of the head and neck.

Secondary Objectives

• To determine the preliminary efficacy of INCB081776 in combination with pembrolizumab plus palliative radiation therapy in subjects with recurrent/metastatic squamous cell carcinoma of the head and neck. The irradiated lesion (lesion A) will not be included in the analysis.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • UW Carbone Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participants must have histologic or cytologic evidence of head and neck squamous cell carcinoma (HNSCC) that is metastatic or recurrent and therefore considered incurable. Cutaneous skin squamous cell carcinomas located in the head and neck region are eligible after discussion with the Sponsor-Investigator.

• Measurable disease that are considered non-amenable to surgery or other curative treatments or procedures, with at least 1 target lesion available for evaluation.

  • The preference is for measurable disease to be selected from a site that has not received any prior radiation or locoregional therapy. However, if a tumor lesion is situated in a previously irradiated area, or in an area subjected to other prior locoregional therapy, the lesion should demonstrate disease progression after the prior treatment.
• Prior cancer treatment must be completed at least 14 days prior to enrollment (for chemotherapy, targeted small molecular therapy, or radiation therapy. Prior treatment with a monoclonal antibody must be completed at least 28 days prior to enrollment. Participants must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline.

• Participants must have two "index" tumors that meet the following criteria:

  • Index tumor A (lesion to receive palliative radiation therapy):

    • is deemed by the treating radiation oncologist to potentially benefit from palliative radiation
    • is at least 1 cm in longest dimension for lesions not located in the bone, if radiating bone, presence of a bone lesion is sufficient.

  • Index tumor B (lesion to undergo biopsy):

    • Is deemed by the treating physician to be amenable to biopsy
    • Is at least 1 cm in longest dimension.
    • Participants must be willing to provide at least 2 research biopsies (up to 3 research biopsies) during the conduct of the study.
    • Note: If a subject is scheduled to have a baseline or on-study tumor biopsy, and the investigator believes that the tumor tissue cannot be obtained safely, then the biopsy may be omitted with approval by the Sponsor-Investigator. The participant may be replaced in order to enroll sufficient number of subjects for biomarker evaluation.
    • Note: Care should be taken to biopsy the same lesions for research samples. The preference is for the same lesion to be biopsied at all time points. If a lesion is no longer amenable for a research biopsy (for examples: due to a decrease in size, becomes inaccessible, is not safe/feasible for a biopsy), then an alternative lesion may be utilized with approval by the Sponsor-Investigator. Index tumor B (lesion to undergo biopsy) must not have received palliative radiation therapy during the study.

• Participants must be willing to provide at least 2 collections of fresh research biopsies (up to 3 fresh research biopsies) during the conduct of this study.

  • Research biopsy #1 (baseline, mandatory). Archival tissue obtained since completion of last therapy may be used.
  • Research biopsy #2 (cycle 1 days 9-14, after treatment with INCB081776 but prior to pembrolizumab, mandatory)
  • Research biopsy #3 (cycle 1 day 37-56, after treatment with INCB081776, pembrolizumab and palliative RT). For participants who had baseline archival tissue collected (no baseline research biopsy was obtained), this fresh core biopsy is mandatory. For participants who underwent a fresh core research biopsy at baseline, this biopsy is optional.
  • Note: If a participant is scheduled to have an on-study tumor biopsy, and the investigator believes that the tumor tissue cannot be obtained safely, then the biopsy may be omitted after discussion with the Sponsor-Investigator. The participant may be replaced in order to enroll sufficient number of subjects for biomarker evaluation.
  • Note: Care should be taken to biopsy the same lesion for the on-treatment samples

Exclusion Criteria:

• Subjects with significant intercurrent illnesses per physician discretion.
• Subjects with a diagnosed auto-immune disease requiring systemic treatment with immunosuppressants.
• Subjects with known genetic conditions causing pre-disposition to RT toxicity (i.e: Li-Fraumeni, ATM deficiency, active scleroderma, etc.).
• Subjects with known retinal or ophthalmologic disorders or conditions. Subjects with macular degeneration, proliferative diabetic retinopathy or diabetic retinopathy with macular edema, retinal vein occlusions, uveitis, central serous retinopathy, leukemic retinopathy, inherited retinal degenerations, known family history of inherited retinal degenerations, and subjects at risk for angle closure glaucoma from pupillary dilation are ineligible. Subjects with other clinically significant abnormalities identified during ophthalmic screening examinations that may confound ocular monitoring are ineligible.

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: INCB081776/Pembrolizumab and RT for HNSCC; Cycle 1 of this clinical trial is 56 days in duration to allow for the systematic addition of each agent to the combination regimen. For cycle 2 and all subsequent cycles, the treatment cycle will be 21 days in length.

Drug: INCB081776; INCB081776 will be given orally on a daily basis. The highest safe/tolerable dose and schedule will be established by the ongoing phase 1 clinical trial of INCB081776 plus INCBMGA00012 (NCT03522142), which is 120 mg daily.; Drug: Pembrolizumab; Immune checkpoint blockade with anti-PD-1 (Pembrolizumab) will be given as 200 mg IV on cycle 1 day 15 and cycle 1 day 36. Starting from cycle 2, pembrolizumab will be given on day 1 on each subsequent cycle.; Radiation: Palliative RT; Palliative RT will be given as either 24 Gy in 3 fractions (8 Gy per fraction) or 20 Gy in 5 fractions (4 Gy per fraction). The palliative radiation therapy dose will be determined based on the clinical judgment of the treating radiation oncology physician. Palliative RT must be completed between cycle 1 day 29 to cycle 1 day 33. After completion of palliative radiation therapy, patients will continue with additional cycles of INCB081776 and pembrolizumab until disease progression, intolerance to the combination regimen, or patient withdrawal.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events (AEs)	Frequency of AEs through physical examinations, by evaluating changes in vital signs, through clinical laboratory blood sample evaluations.	Participants will be followed for 30 days (+/- 7 days) after the last dose of treatment (up to 12 months on study)
Duration of Adverse Events	Duration of AEs through physical examinations, by evaluating changes in vital signs, through clinical laboratory blood sample evaluations.	Participants will be followed for 30 days (+/- 7 days) after the last dose of treatment (up to 12 months on study)
Severity of Adverse Events	Severity of AEs through physical examinations, by evaluating changes in vital signs, through clinical laboratory blood sample evaluations. Severity will be reported by Grade between 1 (mild) and 5 (death).	Participants will be followed for 30 days (+/- 7 days) after the last dose of treatment (up to 12 months on study)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	Defined as the percentage of participants having CR or PR per RECIST 1.1. The irradiated lesion (lesion A) will not be included in the analysis.	up to 12 months
Disease control rate (DCR)	Defined as the percentage of participants having complete response (CR), partial response (PR), or stable disease (SD) per RECIST 1.1.	up to 12 months
Duration of response (DoR)	Defined as the time from earliest date of response until the earliest date of disease progression or death per RECIST 1.1 due to any cause, if occurring sooner than progression.	up to 12 months

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Cancer Institute (NCI); National Institute of Dental and Craniofacial Research (NIDCR)
• Investigators: Principal Investigator: Justine Bruce, MD, University of Wisconsin, Madison; Principal Investigator: Deric Wheeler, PhD, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2024
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: March 5, 2024
• First Submitted That Met QC Criteria: March 5, 2024
• First Posted (Actual): March 13, 2024

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: metastatic
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Neoplastic Processes; Carcinoma; Carcinoma, Squamous Cell; Pathological Conditions, Signs and Symptoms; Squamous Cell Carcinoma of Head and Neck; Neoplasm Metastasis; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: 2023-1722; A534260 (Other Identifier: UW Madison); UW23121 (Other Identifier: UWCCC); P50CA278595 (U.S. NIH Grant/Contract); Protocol Version 6/3/2025 (Other Identifier: UW Madison)

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