Ficerafusp Alfa, Pembrolizumab, and Stereotactic Body Radiotherapy (SBRT) for Head and Neck Squamous Cell Carcinoma (HNSCC)

Phase I/II Trial of Neoadjuvant Combination of Ficerafusp Alfa, Pembrolizumab, and SBRT for Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC)

The study is an open-label phase I/II clinical trial. The study will enroll patients to receive neoadjuvant SBRT plus 1 or 2 doses of neoadjuvant pembrolizumab with concurrent ficerafusp alfa (4 doses) prior to definitive surgical resection for high-risk, locoregionally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC). Approximately 6 weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection followed by SOC adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines. Adjuvant therapy is not part of this study and therefore is not dictated by study protocol.

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Squamous Cell Carcinoma; HPV-Negative Squamous Cell Carcinoma
• Intervention / Treatment: Radiation: Hypofractionated Stereotactic Body Radiotherapy (SBRT); Biological: Pembrolizumab; Drug: Ficerafusp alfa

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Sana Karam, MD, PhD; Phone Number: 314-362-9700; Email: sanadkaram@wustl.edu
• Study Contact Backup: Name: Sidharth Puram, MD, PhD; Phone Number: 314-362-9700; Email: sidpuram@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
      • Sub-Investigator: Peter Oppelt, MD
      • Sub-Investigator: Esther Lu, PhD
      • Sub-Investigator: Jesse Zaretsky, MD, PhD
      • Contact: Sana Karam, MD, PhD; Phone Number: 314-362-9700; Email: sanadkaram@wustl.edu
      • Contact: Sidharth Puram, MD, PhD; Phone Number: 314-362-9700; Email: sidpuram@wustl.edu
      • Principal Investigator: Sana Karam, MD, PhD
      • Principal Investigator: Sidharth Puram, MD, PhD
      • Sub-Investigator: Douglas R Adkins, MD
      • Sub-Investigator: Anthony J Apicelli, MD, PhD
      • Sub-Investigator: Christine Auberle, MD
      • Sub-Investigator: Jennifer De Los Santos, MD
      • Sub-Investigator: Hiram Gay, MD
      • Sub-Investigator: Lannis Hall, MD, MPH
      • Sub-Investigator: Yao Hao, PhD
      • Sub-Investigator: R Alex Harbison, MD, MS
      • Sub-Investigator: Ryan S Jackson, MD
      • Sub-Investigator: Brendan J Knapp, MD
      • Sub-Investigator: Daniel Miller, MD, PhD
      • Sub-Investigator: Patrick Pipkorn, MD
      • Sub-Investigator: Nikhil Rammohan, MD, PhD
      • Sub-Investigator: Jason T Rich, MD
      • Sub-Investigator: Robert D Siegel, MD
      • Sub-Investigator: Wade L Thorstad, MD
      • Sub-Investigator: Gregory R Vlacich, MD, PhD
      • Sub-Investigator: Paul Zolkind, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Newly diagnosed histologically or cytologically confirmed locally advanced, OPC HPV-negative head and neck squamous cell carcinoma (OPSCC) or HNSCC arising from oral cavity, larynx, or hypopharynx.
• Baseline resectable disease per the judgment of the treating surgical oncologist.

• Clinical stage III, IVA, or IVB disease as defined using the 8th (2017) edition of the tumor, node, metastasis (TNM) staging system by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC):

  • T1-2, N1-3 or
  • T3, any N or
  • T4, any N
• Documented tumor PD-L1 CPS ≥ 1 (by PD-L1 IHC pharmDx assay), determined locally.
• Willing to provide blood and newly obtained core or excisional biopsy of tumor lesion pre-treatment and at the time of surgery for pathologic and correlative analyses.
• Age 18 years or older at the time of informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Adequate organ and marrow function as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 9 g/dL (without PRBC transfusion in the prior 7 days)
  • Total serum bilirubin ≤ 1.5 x IULN (except for subjects with documented diagnosis of Gilbert syndrome). For subjects with a documented diagnosis of Gilbert's syndrome, total bilirubin must be ≤ 3.0 × ULN, provided that direct bilirubin is within normal limits
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
  • Creatinine clearance (measured or calculated via the Cockcroft-Gault equation or per institutional standards) ≥ 30 mL/min
  • PT/INR or aPTT ≤ 1.5 x IULN (except for subjects receiving anticoagulant therapy)
• The effects of pembrolizumab and ficerafusp alfa on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 120 days (women) or 90 days (men) after completion of study treatment.
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Currently receiving any other investigational agents.
• Prior history of grade ≥ 2 intolerance or hypersensitivity reactions to other murine proteins, or the active substances of ficerafusp alfa, pembrolizumab, or any of their excipients.
• At higher risk of bleeding, including known bleeding diathesis or current active major bleeding, or recent major bleeding episode (within 4 weeks prior to enrollment).
• Any of the following within 6 months prior to starting study treatment: ST-elevation myocardial infarction, severe/unstable angina, uncontrolled cardiac ventricular arrhythmia, coronary/peripheral artery bypass graft or stent, cerebrovascular accident/stroke less than 6 months prior to enrollment, or congestive heart failure. Subjects with deep vein thrombosis who are hemodynamically stable can enroll if they are on a stable dose of anticoagulants for at least 3 months.
• Active autoimmune disease requiring systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Active systemic infection requiring either hospitalization or parenteral anti-infective therapy within 2 weeks before first dose of study treatment.
• Chronic hepatitis B virus (HBV) infection with active disease meeting the criteria for anti-HBV therapy but not on a suppressive antiviral therapy prior to initiation of study treatment. HBV testing not required in the absence of known history of infection. Note: Subjects who are hepatitis B surface antigen positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. These subjects should remain on antiviral therapy throughout the study treatment period and follow local guidelines for HBV antiviral therapy post completion of study treatment.
• Known history of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible provided they completed curative antiviral therapy at least 4 weeks prior to initiation of study treatment. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) with viral load >0 or CD4<350. HIV testing is not required in the absence of known history of infection.
• Receipt of any organ transplantation, including autologous and allogeneic stem cell transplantation, except for transplants that do not require immunosuppression.
• Known to be diagnosed and/or treated for any other additional malignancy within 2 years prior to randomization with the exception of the following: curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, and curatively resected in situ cervical cancer, and curatively resected in situ breast cancer, and low-risk early stage prostate cancer defined as follows: Stage T1c or T2a with a Gleason score ≤ 6 and prostatic-specific antigen < 10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study entry. Other exceptions may be considered with the PI's consultation. The time requirement for no malignancy for 2 years does not apply to the cancer for which a subject is enrolled in the study.
• Any condition requiring systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 7 days prior to the first dose of study treatment, except for topical, intranasal, intrabronchial, or ocular steroids. Corticosteroid use as premedication for allergic reactions (e.g., intravenous contrast), or as a prophylactic management of AEs related to the therapies specified in the protocol is allowed. The use of physiologic doses of corticosteroids may be approved after consultation with the principle-Investigator.
• Use of a live or live attenuated vaccine within 4 weeks prior to Screening. Note: Administration of killed, recombinant, or inactivated vaccines is allowed.
• Pregnant or breastfeeding. People of childbearing potential must have a negative pregnancy test at screening and within 7 days of first dose of study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Dose Level 1: Dose De-Escalation Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa; Treatment during the Phase 1 Level 1 consists of Stereotactic Body Radiotherapy (SBRT) at 8 Gy x 3 fractions over one week (given on Days 1, 3, and 5), 2 doses of neoadjuvant pembrolizumab at 200 mg (given on D1 and D22), and 4 weekly doses of ficerafusp alfa at 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines.	Radiation: Hypofractionated Stereotactic Body Radiotherapy (SBRT); 1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II; Biological: Pembrolizumab; 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.; Other Names: Keytruda; Drug: Ficerafusp alfa; 750mg intravenously (IV) on Days 1, 8, 15, and 22.; Other Names: BCA101
Experimental: Phase 1 Dose Level -1: Dose De-Escalation Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa; Treatment during the Phase 1 Level -1 consists of Stereotactic Body Radiotherapy (SBRT) at 8 Gy x 3 fractions over one week (given on Days 1, 3, and 5), 1 dose of neoadjuvant pembrolizumab at 200 mg (given on D1), and 4 weekly doses of ficerafusp alfa at 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines.	Radiation: Hypofractionated Stereotactic Body Radiotherapy (SBRT); 1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II; Biological: Pembrolizumab; 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.; Other Names: Keytruda; Drug: Ficerafusp alfa; 750mg intravenously (IV) on Days 1, 8, 15, and 22.; Other Names: BCA101
Experimental: Phase 1 Dose Level -2: Dose De-Escalation Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa; Treatment during the Phase 1 Level -2 consists of Stereotactic Body Radiotherapy (SBRT) at 8 Gy x 3 fractions over one week (given on Days 1 and 4), 1 dose of neoadjuvant pembrolizumab at 200 mg (given on D1), and 4 weekly doses of ficerafusp alfa at 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines.	Radiation: Hypofractionated Stereotactic Body Radiotherapy (SBRT); 1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II; Biological: Pembrolizumab; 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.; Other Names: Keytruda; Drug: Ficerafusp alfa; 750mg intravenously (IV) on Days 1, 8, 15, and 22.; Other Names: BCA101
Experimental: Phase 1 Dose Level -3: Dose De-Escalation Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa; Treatment during the Phase 1 Level -3 consists of Stereotactic Body Radiotherapy (SBRT) at 8 Gy x 3 fractions over one week (given on Day 1), 1 dose of neoadjuvant pembrolizumab at 200 mg (given on D1), and 4 weekly doses of ficerafusp alfa at 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines.	Radiation: Hypofractionated Stereotactic Body Radiotherapy (SBRT); 1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II; Biological: Pembrolizumab; 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.; Other Names: Keytruda; Drug: Ficerafusp alfa; 750mg intravenously (IV) on Days 1, 8, 15, and 22.; Other Names: BCA101
Experimental: Phase 2: Maximum Tolerable Dose (MTD) Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa; Treatment consists of SBRT beginning on D1 at the dose and number of fractions established in phase I, neoadjuvant pembrolizumab 200 mg at the number of doses established in phase I, and 4 weekly doses of ficerafusp alfa 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines.	Radiation: Hypofractionated Stereotactic Body Radiotherapy (SBRT); 1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II; Biological: Pembrolizumab; 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.; Other Names: Keytruda; Drug: Ficerafusp alfa; 750mg intravenously (IV) on Days 1, 8, 15, and 22.; Other Names: BCA101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I only: Maximum tolerated dose (MTD) of SBRT in combination with pembrolizumab plus ficerafusp alfa	The maximum tolerated dose (MTD) is defined as the highest dose level at which 0 or 1 patients of a cohort experience dose-limiting toxicity during the dose limiting toxicity (DLT) window. DLTs are defined in the protocol.	From start of treatment until date of surgery (total estimated time of 7 weeks)
Phase II only: Rate of pathologic complete response (pCR)	Response will be defined according to the systematic pTR system. pTR is defined as the presence of tumor cell necrosis and keratinous debris with giant cell/histiocytic reaction, quantified as a percentage of the overall tumor bed (area pathologic response/area pathologic response plus viable tumor). pCR is defined as follows: 100% of sample characterized by tumor necrosis, keratinous debris, and/or giant cells/histiocytes	At the time of surgery (estimated to be week 7)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase II only: Number and types of Adverse Events (AEs)	As defined by CTCAE v5.0.	From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)
Phase II only: Pathological response rate (PRR)	PRR is categorized as pCR, mPR, and others (pTR-0, pTR-1, pTR-2). Simon's two-stage optimal design will be used for a rate of pCR in phase II. Response will be defined according to the systematic pTR system. pTR is defined as the presence of tumor cell necrosis and keratinous debris with giant cell/histiocytic reaction, quantified as a percentage of the overall tumor bed (area pathologic response/area pathologic response plus viable tumor). pTR is defined as follows: pTR-0: < 10% of sample characterized by tumor necrosis, keratinous debris, and/or giant cells/histiocytes, pTR-1: 10-49%, pTR-2: 50-89%, pTR-3: 90-99% (also referred to as mPR), and pTR-4: 100% (also referred to as pCR).	At time of surgery (estimated to be week 7)
Phase II only: Event-free survival (EFS)	EFS is defined as the time from the first date of treatment to the date of disease progression or death, whichever occurs first.	From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)
Phase II only: Rate of clinical to pathologic down staging (and extent of surgical plan modifications, if any)		At time of surgery (estimated to be week 7)
Phase II only: Overall survival (OS)	OS is defined as the time from the first date of treatment to the date of death. Alive patients are censored at the last follow-up otherwise.	From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Bicara Therapeutics
• Investigators: Principal Investigator: Sana Karam, MD, PhD, Washington University School of Medicine; Principal Investigator: Sidharth Puram, MD, PhD, Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): August 31, 2028
• Study Completion (Estimated): August 31, 2033

Study Registration Dates

• First Submitted: April 20, 2026
• First Submitted That Met QC Criteria: April 20, 2026
• First Posted (Actual): April 27, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Checkpoint inhibitor; Immunotherapy; Targeted therapy; Keytruda; HNSCC; EGFR inhibitor; Radiation therapy; Oral cancer; Oropharyngeal cancer; Head and neck cancer; Neoadjuvant therapy; PD-1 inhibitor; OPSCC; Squamous cell carcinoma; Stereotactic body radiotherapy; Tongue cancer; Laryngeal cancer; Preoperative treatment; Oral cavity cancer; Hypopharyngeal cancer; Locally advance; Throat cancer; Curative treatment; BCA101; Shortened fractionation radiation; Gum cancer; Jaw cancer; Palate cancer; Lip Cancer; Mouth cancer; Voice box cancer; Mandibular cancer; Alveolar ridge cancer; OCC; OCSCC; HP-negative
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Mouth Diseases; Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Jaw Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Bone Neoplasms; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Carcinoma; Neoplasms, Squamous Cell; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Laryngeal Diseases; Lip Diseases; Skull Neoplasms; Tongue Diseases; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Laryngeal Neoplasms; Mouth Neoplasms; Lip Neoplasms; Oropharyngeal Neoplasms; Tongue Neoplasms; Hypopharyngeal Neoplasms; Jaw Neoplasms; pembrolizumab
• Other Study ID Numbers: 202604179

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: Yes
• product manufactured in and exported from the U.S.: Yes