Immunotherapy and Nodal-Sparing Irradiation for T-Cell Induction and Unmasking of Tumor Antigenicity in the Microenvironment for Head and Neck Cancer (INITIUM)

This is a non-comparative randomized Phase 2 study using the INITIUM regimen with or without elective nodal irradiation (ENI) delivered before surgery for resectable head and neck squamous cell carcinoma (HNSCC).

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Cancer Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Pembrolizumab; Radiation: Radiotherapy; Radiation: ENI; Procedure: Surgery

Detailed Description

Patients with surgically resectable HPV-negative HNSCC with no prior history of head and neck radiation and a life expectancy of at least 12 months will be enrolled.

Patients will undergo pre-radiation pembrolizumab for two cycles followed by pre-operative radiotherapy and two additional cycles of pembrolizumab. Radiation will be given to a total dose of 35 Gy in 5 fractions to gross disease, followed by response-directed surgery approximately eight weeks after completion of radiation. Patients randomized to ENI will concurrently receive 27 Gy in 5 fractions to elective nodal regions during radiation to gross disease.

Baseline symptom evaluation will be obtained using validated surveys for head and neck cancer patients: the Functional Assessment of Cancer Therapy for the Head and Neck (FACT-HN) and the MD Anderson Dysphagia Inventory for Head and Neck (MDADI-HN). Tumor biopsies will be performed serially across treatment for translational study at the following time points: baseline, after induction pembrolizumab, on the final day of radiation, and at the time of surgery. If patients sign a secondary consent, quantitative MRI (qMRI) will be performed prior to radiation, on the day of the last fraction of radiation and six weeks after the completion of radiation, prior to surgery.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Medical College of Wisconsin Cancer Center Clinical Trials Office; Phone Number: 8900 866-680-0505; Email: cccto@mcw.edu

Study Locations

• United States
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert & The Medical College of Wisconsin
      • Contact: Musaddiq Awan, MD; Phone Number: mawan@mcw.edu 414-805-4400

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients 18 years or older.
• Patients with surgically resectable squamous cell carcinoma of the oral cavity or HPV-negative squamous cell carcinoma of the oropharynx. Resectability will be determined by the treating surgeon. Patients must have locoregionally advanced disease defined by clinical T3-4 staging and/or clinical node positive staging.
• A CPS score of at least 1 on initial biopsy.
• Zubrod, or Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Pregnancy. It is not known what effects this treatment has on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Non-sterilized female patients of reproductive age and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below.

Female patients must meet one of the following:

• Postmenopausal for at least one year before the screening visit, OR
• Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), OR

• If subject is of childbearing potential (defined as not satisfying either of the above two criteria):

  • Agree to practice two effective methods of contraception (combination methods requires use of two of the following: diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male or female condom, hormonal contraceptive, intrauterine device, etonogestrel implant, etc.) from the time of signing of the informed consent form through 90 days after the last dose of study agent, AND
  • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptom-thermal, post ovulation methods] and withdrawal are not acceptable contraception methods).

Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:

• Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose, OR
• Must also adhere to the guidelines of any study-specific pregnancy prevention program, if applicable, OR
• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptom-thermal, post ovulation methods] and withdrawal are not acceptable methods of contraception.) - Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

• HPV-positive squamous cell carcinoma of the oropharynx.
• Tumor inaccessible for clinic-based biopsy as determined by the treating surgeon.
• Solid organ transplant requiring chronic immunosuppression.
• Autoimmune disease requiring use of steroids or chronic immunosuppression.
• Prior invasive malignancy within the past 3 years (except for T1a surgically treated melanoma with negative margins, any early-stage non-melanomatous skin cancer, early-stage prostate cancer, or differentiated thyroid cancer). Patients with benign non-metastasizing tumors are eligible.
• Life expectancy less than 12 months.
• Performance status Zubrod ≥ 3.

• Patients with prior external beam radiation therapy (RT) to the head and neck that overlaps the expected treatment fields.

  a. Note: Patients receiving prior Iodine-131 therapy will be eligible.

• Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer.
• Body weight ≤ 30 kg.

• Any of the following severe laboratory abnormalities within 30 days of registration, unless corrected prior to it:

  1. Sodium < 125 mmol/L or > 155 mmol/L
  2. Potassium < 3.5 mmol/L or > 6 mmol/L
  3. Glucose > 400 mg/dl
  4. Serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 mg/dl
  5. Magnesium < 0.9 mg/dl or > 3 mg/dl
• Unstable angina and/or congestive heart failure requiring hospitalization within three months of registration.
• Transmural myocardial infarction within three months of registration.
• Medical or psychiatric illness that would compromise the patient's ability to tolerate treatment or limit compliance with study requirements.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 6 months after radiation. This exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Women who are breastfeeding are also excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: INITIUM regimen using ENI; The INITIUM regimen includes two cycles of induction therapy with pembrolizumab, followed by pre-operative hypofractionated radiation (7 Gy × 5 fractions) and two additional cycles of pembrolizumab. Patients will receive ENI to non-clinically and radiographically involved draining nodal basins.	Drug: Pembrolizumab; All patients will undergo induction with pembrolizumab (200 mg) given intravenously every three weeks for two cycles prior to radiation and two cycles after radiation.; Other Names: Keytruda; Radiation: Radiotherapy; All patients will receive 7 Gy daily for 5 fractions to gross disease.; Radiation: ENI; Patients receiving ENI will be treated to 5.4 Gy daily to the elective nodal basins for 5 fractions concurrent with treatment to gross disease.; Procedure: Surgery; Patients will be scheduled for surgery at ten weeks (-7 days) after radiation to allow for maximal tumor regression and healing of any radiation-related mucositis. Surgical resection will be tailored to the treatment response.
Experimental: INITIUM regimen without ENI; The INITIUM regimen includes two cycles of induction therapy with pembrolizumab, followed by pre-operative hypofractionated radiation (7 Gy × 5 fractions) and two additional cycles of pembrolizumab. Patients will NOT receive ENI to non-clinically and radiographically involved draining nodal basins.	Drug: Pembrolizumab; All patients will undergo induction with pembrolizumab (200 mg) given intravenously every three weeks for two cycles prior to radiation and two cycles after radiation.; Other Names: Keytruda; Radiation: Radiotherapy; All patients will receive 7 Gy daily for 5 fractions to gross disease.; Procedure: Surgery; Patients will be scheduled for surgery at ten weeks (-7 days) after radiation to allow for maximal tumor regression and healing of any radiation-related mucositis. Surgical resection will be tailored to the treatment response.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response (pCR) rate to INITIUM-HN with and without ENI.	pCR is defined as no viable tumor in primary tumor or lymph nodes on pathological examination.	Up to 10 weeks post-radiation therapy

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Investigators: Principal Investigator: Musaddiq Awan, MD, Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: August 12, 2026
• First Submitted That Met QC Criteria: August 12, 2026
• First Posted (Actual): August 19, 2026

Study Record Updates

• Last Update Posted (Actual): August 19, 2026
• Last Update Submitted That Met QC Criteria: August 12, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: immunotherapy; elective nodal irradiation
• Additional Relevant MeSH Terms: Therapeutics; Radiotherapy; pembrolizumab; Surgical Procedures, Operative
• Other Study ID Numbers: PRO00059024

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