Combining Immunotherapy Salvage Surgery & IORT Tx Persistent/Recurrent Head & Neck Cancer

  • STATUS
    Recruiting
  • End date
    Dec 31, 2025
  • participants needed
    45
  • sponsor
    Ohio State University Comprehensive Cancer Center
Updated on 10 March 2022

Summary

This phase I trial is to find out the possible side effects of pembrolizumab and radiation therapy before and during surgery in treating patients with head and neck squamous cell cancer that remains despite treatment (persistent) or has come back (recurrent). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays or protons to kill tumor cells and shrink tumors. Giving pembrolizumab and radiation therapy before and during surgery may kill more tumor cells.

Description

PRIMARY OBJECTIVE:

I. To evaluate the potential toxicity of immunotherapy and preoperative radiation combined with intra-operative radiation in patients with recurrent or persistent head and neck squamous cell carcinoma (HNSCC).

SECONDARY OBJECTIVES:

I. To evaluate the clinical efficacy, measured as a locoregional control rate (LCR) and progression-free survival (PFS), of immunotherapy and preoperative radiation combined with intra-operative radiation in patients with recurrent or persistent HNSCC.

II. To evaluate the pre-operative radiation dose effect (0 Gy, 2 Gy X 2, 8 Gy X 2) on anti-tumor immune response in the setting of immunotherapy in patients with recurrent or persistent HNSCC.

III. To evaluate the radiation dose effect (0 Gy, 2 Gy X 2, 8 Gy X 2) on the expression of the deoxyribonucleic acid (DNA) exonuclease Trex1.

IV. To compare the overall survival (OS) of pembrolizumab and pre-operative external beam radiation therapy (EBRT) plus intraoperative radiation therapy (IORT) in subjects with recurrent or persistent HNSCC.

V. To assess the overall safety and tolerability of pembrolizumab and pre-operative EBRT and IORT plus post-operative pembrolizumab versus pre-operative pembrolizumab plus IORT and post-operative pembrolizumab in subjects with with recurrent or persistent HNSCC.

VI. To evaluate whether PD-L1 expression is a predictive biomarker for LCR and PFS.

VII. To evaluate whether TNF-alpha expression is a predictive biomarker for LCR and PFS.

VIII. To evaluate whether NFkappaB expression is a predictive biomarker for LCR and PFS.

IX. To evaluate whether tumor mutational burden is predictive of immunotherapy response.

X. To evaluate the Health Related Quality of Life (HRQoL) as assessed by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-HN35.

EXPLORATORY OBJECTIVES:

I. To evaluate associations between gene expression status of tumor samples and clinical efficacy (LRC, PFS and overall survival [OS]).

II. To evaluate whether mutational burden is a predictive biomarker for LCR and PFS.

III. To explore potential biomarkers associated with clinical efficacy (LRC, PFS, and OS) by analyzing circulating tumor DNA quantitative load with polymerase chain reaction (PCR), chemokines/cytokines and immune cells (e.g. CD8+ T cells, regulatory T cells [Tregs], myeloid derived suppressor cells [MDSCs]) with FACS in blood, tumor tissue and correlating those with clinical outcomes.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) on day 1 of week 1, and undergo salvage surgery during week 4. Beginning week 8, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo intraoperative radiation therapy (IORT) for 1 fraction during week 9. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

ARM B: Patients receive pembrolizumab IV on day 1 of week 1, and undergo low dose EBRT for 2 fractions on 2 consecutive days during week 4. Patients also undergo salvage surgery during week 8. Beginning week 11, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo IORT for 1 fraction during week 11. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

ARM C: Patients receive pembrolizumab IV on day 1 of week 1, and undergo high dose EBRT for 2 fractions on 2 consecutive days during week 4. Patients also undergo salvage surgery during week 8. Beginning week 11, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo IORT for 1 fraction during week 11. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

After completion of study treatment, patients are followed up at 90 and 180 days, then every 90 weeks for 24 months, and then every 6 months up to year 5.

Details
Condition Head and Neck Carcinoma of Unknown Primary, Locally Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Oral Cavity Squamous Cell Carcinoma, Recurrent Pharyngeal Squamous Cell Carcinoma, Resectable Head and Neck Squamous Cell Carcinoma
Treatment quality-of-life assessment, Pembrolizumab, intraoperative radiation therapy, external beam radiation therapy, salvage surgery
Clinical Study IdentifierNCT04754321
SponsorOhio State University Comprehensive Cancer Center
Last Modified on10 March 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Pathologically confirmed either persistent and/ or locoregionally recurrent HNSCC of oral cavity, pharynx, larynx, unknown primary head and neck (H&N) squamous cell carcinoma
Resectable disease as determined by the surgeon and team
Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2
At least 18 years of age
Adequate hematologic, renal, and hepatic function
Must have at least 2 week washout period from prior therapy
Willingness and ability to provide informed consent
Negative pregnancy test for females of reproductive potential
Patients who plan to or have undergone therapy for their cancer, such as surgery and/or chemotherapy and/or radiotherapy and recurred
Disease measurable by computed tomography (CT) or magnetic resonance imaging (MRI)
Prior chemotherapy will be allowed
Prior radiation therapy will be allowed
Tumor tissue from resected site of disease must be provided for biomarker analyses, in addition to urine and blood sample as scheduled per protocol
White blood cell (WBC) >= 2000/uL (obtained within 14 days of randomization)
Neutrophils >= 1500/uL (obtained within 14 days of randomization)
Platelets >= 100 x10^3/uL (obtained within 14 days of randomization)
Hemoglobin > 9.0 g/dL (obtained within 14 days of randomization)
Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) >= 40 mL/min (Cockcroft and Gault or Wright formula may be used according to local practice) (obtained within 14 days of randomization)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (obtained within 14 days of randomization)
Total Bilirubin =< 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (obtained within 14 days of randomization)
Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of nivolumab
Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG])
Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product

Exclusion Criteria

Requirement of immunosuppressive therapy within 14 days of randomization
Salivary gland carcinomas, lip carcinoma, adenocarcinoma of the skin
Prior use of immune checkpoint blockade agent
History of human immunodeficiency virus (HIV), hepatitis B, C: Participants who test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection, those who test positive for human immunodeficiency virus (HIV) or have known acquired immunodeficiency syndrome (AIDS)
Unresectable disease, as determined by the surgeon and team
Subjects with history of grade 3 toxicity with prior immunotherapy
Patients with untreated brain metastasis/es
Subjects with active, known, or suspected autoimmune disease with the exception of skin diseases that do not require systemic treatment (such as alopecia) and type I diabetes
Breastfeeding women
Additional prior malignancy within the previous 3 years (treated or untreated, except for skin carcinomas treated with excision alone and carcinoma in situ of the cervix)
Palliative radiotherapy less than 14 days prior to first dose of study drug
Any history of hypersensitivity to any of the trial medications or solutions they are mixed into
Poorly controlled or serious medical or psychiatric illness likely to interfere with participation and/or compliance in this clinical trial
Prisoners or subjects who are involuntarily incarcerated
Patients not available for follow-up/future contact
Note: Patients on this protocol are not excluded from participation in other clinical trials
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