Bintrafusp Alfa and Stereotactic Body Radiation Therapy for the Treatment of Recurrent or Second Primary Head and Neck Squamous Cell Cancer

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and how well bintrafusp alfa and stereotactic body radiation therapy work in treating patients with head and neck squamous cell cancer that has come back (recurrent) or has occurred after having cancer in the past (second primary). Immunotherapy with bintrafusp alfa may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving bintrafusp alfa and stereotactic body radiation therapy may help to control recurrent head and neck squamous cell cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety, tolerability and feasibility of bintrafusp alfa (M7824) when administered together with stereotactic body radiation therapy (SBRT) reirradiation. (Lead In) II. To evaluate the progression-free survival (PFS) rate of M7824 plus SBRT reirradiation at 1 year. (Phase 2) SECONDARY OBJECTIVES: I. To evaluate the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST). II. To evaluate the 1-year locoregional control (LRC), locoregional failure-free survival (LFFS), distant metastasis (DM) and overall survival (OS) rates. III. To evaluate acute and late toxicity using Common Terminology Criteria for Adverse Events (CTCAE) - version (v) 5.0. IV. To evaluate fibrosis-related toxicities and functional outcomes. V. To evaluate patient reported outcome (PRO) measures of symptoms using MD Anderson Symptom Inventory (MDASI). VI. To evaluate volumetric tumor regression rate and magnetic resonance imaging (MRI) kinetic biomarkers after M7824 plus SBRT. VII. To compare quality-adjusted-life-years (QALY) between M7824 plus SBRT reirradiation and historic SBRT reirradiation control. EXPLORATORY OBJECTIVE: I. Biomarkers will be accessed in the tumor and blood samples and correlated with clinical outcomes and toxicity. OUTLINE: Patients receive bintrafusp alfa intravenously (IV) over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 15 of cycle 1, patients also undergo SBRT over 5 fractions once every other day (QOD) for 2 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 90 days and then every 6 months for 3 years.

Official Title
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Phase I/II Study of M7824 Plus Curative Intent Re-Irradiation With Stereotactic Body Radiation Therapy (SBRT) in Patients With Local-Regionally Recurrent Head and Neck Squamous Cell Carcinoma

Conditions
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Recurrent Head and Neck Squamous Cell Carcinoma, Second Primary Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Bintrafusp Alfa
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically documented local-regional recurrent squamous cell carcinoma of the head and neck, or second primary squamous cell carcinoma of the head and neck Patients must be willing to undergo research biopsy for tissue collection at baseline and at disease progression Previous receipt of at least 30 Gy of radiation for head and neck squamous cell cancer (HNSCC) with overlapping fields Not eligible or poor candidate or patient refusal of surgery for recurrence Evaluable disease apparent on imaging (MRI or computed tomography [CT]) 1 to 3 sites of recurrence (< 60 cm^3 per site, total volume < 100 cm^3) Eastern Cooperative Oncology Group (ECOG) = 0, 1, or 2 White blood count (WBC) >= 2000/L Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 Platelets >= 100,000 cells/mm^3 Hemoglobin >= 9.0 g/dl; Note: The use of transfusion or other intervention to achieve hemoglobin (Hgb) >= 9.0 g/dl is acceptable Serum creatinine =< 1.5 mg/dl or creatinine clearance (CC) >= 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula Total bilirubin =< 1.5 x upper limit of normal (ULN) (except patients with Gilbert syndrome who can have total bilirubin < 3.0 mg/dL) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x the upper limit of normal Negative serum pregnancy test for women of childbearing potential and confirmation within 24 hours of first dose of study drug Exclusion Criteria: Presence of distant metastases Less than six-month disease free interval from end of prior radiotherapy to the head and neck Prior receipt of anti-PD-1/L1 Patients who are pregnant or breast feeding Clinically significant uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal or hematologic disease but not limited to: symptomatic congestive heart failure, unstable angina, or cardiac dysrhythmia not controlled by pacer device; myocardial infarction within 3 months of registration Active autoimmune disorder or immunosuppression (including human immunodeficiency virus [HIV], but excluding endocrine abnormalities that are controlled with replacement medications) Active viral hepatitis Steroid therapy of greater than prednisone 10 mgs a day or equivalent Prior history of invasive non-head and neck cancer within two years, with the exception of screen detected prostate cancer treated with observation only, basal cell and squamous cell carcinoma of the skin, and micro-invasive resected cervical carcinoma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bintrafusp alfa, SBRT)<br>Patients receive bintrafusp alfa IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Beginning day 15 of cycle 1, patients also undergo SBRT over 5 fractions once QOD for 2 weeks in the absence of disease progression or unacceptable toxicity. | Drug: Bintrafusp Alfa<br>* Given IV<br>* Other names: MSB0011359C;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Will use the methods of Gooley to estimate the cumulative incidence of PFS events. A PFS event is defined as death or disease progression, including locoregional recurrence/progression or distant metastases. Logistic regression models will be used to evaluate the effects of the important patient clinical factors including treatment on PFS. | From treatment initiation until a recurrence, progression or occurrence or death, whichever comes first, assessed at 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Proportional hazards regression may be employed for multivariate analysis on time-to-event outcomes. | Up to 3 years | 
| Time to progression | Local control is defined as absence of local failure. The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Proportional hazards regression may be employed for multivariate analysis on time-to-event outcomes. | Up to 1 year | 
| Loco-regional failure free survival rate | Local failure is defined as failure (recurrence or progression) within the prescribed radiation field, including failure within 2 cm of the radiation field. The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Proportional hazards regression may be employed for multivariate analysis on time-to-event outcomes. | From treatment initiation until local failure or death from any cause, whichever occurs first, assessed up to 1 year | 
| Distant metastases rate | The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Proportional hazards regression may be employed for multivariate analysis on time-to-event outcomes. | From treatment initiation until distance metastases or death from any cause, whichever occurs first, assessed up to 1 year | 
| Overall survival rate | The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. Proportional hazards regression may be employed for multivariate analysis on time-to-event outcomes. | From treatment initiation until time to death from any cause, assessed up to 1 year | 
| Incidence of acute and late adverse events | Will be accessed by the Common Terminology Criteria for Adverse Events 5.0. Frequency count and percentage will be provided for categorical variables such as toxicity type and severity. The chi-square test or the Fisher's exact test will be applied to evaluate the association between two categorical variables. | Up to 90 days following the last dose of bintrafusp alfa | 
| Fibrosis-related toxicities | Frequency count and percentage will be provided for categorical variables such as toxicity type and severity. The chi-square test or the Fisher's exact test will be applied to evaluate the association between two categorical variables. | Up to 90 days following the last dose of bintrafusp alfa | 
| Fibrosis-related functional outcomes |  | Up to 24 months | 
| Patient-reported outcome (PRO) measures of symptoms | Will be measured using MD Anderson Symptom Inventory and assessed at the completion of reirradiation, and subsequently every +/- 3-months until 24-months post reirradiation. Generalized linear models for the repeated measures analysis will be performed to assess the change in PROs overtime with important covariates including treatment in the models. | Up to 24 months post reirradiation | 
| Volumetric tumor regression rate |  | Up to 3 years | 
| Magnetic resonance imaging kinetic biomarkers |  | Up to 24 months | 
| Quality-adjusted-life-years | Will be measured between bintrafusp alfa plus stereotactic body radiation therapy (SBRT) reirradiation and historic SBRT reirradiation control. | Up to 24 months |