Durvalumab Before Surgery in Treating Patients With Oral Cavity or Oropharynx Cancer

Study Overview
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Brief Summary
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This pilot clinical trial studies how well durvalumab before surgery works in treating patients with oral cavity or oropharynx cancer. Monoclonal antibodies, such as durvalumab, may interfere with the ability of tumor cells to grow and spread.

Detailed Description
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PRIMARY OBJECTIVES: I. To investigate the effect of durvalumab on local and systemic immune activation by HPV status in patients with oral cavity and oropharynx head and neck squamous cell carcinoma (HNSCC). II. To examine the effects of durvalumab on systemic immune response to HPV and tumor associated antigens. III. To examine the effects of durvalumab on immune regulatory mechanisms. IV. To explore the association between levels of immune-regulatory micro-ribonucleic acid (miR) in plasma and saliva and immune response. SECONDARY OBJECTIVES: I. Investigate the effect of the treatment with durvalumab on the computed tomography (CT) scan and positron emission tomography (PET) scan response. II. Evaluate the safety of a short induction treatment with durvalumab. OUTLINE: Patients receive durvalumab intravenously (IV) over approximately 60 minutes on day 1. Treatment repeats every 2 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Within 3-17 days after last dose administration of durvalumab, patients undergo surgery. Patients may receive an additional dose of durvalumab if time to surgery is longer than 30 days. After completion of study treatment, patients are followed up for 90 days.

Official Title
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Pilot Study to Evaluate the Anti-Tumor Effect of Durvalumab (Medi4736) in Patients With Squamous Cell Carcinoma of the Head and Neck (SCCHN), Human Papilloma Virus (HPV) Positive Versus Negative, When Treated Before Surgery

Conditions
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Human Papillomavirus Infection, Stage I Oral Cavity Squamous Cell Carcinoma, Stage I Oropharyngeal Squamous Cell Carcinoma, Stage II Oral Cavity Squamous Cell Carcinoma, Stage II Oropharyngeal Squamous Cell Carcinoma, Stage III Oral Cavity Squamous Cell Carcinoma, Stage III Oropharyngeal Squamous Cell Carcinoma, Stage IVA Oral Cavity Squamous Cell Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma, Stage IVB Oral Cavity Squamous Cell Carcinoma, Stage IVB Oropharyngeal Squamous Cell Carcinoma, Stage IVC Oropharyngeal Squamous Cell Carcinoma

Intervention / Treatment
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* Biological: Durvalumab
* Other: Laboratory Biomarker Analysis
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed HNSCC of the oral cavity (OC; more than 90% patients have HPV negative cancer) or oropharynx (about 60-80% of patient have HPV positive cancer) Presence of radiologically of clinically documented disease. All radiology studies must be performed within 28 days prior to registration Any stage, considered candidates for surgery and planned for surgery either by robotic or by standard surgical technique Documentation of HPV tested by polymerase chain reaction (PCR) (resulted or pending) Willing to provide consent for an additional tissue biopsy for research purposes, to allow a part of their surgical tumor tissue to be utilized for research (in case tumor tissue has not already been saved in the tumor tissue bank), and to donate samples of blood and saliva collected weekly through the treatment All patients must have provided informed consent for correlative studies Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Patients must have no prior exposure to immune-mediated therapy, including anti- cytotoxic T-lymphocyte protein 4 (CTLA-4), anti-programmed cell death 1, anti-programmed cell death 1 ligand 1 (PD-L1), or anti-programmed cell death ligand 2 antibodies, excluding therapeutic anticancer vaccines At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as > or = 10 mm in the longest diameter (except lymph nodes, which must have a short axis > or = 15 mm) with CT or magnetic resonance imaging (MRI) or clinical measurement and that is suitable for accurate repeated measurements as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines Previous surgery is permitted provided that a minimum of 28 days (4 weeks) have elapsed between any major surgery and date of registration, and that wound healing has occurred Absolute neutrophil count (ANC) >= 1.5 x 10^9/L Platelet count >= 100 x 10^9/L Hemoglobin >= 9.0 g/dL Serum bilirubin =< 1.5 x upper limit of normal (ULN) (institutional upper limit of normal) Total bilirubin is less than or equal to ULN, except the case in which the elevated total bilirubin is not a sign of liver disease, such as the Gilbert Syndrome, in which case a Total Bilirubin less than or equal to 2X ULN is acceptable. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: >= 60 years old and no menses for >= 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry In accordance with National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) policy, protocol treatment is to begin within 2 working days of patient registration Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States of American [USA], European Union [EU] Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations Age 18 years or older at time of study entry. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up Exclusion Criteria: Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrollment in the present study Participation in another clinical study with an investigational product during the last 6 months (mo) Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab Receipt of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) within the last 6 mo (before the first dose of Durvalumab). Mean QT interval corrected for heart rate (corrected QT [QTc]) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's correction Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2) from previous anti-cancer therapy; subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy) Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1 Active or prior documented autoimmune disease within the past 2 years; NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) History of primary immunodeficiency History of allogeneic organ transplant History of hypersensitivity to durvalumab or any excipient Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent Known history of previous clinical diagnosis of tuberculosis Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control Patients with body weight <= 30 kg Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

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 (durvalumab, surgery)<br>Patients receive durvalumab IV over approximately 60 minutes on day 1. Treatment repeats every 2 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Within 3-17 days after last dose administration of durvalumab, patients undergo surgery. Patients may receive an additional dose of durvalumab if time to surgery is longer than 30 days. | Biological: Durvalumab<br>* Given IV<br>* Other names: MEDI4736;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune effector assessed in blood by flow cytometry and in tissue by immunohistochemistry | Concentration of certain immune effector will be assessed in blood pre- and post- treatment. Descriptive statistics, confidence intervals will be calculated and 2-sample t-tests will be performed. Tumor-infiltrating immune-regulator and effector cells will be quantified (0 to 3+) using standing immunofluorescence techniques. Counts and percents will be calculated for these measures overall and by HPV (+/-) groups pre- and post-treatment. Fisher exact tests will be used to compare groups at pre- and post- treatment. Stuart-Maxwell tests (generalizations of the McNemar's Tes | Up to 18 months | 
| Immune-regulatory miR responses as measured in plasma assessed by quantitative reverse transcriptase PCR (qRT-PCR) | Levels of immune-regulatory miRs assessed in blood, saliva and tumor tissue will be assessed pre- and post- treatments. Descriptive statistics, confidence intervals will be calculated and 2-sample t-tests will be performed. In addition, correlations between the different methods will be examined (i.e., correlation between saliva and blood measures, saliva and tumor measures, and blood and tumor measures). | Up to 18 months | 
| Systemic immune response to HPV assessed by enzyme-linked immunosorbent assay (ELISA) | Lab results will be compared between patients who are HPV+ and HPV- using 2 sample t-tests. These measures will be compared in several ways. First, baseline, pre-treatment levels will be examined using descriptive statistics (n, mean, standard deviations, range). These measures will be examined overall and by HPV (+/-) groups. For each measure, and time point, 95% confidence intervals will be estimated. Next, two sample t-tests will be performed to compare levels of the measures at baseline. Next, measures taken post-treatment will be examined in a similar manner (descriptive statistics and 2- | Up to 18 months | 
| Regulatory responses assessed in blood by flow cytometry and in tissue by immunohistochemistry | Concentration of certain regulatory cells will be assessed in blood pre- and post- treatment. Descriptive statistics, confidence intervals will be calculated and 2-sample t-tests will be performed. Tumor-infiltrating immune-regulator and effector cells will be quantified (0 to 3+) using standing immunofluorescence techniques. Counts and percents will be calculated for these measures overall and by HPV (+/-) groups pre- and post-treatment. Fisher exact tests will be used to compare groups at pre- and post- treatment. Stuart-Maxwell tests (generalizations of the McNemar's Tes | Up to 18 months | 
| Immune-regulatory miR responses as measured in saliva assessed by quantitative reverse transcriptase PCR (qRT-PCR) | Levels of immune-regulatory miRs assessed in blood, saliva and tumor tissue will be assessed pre- and post- treatments. Descriptive statistics, confidence intervals will be calculated and 2-sample t-tests will be performed. In addition, correlations between the different methods will be examined (i.e., correlation between saliva and blood measures, saliva and tumor measures, and blood and tumor measures). | Up to 18 months | 
| Immune-regulatory miR responses as measured in tumor tissue assessed by quantitative reverse transcriptase PCR (qRT-PCR) | Levels of immune-regulatory miRs assessed in blood, saliva and tumor tissue will be assessed pre- and post- treatments. Descriptive statistics, confidence intervals will be calculated and 2-sample t-tests will be performed. In addition, correlations between the different methods will be examined (i.e., correlation between saliva and blood measures, saliva and tumor measures, and blood and tumor measures). | Up to 18 months | 
| Systemic immune response to tumor associated antigens assessed by enzyme-linked immunosorbent assay (ELISA) | Lab results will be compared between patients who are HPV+ and HPV- using 2 sample t-tests. These measures will be compared in several ways. First, baseline, pre-treatment levels will be examined using descriptive statistics (n, mean, standard deviations, range). These measures will be examined overall and by HPV (+/-) groups. For each measure, and time point, 95% confidence intervals will be estimated. Next, two sample t-tests will be performed to compare levels of the measures at baseline. Next, measures taken post-treatment will be examined in a similar manner (descriptive statistics and 2- | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) as measured by CTCAE version 4.03 | AEs will be coded using the Medical Dictionary for Regulatory Activities to their organ class by preferred term. Coded AEs will be displayed by frequency, severity, and relationship to treatment (durvalumab) in the safety population. In addition, summary tables will be generated for the following situations: 1. fatigue, diarrhea, nausea and skin rash; 2. Immune-mediated reactions of any grade; 3. other adverse events graded as 3 or more by CTCAE Version 4.03; 4) Durvalumab dose reductions; 5) discontinuations of treatment with durvalumab, with specification of reason for discontinuation; and 6 | Up to 90 days after the last dose of study drug | 
| Standardized Uptake Value (SUV) as measured by PET scans | SUV activity as measured by PET scans will also be compared between groups at each time point and descriptive statistics, confidence intervals will be calculated and 2-sample t-tests will be performed. | Up to 18 months | 
| Tumor volume assessed using RECIST version 1.1 criteria | Tumor volumes will be compared between groups (HPV +/-) pre- and post- treatment. Descriptive statistics, confidence intervals will be calculated and 2-sample t-tests will be performed | Up to 18 months |