Predictive Biomarkers for Response to Nivolumab in Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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Nivolumab is FDA-approved for the treatment of patients with recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC). HNSCC whose disease has progressed within 6 months after platinum-based chemotherapy. The development of predictive biomarkers is needed to optimize patient benefit, minimize risk of toxicities and guide combination strategies.

Detailed Description
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Nivolumab is FDA-approved for the treatment of patients with recurrent/metastatic Head and Neck Squamous Carcinoma (HNSCC) whose disease has progressed within 6 months after platinum-based chemotherapy. The development of predictive biomarkers is needed to optimize patient benefit, minimize risk of toxicities and guide combination strategies. The greatest focus has been on tumor-cell programmed death Ligand 1 (PD-L1) expression. Although PD-L1 positivity enriches for populations with clinical benefit, PD-L1 testing alone is insufficient for patient selection in most malignancies. PD-L1 expression can be transient, and intrapatient and even intratumor heterogeneity in PD- L1 tumor expression can exist. Therefore, tumor sampling at one timepoint might not accurately reflect the state of PD1 axis in a patient. Another important aspect is that PD-L1 immunohistochemistry alone does not take into account factors that could impede the anti-PD1 therapy response such as whether or not active immune cell engagement of the PD1 axis occurs in the tumor microenvironment or other concurrent immune suppressive pathways are present. Assessment of biomarkers at baseline may not predict benefit from immunotherapy. In a phase II study of ipilimumab in patients with metastatic melanoma baseline tumor infiltrating lymphocyte status was not associated with clinical activity. However, increase in tumor infiltrating lymphocyte density in tumor biopsy samples collected after the second dose of ipilimumab was associated with significantly greater clinical activity with ipilimumab compared to samples without increase in lymphocyte density. For a better understanding of the mechanisms of resistance to nivolumab in HNSCC, the investigators propose to study a cohort of longitudinal HNSCC samples from recurrent/metastatic HNSCC patients treated with nivolumab and identify biomarkers of response and resistance. The investigators will specifically focus on modulation of immune phenotype (ImmR) following two cycles of nivolumab as surrogate biomarker for response to nivolumab. The primary endpoint will be the change in the percentage of immune cells that is caused by nivolumab treatment. Secondary endpoint will be safety of performing a biopsy after second nivolumab dose. Translational correlates will be tested in tumour tissue, plasma and germline DNA. Investigator assessment of best overall response (BOR), determined between the date of first dose and the last tumor assessment (TA), will be image-based and scored using the RECIST 1.1. criteria. BOR will be defined as categorical variable with 3 levels { Benefit (complete response (CR), partial response (PR), stable disease (SD) lasting 6 months from the first nivolumab dose), no benefit (PD, progressive disease or SD lasting less than 6 months from the first nivolumab dose), and unknown} Longitudinal tissue biopsies will be collected from HNSCC patients treated with nivolumab . Biopsies will be taken at baseline, 24-72 hours after the second cycle of nivolumab and at progression.

Official Title
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Predictive Biomarkers For Response To Nivolumab In Head and Neck Squamous Cell Carcinoma

Conditions
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HNSCC, DNA Damage, DNA Double Strand Break

Intervention / Treatment
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* Other: Biomarker Research
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent before any trial-related procedure is undertaken Male or female subjects aged ≥18 years Availability of a formalin-fixed, paraffin-embedded tissue sample (FFPE) containing tumor Exclusion Criteria: no inform consent provided

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Recurrent/metastatic HNSCC<br>The investigators will include recurrent/metastatic HNSCC patients who progressed after cisplatin-based chemotherapy and are to be treated with nivolumab. Tumor biopsies will be performed at baseline, after the second cycle and at progression with appropriate written informed consent and the samples will be analyzed. Biomarker research will be performed. The patients will receive intravenously nivolumab at dose of 240 mg every 2 weeks (240mg q2w). The patients will undergo tumor biopsy at baseline and within 24-72h after the second administration of treatment, and at progression of their disease. | Other: Biomarker Research<br>* The investigators will include recurrent/metastatic HNSCC patients who progressed after cisplatin-based chemotherapy and are to be treated with nivolumab 240mg IV q 2 weeks. Patient samples will be collected with appropriate written informed consent and analyzed.<br>Drug: Nivolumab<br>* The investigators will include recurrent/metastatic HNSCC patients who progressed after cisplatin-based chemotherapy and are to be treated with nivolumab 240mg IV q 2 weeks.<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the percentage of immune cells in post treatment compared to baseline biopsies | Primary endpoint will be the change in mean percentage of immune cells that is caused by the nivolumab treatment | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of performing a biopsy after second nivolumab dose | Incidence of adverse events attributable to nivolumab treatment | 6 weeks | 
| Best overall response rate (BOR) according to RECIST 1.1 criteria | BOR will be defined as categorical variable with 3 levels { Benefit (complete response (CR), partial response (PR), stable disease (SD) lasting 6 months from the first nivolumab dose), no benefit (PD, progressive disease or SD lasting less than 6 months from the first nivolumab dose), and unknown} | One year | 
| Number of participants with tolerability to the treatment. | NCI common toxicity criteria will be used | From the 1st day of therapy and every week for 4 weeks maximum and 30 days after last therapy administration ] | 
| The burden of somatic non-synonymous mutations in association with BOR and survival | Targeted gene sequencing using next generation sequencing will be performed | At baseline | 
| The interferon-gamma gene signature in association with BOR and survival | Nanostring gene expression profiling, multiple tumor, inflammatory- and immune related genes will be analyzed by multiplex Nanostring technology by using the nCounter PanCancer Immune Profiling 770-plex gene expression Panel | At baseline | 
| The expression of PD-L1 in association with BOR and survival | PD-L1 will be assessed in tumor cells and immune cells by immunohistochemistry | At baseline and at 4 weeks | 
| The expression of human leukocyte antigens, HLA class I and HLA class II molecules in association with BOR and survival | It will be assessed at RNA and protein level | At baseline | 
| The presence of adaptive immunity cell populations | The assessment will be performed using multiplex imaging | At baseline and at 4 weeks | 
| The expression of PD-L2 in association with BOR and survival | PD-L2 will be assessed in tumor cells and immune cells by immunohistochemistry | At baseline and at 4 weeks | 
| PD-L1 expression in circulating tumor cells (CTCs) in association with BOR and survival | The assessment will be performed with Parsotrix system | At baseline and at 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HNSCC, DDR, DNA damage, DNA damage repair, PD-L1, PD-1, NIVOLUMAB, Head and Neck cancer