The Effect of Prebiotic Inulin on Patients Affected by R/M HNSCC Treated With Immune Checkpoint Inhibitors

Study Overview
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Brief Summary
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The PRINCESS study is a hypothesis-generating, interventional, open-label, non pharmacological trial designed to characterize the translational and clinical implications of the regular assumptions of inulin on Gut Microbiota, circulating cytokines and immune cells dynamics during ICIs +/- chemotherapy on patients affected by R/M HNSCC.

Official Title
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The Effect of Prebiotic Inulin on Patients Affected by Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) Treated With Immune Checkpoint Inhibitors (ICIs): Princess Study

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Dietary Supplement: inulin
* Drug: Pembrolizumab
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent to study procedures; Male or female, age > 18 years (at the time consent is obtained); Histological or cytological documentation of HNSCC that was diagnosed as recurrent or metastatic and considered incurable by local therapies; Indication to be treated with ICIs monotherapy, either pembrolizumab or nivolumab or in combination with chemotherapy, according to standard clinical practice; ECOG Performance PS score < 2; Adequate kidney, liver and bone marrow function; Will and ability to comply with the protocol. Exclusion Criteria: Disease that is suitable for local therapy administered with curative intent; Prior therapy with anti-PD-1 or anti-PD-L1 agents; History of severe allergic reactions or hypersensitivity to trial drugs or any of their excipients; Major surgery < 28 days prior to receiving the first dose of study medication; Toxicity from previous anticancer treatment that includes: Grade 3/4 toxicity considered related to prior therapy and that led to treatment discontinuation; toxicity related to prior treatment that has not resolved to > Grade 1; Central nervous system (CNS) metastases and/or carcinomatous meningitis; with the following exception: patients with asymptomatic CNS metastases who are clinically stable and have no requirement for steroids for at least 14 days prior to the first dose of trial treatment. Patients with carcinomatous meningitis or leptomeningeal spread are excluded regardless of clinical stability. Other additional malignancies that are progressing or require active treatment within the last 5 years with the exception of localized basal and squamous cell carcinoma of the skin or cervical cancer in situ. Active autoimmune disease or syndrome that required systemic treatment within the past 2 years (with use of corticosteroids or immunosuppressive drugs). Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Systemic steroid therapy (≥10 mg oral prednisone per day or equivalent) or other immunosuppressive agents within 7 days prior to the first dose of trial treatment. Diagnosis of current pneumonitis or history of non-infectious pneumonitis that required steroids or other immunosuppressive agents; Diagnosis of active infection that required systemic antibiotics therapy, orally or intravenous;. Clinically significant cardiovascular disease within the 6 months prior to the first dose of trial treatment with a New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF); symptomatic pericarditis. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness; Any serious and/or unstable medical conditions, psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Receipt of any live vaccine within 30 days of planned start of study therapy. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Pembrolizumab in monotherapy or in combination with chemotherapy (platinum + 5 FU) in standard clinical practice according to the international and local guidelines + inulin | Dietary Supplement: inulin<br>* Inulin will be given to enrolled patients according to manufacturer label indications. ICIs (i.e. nivolumab and pembrolizumab) alone or in combination with chemotherapy, if clinically indicated, and their administration scheduling will be planned as per international and local guidelines.<br>Drug: Pembrolizumab<br>* Pembrolizumab in monotherapy or in combination with chemotherapy (platinum + 5 FU) in standard clinical practice according to the international and local guidelines + inulin<br>|
| Experimental: Arm B<br>Nivolumab in monotherapy or in combination with chemotherapy (platinum + 5 FU) in standard clinical practice according to the international and local guidelines + inulin | Dietary Supplement: inulin<br>* Inulin will be given to enrolled patients according to manufacturer label indications. ICIs (i.e. nivolumab and pembrolizumab) alone or in combination with chemotherapy, if clinically indicated, and their administration scheduling will be planned as per international and local guidelines.<br>Drug: Nivolumab<br>* Nivolumab in monotherapy or in combination with chemotherapy (platinum + 5 FU) in standard clinical practice according to the international and local guidelines + inulin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alpha diversity and Beta diversity analysis in the Gut Microbiota | Comparison of gut microbiota diversity with Shannon index in faeces samples. The analyses were conducted using QIIME software | 12 month | 
| Evaluation of circulating cytokines dynamics | Analysis of multiple cytokines for identify a cytokine signature related to a patient's outcome and be able to recognize patients who will benefit from treatment. Plasma Levels of 18 Cytokines TGF-, TNF-, VEGF, INF-, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, CCL-2, CCL4, CCL-22, and CXCL-10 were evaluated with the Ella Simple Plex system (ProteinSimple™, San Jose, CA, USA)The concentrations were expressed in pg/mL. IL-21 was assessed with the ELISA method (R & D System, Minneapolis, MN, USA). The measured optical densities were expressed as pg/mL. | 12 month | 
| Rate and evaluation of modification of circulating immune-phenotype dynamics | Rate and evaluation of modification of main circulating immune characters as T lymphocytes, B Lymphocytes, Tregs, neutrophils, Natural Killer, NKT, MDSC during study combination treatment | 12 month | 
| Evaluation of Immune-predictive molecules | Evaluation of immunomodulatory molecules (PD-1; PD-L1/2; HLA- E; TIM3; LAG3; OX40; VISTA; ICOS) will be assessed at each established time point | 12 month | 
| Overall Survival Rate | OS and the correlation with GM diversity and circulating cytokines and immune cells dynamics. | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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microbiome, inulin, Immune Checkpoint Inhibitors, chemotherapy, cytokines, immune cells, HNSCC, Recurrent/Metastatic, Head and Neck Squamous Cell Carcinoma, Carcinoma, Head and Neck Carcinoma