Fecal Microbiota Transplantation to Improve Efficacy of Immune Checkpoint Inhibitors in Renal Cell Carcinoma

Study Overview
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Brief Summary
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Renal cell carcinoma (RCC) is the sixth most common cancer in men and the eighth in women in the USA. In Italy RCC incidence was 11500 new cases in 2017, while mortality was 3371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel therapeutic option based on the restoration of healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection, and preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of this study is to evaluate, through a randomized controlled trial, the efficacy of targeted FMT (from donors who are responding to ICI. in improving response rates to ICIs in subjects with aRCC.

Detailed Description
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Renal cell carcinoma (RCC) is the sixth most common cancer in men and the eighth in women in the USA. In Italy RCC incidence was 11500 new cases in 2017, while mortality was 3371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel therapeutic option based on the restoration of healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection, and preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of the study is to evaluate, through a randomized controlled trial, the efficacy of targeted FMT (from donors who are responding to ICI) in improving response rates to ICIs in subjects with aRCC. So, the investigators will investigate, through a randomized controlled trial, if donor FMT will be more effective than placebo FMT in improving response to ICIs in patients with renal cell carcinoma. Patients will undergo the first infusion by colonoscopy. Then, patients will receive frozen fecal capsules (8 capsules t.i.d.) at 3 and 6 months after the first FMT. Fifty patients will be enrolled. Sample size calculation was based on the hypothesis of the superiority of FMT+SOC over SOC alone. The 1-year PFS rate for SOC has been reported to be nearly 60%. The alternative hypothesis is that FMT can improve the 1-year PFS rate from 60% to 80% wen associated to SOC. A total of 50 patients will enter this two-treatment parallel-design study. The probability is 80 percent that the study will detect a treatment difference at a one-sided 5.0 percent significance level, if the true hazard ratio is 0.436. This is based on the assumption that the accrual period will be 18 months and the follow up period will be 12 months and the median survival is 15.1 months. The total number of events will be 35. Microbiome analysis will be performed with shotgun sequencing techniques.

Official Title
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Targeting Gut Microbiota to Improve Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Biological: donor FMT
* Other: Placebo FMT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed aRCC Metastatic disease (measurable and not-measurable) Radiological assessment within 8 wks before enrollment Patient eligible to therapy with ICI for aRCC (or started within 8 wks) Ability to provide written informed consent Ability to be compliant with the scheduled procedures Exclusion Criteria: Major comorbidities Concomitant GI or autoimmune disorders, or HIV, HBV, HCV infection Continuative corticosteroid therapy Previous treatment with systemic immune-suppressants or immune-modulatory drugs Antibiotic therapy within 4 weeks prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donor FMT<br>Patients enrolled in this arm will receive donor FMT | Biological: donor FMT<br>* This intervention is represented by the administration, in the recipients' gut, of donor microbiota through FMT<br>|
| Placebo Comparator: Placebo FMT<br>Patients enrolled in this arm will receive placebo FMT (that will be made of saline solution) | Other: Placebo FMT<br>* This intervention is represented by the administration, in the recipients' gut, of a placebo through FMT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who will be free from tumor progression, as assessed by RECIST criteria v. 1.1. | The investigators will evaluate the number of participants who will be free from tumor progression, as assessed by RECIST criteria v. 1.1., after treatments, at 12 month-follow-up | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who will obtain a partial or a complete tumor response to immunotherapy, as assessed by RECIST criteria v. 1.1, after treatments | The investigators will evaluate the number of participants who will obtain a partial or a complete tumor response to immunotherapy, as assessed by RECIST criteria v. 1.1, after treatments, at 12 month-follow-up | 12 months | 
| Number of participants who will die for any reason (overall survival) | The investigators will evaluate the number of participants who will die for any reason throughout the study period (12 months) | 12 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | The number of participants with treatment-related adverse events (assessed by CTCAE v4.0) will be recorded throughout the study period (12 months) | 12 months | 
| Number of participants with significant increase in alpha-diversity (assessed by Shannon index) and beta-diversity (assessed by Bray-Curtis dissimilarity) of their gut microbiota after treatments | Throughout the study period (12 months) the investigators will evaluate the number of participants with significant increase in alpha-diversity (assessed by Shannon index) and beta-diversity (assessed by Bray-Curtis dissimilarity) of their gut microbiota after treatments, compared with baseline | 12 months |