Clinical trial NCT04758507: Fecal Microbiota Transplantation to Improve Efficacy of Immune Checkpoint Inhibitors in Renal Cell Carcinoma
Official title: Targeting Gut Microbiota to Improve Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Renal Cell Carcinoma
Lead sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Sponsor class: OTHER
First posted: 2021-02-17
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized controlled trial
Primary purpose: TREATMENT

Brief summary: 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: 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 36 months and the follow up period will be 36 months and the median survival is 15.1 months. The total number of events will be 37.

Eligibility criteria: 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

Primary outcomes:
measure: Number of participants who will be free from tumor progression, as assessed by RECIST criteria v. 1.1.
timeFrame: 12 months
Secondary outcomes:
measure: 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
timeFrame: 12 months
measure: Number of participants who will die for any reason (overall survival)
timeFrame: 12 months
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 12 months
measure: 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
timeFrame: 12 months
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Digestive Disease Center
city: Rome
country: Italy
facility: Gianluca Ianiro
Study officials:
affiliation: Fondazione Policlinico Gemelli IRCCS
name: Gianluca Ianiro, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ianiro G, Rossi E, Thomas AM, Schinzari G, Masucci L, Quaranta G, Settanni CR, Lopetuso LR, Armanini F, Blanco-Miguez A, Asnicar F, Consolandi C, Iacovelli R, Sanguinetti M, Tortora G, Gasbarrini A, Segata N, Cammarota G. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma. Nat Commun. 2020 Aug 28;11(1):4333. doi: 10.1038/s41467-020-18127-y.
citation: Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, Adler K, Dick-Necula D, Raskin S, Bloch N, Rotin D, Anafi L, Avivi C, Melnichenko J, Steinberg-Silman Y, Mamtani R, Harati H, Asher N, Shapira-Frommer R, Brosh-Nissimov T, Eshet Y, Ben-Simon S, Ziv O, Khan MAW, Amit M, Ajami NJ, Barshack I, Schachter J, Wargo JA, Koren O, Markel G, Boursi B. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021 Feb 5;371(6529):602-609. doi: 10.1126/science.abb5920. Epub 2020 Dec 10.
citation: Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, Deblasio RN, Menna C, Ding Q, Pagliano O, Zidi B, Zhang S, Badger JH, Vetizou M, Cole AM, Fernandes MR, Prescott S, Costa RGF, Balaji AK, Morgun A, Vujkovic-Cvijin I, Wang H, Borhani AA, Schwartz MB, Dubner HM, Ernst SJ, Rose A, Najjar YG, Belkaid Y, Kirkwood JM, Trinchieri G, Zarour HM. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021 Feb 5;371(6529):595-602. doi: 10.1126/science.abf3363.
citation: Cammarota G, Ianiro G, Kelly CR, Mullish BH, Allegretti JR, Kassam Z, Putignani L, Fischer M, Keller JJ, Costello SP, Sokol H, Kump P, Satokari R, Kahn SA, Kao D, Arkkila P, Kuijper EJ, Vehreschild MJG, Pintus C, Lopetuso L, Masucci L, Scaldaferri F, Terveer EM, Nieuwdorp M, Lopez-Sanroman A, Kupcinskas J, Hart A, Tilg H, Gasbarrini A. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019 Dec;68(12):2111-2121. doi: 10.1136/gutjnl-2019-319548. Epub 2019 Sep 28.