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Fecal Microbiota Transplantation in Diarrhea Induced by Tyrosine-kinase Inhibitors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04040712
Recruitment Status : Active, not recruiting
First Posted : August 1, 2019
Last Update Posted : August 1, 2019
Sponsor:
Information provided by (Responsible Party):
Giovanni Cammarota, Catholic University of the Sacred Heart

Brief Summary:
Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with metastatic renal cell carcinoma, and are commonly used as first-line option for this condition, but their use is encumbered by side effects, mainly diarrhea, for which there are no standardized strategies. Increasing evidence suggests that gut microbiota could influence the development of TKIs-induced diarrhea. In theory, the therapeutic modulation of gut microbiota could be an approach to alleviate TKI-induced diarrhea. Fecal microbiota transplantation (FMT) is the infusion of fecal microbiota from a healthy donor in the gut of a recipient with the aim of curing a specific disease. It has been increasingly recognized as a highly effective treatment against recurrent Clostridium difficile infection.To date, the effects of FMT on chemotherapy-related diarrhea are unknown. This study will evaluate, through a randomized controlled design, the efficacy of fecal microbiota transplantation (FMT), compared with sham FMT, in treating TKI-induced diarrhea in patients with metastatic renal cell carcinoma.

Condition or disease Intervention/treatment Phase
Diarrhea Caused by Drug (Disorder) Renal Cell Cancer Other: Donor FMT Other: Sham FMT Not Applicable

Detailed Description:

Despite the improvement in diagnosis and management, renal cell carcinoma (RCC) remains one of the most burdensome urological cancers, being the sixth most common malignancy in men and the 10th in women, accounting, respectively, for 5% and 3% of all cancers. Moreover, the incidence of RCC is increasing, especially in Western countries, accounting for nearly 60000 new cases per year in the United States. A considerable proportion of patients present with metastatic disease at diagnosis, and there are more than 140000 RCC-dependent deaths per year worldwide according to the World Health Organization.

Sunitinib and pazopanib are oral multi-targeted receptor tyrosine kinase inhibitors (TKIs) that have dramatically improved the survival of patients with metastatic RCC, and are commonly used as first-line option for this condition.

However, long-term use of these drugs is prevented by the development of toxicity. Diarrhea is one of the most common side effects of TKIs, occurring in nearly 50% of patients. It decreases the quality of life of these patients, and often requires dose reduction and drug discontinuation, potentially decreasing the efficacy of TKIs.

To date there are no standardized strategies for TKIs-related diarrhea, and current recommendations are supported by few evidence or real-life experience. Recommended treatment options include anti-motility agents, which are not targeted to act on the pathogenic pathways of diarrhea.

Increasing evidence suggests that gut microbiota could influence the development of TKIs-induced diarrhea. Overall, chemotherapy is known to drive, through the development of mucositis, deep compositional and functional alterations of gut microbiota. Mucositis occurs commonly after treatment with TKIs, and a specific dysbiotic profile has been found in patients with TKIs-induced diarrhea.

In theory, the therapeutic modulation of gut microbiota could be an approach to alleviate TKI-induced diarrhea. Although probiotics have been suggested as a possible treatment option for this condition, few evidence supports this indication.

Fecal microbiota transplantation (FMT) is the infusion of fecal microbiota from a healthy donor in the gut of a recipient with the aim of curing a specific disease. It has been increasingly recognized as a highly effective treatment against recurrent Clostridium difficile infection.

FMT has been also examined as a potential approach for other disorders associated with a disruption of gut microbiota, including ulcerative colitis or metabolic syndrome.

To date, the effects of FMT on chemotherapy-related diarrhea are unknown. The aim of this study is to investigate the efficacy of fecal microbiota transplantation (FMT), compared with sham FMT, in treating TKI-induced diarrhea in patients with metastatic RCC

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Fecal Microbiota Transplantation to Treat Diarrhea Induced by Tyrosine-kinase Inhibitors in Patients With Metastatic Renal Cell Carcinoma: a Randomized Clinical Trial.
Actual Study Start Date : July 1, 2018
Actual Primary Completion Date : November 30, 2018
Estimated Study Completion Date : October 30, 2019


Arm Intervention/treatment
Experimental: Donor FMT
Fecal microbiota transplantation using stools from healthy donors
Other: Donor FMT
Fecal microbiota transplantation using stools from healthy donors

Sham Comparator: Sham FMT
Sham fecal microbiota transplantation
Other: Sham FMT
Sham fecal microbiota transplantation




Primary Outcome Measures :
  1. rate of patients who experience resolution of diarrhea 4 weeks after the end of treatments [ Time Frame: 4 weeks ]
    rate of patients who experience resolution of diarrhea 4 weeks after the end of treatments


Secondary Outcome Measures :
  1. rate of patients who need to stop or reduce treatment with tyrosine-kinase inhibitors [ Time Frame: 4 weeks ]
    rate of patients who need to stop or reduce treatment with tyrosine-kinase inhibitors

  2. rate of patients who need to take anti-diarrheal drugs (loperamide) during follow-up. [ Time Frame: 4 weeks ]
    rate of patients who need to take anti-diarrheal drugs (loperamide) during follow-up.

  3. rate of patients who experience resolution of diarrhea 1 week after the end of treatments [ Time Frame: 1 week ]
    rate of patients who experience resolution of diarrhea 1 week after the end of treatments



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18 years old or older
  • treatment with pazopanib or sunitinib for metastatic RCC diagnosed at histology and measurable according to RECIST criteria version 1.1
  • development of diarrhea of 2-3 grade according to Common Terminology Criteria (CTC) for Adverse Events (AE) version 4.0 induced by these drugs. P
  • execution of a CT scan no earlier than 4 weeks before enrollment
  • good or intermediate prognostic assessment (according to criteria of the prognostic system of the International Metastatic RCC Database Consortium)
  • performance status equal or lower than 2
  • blood count, hepatic and kidney testing within normal limit
  • ability to give their consent to be included in the study.

Exclusion criteria:

  • another known cause of diarrhea (e.g. infectious gastroenteritis. Clostridium difficile infection, celiac disease, inflammatory bowel disease, irritable bowel syndrome, chronic pancreatitis, biliary salt diarrhea)
  • previous colorectal surgery or cutaneous stoma
  • food allergies
  • recent (<6 weeks) therapy with drugs that could possibly alter gut microbiota (e.g. antibiotics, probiotics, proton pump inhibitors, immunosuppressants, metformin)
  • another cancer (except for surgically treated basocellular carcinoma)
  • brain metastases
  • decompensated heart failure or heart disease with ejection fraction lower than 30%
  • severe respiratory insufficiency
  • psychiatric disorders
  • pregnancy
  • unable to give informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04040712


Locations
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Italy
Fondazione Policlinico Universitario "A. Gemelli" IRCCS
Rome, Italy, 00168
Sponsors and Collaborators
Catholic University of the Sacred Heart

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Responsible Party: Giovanni Cammarota, Professor, Catholic University of the Sacred Heart
ClinicalTrials.gov Identifier: NCT04040712    
Other Study ID Numbers: FMT-TKI-001
First Posted: August 1, 2019    Key Record Dates
Last Update Posted: August 1, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Giovanni Cammarota, Catholic University of the Sacred Heart:
fecal microbiota transplantation
microbiota
chemotherapy
diarrhea
renal cell carcinoma
Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Diarrhea
Signs and Symptoms, Digestive
Signs and Symptoms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases