Probiotic Yogurt Supplement in Reducing Diarrhea in Patients With Metastatic Kidney Cancer Being Treated With Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitor

Assessment of the Role of Bifidobacterium-Containing Food Supplement Activia™ and Bacteriomic Profiling and Other Biomarkers Associated With Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor (VEGF-TKI)-Induced Diarrhea in Patients With Metastatic Renal Cell Carcinoma (mRCC)

This randomized clinical trial studies how well probiotic yogurt supplement works in reducing diarrhea in patients with kidney cancer that has spread from the primary site to other places in the body (metastatic) and that are being treated with vascular endothelial growth factor-tyrosine kinase inhibitor therapy. Studying samples of blood and stool from patients who eat probiotic yogurt and those who avoid probiotic yogurt may help doctors plan better treatment.

Study Overview

• Status: Completed
• Conditions: Metastatic Renal Cell Carcinoma; Diarrhea; Stage IV Renal Cell Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Dietary supplement: Micronutrient-Fortified Probiotic Yogurt; Drug: VEGF-TKI

Detailed Description

PRIMARY OBJECTIVES:

I. To determine if adding Activia yogurt (containing Bifidobacterium lactis DN-173 010) to the diet of patients with metastatic renal cell carcinoma (mRCC) increases the level of Bifidobacterium spp in stool.

SECONDARY OBJECTIVES:

I. To determine if Activia reduces the incidence of diarrhea for mRCC patients treated with vascular endothelial growth factor - tyrosine kinase inhibitor (VEGF-TKI) therapy.

II. To compare pre-treatment levels of circulating T regulatory (Treg) cells and levels of peripheral signal transducers and activators of transcription 3 (STAT3) in patients with and without diarrhea with VEGF-TKI therapy, and correlate with Bifidobacterium, other bacteria, and Activia.

III. To determine if patients with the diarrhea in mRCC patients treated with VEGF-TKI therapy have a lower baseline of Bifidobacterium spp.

IV. To assess the change in global stool bacteriomic profile of patients receiving therapy with VEGF-TKI therapy with or without Activia.

V. To better assess the feasibility of stool collection and bacteriomic profiling.

VI. To explore association between psychosocial symptoms (anxiety and depression) and bacteriomic profile and gastrointestinal toxicity in mRCC patients receiving VEGF-TKI therapy therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive probiotic supplement Activia yogurt twice daily (QD) during weeks 2-13 of VEGF-TKI treatment.

ARM II: Patients avoid any intake of yogurt or yogurt-containing foods and refrain from taking/consuming other probiotic supplements for 3 months.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Cytologically or pathologically verified diagnosis of renal cell carcinoma (RCC)
• Diagnosis of RCC that is defined as metastatic by standard criteria (American Joint Committee on Cancer [AJCC] 7th edition, 2010)
• Planned treatment with any VEGF-TKI, treatment has not yet begun
• Ability to understand and the willingness to sign a written informed consent
• Ability to read and write English

• Documented consent to participation to include the following study specific procedures:

  • Be able to provide up to six serial stool collections at home and deliver to FedEx location that day as per standard operating procedure
  • Have three 10-ml blood samples taken during a routine clinic visit
  • To not take probiotic supplements except as oriented
  • If randomized to the probiotic-supplemented group (the yogurt-based supplement Activia), be willing to comply with daily intake and record this intake as a component of a dietary log; the patient will be asked not to take any yogurt or yogurt-containing foods beyond this
  • If randomized to the probiotic-restricted group, agree not to consume yogurt or yogurt-containing foods
  • Maintain a dietary log and stool frequency log

Exclusion Criteria:

• Patients with a known intolerance to lactose or other constituents of Activia
• Patients with irritable bowel syndrome, Crohn's disease, or other clinically significant gastrointestinal (GI) related condition that might confound the VEGF-TKI-related-diarrhea endpoint
• Patients taking antibiotics or who plan to begin taking antibiotics
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures (including compliance issues related to feasibility/logistics)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (probiotic yogurt supplement); Patients receive probiotic supplement Activia yogurt QD during weeks 2-13 of VEGF-TKI treatment.	Other: Laboratory Biomarker Analysis; Correlative studies; Dietary supplement: Micronutrient-Fortified Probiotic Yogurt; Receive Activia yogurt; Drug: VEGF-TKI; Must be received as standard of care chemotherapy
Active Comparator: Arm II (no intervention); Patients avoid any intake of yogurt or yogurt-containing foods and refrain from taking/consuming other probiotic supplements for 3 months.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: VEGF-TKI; Must be received as standard of care chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Overall Response	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR	Up to 3 years
Number of Participants With Diarrhea	The rate of all grade diarrhea as graded by the Common Terminology Criteria for Adverse Events version 4.0 will be compared in the patients who receive the dietary supplement and those who do not. A Fisher's exact test with a 0.050 one-sided significance level will be used.	Up to 13 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	Estimated using the product-limit method of Kaplan and Meier. Failure defined as disease progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	Up to 36 months
Clinical Benefit Rate	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial response (PR): At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR; Stable disease (SD): Neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD; Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). Clinical Benefit Rate (CBR) = CR + PR + SD at 6 months	Up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bacteriomic profiles	The association between the subclusters and phenotypic variables will be studied. Principle coordinate analysis will be used to examine possible correlation between phylum/genus and other phenotypic variables.	Up to 2.5 years
Feasibility of stool collection measured by compliance with specimen submission		Up to 13 weeks
Feasibility of bacteriomic profiling measured by viable bacteriomic profile results	Reasons for inability to perform analysis will be noted (for instance, insufficient DNA collection)	Up to 13 weeks
Operational taxonomic units (OTUs) with summary of bacteriomic profiles	The relative abundance of OTUs will be calculated at phylum-, class-, order-genus- and species-level taxa. Weighted and unweighted UniFrac distances between samples will be calculated with a de novo tree constructed from representative sequences defining each OTU. A table of OTU counts will be generated and used in combination with the tree to calculate beta diversity. Principle coordinate analysis will be used to examine possible correlation between phylum/genus and other phenotypic variables.	Up to 2.5 years
Short read sequences	Quantitative insights into microbial ecology will be used to cluster V5-15S rRna Solexa read for each sample, at the level of 97% nucleotide sequence identity. A closed-reference OUT picking protocol with USEARCH against Greengenes database will be used. Taxonomy will be assigned using RDP classifier 2.4.	Up to 2.5 years

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Sumanta Pal, City of Hope Medical Center

Publications and helpful links

General Publications

• Dizman N, Hsu J, Bergerot PG, Gillece JD, Folkerts M, Reining L, Trent J, Highlander SK, Pal SK. Randomized trial assessing impact of probiotic supplementation on gut microbiome and clinical outcome from targeted therapy in metastatic renal cell carcinoma. Cancer Med. 2021 Jan;10(1):79-86. doi: 10.1002/cam4.3569. Epub 2020 Nov 1.

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2016
• Primary Completion (Actual): December 19, 2021
• Study Completion (Actual): December 19, 2021

Study Registration Dates

• First Submitted: July 27, 2016
• First Submitted That Met QC Criteria: October 24, 2016
• First Posted (Estimated): October 26, 2016

Study Record Updates

• Last Update Posted (Estimated): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Signs and Symptoms, Digestive; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Carcinoma; Diarrhea; Physiological Effects of Drugs; Micronutrients; Trace Elements
• Other Study ID Numbers: 16088 (City of Hope Medical Center); NCI-2016-01068 (Registry Identifier: CTRP (Clinical Trial Reporting Program))