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CBM588, Nivolumab, and Ipilimumab in Treating Patients With Stage IV or Advanced Kidney Cancer

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: NCT03829111
Recruitment Status : Active, not recruiting
First Posted : February 4, 2019
Last Update Posted : January 2, 2024
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Study Description
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Brief Summary:
This phase I trial studies how well CBM588 works when given together with nivolumab and ipilimumab in treating patients with kidney cancer that is stage IV or has spread to other places in the body (advanced). CBM588 is a probiotic that may help to increase the effect of immunotherapy. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving CBM588, nivolumab, and ipilimumab may work better in treating patients with kidney cancer.

Condition or disease Intervention/treatment Phase
Advanced Renal Cell Carcinoma Clear Cell Renal Cell Carcinoma Metastatic Renal Cell Carcinoma Stage III Renal Cell Cancer AJCC v8 Stage IV Renal Cell Cancer AJCC v8 Unresectable Renal Cell Carcinoma Drug: Clostridium butyricum CBM 588 Probiotic Strain Biological: Ipilimumab Biological: Nivolumab Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the effect of clostridium butyricum CBM 588 probiotic strain (CBM588) (in combination with nivolumab/ipilimumab) on the gut microbiome in patients with metastatic renal cell carcinoma (mRCC).

SECONDARY OBJECTIVES:

I. To evaluate the effect of CBM588 on the clinical efficacy of the nivolumab/ipilimumab combination.

II. To assess the effect of CBM588 on systemic immunomodulation of the nivolumab/ipilimumab combination in patients with mRCC.

III. To assess the effect of CBM588 on toxicities such as diarrhea and nausea using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 criteria with the nivolumab/ipilimumab combination in patients with mRCC.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive clostridium butyricum CBM 588 probiotic strain orally (PO) twice daily (BID), nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, treatment with clostridium butyricum CBM 588 probiotic strain and nivolumab repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and periodically thereafter.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study to Evaluate the Biologic Effect of CBM588 in Combination With Nivolumab/Ipilimumab for Patients With Metastatic Renal Cell Carcinoma
Actual Study Start Date : May 14, 2019
Estimated Primary Completion Date : June 11, 2024
Estimated Study Completion Date : June 11, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Arm I (nivolumab, ipilimumab)
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
 Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
Experimental: Arm II (CBM588, nivolumab, ipilimumab)
Patients receive clostridium butyricum CBM 588 probiotic strain PO BID, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, treatment with clostridium butyricum CBM 588 probiotic strain and nivolumab repeats every 28 days in the absence of disease progression or unacceptable toxicity.
 Drug: Clostridium butyricum CBM 588 Probiotic Strain
Given PO
Other Names:
  • C. butyricum CBM 588 Probiotic Strain
  • C. butyricum MIYAIRI Strain
  • C. butyricum Strain MIYAIRI 588
  • CBM 588
  • CBM588
  • Clostridium butyricum MIYAIRI 588
  • Clostridium butyricum MIYAIRI 588 Probiotic Strain
  • MIYAIRI 588
  • MIYAIRI 588 Strain of C. butyricum

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo


Outcome Measures
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Primary Outcome Measures :
  1. Change in Bifidobacterium composition of stool [ Time Frame: Baseline up to week 12 ]
    Will be assessed for patients on both arms.


Secondary Outcome Measures :
  1. Change in Shannon index [ Time Frame: Baseline up to week 12 ]
    Using translational methods, will compute the Shannon index at baseline for a comparison of microbial diversity.

  2. Best overall response [ Time Frame: Up to 2 years ]
    Will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST). The association between treatment arm and overall response as per RECIST criteria (response observed versus [vs] not observed) will be examined using Fisher's exact test.

  3. Progression-free survival (PFS) [ Time Frame: From enrollment to progression, assessed up to 2 years ]
    The difference in progression free survival across the two groups will be explored graphically using Kaplan-Meier survival plots. Median PFS time for each of the two arms will be reported and Cox proportional hazards model will be used to estimate the hazard ratio and its confidence interval.


Other Outcome Measures:
  1. Change in proportion of circulating regulatory T-cells (Tregs) [ Time Frame: Baseline up to 2 years ]
    Using translational methods will estimate the proportion of Tregs in the blood. This will be assessed graphically across serial timepoints of blood collection to ascertain any trends. Will compare the proportion of circulating Tregs with nivolumab/ipilimumab alone versus nivolumab/ipilimumab with clostridium butyricum CBM 588 probiotic strain (CBM588).

  2. Change in proportion of circulating myeloid-derived suppressor cells (MDSCs) [ Time Frame: Baseline up to 2 years ]
    Using translational methods will estimate the proportion of MDSCs in the blood. This will be assessed graphically across serial timepoints of blood collection to ascertain any trends. Will compare the proportion of circulating MDSCs with nivolumab/ipilimumab alone versus nivolumab/ipilimumab with CBM588.

  3. Change in IL-6, IL-8, and other cytokines/chemokines levels [ Time Frame: Baseline up to 2 years ]
    Using translational methods will estimate the proportion of serum cytokines in the blood. This will be assessed graphically across serial timepoints of blood collection to ascertain any trends. Will compare the IL-6, IL-8, and other cytokines/chemokines with nivolumab/ipilimumab alone versus nivolumab/ipilimumab with CBM588.

  4. Change in toxicities [ Time Frame: Baseline up to 2 years ]
    Will compare toxicities, such as diarrhea and nausea, using Common Terminology Criteria for Adverse Events version 5 with nivolumab/ipilimumab alone versus nivolumab/ipilimumab with CBM588.


Eligibility Criteria
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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:

  • Be willing and able to provide informed consent for the trial
  • Histological confirmation of RCC with a clear-cell component
  • Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer [AJCC] stage IV) RCC
  • Intermediate or poor risk disease by International Metastatic RCC Database Consortium (IMDC) classification

  • No prior systemic therapy for RCC with the following exception:

    • One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets PD-1 or PD-L1 and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2
  • Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Any ethnicity or race
  • Calculated creatinine clearance >= 30 milliliters per minute (mL/min) per the Cockcroft and Gault formula or serum creatinine < 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN if liver metastases are present)
  • Total bilirubin < 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin up to 3.0 mg/dL)
  • White blood cells (WBC) > 2,000/mm^3
  • Neutrophils > 1,500/mm^3
  • Platelets > 100,000/mm^3

Exclusion Criteria:

  • Presence of untreated brain metastases. Patients with treated brain metastases must be stable for 4 weeks after completion of treatment and have documented stability on pre-study imaging. Patients must have no clinical symptoms from brain metastases and have no requirement for systemic corticosteroids amounting to > 10 mg/day of prednisone or its equivalent for at least 2 weeks prior to first dose of study drug. Patients with known leptomeningeal metastases are excluded, even if treated

    • Not recovered to =< grade 1 toxicities related to any prior therapy before administration of study drug
  • Favorable risk disease by IMDC classification
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
  • Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll
  • Active interstitial lung disease (ILD)/pneumonitis or history of ILD/pneumonitis requiring treatment with systemic steroids
  • Baseline pulse oximetry less than 92% "on room air"
  • Current use, or intent to use, probiotics, yogurt or bacterial fortified foods during the period of treatment
  • Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  • Uncontrolled adrenal insufficiency
  • Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results
  • Not recovered to =< grade 1 toxicities related to any prior therapy before administration of study drug
  • Women who are pregnant or breastfeeding
  • History of myocarditis or congestive heart failure (as defined by New York Heart Association functional classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction 6 months prior to study entry
  • White blood cells (WBC) < 2,000/mm^3
  • Neutrophils < 1,500/mm^3
  • Platelets < 100,000/mm^3
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) (> 5 x ULN if liver metastases are present)
  • Total bilirubin > 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin 3.0 mg/dL)
  • Calculated creatinine clearance < 30 millimeters per minute (mL/min) per the Cockcroft and Gault formula or serum creatinine > 1.5 x upper limit of normal (ULN)
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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): NCT03829111


Locations
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United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Sumanta K Pal City of Hope Medical Center
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03829111    
Other Study ID Numbers: 18523
NCI-2019-00248 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
18523 ( Other Identifier: City of Hope Comprehensive Cancer Center )
P30CA033572 ( U.S. NIH Grant/Contract )
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: January 2, 2024
Last Verified: December 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Female Urogenital Diseases
 Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Kidney Diseases
Urologic Diseases
Male Urogenital Diseases
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action