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