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

PRIMARY OBJECTIVES:

I. To determine the effect of 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.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over
60 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 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive CBM588 orally (PO) twice daily (BID), nivolumab IV over 60 minutes
on day 1, and ipilimumab IV over 60 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 CBM588 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:

- 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

- 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

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

- 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

- 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

- Grade 1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse
Events [CTCAE] version [v]4) or baseline before administration of study drug

- Women who are pregnant or breastfeeding

- 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)

- Serum creatinine > 1.5 x upper limit of normal (ULN)