Adding a Live Biotherapeutic Product (CBM588) to Pembrolizumab for the Treatment of Renal Cell Cancer After Surgery

PRIMARY OBJECTIVE:

I. To determine if the Clostridium butyricum CBM588 strain (CBM588) increases interleukin (IL)-12 production in patients with high-risk, resected renal cell carcinoma (RCC) receiving pembrolizumab.

SECONDARY OBJECTIVES:

I. To determine if CBM588 improves recurrence-free survival (RFS) in patients with high-risk, resected renal cell carcinoma (RCC) receiving pembrolizumab.

II. To determine if CBM588 improves overall survival (OS) in patients with high-risk, resected renal cell carcinoma (RCC) receiving pembrolizumab.

III. To characterize global changes in stool microbiome profile in patients with high-risk, resected RCC receiving pembrolizumab with or without CBM588.

IV. To characterize changes in circulating cytokine and immune cell populations in patients with high-risk, resected RCC receiving pembrolizumab with or without CBM588.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive CBM588 orally (PO) twice daily (BID) on days 1-21 or days 1-42 of each cycle and pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 21 or 42 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples and computed tomography (CT) throughout the study.

ARM 2: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 or 42 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples and CT throughout the study.

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

Inclusion criteria

• Be willing and able to provide informed consent for the trial
• Histological confirmation of renal cell carcinoma (RCC) with a clear-cell or sarcomatoid component
• Pathologic stage of pT2, G4 or sarcomatoid, N0M0; pT3, any grade, N0M0; pT4, any grade, N0M0; pTany, any grade, N+M0; or M1 no evidence of disease (NED) after resection
• No prior systemic immunotherapy for RCC
• Eastern Cooperative Oncology Group (ECOG) performance status < 2
• Males and females, ages ≥ 18
• 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)
• Adequate bone marrow function defined by any of the following laboratory test findings: white blood cells (WBC) > 2,000/mm^3, neutrophils > 1,500/mm^3, platelets > 100,000/mm^3
• Female subjects of child-bearing potential and female partners of male subjects must agree to use a highly effective method of contraception during treatment and for at least 5 months after the last dose

• Highly effective methods of contraception include: tubal ligation, an approved hormonal contraceptive such as oral contraceptives, patches, implants, injections, rings or hormonally impregnated intrauterine device (IUD), or IUD

Exclusion criteria

• Prior radiation or anti-PD1, anti-PDL1, or anti-CTLA-4 therapy for RCC
• 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, prebiotics, yogurt, bacterial fortified foods and other natural supplements ≤ 2 weeks prior to treatment initiation and 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