Adding Biotherapy or Placebo to Standard Treatment for Advanced Kidney Cancer

Advanced Clear Cell Renal Cell Carcinoma, Metastatic Clear Cell Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8

This phase III trial compares the effect of adding live biotherapy, MO-03, to standard of care (SOC) immunotherapy, including ipilimumab, nivolumab, axitinib, pembrolizumab, cabozantinib, and lenvatinib, to SOC immunotherapy alone in treating patients with clear cell renal cell cancer that may have spread from where it first started (primary site) to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started to other places in the body (metastatic). Studies have shown that gut health (the gut microbiome) may impact the effectiveness of immunotherapy. The microbiome includes all of the bacteria and organisms naturally found in the digestive tract. MO-03, a type of biotherapy, contains material from living organisms that may help keep the digestive tract healthy and may help to increase the effect of immunotherapy. Immunotherapy with monoclonal antibodies, such as ipilimumab, nivolumab, pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Axitinib, cabozantinib, and lenvatinib are a type of angiogenesis inhibitor and tyrosine kinase inhibitor (TKI) that block certain proteins which may help keep tumor cells from growing and may also help prevent the growth of new blood vessels that tumors need to grow. Adding MO-03 to SOC immunotherapy may be more effective than SOC immunotherapy alone in treating patients with advanced or metastatic clear cell renal cell cancer.

PRIMARY OBJECTIVE: I. To compare investigator assessed progression-free survival of participants with advanced clear cell renal cell carcinoma (ccRCC) randomized to standard of care immunotherapy (IO)-based combination regimen plus placebo versus IO-based combination regimen plus clostridium butyricum CBM 588 probiotic strain (MO-03) in an intent-to-treat analysis. SECONDARY OBJECTIVES: I. For the safety run-in: To assess the safety of MO-03 when added to each of the following standard frontline treatment regimens for advanced renal cell carcinoma: cabozantinib/nivolumab, axitinib/pembrolizumab (MK-3475) and lenvatinib/pembrolizumab (MK-3475) in the first 50 randomized patients after receiving at least two cycles of treatment. II. To compare investigator assessed Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response (confirmed and unconfirmed complete response and partial response) between the study arms. III. To compare overall survival (OS) between the study arms. IV. To compare investigator assessed progression free survival (PFS) rates between the study arms at 12 months and at 24 months. V. To evaluate the qualitative and quantitative toxicities between the study arms. ADDITIONAL OBJECTIVES: I. To compare time to subsequent systemic therapy between the study arms. II. To evaluate the potential impact of concomitant medications, specifically antibiotics, proton pump inhibitors (PPI) and steroids, on the activity of MO-03 in combination with standard immune checkpoint inhibitors (ICI) based regimen. TRANSLATIONAL MEDICINE BANKING OBJECTIVE: I. To bank archival tissue, blood and stool samples for future contemporary translational studies. OUTLINE: Patients are randomized to 1 of 2 arms and are assigned to 1 of 4 regimens based on risk status. ARM 1: Patients receive MO-03 orally (PO) twice daily (BID) on days 1-42 of each cycle. Cycles repeat every 42 days for up to 3 years in the absence of disease progression or unacceptable toxicity. In addition, intermediate or poor-risk patients also receive SOC immunotherapy regimens 1, 2, 3, or 4 and favorable risk patients receive SOC immunotherapy regimens 2, 3, or 4. ARM 2: Patients receive placebo PO BID on days 1-42 of each cycle. Cycles repeat every 42 days for up to 3 years in the absence of disease progression or unacceptable toxicity. In addition, intermediate or poor-risk patients also receive SOC immunotherapy regimens 1, 2, 3, or 4 and favorable risk patients receive SOC immunotherapy regimens 2, 3, or 4. REGIMEN 1: Patients receive SOC ipilimumab intravenously (IV) over 30-90 minutes and nivolumab IV or nivolumab and recombinant human hyaluronidase subcutaneously (SC) every 21 days for up to 4 infusions in the absence of disease progression or unacceptable toxicity. After completing 4 infusions, patients continue to receive nivolumab IV or nivolumab and recombinant human hyaluronidase SC every 14 or 28 days in the absence of disease progression or unacceptable toxicity. REGIMEN 2: Patients receive SOC axitinib PO BID for up to 3 years in the absence of disease progression or unacceptable toxicity. Patients also receive SOC pembrolizumab IV every 21 or 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. REGIMEN 3: Patients receive SOC cabozantinib PO once daily (QD) for up to 3 years in the absence of disease progression or unacceptable toxicity. Patients also receive SOC nivolumab IV or nivolumab and recombinant human hyaluronidase SC every 14 or 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. REGIMEN 4: Patients receive SOC lenvatinib PO QD for up to 3 years in the absence of disease progression or unacceptable toxicity. Patients also receive SOC pembrolizumab IV every 21 or 42 days for up to 2 years in the absence of disease progression or unacceptable toxicity. All patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the study. Additionally, patients with suspected bone metastasis may undergo bone scan throughout the study and patients with suspected brain metastasis may undergo brain MRI throughout the study After completion of study treatment, patients are followed every 6 months for the first 2 years then once a year for years 3-5.

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