Phase III Double-Blinded Trial of Immune-Based Therapy with a Live Biotherapeutic MO-03 or Placebo for Frontline Therapy of Advanced Clear Cell Renal Cell Carcinoma.

Inclusion Criteria: - Participants must have histologically confirmed renal cell carcinoma (RCC) with clear cell component that is advanced (not amenable to curative surgery or radiation therapy) or metastatic RCC at the time of registration on study - Participants must have measurable/evaluable disease by RECIST 1.1 criteria. Participants with only bone metastases or only pleural effusions are considered evaluable disease and are eligible - Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease must not require immediate central nervous system (CNS) specific treatment at the time of study registration or anticipated treatment during the first cycle of therapy - Participants must not be currently enrolled or plan to participate in treatment studies while enrolled on this study - Participants must not plan to take any over the counter probiotic supplements at time of study registration and while on protocol treatment - NOTE: Vitamin and electrolyte or mineral supplements are permitted - Participants must not have had prior systemic therapy for advanced or metastatic RCC or any treatment with immune based combination therapy - NOTE: Participants can have prior neo/adjuvant treatment with an anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 antibody or other therapies for any current or prior malignancy if > 12 months prior to registration - Participants must not be receiving steroid replacement therapy for adrenal insufficiency greater than 50 mg daily of hydrocortisone or prednisone equivalent dose at the time of registration - Participants must not require the use of systemic corticosteroids > 10 mg/day of prednisone or its equivalent for any reason other than replacement therapy for adrenal insufficiency - Participants must not have received any systemic antibiotics within 7 days prior to registration - NOTE: Uncontrolled infections must be completely resolved - Participants must be ≥ 18 years old at the time of registration - Participants must have a Zubrod performance status 0-2 within 28 days of registration - Participants must be able to safely receive at least one of the standard of care regimens, per the current Food and Drug Administration (FDA)-approved package inserts, treating investigator's discretion, and institutional guidelines - NOTE: Participants with favorable risk as defined by the International Metastatic RCC Database Consortium (IMDC) must plan to receive one of the TKI+ immunotherapy treatment combinations. They are not able to receive regimen 1 (ipilimumab + nivolumab) for this study - Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications - Participants must have serum creatinine ≤ 2 x ULN (upper limit of normal). This specimen must have been drawn and processed within 28 days prior to registration - Hemoglobin ≥ 8 g/dL (within 28 days prior to registration) - Leukocytes ≥ 3 x 10^3/uL (within 28 days prior to registration) - Absolute neutrophil count ≥ 1.5 x 10^3/uL (within 28 days prior to registration) - Platelets ≥ 100 x 10^3/uL (within 28 days prior to registration) - Total bilirubin ≤ institutional upper limit of normal (ULN) unless history of Gilbert's disease (within 28 days prior to registration) Participants with history of Gilbert's disease must have total bilirubin ≤ 5 x institutional ULN - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x institutional ULN (< 5 x institutional ULN if liver metastases are present) (within 28 days prior to registration) - Participants must have alkaline phosphate measured as a part of the liver function assessment within 28 days prior to registration - Participants must have albumin corrected calcium measured within 28 days prior to registration - Participants with a history human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load on the most recent test results obtained within 6 months prior to registration - Participants with a history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration - Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration - Participants must not have uncontrolled blood pressure and hypertension within 28 days prior to registration - Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen - Participants must not have any known history of an autoimmune disease that prohibits the use of immune checkpoint therapy - Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen - Participants must be offered the opportunity to participate in specimen banking - Participants who have the ability to complete questionnaires in English or Spanish must be offered the opportunity to participate in the patient-reported outcome study - NOTE: As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system. - Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines - For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations