CBM588 Capsules in Combination With Nivolumab and Ipilimumab for the Treatment of Advanced Stage Kidney Cancer

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Assent, when appropriate, will be obtained per institutional guidelines

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies

• If unavailable, exceptions may be granted with study principle investigator (PI) approval

• Eastern Cooperative Oncology Group (ECOG) ≤ 2

• Age ≥ 18 years

• Histologically confirmed renal cell carcinoma with clear cell renal cell carcinomacomponent or sarcomatoid component

• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer [AJCC] stage IV) renal cell carcinoma withintermediate- or poor-risk disease by International Metastatic Renal Cell CarcinomaDatabase Consortium (IMDC) criteria

• No prior systemic therapy for renal cell carcinoma (RCC) with the followingexception:

• One prior adjuvant or neoadjuvant therapy for completely resectable RCC ifrecurrence occurred at least 6 months after the last dose of adjuvant orneoadjuvant therapy

• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

• Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prioranti-cancer therapy

• Absolute neutrophil count (ANC) ≥ 1500/uL without granulocyte colony-stimulatingfactor support

• White blood cell count ≥ 2500/uL

• Platelets ≥ 100,000/uL without transfusion

• Hemoglobin ≥ 8 g/dL

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP) ≤ 3 x upper limit of normal (ULN). ALP ≤ 5 x ULN with documentedbone metastases

• Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN)

• Serum albumin ≥ 2.8 g/dl

• Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastintime (PTT) test < 1.3 x the laboratory ULN

• Serum calculated creatinine clearance ≥ 50mL/min using the Cockcroft-Gault equation

• Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 5 months after the last dose of nivolumab for women with childbearing potential,and 7 months after the last dose of nivolumab for men

• Female subjects of childbearing potential must not be pregnant at screening. Femalesubjects are considered to be of childbearing potential unless one of the followingcriteria is met: documented permanent sterilization (hysterectomy, bilateralsalpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence ofother biological or physiological causes. In addition, females < 55 years-of-agemust have a serum follicle stimulating (FSH) level > 40 mIU/mL to confirmmenopause).

• Note: Documentation may include review of medical records, medicalexaminations, or medical history interview by study site

Exclusion Criteria:

• Prior treatment with ipilimumab and/or nivolumab

• Current use, or intent to use, probiotics, yogurt, or bacterial fortified foodsduring the period of treatment

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to study agent

• Active interstitial lung disease (ILD)/pneumonitis or history of ILD/pneumonitisrequiring treatment with systemic steroids

• Known medical condition (e.g., a condition associated with diarrhea or acutediverticulitis) that, in the investigator's opinion, would increase the riskassociated with study participation or study drug administration or interfere withthe interpretation of safety results

• Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment

• Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible

• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksprior to first dose of study treatment after radiotherapy or at least 4 weeks priorto first dose of study treatment after major surgery (e.g., removal or biopsy ofbrain metastasis). Subjects must have complete wound healing from major surgery orminor surgery before first dose of study treatment. Eligible subjects must beneurologically asymptomatic and without corticosteroid treatment at the time offirst dose of study treatment

• Administration of a live, attenuated vaccine within 30 days before first dose ofstudy treatment

• The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions:

• Any condition requiring systemic treatment with either corticosteroids (> 10 mgdaily prednisone equivalent) or other immunosuppressive medications within 14days before first dose of study treatment. Note: Inhaled, intranasal,intra-articular, or topical steroids are permitted. Adrenal replacement steroiddoses ≤ 10 mg daily prednisone equivalent are permitted. Transient short-termuse of systemic corticosteroids for allergic conditions (e.g., contrastallergy) is also allowed

• Active infection requiring systemic treatment. Acute or chronic hepatitis B orC infection, known human immunodeficiency virus (HIV) or acquiredimmunodeficiency syndrome (AIDS)-related illness requiring systemic treatments,or known positive test for tuberculosis infection where there is clinical orradiographic evidence of active mycobacterial infection

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis onscreening chest CT scan

• Malabsorption syndrome

• Uncompensated/symptomatic hypothyroidism

• Moderate to severe hepatic impairment (Child-Pugh B or C)

• Requirement for hemodialysis or peritoneal dialysis

• History of solid organ or allogenic stem cell transplant

• Other clinically significant disorders that would preclude safe studyparticipation

• Any active, known, or suspected autoimmune disease will be excluded, withthe following exceptions:

• Type 1 diabetes mellitus

• Hypothyroidism only requiring hormone replacement

• Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiringsystemic treatment

• Conditions not expected to recur in the absence of an externaltrigger

• Pregnant or lactating females

• Inability to swallow tablets/capsules or unwillingness or inability to receive IVadministration

• Previously identified allergy or hypersensitivity to components of the studytreatment formulations or history of severe infusion-related reactions to monoclonalantibodies. Subjects with rare hereditary problems of galactose intolerance, theLapp lactase deficiency or glucose-galactose malabsorption are also excluded

• Any other active malignancy at time of first dose of study treatment or diagnosis ofanother malignancy within 3 years prior to first dose of study treatment thatrequires active treatment, except for locally curable cancers that have beenapparently cured, such as basal or squamous cell skin cancer, superficial bladdercancer, or carcinoma in situ of the prostate, cervix, or breast

• Exclusion of subjects with a history of myocarditis or congestive heart failure (asdefined by New York Heart Association Functional Classification III or IV), as wellas unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection,or myocardial infarction 6 months prior to study entry

• Exclusion of subjects whose baseline pulse oximetry is less than 92% on room air

• Any other condition that would, in the investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)