Dose Finding Study of CBM588 in Combination With Nivolumab/Ipilimumab in Advanced Stage Renal Cell Carcinoma

Inclusion Criteria:

Informed Consent and Willingness to Participate

1. Documented informed consent of the participant and/or legally authorizedrepresentative.

2. Agreement to allow the use of archival tissue from diagnostic tumor biopsies AgeCriteria, Performance status

3. ECOG ≤ 2

4. Age ≥ 18 years Nature of Illness and Illness Related Criteria

5. Histologically confirmed renal cell carcinoma with clear cell renal cell carcinomacomponent or sarcomatoid component.

6. Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCCStage IV) renal cell carcinoma with intermediate- or poor-risk disease by IMDCcriteria

7. No prior systemic therapy for RCC with the following exception: i. One prior adjuvant or neoadjuvant therapy for completely resectable RCC ifrecurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvanttherapy.

8. Measurable disease by RECIST 1.1

9. Fully recovered from the acute toxic effects (except alopecia) to ≤ Grade 1 to prioranti-cancer therapy Clinical Laboratory and Organ Function Criteria

10. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulatingfactor support.

11. White blood cell count ≥ 2500/µL.

12. Platelets ≥ 100,000/µL without transfusion.

13. Hemoglobin ≥ 8 g/dL

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

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

16. Serum albumin ≥ 2.8 g/dl.

17. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN

18. Serum calculated creatinine clearance ≥ 50mL/min using the Cockcroft-Gault equation:i. Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72) ii. Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 Contraception

19. 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.

20. 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).

Exclusion Criteria:

Prior and concomitant therapies and supplements

1. Prior treatment with ipilimumab and/or nivolumab

2. Current use, or intent to use, probiotics, yogurt, or bacterial fortified foodsduring the period of treatment. Other illnesses or conditions

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

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

5. 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.

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

7. 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.

8. 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 or minor surgery beforefirst dose of study treatment. Eligible subjects must be neurologically asymptomaticand without corticosteroid treatment at the time of first dose of study treatment.

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

10. The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions: i. Any condition requiring systemictreatment with either corticosteroids (> 10 mg daily prednisone equivalent) or otherimmunosuppressive medications within 14 days before first dose of study treatment.Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted.Adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent are permitted.Transient short-term use of systemic corticosteroids for allergic conditions (e.g.,contrast allergy) is also allowed. ii. Active infection requiring systemictreatment. Acute or chronic hepatitis B or C infection, known human immunodeficiencyvirus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness requiringsystemic treatments, or known positive test for tuberculosis infection where thereis clinical or radiographic evidence of active mycobacterial infection. iii. Historyof idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis,idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CTscan. iv. Malabsorption syndrome. v. Uncompensated/symptomatic hypothyroidism. vi.Moderate to severe hepatic impairment (Child-Pugh B or C). vii. Requirement forhemodialysis or peritoneal dialysis. viii. History of solid organ or allogenic stemcell transplant ix. Other clinically significant disorders that would preclude safestudy participation: 1). Any active, known, or suspected autoimmune disease will beexcluded, with the following exceptions:

11. Type 1 diabetes mellitus.

12. Hypothyroidism only requiring hormone replacement.

13. Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemictreatment.

14. Conditions not expected to recur in the absence of an external trigger.

15. Pregnant or lactating females.

16. Inability to swallow tablets/capsules or unwillingness or inability to receive IVadministration.

17. 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, the Lapp lactasedeficiency or glucose-galactose malabsorption are also excluded.

18. 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.

19. 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.

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

21. 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. Noncompliance

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