Phase 1b/2 Trial of Ipilimumab, Nivolumab, and Ciforadenant (Adenosine A2a Receptor Antagonist) in First-line Advanced Renal Cell Carcinoma.

Inclusion Criteria:

Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:

1. Willing and able to provide a signed and dated written informed consent

2. Male or female ≥ 18 years of age

3. Confirmed diagnosis of clear cell RCC

4. Stage IV metastatic renal cell carcinoma per American Joint Committee on Cancer

5. No prior systemic therapy for advanced RCC

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 2)

7. At least one measureable lesion as defined by RECIST 1.1

• A tumor lesion situated in a previously irradiated area is considered ameasureable/target lesion only if subsequent disease progression has been documentedin the lesion

8. Has submitted an archival tumor tissue sample or newly obtained core or incisionalbiopsy of a tumor lesion not previously irradiated. Formalin-fixed parrafin-embeddedtissue blocks are preferred to slides. Newly obtained biopsies are preferred toarchived tissue but not necessary. Details pertaining to tumor tissue submission canbe found in the Lab Procedures Manual

9. Willing and able to under go bone and brain scans at baseline and continue to havescans performed if positive at screening.

10. Adequate organ function within 21 days prior to first dose of protocol-indicatedtreatment, including:

• White blood cell (WBC) ≥ 2,000 /µL

• Absolute neutrophil count (ANC) ≥ 1,500/µL

• Platelets ≥ 100,000/µL

• Hemoglobin (Hgb) ≥ 9.0 g/d without requirement for transfusion in prior 4 weeks

• Serum creatinine ≤ 2 times institutional upper limit of normal (ULN), orcalculated creatinine clearance ≥ 40 mL/min (per the Cockcroft-Gault formula,Appendix 3)

• Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who musthave total bilirubin < 3.0 mg/dL)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN

11. Women must not be breastfeeding while taking the study drug and for up to fivemonths after the last dose of study drug

12. Women of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test within 24 hours prior to receiving first dose of protocol-indicatedtreatment

• "Women of childbearing potential" (WOCBP) is defined as any female who hasexperienced menarche who has not undergone surgical sterilization (hysterectomyor bilateral oophorectomy) or is not postmenopausal

• Menopause is defined clinically as 12 months of amenorrhea in a woman over 45years of age in the absence of other biological or physiological causes

• If menopausal status is considered for the purpose of evaluating childbearingpotential, women < 62 years of age must have a documented serum folliclestimulating hormone (FSH) level within laboratory reference range forpostmenopausal women, in order to be considered postmenopausal and not ofchildbearing potential

13. Women of childbearing potential (WOCBP) must agree to follow instructions foracceptable contraception Appendix 4 from the time of signing consent, and for 23weeks after their last dose of protocol-indicated treatment

14. Men not azoospermic who are sexually active with WOCBP must agree to followinstructions for acceptable contraception (Appendix 4), from the time of signingconsent, and for 31 weeks after their last dose of protocol-indicated treatment

Exclusion Criteria:

Patients meeting any of the following criteria will be excluded from the trial:

1. Prior systemic treatment including neoadjuvant or adjuvant therapy <6 months fromprotocol initiation is not allowed including an immune checkpoint inhibitor or TKI

2. ≤ 28 days before first dose of protocol-indicated treatment:

• Major surgery requiring general anesthesia

• Suspected or confirmed SARS-CoV-2 infection

3. ≤ 14 days before first dose of protocol-indicated treatment:

• Radiosurgery or radiotherapy

• Minor surgery. (Note: Placement of a vascular access device is not consideredminor or major surgery)

• Active infection requiring infusional treatment

4. Known or suspected clinically significant active bleeding including activehemoptysis

5. Inability to swallow oral medication; or the presence of a poorly controlledgastrointestinal disorder that could significantly affect the absorption of oralstudy drug - e.g. Crohn's disease, ulcerative colitis, chronic diarrhea (defined as > 4 loose stools per day), malabsorption, or bowel obstruction

6. Central nervous system (CNS) metastasis, unless asymptomatic and stable with imagingof the head by MRI unless contraindicated for the patient in which case CT isacceptable showing no change in CNS disease status for at least two (2) weeks priorto initiating protocol-indicated treatment

7. Any condition requiring systemic treatment with either corticosteroids (> 10 mg/dayprednisone or equivalent daily) or other immunosuppressive medications within 14days prior to initiating protocol-indicated treatment

• In the absence of active autoimmune disease: Subjects are permitted the use ofcorticosteroids with minimal systemic absorption (e.g. topical, ocular,intra-articular, intranasal, and inhalational) ≤ 10 mg/day prednisone or equivalentdaily; and physiologic replacement doses of systemic corticosteroids ≤ 10 mg/dayprednisone or equivalent daily (e.g. hormone replacement therapy needed in patientswith hypophysitis)

8. Active, known or suspected autoimmune disease

• Subjects with type I diabetes mellitus; hypothyroidism only requiring hormonereplacement; skin disorders such as vitiligo, psoriasis or alopecia not requiringsystemic treatment; or conditions not expected by the investigator to recur in theabsence of an external trigger are permitted to enroll

9. Known psychiatric condition, social circumstance, or other medical conditionreasonably judged by the investigator to unacceptably increase the risk of studyparticipation; or to prohibit the understanding or rendering of informed consent oranticipated compliance with and interpretation of scheduled visits, treatmentschedule, laboratory tests and other study requirements