A Study of Cemiplimab and Fianlimab in People With Clear Cell Renal Cell Carcinoma

Inclusion Criteria:

1. Age ≥ 18 years at the time of informed consent.

2. Patient must be able to provide informed consent, or a legal authorizedrepresentative (LAR) must be identified to provide consent in cases where thepatient cannot.

3. Signed and dated IRB-approved Informed Consent Form

4. Patients must be planned for nephrectomy for high risk non-metastatic clear cellrenal cell carcinoma.

• Non-metastatic disease will be defined by no evidence of metastases other thanregional lymphadenopathy as assessed by imaging of the chest, abdomen andpelvis with CT of the chest and MR of the abdomen/pelvis (CT abdomen/pelviswill suffice for those unable to undergo MR imaging).

• 'High-risk non-metastatic' is defined as those patients with a 12-yearprobability of metastases of ≥ 40% as per an established pre-operative nomogram

5. Patients must undergo baseline biopsy to confirm clear cell histology prior totreatment initiation.

6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance statusof 0 or 1

7. Patients must have adequate organ and bone marrow function, defined by the followinglaboratory results obtained within 14 days prior to the first study treatment: i. ANC ≥ 1500 cells/μL (without granulocyte colony stimulating factor support within 2 weeks prior to Cycle 1, Day 1) ii. WBC counts ≥ 2500/μL and ≤ 15,000/μL withoutG-CSF iii. Absolute Lymphocyte count ≥ 500/μL iv. Platelet count ≥100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1) v. Hemoglobin ≥9.0 g/dL (without transfusion within 2 weeks prior to Cycle 1, Day 1) vi. Alanineaminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 X upper limit of normal (ULN). ALP ≤ 5 x ULN if patient has documentedbone metastases.

vii. Serum bilirubin ≤ 1.5 x ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 2 x ULN may be enrolled.

viii. Creatinine ≤ 2.0 x ULN or Estimated Glomerular Filtration Rate (eGFR) ≥ 40mL/min using the CKD-EPI formula.

Exclusion Criteria:

1. Prior receipt of any systemic therapy for renal cell carcinoma.

2. Prior receipt of any immune checkpoint inhibitor therapy for any indication.

3. Inability to safely delay surgery by 9 weeks as per surgeon's discretion.

4. Patients who are receiving any other investigational agents.

5. History of allergic reactions or known hypersensitivity attributed to the activesubstances or to any of the excipients

6. History of severe hypersensitivity reaction to any monoclonal antibody.

7. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection requiring therapy, symptomatic congestive heart failure, unstable anginapectoris, or uncontrolled cardiac arrhythmia.

8. Patients with a history of myocarditis.

9. Patients with Troponin TnT or troponin I TnI > 2x institutional ULN at baseline.

° Patients with TnT or TnI levels between > 1 to 2x ULN are permitted if repeatlevels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are > 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered fortreatment by the investigator based on the medical judgement in the patient's bestinterest.

10. Patients with active autoimmune disease or recent history (within 2 years) ofautoimmune disease that might recur, which may affect vital organ function, orrequire immune suppressive treatment including systemic corticosteroids, should beexcluded. These include but are not limited to patients with a history of immunerelated neurologic disease, multiple sclerosis, autoimmune (demyelinating)neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune diseasesuch as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxicepidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndromeshould be excluded because of the risk of recurrence or exacerbation of disease.Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,residual hypothyroidism due to autoimmune condition only requiring hormonereplacement, psoriasis not requiring systemic treatment, or conditions not expectedto recur in the absence of an external trigger (precipitating event).

11. Patients should be excluded if they have a condition requiring systemic treatmentwith either corticosteroids or other immunosuppressive medications within 14 days ofstudy drug administration. Patients are permitted to use topical, ocular,intra-articular, intranasal, and inhalational corticosteroids (with minimal systemicabsorption). A brief course of corticosteroids for prophylaxis (e.g., contrast dyeallergy) or for treatment of non-autoimmune conditions (e.g., delayed-typehypersensitivity reaction caused by contact allergen) is permitted.

12. Diagnosis of another malignancy within 2 years before first dose of study treatment,except for superficial skin cancers, or localized, low grade tumors deemed cured andnot treated with systemic therapy.

13. Prior allogeneic stem cell transplant or solid organ transplant.

14. History or current evidence of significant (CTCAE grade ≥2) local or systemicinfection (eg, cellulitis, pneumonia, septicemia) requiring systemic antibiotictreatment within 2 weeks prior to the first dose of trial medication.

15. Use of live vaccines against infectious disease (e.g. varicella) within 30 days ofinitiation of study therapy. Killed vaccinations (e.g. influenza) are allowed at anyappropriate time before and during the study. If a patient intends to receive aCOVID19 vaccine before the start of study drug, participation in the study should bedelayed at least 1 week after any COVID-19 vaccination. During the treatment period,it is recommended to delay COVID-19 vaccination until patients are receiving andtolerating a steady dose of study drug. A vaccine dose should not be less than 48hours before or after study drug dosing.

16. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B orhepatitis C virus (HBV or HCV) infection; or diagnosis of immunodeficiency that isrelated to, or results in chronic infection.

• Patients with known HIV infection who have controlled infection (undetectableviral load on HIV RNA PCR) and CD4 count above 350 (either spontaneously or ona stable antiviral regimen) are permitted. For patients with controlled HIVinfection, monitoring will be performed per local standards.

• Patients with HBV (hepatitis B surface antigen positive; HBsAg+) who havecontrolled infection (serum HBV DNA PCR that is below the limit of detectionand receiving anti-viral therapy for HBV) are permitted. Patients withcontrolled infections must undergo periodic monitoring of HBV DNA. Patientsmust remain on anti-viral therapy for at least 6 months after the last dose ofcemiplimab.

• Patients who are HCV antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR, either spontaneously or in response to successfulprior course of anti-HCV therapy) are permitted.

• Patients with HIV or hepatitis must be reviewed by a qualified specialist (eg,infectious disease or hepatologist) managing this disease prior to commencingand regularly throughout the duration of their participation in the trial

17. Women with a positive serum beta-hCG pregnancy test at screening/baseline visit. Ifpositive, pregnancy must be ruled out by ultrasound for patient to be eligible.

18. Breast-feeding women.

19. Women of childbearing potential (WOCBP) who are sexually active and are not willingto practice highly effective contraception prior to the first treatment, during thestudy, and for at least 6 months after the last dose. Highly effective contraceptivemeasures include:

• stable use of combined (estrogen and progestogen containing) hormonalcontraception (oral, intravaginal, transdermal) or progestogen-only hormonalcontraception (oral, injectable, implantable) associated with inhibition ofovulation initiated 2 or more menstrual cycles prior to screening;

• intrauterine device; intrauterine hormone-releasing system;

• bilateral tubal occlusion/ligation;

• vasectomized partner (provided that the male vasectomized partner is the solesexual partner of the WOCBP study participant and that the vasectomized partnerhas obtained medical assessment of surgical success for the procedure); and/or

• sexual abstinence - Sexual abstinence is considered a highly effective methodonly if defined as refraining from heterosexual intercourse during the entireperiod of risk associated with the study drugs. The reliability of sexualabstinence needs to be evaluated in relation to the duration of the clinicaltrial and the preferred and usual lifestyle of the subject.

20. Male study participants with WOCBP partners are required to use condoms during thestudy and until 6 months after the last dose of study treatment unless they arevasectomized or practice sexual abstinence.

21. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assistedreproduction during the entire trial and until 6 months after last treatment.

22. All men must agree not to donate sperm during the trial and for 6 months afterreceiving the last therapy dose.