Phase II Trial of Immunotherapy in Patients With Carcinomas Arising From the Renal Medulla

Inclusion Criteria:

1. Patients with locally advanced or metastatic RMC histologically confirmed by expertpathology review and loss of SMARCB1 staining by immunohistochemistry. Patients withadvanced or metastatic unclassified renal cell carcinoma with medullary phenotype (arare SMARCB1 negative RMC variant occurring in individuals without sicklehemoglobinopathies) are also eligible.

2. Patients will be eligible regardless of whether they have had prior nephrectomy orstill have their primary tumor in-situ.

3. Patients must have at least one measurable site of disease, defined as a lesion thatcan be accurately measured in at least one dimension (longest diameter to berecorded) and measures ≥ 15 mm with conventional techniques or ≥ 10 mm with moresensitive techniques such as MRI or CT scan. If the patient has had previousradiation to the marker lesion(s), there must be evidence of progression since theradiation.

4. Patients should be willing to provide a newly obtained fresh core biopsy of a tumorlesion. Not required if there is a recently obtained fresh specimen on an IRBapproved correlated trial up to 6 weeks (42 days) prior to initiation of treatmenton Day 1.

5. Patients can be either naïve for any previous systemic treatment or have had anynumber of prior systemic therapies. However, patients must not have received prioranticancer therapy with antiPD1, anti-PD-L1, anti-CTLA-4, or anti-LAG-3 immunecheckpoint inhibitors.

6. There must be evidence of progression on or after last treatment regimen received.

7. ECOG performance status 0-2 o NOTE: If subject is unable to walk due to paralysis, but is mobile in awheelchair, subject is considered to be ambulatory for the purpose of assessingtheir performance status.

8. Age (at the time of consent/assent): ≥ 18 years

9. Consent to MD Anderson companion laboratory protocol 2014-0938

10. Within 14 days of the first dose of the study drugs (cycle 1 day 1), patients musthave adequate organ and marrow function as defined below:

• Hemoglobina ≥9 g/dl (treatment allowed)

• Absolute neutrophil countb ≥1,000/µL

• Platelets ≥75,000/µL

• total bilirubin ≤ 1.5 mg/dl

• AST(SGOT) or ALT (SGPT) ≤ 2.5 X institutional ULN, except in known hepaticmetastasis, wherein may be ≤ 5 x ULN

• Serum Creatininec ≤ 1.5 x ULN by gender (as long as patient does not requiredialysis) aMay receive transfusion b Without growth factor support (filgrastimor pegfilgrastim) for at least 14 days c If creatinine is not <1.5×ULN, thencalculate by Cockcroft-Gault methods or local institutional standard and CrClmust be >30 mL/kg/1.73 m2 11 INR and PTT ≤ 1.5 x ULN prior to registration fortreatment. Therapeutic anticoagulation with warfarin is allowed if target INR ≤ 3 on a stable dose of warfarin or on a stable dose of low molecular weight (LMW) heparin for > 2 weeks (14 days) at the time of registration fortreatment. 12 Patients with controlled brain metastases are allowed on protocol if theyhad solitary brain metastases that was surgically resected or treated withradiosurgery or Gamma knife, without recurrence or edema for 1 month (4 weeks). 13 Women of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of the study drug. 14 Women must not bebreastfeeding. 15 WOCBP must agree to follow instructions for method(s) ofcontraception from the time of registration for treatment for the duration oftreatment with study drug (s) plus 5 half-lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post treatmentcompletion. Men must agree to effective contraception from the time ofregistration for treatment to 7 months post last treatment with nivolumab. 16WOCBP who are continuously not heterosexually active are exempt fromcontraceptive requirements. However, WOCBP must still undergo pregnancy testingas described in these sections.

Exclusion Criteria:

1. Patients must not have any other malignancies within the past 2 years except for insitu carcinoma of any site, or adequately treated (without recurrence post-resectionor post-radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomasof the skin.

2. Patients currently receiving anticancer therapies or who have received anticancertherapies (including chemotherapy and targeted therapy) within 2 weeks (14 days)prior to study Day 1 are excluded. Patients who have completed palliative radiationtherapy more than 14 days prior to the first dose of the combination immunotherapyare eligible.

3. Patients with persistent grade ≥2 adverse events from prior systemic therapies thatwould confound timely detection of immune-related adverse events or otherwise hinderpatient participation in the clinical trial.

4. Patients, who have had a major surgery or significant traumatic injury (injuryrequiring > 4 weeks (28 days) to heal) within 4 weeks (28 days) of start of studydrug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that are expected to requiremajor surgery, other than cytoreductive nephrectomy ± retroperitoneal lymph nodedissection, during the course of the study.

5. Patients who have organ allografts.

6. Known or suspected autoimmune disease. Patients with a history of inflammatory boweldisease (including Crohn's disease and ulcerative colitis) and autoimmune disorderssuch as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], SystemicLupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] areexcluded from this study. Patientswith a history of Hashimoto's thyroiditis onlyrequiring hormone replacement, Type I diabetes, or psoriasis not requiring systemictreatment, or conditions not expected to recur in the absence of an external triggerare allowed to participate.

7. Known history of testing positive for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS).

8. Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test orpositive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCVantibody test indicating acute or chronic infection. If hepatitis C antibody test ispositive then active infection has to be confirmed by hepatitis C RNA testing forthe patient to be excluded.

9. Any underlying medical condition, which in the opinion of the Investigator, willmake the administration of study drug hazardous or obscure the interpretation ofadverse events, such as a condition associated with frequent diarrhea, uncontrollednausea or vomiting. Patients with active COVID-19 disease as indicated by a positivepolymerase reaction (PCR) test are excluded. Patients with previous COVID-19 disease are allowed if ≥30 days from last positivetest, and COVID-19 symptoms have resolved and/or PCR test is now negative

10. Patients must not have received prior anticancer therapy with anti-LAG-3 immunecheckpoint inhibitors.

11. Patients receiving any concomitant systemic therapy for renal cell cancer areexcluded.

12. Patients must not be scheduled to receive another experimental drug while on thisstudy.

13. Patients who are on high dose steroid (e.g., > 10mg prednisone daily or equivalent)or other more potent immune suppression medications (e.g., infliximab). Topical,inhaled, intra-articular, ocular, or intranasal corticosteroids (with minimalsystemic absorption) are allowed. A brief course (<48 hours) of systemiccorticosteroids for prophylaxis (eg, from contrast dye allergy) is permitted. Physiological corticosteroid replacement therapy for adrenal insufficiency is alsopermitted.

14. Troponin T (TnT) or I (TnI) > 2 × institutional ULN. Participants with TnT or TnIlevels between > 1 to 2 × ULN will be permitted if a repeat levels within 24 hoursare ≤ 1 x ULN. If TnT or TnI levels are between >1 to 2 × ULN within 24 hours, theparticipant may undergo a cardiac consultation and be considered for treatment,following cardiologist recommendation. When repeat levels within 24 hours are notavailable, a repeat test should be conducted as soon as possible. If TnT or TnIrepeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiacconsultation and be considered for treatment, following cardiologist recommendation.Notification of the decision to enroll the participant following cardiologistrecommendation has to be made to the MD Anderson Medical Monitor or designee.

15. Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% byeither transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTEpreferred test) within 6 months prior to start of study treatment.

16. Active myocarditis, regardless of etiology.

17. Patients who have any severe and/or uncontrolled medical conditions or otherconditions that could affect their participation in the study such as:

18. Symptomatic congestive heart failure of New York heart Association Class III orIV

19. Unstable angina pectoris, symptomatic congestive heart failure, myocardialinfarction within 6 months of start of study drug, serious uncontrolled cardiacarrhythmia or any other clinically significant cardiac disease

20. Severely impaired lung function as defined as 02 saturation that is 92% or lessat rest on room air

21. Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (ifunfasted glucose elevation, treating physician will evaluate per standard ofcare)

22. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection andwithout improvement) despite appropriate antibiotics or other treatment

23. Known active or symptomatic viral hepatitis or chronic liver disease.Uncontrolled adrenal insufficiency

24. Patients with a history of major psychiatric illness judged unable to fullyunderstand the investigational nature of the study and the risks associatedwith the therapy.

25. Patients must not have history of other diseases, metabolic dysfunction, physicalexamination finding, or clinical laboratory finding giving reasonable suspicion of adisease or condition that contraindicates the use of nivolumab or relatlimab or thatmight affect the interpretation of the results of the study or render the subject athigh risk from treatment complications.

26. Patients should not receive immunization with attenuated live vaccines within oneweek (7 days) of registration for treatment or during study period. a. Note: Seasonal influenza vaccines for injection are generally inactivated fluvaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®)are live attenuated vaccines, and are not allowed.

27. Uncontrolled brain or leptomeningeal metastases, including patients who continue torequire glucocorticoids for brain or leptomeningeal metastases.

28. Female patients who are pregnant or breast feeding, or adults of reproductivepotential who are not using effective birth control methods as defined above.

29. Any patients who cannot be compliant with the appointments required in this protocolmust not be enrolled in this study.