Avelumab (Bavencio) With IL-15 in Subjects With Clear-Cell Renal Carcinoma

• INCLUSION CRITERIA:
• Patients must have histologically proven metastatic clear cell renal carcinoma withgreater than or equal to 5% expression of programmed death-ligand 1 (PD-L1) on thetumor cells confirmed by immunohistochemistry (IHC) in the national Cancer Institute (NCI) Lab of Pathology. Archival tumor sample may be used but if archival tissue isnot available or is not adequate, tissue biopsy will be required.
• Patients must have failed or relapsed and have progressive disease after at least 2prior therapies that include multityrosine kinase inhibitor (mTKI) like axitinib orsunitinib and an anti-Programmed cell death protein 1 (PD1) or PD-L1 (ICI) therapylike nivolumab which could have been administered in combination with an anti-clusterof differentiation 152 (CTLA4) agent like ipilimumab. Patients who received an immunecheckpoint inhibitor (ICI) in combination with a mTKI would be eligible for the trialif they received another appropriate treatment. Adjuvant or neoadjuvant with eithertype of agent would not fulfill this requirement only treatment for metastatic diseasewill be considered to satisfy this criterion.
• Disease must be measurable with at least one measurable lesion by the ResponseEvaluation Criteria in Solid Tumors (Recist) v1.1 criteria that is different from thelesion biopsied.
• Age >=18 years NOTE: Because no dosing or adverse event data are currently available on the use ofrecombinant human Interleukin-15 (rhIL-15) in combination with avelumab in patients <18years of age, children are excluded from this study, but may be eligible for futurepediatric trials
• Eastern Cooperative Oncology Group (ECOG) performance status <= 1 (Karnofsky >=80%)
• Adequate organ and marrow function as defined below:
• absolute neutrophil count greater than or equal to 1,500/mcL
• absolute lymphocyte count greater than or equal to 500/mcL
• Hemoglobin greater than or equal to 10 g/dL
• Platelets greater than or equal to 100,000/mcL
• total bilirubin less than or equal to 1.5 X institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/Alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT)less than or equal to 2.5 X institutional ULN
• Serum creatinine less than or equal to 1.5 X institutional ULN OR
• Creatinine clearance greater than or equal to 50 mL/min/1.73 m^2 for patients withcreatinine levels >1.5 institutional ULN
• Negative serum or urine pregnancy test at screening for women of childbearingpotential (WOCBP). NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergonesuccessful surgical sterilization or who is not postmenopausal. WOCBP must have a negativepregnancy test (human chorionic gonadotropin (HCG) blood or urine) during screening.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, forthe duration of study participation, and 1 month after completion of rhIL-15 andavelumab administration. Should a woman become pregnant or suspect she is pregnantwhile she or her partner is participating in this study, she should inform hertreating physician immediately.
• Ability of subject to understand and the willingness to sign a written informedconsent document.

EXCLUSION CRITERIA:

• Chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C).
• Persisting toxicity related to prior therapy of grade > 1, with the exception of thefollowing: alopecia, sensory neuropathy grade <= 2, or other grade <= 2 notconstituting a safety risk based on investigator's judgement.
• Patients who are receiving any other investigational agents
• Current use of immunosuppressive medication, EXCEPT for the following:
• Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,intra-articular injection)
• Systemic corticosteroids at physiologic doses <= 10 mg/day of prednisone orequivalent; or,
• Steroids as premedication for hypersensitivity reactions (e.g., computedtomography (CT) scan premedication).
• Patients with known brain metastases should be excluded from this clinical trialbecause of their poor prognosis and because they often develop progressive neurologicdysfunction that would confound the evaluation of neurologic and other adverse events.
• Patients with previous malignant disease other than the target malignancy within thelast 5 years with the exception of basal or squamous cell carcinoma of the skin orcervical carcinoma in situ.
• Patients with history of any organ transplantation
• Vaccination within 4 weeks of the first dose of avelumab. Vaccination with a livevaccine while on trial is prohibited. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuatedvaccines, and are not allowed.
• Patients with history of allergic reactions attributed to compounds of similarchemical or biologic composition to rhIL-15 or avelumab.
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoingor active infection requiring systemic therapy, or psychiatric illness/socialsituations that would limit compliance with study requirements.
• Inability or refusal to practice effective contraception during therapy or thepresence of pregnancy or active breastfeeding. Based on its mechanism of action,avelumab can cause fetal harm when administered to a pregnant woman. Animal studieshave demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased riskof immune-mediated rejection of the developing fetus resulting in fetal death. Thesepotential risks may also apply to other agents used in this study.
• Patients with active bacterial infections, documented human immunodeficiency virus (HIV) infection or positive screening serology, polymerase chain reaction (PCR)evidence for active or chronic hepatitis B or hepatitis C, or positive screeninghepatitis B virus (HBV)/hepatitis C virus (HCV) serology without documentation ofsuccessful curative treatment
• Patients with active or history of any autoimmune disease, including asthma requiringchronic inhaled or oral corticosteroids, or with history of asthma requiringmechanical ventilation; patients with a history of mild asthma that are on or can beswitched to non-corticosteroid bronchodilator regimens are eligible
• Cardiovascular disease: Clinically significant (i.e., active) cardiovascular disease:cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardialinfarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (greater than or equal to New York Heart Association Classification Class II), orserious cardiac arrhythmia requiring medication
• Other severe acute or chronic medical conditions including immune colitis,inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatricconditions including recent (within the past year) or active suicidal ideation orbehavior; or laboratory abnormalities that may increase the risk associated with studyparticipation or study treatment administration or may interfere with theinterpretation of study results and, in the judgment of the investigator, would makethe patient inappropriate for entry into this study.