Perioperative Lenvatinib With Pembrolizumab in Patients With Locally Advanced Nonmetastatic Clear Cell Renal Cell Carcinoma

Inclusion Criteria:

• Patients with a renal mass consistent with a clinical stage >= T3Nx or TanyN+ ordeemed unresectable by surgeon

• Renal cell carcinoma with clear cell component on pre-treatment biopsy of theprimary tumor

• The participant (or legally acceptable representative if applicable) provideswritten informed consent and the willingness and ability to comply with all aspectsof the protocol

• Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 1

• Absolute neutrophil count (ANC) >= 1500/uL (specimens must be collected within 72hours prior to the start of study treatment)

• Platelets >= 100 000/uL (specimens must be collected within 72 hours prior to thestart of study treatment)

• Hemoglobin >= 9.0 g/dL (specimens must be collected within 72 hours prior to thestart of study treatment) or ≥5.6 mmol/La

Renal:

Creatinine =≤1.5 × ULN OR Measured or calculatedb creatinine clearance (GFR can also be used in place of creatinine or CrCl)=≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN.

Hepatic:

Total bilirubin=≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT)=≤2.5 × ULN (≤5 × ULN for participants with liver metastases)

Coagulation:

International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT)=≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.

ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.

• Criteria must be met without erythropoietin dependency and without packed red bloodcell (pRBC) transfusion within last 2 weeks.

• Creatinine clearance (CrCl) should be calculated per institutional standard.

• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x upperlimit of normal (ULN) unless participant is receiving anticoagulant therapy aslong as PT or activated partial thromboplastin time (aPTT) is withintherapeutic range of intended use of anticoagulants (specimens must becollected within 72 hours prior to the start of study treatment)

• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant isreceiving anticoagulant therapy as long as PT or aPTT is within therapeuticrange of intended use of anticoagulants (specimens must be collected within 72hours prior to the start of study treatment)

• Serum creatinine =< 1.5 x ULN OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine orcreatinine clearance [CrCl]) >= 40 mL/min (>= 0.67 mL/sec) for participant withcreatinine levels > 1.5 x institutional ULN (specimens must be collected within 72 hours prior to the start of study treatment)

• Creatinine clearance (CrCl) calculated per the Cockcroft and Gault formula

• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants withtotal bilirubin levels > 1.5 x ULN (specimens must be collected within 72 hoursprior to the start of study treatment)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x ULN for participants with liver metastases) (specimens must becollected within 72 hours prior to the start of study treatment)

• All females must have a negative serum or urine pregnancy test (minimumsensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin [beta-hCG]) at the screening visit and the baseline visit. A pregnancy testneeds to be performed within 72 hours of the first dose of study drug. Women ofchildbearing potential (WOCBP) must agree to use a highly effective method ofcontraception for the entire study period and for 120 days after studydiscontinuation

• Male subjects who are partners of women of childbearing potential must use acondom and their female partners of childbearing potential must use a highlyeffective method of contraception beginning at least 1 menstrual cycle prior tostarting study drugs, throughout the entire study period, and for 120 daysafter the last dose of study drug, unless the male subjects are totallysexually abstinent or have undergone a successful vasectomy with confirmedazoospermia or unless the female partners have been sterilized surgically orare otherwise proven sterile

Exclusion Criteria:

• Evidence of metastatic disease on pre-treatment imaging

• The subject has received of any type of cytotoxic, biologic or other systemicanticancer therapy for kidney cancer

• The subject has received any other type of investigational agent within 28 daysbefore the first dose of study treatment

• Excluding the primary tumor leading to enrollment in this study, any other activemalignancy (except for localized prostate cancer, definitively treated melanomain-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of thebladder or cervix) within the past 24 months

• Prior treatment with lenvatinib or any agent directed against PD-1, PD-L1 or PD-L2,or another stimulatory or co inhibitory T-cell receptor (e.g. CTLA-4, OX 40, CD137)

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment

• Subjects having > 1+ proteinuria on urinalysis will undergo 24-hour urine collectionfor quantitative assessment of proteinuria. Subjects with urine protein >= 1g/24-hour will be ineligible

• Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other conditionthat might affect the absorption of lenvatinib

• The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions:

• Cardiovascular disorders:

• New York Heart Association congestive heart failure of grade II or above,unstable angina, myocardial infarction within the past 6 months, orserious cardiac arrhythmia associated with significant cardiovascularimpairment within the past 6 months

• Uncontrolled hypertension defined as sustained blood pressure (BP) > 150mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensivetreatment

• Prolongation of corrected QT (QTc) interval to > 480 msec perelectrocardiogram (ECG) within 28 days before first dose of studytreatment

• Clinically significant hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) ofred blood, or other history of significant bleeding (e.g. pulmonary hemorrhage)within 3 weeks prior to the first dose of study drug

• Serious non-healing wound/ulcer/bone fracture

• History of organ allograft (subject has had an allogenic tissue/solid organtransplant)

• Biologic response modifiers (e.g. granulocyte colony-stimulating factor) within 4weeks before study entry. Chronic erythropoietin therapy is permitted provided thatno dose adjustments were made within 2 months before first dose of study treatment

• Subjects must have recovered adequately from any toxicity and/or complications frommajor surgery prior to starting therapy

• Has received a live or live-attenuated vaccine within 30 days prior to the firstdose of study drug. Examples of live vaccines include, but are not limited to, thefollowing: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever,rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenzavaccines for injection are generally killed virus vaccines and are allowed; however,intranasal influenza vaccines (e.g. FluMist are live attenuated vaccines and are notallowed

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease

• Has an active infection requiring systemic therapy

• Has a known history of active Hepatitis B (e.g., hepatitis B surface antigen [HBsAg]) or hepatitis C (e.g., HCV RNA qualitative is detected)

• Has uncontrolled HIV defined by a CD4+ count < 350 cells/uL, an AIDS-definingopportunistic infection within the last 12 months prior to study enrollment ordocumented multidrug resistance that prevents effective HIV therapy

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator