Axitinib With or Without Anti-OX40 Antibody PF-04518600 in Treating Patients With Metastatic Kidney Cancer

Inclusion Criteria:

• Willing and able to provide informed consent

• Histological confirmation of renal cell carcinoma (RCC) with a predominantly (> 50%)clear cell component

• Metastatic RCC

• Must have had a nephrectomy (radical or partial) and must provide the cell blockfrom the nephrectomy

• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)1.1 criteria

• Must have progression of disease within 6 months of study enrollment after treatmentwith only one of the following:

• Two prior lines of therapy: a VEGF inhibitor (other than axitinib), followed bya single agent PD-1/PDL-1 antibody, or

• One prior line of therapy: combination of a VEGF inhibitor (other thanaxitinib) AND a PD1/PDL1 antibody, or

• Additional prior systemic treatments not allowed

• Must agree to a fresh core or excisional biopsy from a metastatic site within a 12-week window prior to enrollment; if such a biopsy is already available, cellblocks must be provided; (Note: fine needle aspiration [FNA] and bone metastasessamples are not acceptable for submission); specimens from the nephrectomy and freshbiopsy must be received and assessed for adequacy of tissue by the Data CoordinatingCenter (DCC) (University of Southern California [USC]) prior to randomization

• Zubrod performance status of =< 2

• Women of childbearing potential must use method(s) of contraception; the individualmethods of contraception should be determined in consultation with the treatingphysician or investigator

• Women of childbearing potential must have a negative serum pregnancy test within 24hours prior to the administration of the investigational product; female patientswho are not of childbearing potential as defined below, are eligible to be included (ie, meet at least one of the following criteria):

• Have undergone a documented hysterectomy and/or bilateral oophorectomy

• Have medically confirmed ovarian failure; or

• Achieved postmenopausal status, defined as follows: cessation of regular mensesfor at least 12 consecutive months with no alternative pathological orphysiological cause; a serum follicle stimulating hormone (FSH) level withinthe laboratory's reference range for postmenopausal women

• Women must not be breastfeeding

• Men who are sexually active with women of childbearing potential must use anycontraceptive method with a failure rate of less than 1% per year

• Contraception should be continued using two highly effective methods for a period of 90 days

• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 40 mL/min (measured or calculated using the Cockcroft-Gault formula) using actualweight (ideal or adjusted weights are unacceptable)

• White blood cells (WBC) >= 2000/uL

• Neutrophils >= 1500/uL

• Platelets >= 100x10^3/uL

• Hemoglobin >= 9g/dL

• Aspartate aminotransferase (AST) =< 3 x ULN

• Alanine aminotransferase (ALT) =< 3 x ULN

• Bilirubin =< 1.5 x ULN

Exclusion Criteria:

• Patients with known symptomatic brain metastases requiring systemic corticosteroids;patients with previously diagnosed brain metastases are eligible if they havecompleted their treatment and have recovered from the acute effects of radiationtherapy or surgery prior to the start of study medication, have discontinuedcorticosteroid treatment for these metastases for at least 4 weeks and areneurologically stable; mild neurological deficit is allowed, if it does notinterfere with the ability to judge the safety on the trial

• Prior treatment with an mTOR inhibitor (including, but not limited to, everolimus,temsirolimus, sirolimus, and ridaforolimus)

• Prior treatment with axitinib

• History of or active autoimmune disorders (including but not limited to: Crohn'sdisease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave'sdisease) and other conditions that compromise or impair the immune system

• Active bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiencysyndrome (AIDS) -related illness

• Any condition requiring systemic treatment with either corticosteroids (> 10 mgdaily prednisone equivalent) or other immunosuppressive medications within 14 daysprior to the first dose of study drug; inhaled steroids and adrenal replacementsteroid doses > 10 mg daily prednisone equivalent are permitted in the absence ofactive autoimmune disease

• Uncontrolled adrenal insufficiency

• Any known active chronic liver disease

• Prior malignancy active within the previous 3 years except for locally curablecancers that have been apparently cured, such as basal or squamous cell skin cancer,superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast

• Known medical condition (e.g., a condition associated with diarrhea or acutediverticulitis) that, in the investigator's opinion, would increase the riskassociated with study participation or study drug administration or interfere withthe interpretation of safety results

• Prior treatment with an anti-CD137, or OX40 antibody, or any other antibody or drugspecifically targeting T-cell co-stimulation or checkpoint pathways except anti-PD1,anti-PDL1/2 antibodies or ipilimumab

• Major surgery less than 6 weeks prior to the first dose of study drug; minor surgeryless than 4 weeks prior to the first dose of study drug

• Anti-cancer therapy less than 6 weeks prior to the first dose of study drug (lessthan 28 days for bevacizumab) or palliative, focal radiation therapy less than 14days prior to the first dose of study drug

• Presence of toxicities attributed to prior therapy other than alopecia that have notresolved to grade 1 (National Cancer Institute [NCI] Common Terminology Criteria forAdverse Events [CTCAE] version 4) or baseline before administration of study drug

• History of grade 3 or higher immune-mediated adverse event (including AST/ALTelevations that where considered drug related and cytokine release syndrome) thatwas considered related to prior immune-modulatory therapy (e.g., checkpointinhibitors, costimulatory agents etc.) or any grade immune-related adverse events (AEs) that required immune suppressive therapy

• Patients with intolerance to or who have had a severe (>= grade 3) allergic oranaphylactic reaction to antibodies or infused therapeutic proteins, or patients whohave had a severe allergic or anaphylactic reaction to any of the substancesincluded in the investigational product (including excipients)

• Patients with a previous history of adriamycin treatment and are at risk of cardiacfailure (New York Heart Association [NYHA] class II or above)

• Any one of the following currently or in the previous 6 months:

• Myocardial infarction

• Congenital long QT syndrome

• Torsade's de points

• Arrhythmias (including sustained ventricular tachyarrhythmia and ventricularfibrillation), and left anterior hemiblock (bifascicular block)

• Unstable angina, coronary/peripheral artery bypass graft

• Symptomatic congestive heart failure (congestive heart failure [CHF] New YorkHeart Association class III or IV)

• Cerebrovascular accident, transient ischemic attack or symptomatic pulmonaryembolism or other clinical significant episode of thrombo-embolic disease (Cases must be discussed in detail with study chair to judge eligibility;anticoagulation (heparin only, no vitamin-K antagonists or factor Xainhibitors) will be allowed if indicated)

• Ongoing cardiac dysrhythmias of NCI CTCAE grade >= 2, atrial fibrillation ofany grade, or QT correction using Fridericia's correction formula (QTcF)interval > 470 msec at screening (except in case of right bundle branch block,these cases must be discussed with sponsor's medical monitor)

• Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and, in the judgment of the investigator, would make the patientinappropriate for entry into this study

• Concurrent use of any medications or substances; these include steroids as they mayinterfere with PF-04518600 (OX40 Ab); also strong CYP3A4/5 inhibitors should beavoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir,nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole)

• Presence of a malabsorption syndrome, gastrointestinal disorder, or gastrointestinalsurgery that could affect the absorption of axitinib

• History of severe hypersensitivity reaction to any monoclonal antibody

• Women who are pregnant or breastfeeding

• Women with a positive pregnancy test

• Prisoners or patients who are involuntarily detained