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 clear cell renal cell carcinoma (RCC)
• Metastatic RCC
• Must provide the cell block or a minimum of 10 (preferably 15) slides from the nephrectomy or diagnostic biopsy * When available, cell blocks or a minimum of 10 (preferably 15) slides of a core or excisional biopsy from a metastatic site within 6 months prior to enrollment must be provided; if such a biopsy is not available, an optional fresh biopsy at the discretion of the treating physician per institutional biopsy is strongly recommended
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)1.1 criteria
• Prior treatment with a PD1/PDL1 antibody (Ab) (as single agent or in combination with a drug or drugs) in metastatic setting is required
• Other lines of therapy before and after PD1/PDL1 Ab therapy are allowed
• Prior therapy with axitinib is allowed if enrollment occurs >12 months after the last dose of axitinib
• Confirmation of specimen availability is required prior randomization; all tissue specimen must be received by Clinical Investigations Support Office‐ Multi site Coordinating Center (CISO-MCC) within 30 days of enrollment
• Zubrod performance status of =< 2
• Women of childbearing potential must use method(s) of contraception; the individual methods of contraception should be determined in consultation with the treating physician or investigator
• Women of childbearing potential must have a negative serum pregnancy test within 24 hours prior to the administration of the investigational product; female patients who 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 menses for at least 12 consecutive months with no alternative pathological or physiological cause; a serum follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal women
• Women must not be breastfeeding
• Men who are sexually active with women of childbearing potential must agree to use 2 contraceptive methods with a failure rate of less than 1% per year * NOTE: Contraception should be continued using two highly effective methods for a period of 90 days after the last dose of treatment
• Measured of calculated creatinine clearance (CrCl) >= 30 mL/min using the Cockcroft-Gault formula using actual weight (NOT ideal or adjusted weights) (within 14 days prior to randomization)
• White blood cells (WBC) >= 2000/uL (within 14 days prior to randomization)
• Neutrophils >= 1500/uL (within 14 days prior to randomization)
• Platelets >= 100x10^3/uL (within 14 days prior to randomization)
• Hemoglobin >= 9g/dL (within 14 days prior to randomization)
• Aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) (within 14 days prior to randomization)
• Alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to randomization)
• Bilirubin =< 1.5 x ULN (within 14 days prior to randomization)

Exclusion Criteria

• Patients with known symptomatic brain metastases requiring systemic corticosteroids; patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable; mild neurological deficit is allowed, if it does not interfere with the ability to judge the safety on the trial
• History of or active autoimmune disorders (including but not limited to: Crohn’s disease, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, Grave’s disease) and other conditions that compromise or impair the immune system
• Known active bacterial, fungal or viral infection including hepatitis B (hepatitis B virus [HBV]), hepatitis C (hepatitis C virus [HCV]), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) -related illness; routine testing is not required; however, treating physicians may use their discretion to determine whether testing is necessary
• Uncontrolled adrenal insufficiency
• Any known active chronic liver disease
• Prior malignancy requiring systemic therapy is excluded
• Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results
• Prior treatment with an anti-CD137, or OX40 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways except anti-PD1, anti-PDL1/2 and CTLA-4 antibodies
• Major surgery less than 6 weeks prior to the first dose of study drug; minor surgery less than 4 weeks prior to the first dose of study drug; insertion of vascular access device >= 7 days prior to 1st dose of study drug is allowed
• Anti-cancer therapy or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug
• Presence of toxicities attributed to prior therapy other than alopecia that have not resolved to grade 1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4) or baseline before administration of study drug
• History of grade 3 or higher immune-mediated adverse event including AST/ALT elevations and cytokine release syndrome related to prior immune-modulatory therapy (eg, checkpoint inhibitors, co-stimulatory agents etc.); endocrinopathies and skin rash are allowed at the discretion of treating physician; study principal investigator (PI) is available for discussion of individual cases
• Patients with intolerance to or who have had a severe (>= grade 3) allergic or anaphylactic reaction to antibodies or infused therapeutic proteins, or patients who have had a severe allergic or anaphylactic reaction to any of the substances included in the investigational product (including excipients)
• Patients with a previous history of anthracycline treatment are excluded
• 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 ventricular fibrillation), and left anterior hemiblock (bifascicular block); rate controlled atrial fibrillation is allowed. * Unstable angina, coronary/peripheral artery bypass graft * Symptomatic congestive heart failure (congestive heart failure [CHF] New York Heart Association class III or IV) * Cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism 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 Xa inhibitors] will be allowed if indicated) * Ongoing cardiac dysrhythmias of NCI CTCAE grade >= 2, atrial fibrillation of any 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 laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
• Patients using strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) are excluded unless the strong CYP3A4/5 inhibitor agent can be changed
• Presence of a malabsorption syndrome, gastrointestinal disorder, or gastrointestinal surgery 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