Pembrolizumab and Cabozantinib S-malate in Treating Patients with Locally Advanced, Recurrent, or Metastatic Kidney Cancer

Inclusion Criteria

• Subjects must have histological or cytological documentation of renal cell carcinoma
• Subjects must have locally advanced, recurrent, or metastatic disease
• Be willing and able to provide written informed consent/assent for the trial
• Stated willingness to comply with all study procedures and be available for the duration of the trial
• Have measurable or evaluable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 from toxicities related to any prior treatments, unless adverse events (AE[s]) are clinically non-significant and/or stable on supportive therapy
• Confirmed availability of representative archival tumor specimens in paraffin blocks (preferred) or >= 10 unstained slides, with an associated pathology report * Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, or punch biopsies for cutaneous, subcutaneous, or mucosal lesions * Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable * A subject with insufficient or unavailable archival tissue may be eligible, upon discussion with the principal investigator, if the subject is willing to consent to undergo a pretreatment core, punch, or excisional/incisional biopsy sample collection of the tumor
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,500 /mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN
• Urine protein =< 1+ or =< 30 mg/dL OR urine protein/creatinine ratio =< 1
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN; for subjects with Gilbert’s disease =< 3 mg/dL
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases
• Albumin >= 2.5 mg/dL
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Female participants of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication and should not be breastfeeding; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication * Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participants.
• Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy and refrain from donating sperm during this period * Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy equivalent to >= 10 mg/day of prednisone, or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)
• Has had prior treatment with pembrolizumab
• Has had prior treatment with cabozantinib
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier * Note: Subjects with stable, treated hypothyroidism or adrenal insufficiency may qualify for the study
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: subjects with =< grade 2 hypertension managed with medication are an exception to this criterion and may qualify for the study * Note: subjects with =< grade 2 endocrinopathy (e.g. hypothyroidism or adrenal insufficiency managed with medication) are an exception to this criterion and may qualify for the study
• Has had major surgery within 4 weeks or minor surgery within 2 weeks prior to study day 1; subjects must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Prior treatment with immune checkpoint inhibitors is allowed, provided that no treatment-related grade >= 3 adverse events (other than grade 3 endocrinopathy managed with replacement therapy) were observed and at least a minimum of 28 days have elapsed between the last dose of prior treatment and the proposed cycle 1 day 1
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, carcinoma in situ or superficial bladder cancer, low-grade prostate cancer, intraductal papillary mucinous neoplasm (IPMN), and other low grade cancers that is suitable for active surveillance in the opinion of the investigator
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; active CNS metastases will be defined as brain lesions that 1) require intervention with surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT) or 2) require anti-epileptic therapy, systemic steroid treatment, or intrathecal therapy; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks after completion of focal therapy brain metastases and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed
• Has history of solid organ transplantation
• Has history of osteonecrosis of the jaw
• Has history of reversible posterior leukoencephalopathy syndrome
• Has history of wound dehiscence or complications requiring medical intervention within 6 months of study entry
• Has history of (non-infectious) pneumonitis that required steroids or active, non-infectious pneumonitis
• Has an active infection requiring systemic therapy with IV antibiotics
• Has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders: ** Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias ** Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment ** Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before randomization * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: ** Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction ** Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization; complete healing of an intra-abdominal abscess must be confirmed before study initiation * Has clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon within 3 months before randomization * Known endobronchial disease manifestation; patients with suspected endobronchial disease on imaging who have no evidence of endobronchial disease on bronchoscopy are allowed; patients with treated endobronchial disease are also allowed provided they are stable * Lesions invading major pulmonary blood vessels
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has an inability to swallow tablets or capsules
• Has a previously identified allergy or hypersensitivity to components of the study treatment formulations
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study therapy; administration of killed vaccines is allowed * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed