Everolimus in Treating Patients with Sporadic Angiomyolipomas

Inclusion Criteria

• A diagnosis of renal AML > 3 cm confirmed on pre-enrollment DCE-MRI; a previous diagnosis or treatment of a different AML lesion is allowed
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Absolute neutrophil count > 1,500/mcL
• Hemoglobin >= 10 g/dL
• Platelets > 100,000/mcL
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (serum glutamic oxaloacetic transaminase [SGOT]/serum glutamate pyruvate transaminase [SGPT]) < 2.5 x ULN
• Total bilirubin =< 2.0mg/dL
• Renal function estimated glomerular filtration rate (eGFR) > 30 mL/min via calculated creatinine clearance
• Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L
• Fasting triglycerides =< 300 mg/dL or =< 1.71 mmol/L
• Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document

Exclusion Criteria

• History of tuberous sclerosis, lymphangioleiomyomatosis (LAM) or any active malignancy
• Active treatment with any other investigational agents
• Administration of any investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment
• Concurrent therapy given to treat cancer
• Patients must not have received any prior treatment for AML
• Diagnosis of any other malignancy within 3 years prior to registration, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix or melanoma in-situ or low grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation or castration)
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to: * Active peptic ulcer disease * Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or other gastrointestinal conditions with increased risk of perforation * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
• Active diarrhea of any grade
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: * Malabsorption syndrome * Major resection of the stomach or small bowel resulting in dumping syndrome or clinical signs of malabsorption
• Active or prior history of human immunodeficiency virus (HIV) infection, hepatitis B or C (screening for all three is mandatory prior to study)
• Presence of any active or ongoing infection
• Any known uncontrolled underlying pulmonary disease by history, physical exam or if applicable pulmonary function tests (PFTs) (e.g. forced expiratory volume in 1 second [FEV1] or carbon monoxide diffusing capability [DLCO] 50% or less of predicted or oxygen [O2] saturation 88% or less at rest on room air)
• History of any one or more of the following cardiovascular conditions within the past 6 months: * Cardiac angioplasty or stenting * Myocardial infarction * Unstable angina * Coronary artery bypass graft surgery * Symptomatic peripheral arterial vascular disease
• History of class III or IV congestive heart failure, as defined by the New York Heart Association Classification of Congestive Heart Failure
• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months; Note: patients with recent DVT who have been treated with therapeutic anticoagulation agents for at least 6 weeks are eligible as long as their INR is stable and within inclusion criteria above
• Corrected QT interval (QTc) > 480 milliseconds as corrected by the Fridericia formula
• Poorly controlled hypertension, defined as systolic blood pressure (SBP) of >= 140 mmHg or diastolic blood pressure (DBP) of >= 90mmHg; Note: screening/baseline blood pressure (BP) must be assessed with three measurements at approximately 2-minute intervals; the mean SBP/DBP values from the three readings must be < 140/90 mmHg in order for a subject to be eligible for the study; if the subject’s initial screening SBP/DBP is >= 140/90 mmHg, initiation or adjustment of antihypertensive medication(s) is permitted in an attempt to control the subject’s BP level to below 140/90 mmHg; optimal blood pressure control must be achieved before registration and monitored
• Evidence of active bleeding or bleeding diathesis
• Patients must not have uncontrolled diabetes mellitus (defined by a hemoglobin [Hgb] A1c > 8) obtained within 14 days prior to registration; optimal glucose control (Hgb A1c =< 8) must be achieved before registration and monitored during protocol treatment
• Unable or unwilling to discontinue use of prohibited medications within 14 days prior to randomization and while on treatment: * No chronic treatment with systemic steroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed * Growth factors (e.g. granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [G-GM-CSF], erythropoietin, platelets growth factors etc.) are not to be administered prophylactically but may be prescribed by the treating physician for rescue from severe hematologic events * Live vaccines must not be administered to patient * Drugs known to be strong inhibitors or inducers of the isoenzyme cytochrome P450 family 3 subfamily A member 4 (CYP3A4) must not be administered as systemic therapy; drugs or substances known to be moderate inhibitors or inducers of CYP3A should be avoided if possible or used subject to caution; co-administration with strong or moderate inhibitors of P-glycoprotein (PgP) should be avoided if possible, or used subject to caution; concomitant use of Seville orange, star fruit, grapefruit and their juices should be avoided
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to everolimus that in the opinion of the investigator contraindicates their participation
• Prior or current use of systemic anti-vascular endothelial growth factor (VEGF) inhibitors, cytokines or mammalian target of rapamycin (mTOR) inhibitors (e.g. interferon, interleukin 2)
• Patients with Child-Pugh A-C liver disease
• Pregnant or nursing (lactating) women
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during the study and 8 weeks after stopping treatment; highly effective contraception methods include total abstinence, male partner sterilization (with post-vasectomy documentation of the absence of sperm in the ejaculate), or a combination of any two of the following: * Use of oral, injected or implanted hormonal methods of contraception o In case of use of oral contraception, women should have been stable on the oral agent before taking study treatment * Placement of an intrauterine device (IUD) or intrauterine system (IUS) * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository Women are considered to be physiologically capable of becoming pregnant unless: * They have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms); * They have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization ** In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential
• Male patients whose sexual partner(s) are WOCBP must agree to use adequate contraception as defined above during the study and for 8 weeks after the end of treatment; condom use is required by all male patients in order to prevent delivery of the drug via seminal fluid
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures; patients with low risk prostate and bladder cancer will be excluded (use American Urological Association [AUA] guidelines for bladder patients)