EVEREST: EVErolimus for Renal Cancer Ensuing Surgical Therapy, A Phase III Study
Patients must have histologically or cytologically confirmed renal cell carcinoma (clear cell or non-clear cell allowed, but collecting duct or medullary carcinomas excluded).
Patients must be considered pathologically either Intermediate High Risk or Very High Risk, defined as follows:
Intermediate High Risk
pT1b G3-4, N0 (or pNX where clinically N0), M0
pT2a-b G1-2, N0 (or pNX where clinically N0), M0
pT2 a-b G3-4, N0 (or pNX where clinically N0), M0
pT3a G1-2, N0 (or pNX where clinically N0), M0 (as long as pT3a is not due to adrenal involvement)
Very High Risk Group
pT3a G3-4, N0 (or pNX where clinically N0), M0 (or any Grade pT3a if due to adrenal involvement)
pT3b-c G any, N0 (or pNX where clinically N0), M0
pT4 G any, N0 (or pNX where clinically N0), M0
pT any G any, N+ (fully resected), M0
Patients must not have a history of distant metastases.
Patients with microvascular invasion of the renal vein of any grade or stage (as long as M0) are also eligible.
Patients must have undergone a full surgical resection (radical nephrectomy or partial nephrectomy), including removal of all clinically positive nodes. Surgical margins must be negative. Patients with positive renal vein margins are eligible unless there is invasion of the renal vein wall at the margin (provided no other margins are positive).
Patients must plan to start study drug within 84 days after the date of full surgical resection.
Patients must have recovered from any surgical related complications.
Patients with bilateral renal tumors are eligible provided both tumors have undergone full surgical resection and at least one of the tumors meets all eligibility criteria above.
Patients must plan to start study drug within 84 days after the date of the resection of the first tumor.
Patients must not have any evidence of residual or metastatic renal cell cancer on CT scan of the chest, abdomen, and pelvis, all with oral and IV contrast (MRI scans of the abdomen and pelvis with gadolinium and a non-contrast CT of the chest may be substituted if patient is not able to have CT scans with intravenous contrast) after nephrectomy and within a maximum of 28 days prior to registration. Non-contract CT of the chest/abdomen/pelvis should only be performed if, in the opinion of the investigator, it is in the best medical interest of the patient to not receive IV contrast of any form. NOTE: PET/CT is not an acceptable imaging alternative.
Patients must be offered the opportunity to participate in specimen banking for future use to include the translational medicine studies that are part of this protocol.
Patients must not have received any prior anti-cancer therapy (except for radical or partial nephrectomy noted above) for renal cell carcinoma, including systemic therapy in the adjuvant or neoadjuvant setting, immunotherapy, investigational therapy, surgical metastastectomy, or radiation therapy.
Patients must not be planning to receive other anti-cancer agents including investigational agents while on protocol treatment.
Patients must not be receiving chronic, systemic treatment with corticosteroids or other immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
Patients must not have received immunization with an attenuated live vaccine within seven days prior to registration nor have plans to receive such vaccination while on protocol treatment.
Patients must not be taking, nor plan to take while on protocol treatment, strong CYP3A4 inhibitors, (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, fluvoxamine, nefazodone, nelfinavir, ritonavir) and/or CYP3A4 inducers (e.g. phenytoin, rifampin, rifabutin) within 14 days prior to randomization.
Patients must not have any Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia.
Patients must not have any known uncontrolled underlying pulmonary disease (e.g. FEV1 or DLCO 50% or less of predicted OR O2 saturation 88% or less at rest on room air).
Patients must not have any known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients.
Patients must have absolute neutrophil count (ANC) ≥ 1,500/mcL, platelet count ≥ 100,000/mcL and hemoglobin ≥ 9.0 g/dl obtained within 28 days prior to registration.
Patients must have serum creatinine ≤ 2.0 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) ≥ 30mL/min obtained within 28 days prior to registration. Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 72 x creatinine (mg/dl)
Patients must have bilirubin ≤ 1.5 x ULN, and SGOT and SGPT ≤ 2.5 x ULN obtained within 28 days prior to registration.
Patients must NOT have liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh Class C). NOTE: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.
Patients must not have a known history of HIV seropositivity.
Fasting cholesterol, triglycerides and glucose must be obtained within 28 days prior to registration to establish a baseline value for future toxicity assessments.
Patients must be able to take oral medications. Patient may not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
Patients must have a Zubrod Performance Status of 0 or 1.
All patients must be 18 years of age or older.
No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.
Patients must not be pregnant or nursing due to animal studies that have shown reproductive toxicity effects. Women/men of reproductive potential must have agreed to use an effective contraceptive method during protocol treatment and up to 8 weeks after ending protocol treatment.
All patients will be randomized to receive either everolimus or placebo daily for nine six-week cycles.
Everolimus or matched placebo, 2 tablets will be taken orally every day for 54 weeks.
Study drug is provided free of charge.