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A Randomized Phase II Study of Everolimus (Afinitor) vs. Sunitinib (Sutent) in Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma (ASPEN)
- The primary objective will be to compare the anti-tumor activity of everolimus and sunitinib in subjects with mRCC with non-clear cell pathology, as measured by progression-free survival (PFS) following treatment initiation according to RECIST criteria. In addition, the rates of PFS will be compared at 6, 12 and 24 months.
- A secondary objective will be to compare the antitumor activity of these agents against historic interferon-treated controls from the phase III sunitinib trial of untreated patients with RCC using the log-rank test. Other secondary objectives will be to compare the safety, tolerability, and quality-of-life associated with everolimus or sunitinib administration in this population, to compare the overall response rates and degree of tumor shrinkage in each arm, overall survival in each arm, and to compare the time to new metastases in each arm. Finally, tumor, plasma and urine biomarkers will be correlated with response and PFS in patients with advanced non clear cell RCC treated with everolimus or sunitinib, with an emphasis on mTOR pathway and VEGF pathway activation, DNA polymorphisms and mutational analysis, and longitudinal plasma/urine angiokine levels.
- Histologically confirmed advanced RCC, with non-clear cell pathology. Pathology must consist predominantly (≥ 50%) of papillary or chromophobe or undifferentiated histology. Mixtures of these non-clear cell variants are allowed.
- RCC tumor tissue available for correlative sciences, from either primary or metastatic site or both.
- At the time of screening, at least 4 weeks since prior palliative radiation therapy and/or major surgery, and resolution of all toxic effects of prior therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 4.0) Grade ≤ 1.
- Subject must have radiographic evidence of metastatic disease, with at least 1 measurable lesion per RECIST 1.1 criteria (Attachment 1)].
- Age ≥ 18 years.
- Adequate laboratory parameters:
- leukocytes ≥ 3,000/uL
- absolute neutrophil count ≥ 1,500/uL
- platelets ≥ 100,000/uL
- hemoglobin ≥ 9.0 g/dl
- total bilirubin ≤ 1.5 x institutional ULN
- AST(SGOT)/ALT(SGPT) ≤ 2.5x institutional ULN
- creatinine ≤ 2.0x institutional upper limit
- Total cholesterol ≤ 300 mg/dl OR ≤ 7.75 mmol/L
- Triglycerides ≤ 2.5x institutional upper limit
- Glucose ≤ 220 mg/dl
- INR and PTT ratio (if not on anticoagulation on low molecular weight heparin) ≤ 1.5x institutional upper limit Anticoagulation is allowed if target INR ≤ 3.0x institutional upper limit on stable dose of warfarin or other oral vitamin K antagonist or on a stable dose of LMW heparin for ≥ 2 weeks at time of randomization.
- Karnofsky Performance Status ≥ 60 (Attachment 2).
- Life expectancy of at least 3 months.
- Written, signed, dated, and witnessed IRB or IEC approved informed consent form (ICF) before any screening procedures are performed.
- Subjects with active central nervous system (CNS) metastases. CNS metastases are allowed provided they have been treated and have been stable without new or growing lesions for 6 weeks.
- Prior systemic therapy for RCC, including mTOR and anti-angiogenic therapy, chemotherapy, biologic or experimental therapy.
- Collecting duct, medullary, small cell, oncocytoma, or lymphoma-type pathology is not allowed. Sarcomatoid variants of papillary or chromophobe carcinoma is permitted but not if clear cell features are predominant (> 50% involvement).
- Subjects receiving known strong CYP3A4 isoenzyme inhibitors and/or inducers (Attachment 3). Subjects on acceptable CYP3A4 isoenzyme inhibitors and/or inducers are eligible, provided they have been taking a stable regimen for at least 4 weeks prior to screening. Agents not appearing in Attachment 3 are permitted.
- Major surgery, open biopsy, traumatic injury, or radiotherapy within 4 weeks of the screening visit.
- Subjects who have not recovered from prior biopsy, surgery, traumatic injury, and/or radiation therapy.
- Presence of a non-healing wound or ulcer.
- Grade ≥ 3 hemorrhage within the past month.
- Hypertension with systolic blood pressure of ≥ 180 mm Hg and/or diastolic pressure ≥ 100 mm Hg. Anti-hypertensive medications are permitted.
- Subjects with American Heart Association (AHA) Class 2-4 heart disease (Attachment 4) or any history of congestive heart failure with an ejection fraction < 50%, or history of unstable angina, myocardial infarction, coronary artery bypass graft, cerebrovascular accident, transient ischemic attack, or pulmonary embolism within 6 months of entry.
- Diabetes mellitus with glycosylated hemoglobin A1c (HbgA1c) > 10% despite therapy. Note: Optimal glycemic control should be achieved before starting trial therapy.
- A history of interstitial pneumonitis.
- Subjects with active autoimmune disorder(s) being treated with immunosuppressive agents within 4 weeks prior to the screening visit.
- Subjects receiving immunosuppressive agents and those with chronic viral/bacterial/fungal illnesses such as human immunodeficiency virus (HIV). Replacement doses of corticosteroids are permitted. See below for eligibility of HBV/HCV-infected individuals.
- Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
- Active infection(s), active antimicrobial therapy or serious intercurrent illness.
- History of other prior malignancy in past 5 years, other than basal cell carcinoma, squamous cell carcinoma of the skin, cervical carcinoma in situ, localized prostate cancer, or superficial bladder cancer.
- Pregnant or nursing women, women who are of childbearing potential who are not using a medically acceptable contraceptive method, or men who are not using a medically acceptable contraceptive method with partners of childbearing potential. Agreement to use medically acceptable contraceptive methods for 3 months after the last dose of everolimus and/or sunitinib. A woman of childbearing potential is defined as a woman who is biologically capable of becoming pregnant. Male patients whose sexual partner(s) are women of childbearing potential who are not willing to use adequate contraception, during the study and for 3 months after the end of treatment.
- Any other major medical or psychiatric illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study, including inability to absorb oral medications and history of noncompliance to medical regimens.
- Known hypersensitivity to any of the components in everolimus, other rapamycins, or sunitinib or other medical reasons for not being able to receive adequate premedication (for example, antihistamine or anti-inflammatory agents).
- Subjects that are taking agents that significantly prolong the QTc interval and who are unable to stop these medications prior to study initiation are not eligible (Attachment 3).
- Proteinuria on urine dipstick > 2+. If > 2+, a patient is eligible if a spot urine protein/ creatinine ratio < 2 or 24 hour urine protein < 2 grams per 24 hours. (See Attachment 10)
- Severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air.
- Advanced 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.
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