A Phase II Trial of Everolimus and Bevacizumab in Advanced Non-Clear Cell Renal Cell Carcinoma (RCC)
- Advanced renal cell carcinoma of non-clear cell histology, histologically confirmed
by MSKCC pathology. Subtypes include papillary (type 1 and 2), chromophobe,
collecting duct (also Bellini duct), medullary and unclassified RCC. Advanced disease
is defined as unresectable, locally recurrent disease or metastatic disease.
Availability of additional tissue for correlative studies is NOT in inclusion
- Evidence of unidimensionally measurable disease per RECIST 1.1 (Eisenhauer, Therasse
et al. 2009). Resolution of all acute toxic effects of prior radiotherapy or surgical
procedures to NCI CTCAE Version 4.0 grade ≤1.
- Adequate organ function as defined by the following criteria:
- Absolute neutrophil count (ANC) ≥1,500/μL
- Platelets ≥100,000/μL
- Hemoglobin ≥9.0 g/dL
- Serum calcium ≤12.0 mg/dL
- Serum creatinine ≤1.5 x ULN
- Total serum bilirubin ≤1.5 x ULN
- Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT])
and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤2.5
x local laboratory upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver
function abnormalities are due to underlying malignancy
- INR ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of
warfarin or on a stable dose of LMW heparin for >2 weeks at time of study entry.)
- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5
x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can
only be included after initiation of appropriate lipid lowering medication.
Karnofsky performance status ≥ 70 %.
- 18 years of age or older.
- Ability to swallow oral medication.
- Signed and dated informed consent document indicating that the subject (or legally
acceptable representative) has been informed of all pertinent aspects of the trial
prior to undergoing study screening procedures.
- Subject's willingness and ability to comply with scheduled visits, treatment plans,
laboratory tests, and other study procedures.
- Patients who have received prior systemic therapy for their RCC with VEGF pathway
inhibitor (such as sunitinib, sorafenib, and bevacizumab) or with mTOR inhibitors
(such as sirolimus, temsirolimus, everolimus, or deforolimus).
- Patients within 28 days post major surgery (e.g., intra-thoracic, intra-abdominal or
intra-pelvic), open biopsy, or significant traumatic injury to avoid wound healing
complications. Minor procedures and percutaneous biopsies or placement of vascular
access device require 7 days prior to study entry.
- Patients who had radiation therapy within 28 days prior to start of study treatment
(palliative radiotherapy to bone lesions allowed if completed 2 weeks prior to study
Patients with evidence or history of central nervous system (CNS) metastases or spinal
cord compression, unless prior treatment with surgery or radiotherapy AND no progression
of CNS disease within 6 months prior to enrollment.
- Patients with a history of abdominal fistula, gastrointestinal perforation, or
intraabdominal abscess within 6 months prior to study enrollment.
- Patients with proteinuria on screening urinalysis confirmed to be >1g /24h by 24 hour
- Patients with inadequately controlled hypertension (defined as a blood pressure of >
150 mmHg systolic and/or > 100 mmHg diastolic on medication), or any prior history of
hypertensive crisis or hypertensive encephalopathy.
Patients receiving chronic systemic treatment with corticosteroids (dose of ≥ 10 mg/day
methylprednisone equivalent) or another immunosuppressive agent. Inhaled and topical
steroids are acceptable.
- Patients with a known history of HIV seropositivity.
- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as: unstable
angina pectoris (at any time), symptomatic congestive heart failure (NYHA II, III,
IV) (at any time), serious uncontrolled cardiac arrhythmia (at any time), myocardial
infarction or cerebrovascular accidents ≤ 6 months prior to first study treatment or
history of left ventricular dysfunction
- symptomatic intrinsic lung disease requiring oxygen supplementation at baseline
- poorly controlled diabetes as defined by fasting serum glucose >2.0 x ULN
- any active (acute or chronic) or uncontrolled infection/disorders that impair
the ability to evaluate the patient or for the patient to complete the study
- liver disease such as cirrhosis or decompensated liver disease.
- Patients who have a history of another primary malignancy and are off treatment for ≤
3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the
- Female patients who are pregnant or breast feeding
- Patients who are using other investigational agents or who had received
investigational drugs ≤ 4 weeks prior to study treatment start.
- Patients who have received attenuated live vaccines within one week of study entry.
Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral
polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.