Treatment of Refractory Metastatic Renal Cell Carcinoma With Bevacizumab and RAD001 (Everolimus)

Phase 2

Terminated

Conditions: Kidney Neoplasms
Kidney (Renal Cell) Cancer

Interventions: Drug: Everolimus
Drug: Bevacizumab

Registration Number: NCT00651482

Lead Sponsor: Sandy Srinivas

Brief Summary: To determine the safety and efficacy of the combination of bevacizumab and everolimus (RAD001) for the treatment of metastatic renal cell cancer

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 10

Inclusion Criteria

Signed Informed Consent Form
Histologically confirmed metastatic RCC that is predominantly clear cell Measurable disease, as defined by RECIST
Age ≥ 18 years
ECOG performance status of 0 or 1
No more than 1 prior targeted therapy (eg, sorafenib, sunitinib) (prior cytokine therapy allowed)
No more than 2 prior systemic therapies
Ability and capacity to comply with the study and follow-up procedures

General Exclusion Criteria

Inability to comply with study and/or follow-up procedures
Life expectancy of < 12 weeks
Inadequate organ function, as evidenced by any of the following at screening:
- Absolute neutrophil count (ANC) < 1500/uL
- Platelet count ≤ 100 x 10^9/L
- Total bilirubin ≥ 1.5 x upper limit of normal (ULN)
- AST and/or ALT > 2.5 x ULN for patients without evidence of liver metastases, or 5 x ULN for patients with documented liver metastases
- Serum creatinine > 2.0 mg/dL
- Hemoglobin < 9 g/dL (may be transfused or receive epoetin alfa to maintain or exceed this level)
Active infection or fever > 38.5°C within 3 days of starting treatment
Women who are pregnant or breast feeding,
Able to conceive and unwilling to practice an effective method of birth control.
History of other malignancies within 5 years prior to Day 1 except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal cell carcinoma, squamous-cell carcinoma of the skin, carcinoma in situ of the cervix, early-stage bladder cancer, or low-grade endometrial cancer
Malignancies that have undergone a putative surgical cure (i.e., localized prostate cancer post-prostatectomy) within 5 years prior to Day 1 may be discussed with the Principal Investigator.
Any other medical conditions (including mental illness or substance abuse) deemed by the clinician to be likely to interfere with a patient's ability to provide informed consent, cooperate, or participate in the study, or to interfere with the interpretation of the results.
Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study

Disease-Specific Exclusion Criteria

RCC with predominantly sarcomatoid features
Radiotherapy for RCC within 28 days prior to Day 1, with the exception of single-fraction radiotherapy given for the indication of pain control
Prior treatment with bevacizumab or any mTOR inhibitor (eg, temsirolimus, sirolimus, or everolimus)
Current need for dialysis

Bevacizumab-Specific Exclusions

Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
Any prior history of hypertensive crisis or hypertensive encephalopathy
New York Heart Association (NYHA) Grade II or greater congestive heart failure
History of myocardial infarction or unstable angina within 6 months prior to study enrollment
History of stroke or transient ischemic attack within 6 months prior to study enrollment
Known CNS disease, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.
Significant vascular disease (eg, aortic aneurysm, aortic dissection)
Symptomatic peripheral vascular disease
Evidence of bleeding diathesis or coagulopathy that is not intentionally pharmacologically-induced
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
Serious, non-healing wound, ulcer, or bone fracture
Proteinuria at screening as demonstrated by a urine protein:
Creatinine (UPC) ratio ≥ 1.0. If UPC ratio ≥ 1.0, the patient must undergo a 24 hour urine collection which must demonstrate ≤ 1g of protein in 24 hours to be eligible.
Known hypersensitivity to any component of bevacizumab

RAD001-Specific Exclusion Criteria

Known hypersensitivity to any component of RAD001
Chronic treatment with systemic steroids or another immunosuppressive agent
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
Severely impaired lung function (spirometry and DLCO < 50% of normal and O2 saturation 88% or less at rest on room air)
If O2 saturation is ≤ 88% at rest on screening, pulmonary function tests (PFTs) will be ordered to confirm normal pulmonary function and eligibility.
Fasting total cholesterol > 350 mg/dL
Fasting triglyceride level > 400 mg/dL or >2.5 x ULN
Fasting serum glucose > 250 mg/dL
Serum phosphorus < 2.0 mg/dL
Serum corrected calcium < 8.0 mg/dL

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Bevacizumab + RAD001 (everolimus)	Everolimus	Study treatment, consisting of bevacizumab + everolimus, was administered as 28-day cycles Bevacizumab 10 mg/kg administered by IV infusion every 14 days (dose suspension permitted, dose reduction not permitted) Everolimus 10 mg daily was administered orally (dose reduction to 5 mg daily and then 5 mg every other day, was permitted as needed for toxicity or tolerability)
Bevacizumab + RAD001 (everolimus)	Bevacizumab	Study treatment, consisting of bevacizumab + everolimus, was administered as 28-day cycles Bevacizumab 10 mg/kg administered by IV infusion every 14 days (dose suspension permitted, dose reduction not permitted) Everolimus 10 mg daily was administered orally (dose reduction to 5 mg daily and then 5 mg every other day, was permitted as needed for toxicity or tolerability)

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	24 months	Progression-free survival (PFS) per RECIST criteria

Secondary Outcome Measures

Name	Time	Method
Objective Response (OR) Duration	24 months
Objective Response (OR)	24 months	Number of subjects with objective response (OR)
Time-to-Treatment Failure (TTF)	24 months
Overall Survival (OS)	44 months
Number of Subjects With Drug-related SAEs	24 months
Total Number of Drug-related SAEs	24 months
Treatment Discontinuation Due to Toxicity	24 months	Number of subjects whose treatment was discontinued due to toxicity
Treatment Discontinuation Due to Disease Progression	24 months	Number of subjects whose treatment was discontinued due to disease progression