A Phase I/II Trial of CCI-779 and Bevacizumab in Stage IV Renal Cell Carcinoma
A Phase I/II Trial of CCI-779 and Bevacizumab in Stage IV Renal Cell Carcinoma
This phase I/II trial is studying the side effects and best dose of CCI-779 and bevacizumab and to see how well they work in treating patients with metastatic or unresectable kidney cancer. Drugs used in chemotherapy, such as CCI-779, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of kidney cancer by blocking blood flow to the tumor. Giving CCI-779 together with bevacizumab may kill more tumor cells.
PRIMARY OBJECTIVES:
I. To determine the maximally tolerated dose (MTD) and recommended dosing for the combination of CCI-779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase I) II. To determine the proportion of patients with metastatic renal cell cancer who are progression free at 6 months. (Phase II)
SECONDARY OBJECTIVES:
I. To determine the toxicity of the combination of CCI 779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase II) II. To determine the clinical response rate of CCI 779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase II) III. To determine the time to progression (TTP), disease free survival, and overall survival of CCI 779 and Bevacizumab in patients with metastatic renal cell cancer. (Phase II)
TERTIARY OBJECTIVES:
I. To identify predictive molecular markers of response, both at the tumor level and in the plasma/serum level, in an exploratory manner.
II. To correlate blood markers of angiogenesis with clinical activity of the combination of CCI-779 and Bevacizumab.
OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study. Patients are stratified according to study phase (I vs II).
Phase I: Patients receive CCI-779 IV on days 1, 8, 15, and 22 and bevacizumab IV on days 1 and 15.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of CCI-779 and bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive CCI-779 and bevacizumab as in phase I at the MTD determined in phase I. After completion of study treatment, patients are followed every 3 months until disease progression and then every 6 months for up to 3 years after study entry.
Inclusion Criteria:
Histologically confirmed metastatic or unresectable renal cell cancer
Must have a component of conventional clear cell histology
The following histologies are excluded:
Measurable disease, defined as ≥ 1 lesion ≥ 2.0 cm in the longest diameter by conventional techniques OR ≥ 1.0 cm by spiral CT scan
Tumor tissue (from primary tumor or metastases) available AND patient is willing to donate blood for research studies (phase II only)
No CNS metastases by head CT scan or MRI
Performance status - ECOG 0-2
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 9.0 g/dL
No evidence of bleeding diathesis or coagulopathy
No history of clinically significant bleeding or active bleeding
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN if liver metastases are present)
AST ≤ 2.5 times ULN (5 times ULN if liver metastases are present)
PT/INR ≤ 1.5
Creatinine ≤ 1.5 times ULN
Urine protein ≤ 1+ by dipstick or urinalysis
Urine protein < 1,000 mg on a 24-hour urine collection
No cerebrovascular accident within the past 6 months
No peripheral vascular disease with claudication on < 1 block
No New York Heart Association class II-IV congestive heart failure
No angina pectoris requiring nitrate therapy
No myocardial infarction within the past 6 months
No uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 160 mm Hg and/or diastolic BP ≥ 90 mm Hg despite medication
No cardiac arrhythmias
No other significant cardiovascular disease
No ongoing hemoptysis
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for at least 3-4 months after study participation
Fasting cholesterol ≤ 350 mg/dL
Triglycerides ≤ 1.5 times ULN (may achieve using lipid lowering agents)
No known hypersensitivity to recombinant human antibodies
No significant traumatic injury within the past 4 weeks
No serious or non-healing wound, ulcer, or bone fracture
No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 4 weeks
No pathological conditions that confer a high risk of bleeding (e.g., tumor involving major vessels or known varices)
No diabetes
No other currently active malignancy except nonmelanoma skin cancer
No other uncontrolled serious medical or psychiatric condition
At least 4 weeks since prior biologic response modifiers for metastatic disease
No prior bevacizumab or mTOR inhibitors
At least 4 weeks since prior chemotherapy for metastatic disease
Prior palliative radiotherapy to metastatic lesions allowed provided there is ≥ 1 measurable and/or evaluable lesion that has not been irradiated
At least 4 weeks since prior and no concurrent radiotherapy
Prior nephrectomy allowed
More than 4 weeks since prior major surgery or open biopsy
More than 1 week since prior core biopsy
No concurrent major surgery
At least 4 weeks (2 weeks for vascular endothelial growth factor [VEGF] receptor tyrosine kinase inhibitor [RTKI] therapy) since prior and no more than 2 therapies (phase II)
Concurrent full-dose warfarin or low molecular weight heparin allowed provided dose is stable AND INR requirements are met
Concurrent zoledronate for bone metastases and/or hypercalcemia allowed provided therapy was initiated prior to study entry