CCI-779 and Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney Cancer

• Dose-limiting toxicity (DLT) (Phase I) [ Time Frame: Patients observed a minimum of 4 weeks (one full course) for each dose level. ] [ Designated as safety issue: Yes ]
  Hematologic DLT measures will be assessed using continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization via Common Terminology Criteria for Adverse Events (CTCAE) version 3 standard toxicity grading. Non-hematologic DLTs such as dyspnea and renal will be evaluated via CTCAE only. The maximum tolerated dose level (MTD) will be defined as the highest safely tolerated dose where ≤1 out of 6 patients experience DLT with the next higher dose having at least 2 patients who experience DLT.
• Proportion of progression-free patients compared to those with disease progression (Phase II) [ Time Frame: 6 months after study entry ] [ Designated as safety issue: No ]
  Determination of progression will be made according to Response Evaluation Criteria in Solid Tumors (RECIST). The proportion of progression-free patients will be estimated by the number of successes divided by the total number of evaluable patients. Ninety percent confidence intervals for the success proportion will be calculated. All patients meeting the eligibility criteria who have signed a consent form and begun treatment will be considered evaluable. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred.

• Number of confirmed clinical responses (Phase I and II) [ Time Frame: Up to 3 years from study registration ] [ Designated as safety issue: No ]
  A confirmed clinical tumor response is defined to be either a Complete Response (CR) or Partial Response (PR) noted as the objective status on 2 consecutive evaluations at least ≥4 weeks apart. Clinical outcomes will be summarized by simple descriptive summary statistics and 95% confidence intervals calculated assuming that the incidence of response is binomially distributed. Objective response to treatment will be evaluated using the RECIST criteria.
• Time to progression (Phase I and II) [ Time Frame: Up to 3 years from study registration ] [ Designated as safety issue: No ]
  The time to progression is defined as the time from registration to the time of progression. Those who die will be considered to have had disease progression unless documented evidence clearly indicates no progression has occurred. The distribution of time to progression will be estimated using the method of Kaplan-Meier.
• Overall survival (Phase I and II) [ Time Frame: Up to 3 years from study registration ] [ Designated as safety issue: No ]
  The overall survival or survival time is defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier.
• Time to treatment failure (Phase I and II) [ Time Frame: Up to 3 years from study registration ] [ Designated as safety issue: No ]
  Time to treatment failure is defined as the time from study entry to the date patients end treatment. Time to treatment failure will be evaluated using the method of Kaplan-Meier.
• Levels of molecular markers of response as assessed by VHL status and immunohistochemistry (IHC) on tumor tissue (Phase II) [ Time Frame: At baseline (within 7 days of treatment initiation) and during treatment (depending on tumor specimen availability) ] [ Designated as safety issue: No ]
  IHC studies will be performed for the following markers: total VEGF, VEGF receptor-2 and phosphorylated VEGF receptor-2 (KDR), total AKT and phospho-AKT, PTEN and phospho- PTEN, HIF-1 alpha. VHL status of the tumor will be performed by both mutational and methylation analysis of tumor tissue from paraffin embedded slides, using standard methods that are currently in use in the Mayo Clinic. Briefly, DNA is extracted from tumor tissue and multiple exons of the gene of interest are co-amplified by multiplex PCR. The DNA is sequenced and analyzed using the software package Mutation Surveyor.
• Correlation of blood markers of angiogenesis with clinical activity of the combination of CCI-779 and Bevacizumab as assessed by levels of VEGF and sFLT-1 in addition to in vitro plasma angiogenic activity (Phase II) [ Time Frame: At baseline (within 7 days of treatment initiation) and every 4 weeks during therapy ] [ Designated as safety issue: No ]
  Vascular endothelial growth factor (VEGF) and sFLT-1 (VEGF receptor 1) will be measured from serum by enzyme-linked immunosorbent assay (ELISA). The plasma angiogenic activity assays that will be performed are a 72 hour endothelial proliferation assay and a matrigel tube formation assay. Changes in these blood markers will be explored graphically to evaluate the effect of treatment and to relate this to clinical outcome and toxicity incidence.

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.

• Clear Cell Renal Cell Carcinoma
• Recurrent Renal Cell Cancer
• Stage IV Renal Cell Cancer

• Biological: APC8015 vaccine/bevacizumab
• Drug: bevacizumab/temsirolimus

Inclusion Criteria:

• Histologically confirmed metastatic or unresectable renal cell cancer

  • Must have a component of conventional clear cell histology

  • The following histologies are excluded:

    • True papillary
    • Sarcomatoid features without any clear cell component
    • Chromophobe
    • Oncocytoma
    • Collecting duct tumors
    • Transitional cell carcinoma
• 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

  • Patients on full-dose warfarin or stable-dose low molecular weight heparin must have INR > 1.5 but ≤ 3
• 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

  • Patients are not considered to have a currently active malignancy if they have completed anticancer therapy AND are considered to be at < 30% risk of relapse
• 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 chemotherapyfor 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)

  • One of these therapies must have included a RTKI agent administered for a minimum of 4 weeks
• 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