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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Trial of CCI-779 and Bevacizumab in Stage IV Renal Cell Carcinoma

Conditions
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Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Cancer, Stage IV Renal Cell Cancer

Intervention / Treatment
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* Drug: CCI-779
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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 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) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CCI-779 and bevacizumab<br>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. | Drug: CCI-779<br>* CCI-779 is taken IV on days 1, 8, 15, 22 of a 28-day cycle. Dose level is dependent on phase.<br>* Other names: WAY-130779;Drug: Bevacizumab<br>* Bevacizumab is taken IV on Days 1 and 15 of a 28-day cycle. Dose Level determined by phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity (DLT) (Phase I) | For this protocol, dose limiting toxicity (DLT) will be defined as an adverse event attributed (definitely, probably, or possibly) to the study treatment in the first four weeks of combination therapy, and meeting the following criteria: Grade 4 Absolute neutrophil count (ANC) for 5+ days. Grade 4 anemia or thrombocytopenia of any duration. Serum Creatinine 2 times baseline or 2x upper limit of normal if baseline levels not normal. Any other non-hematologic grade 3 or higher as per NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0, except fatigue and grade 3 Hypertension that is will be controlled with oral medication. Grade 3 triglycerides will be a DLT for patients who have Grade 3 in spite of appropriate lipid lowering drug therapy. The maximum tolerated dose level (MTD) will be defined as the highest safely tolerated dose where 1 or 0 out of 6 patients experience DLT with the next higher dose. | Patients observed a minimum of 4 weeks (one full course). The maximum number of cycles observed was 16 cycles. | 
| Proportion of Progression-free Patients at 6 Months (Phase II) | Determination of progression will be made according to Response Evaluation Criteria in Solid Tumors (RECIST). A progression (PD) is defined as having at least a 20% increase in the sum of the longest dimension of target lesions taking as reference the smallest sum of the largest dimension recorded at baseline.The proportion of progression-free patients will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five 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. | 6 months after study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Best Response Rate of CCI-779 and Bevacizumab in Patients With Metastatic Renal Cell (Phase II) | The number of participants with clinical tumor response to treatment will be evaluated using the Response Evaluation Criteria In Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the largest dimension (LD) of target lesions taking as reference the baseline sum LD. | Up to 3 years from study registration | 
| Time to Progression (Phase II) | 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. | Up to 3 years from study registration | 
| Overall Survival (Phase I and II) | 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. | Up to 3 years from study registration |