A Study to Evaluate the Effectiveness of 5-Azacitidine and Bevacizumab in Advanced Renal Cell Carcinoma

Study Overview
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Brief Summary
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To identify the maximum tolerable dose and assess qualitative/quantitative toxicities in patients with advanced renal cell cancer treated with combination of 5-azacitidine and bevacizumab.

Detailed Description
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In this study, the investigator will assess progression-free and overall survival of patients with advanced renal cell carcinoma treated with 5-azacitidine in combination with bevacizumab. Patients will continue on treatment until either disease progression or development of other criteria for withdrawal.

Official Title
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A Phase I/II Study Evaluating The Efficacy OF 5-Azacitidine And Bevacizumab In Advanced Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age > 18 years old ECOG Performance Status 0, 1 or 2 Adequate bone marrow, liver and renal function as assessed by the following: Hemoglobin > 9.0 g/dl Absolute neutrophil count(ANC)>1,500/mm3 Platelet count >100,000/mm3 Total bilirubin < 1.5 times ULN ALT and AST < 2.5 times the ULN (< 5 x ULN for patients with liver involvement) Creatinine < 1.5 times ULN Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for duration of study. Men should use adequate birth control for at least 3 months after the last administration of Bevacizumab. Ability to understand and willingness to sign written informed consent. A signed informed consent must be obtained prior to any study specific procedures. Patients not on anticoagulation must have an INR < 1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of treatment and monitored at least weekly, or as defined by the local standard of care, until INR is stable. Must have histologically or cytologically confirmed renal cell carcinoma which is metastatic (M1). Patients with unresectable primary tumors (but MO) are eligible. Must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension. Soft tissue disease that has been radiated in the 2 months prior to registration is not assessable as measurable disease. Soft tissue disease within a prior radiation field must have progressed to be considered assessable. X-rays, scans or physical examinations used for tumor measurement must have been completed within 28 days prior to registration. X-rays, scans or physical examinations for non-measurable disease must have been completed within 42 days prior to registration. Patients with metastatic disease who have a resectable primary tumor and deemed a surgical candidate may have undergone resection and have recovered from surgery. At least 28 days must have elapsed since surgery and must have recovered from any adverse effects of surgery. Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio. For UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1,000mg for patient enrollment. The urine protein used to calculate the UPC ratio must be obtained within 28 days prior to registration. NOTE: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1gm. UPC ratio is calculated using one of the following formulas: [urine protein]/[urine creatinine] - if both protein and creatinine are reported in mg/dL May have received prior immunotherapy with either interferon (IFN) and/or Interleukin-2 (IL-2) or the combination of IFN/IL2 or prior chemotherapy (ie, gemcitabine and capecitabine). Must have failed at least 1 prior biologic agent (sunitinib, sorafenib, or temsorlimus). No limit on the number of prior therapies. At least 14 days must have elapsed since the last treatment. Must have recovered from any adverse effects of prior therapy. May have received prior radiation therapy. At least 21 days must have elapsed since completion of prior radiation therapy. Must have recovered from all associated toxicities at the time of registration. Pregnant or nursing women not eligible because of potential teratogenic side effects of 5-azacitidine and bevacizumab on the developing fetus or nursing infant. Women and men of reproductive potential must have agreed to use an effective contraceptive method. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-azacitidine or bevacizumab are not eligible. Involvement in correlative studies must be offered to all patients but is not required. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which patient is currently in complete remission, or any other cancer from which patient has been disease-free for 2 years. Must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines. Exclusion Criteria Cardiac disease: Congestive heart failure > class II NYHA. Must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of brain to exclude brain metastasis. Patients who have received prior bevacizumab are eligible for phase I portion of study but ineligible for phase II study. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. Active clinically serious infection > CTCAE Grade 2. Thrombosis or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months. Patients with tumor related IVC thrombosis are eligible. Serious non-healing wound, ulcer, or bone fracture. Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: 5-azacitidine<br>A traditional 3+3 dose escalation trial was implemented. Successive cohorts of patients (3 participants/cohort) received bevacizumab at the standard dose of 10mg/kg in combination with escalating doses of 5-azacitidine. If no dose limiting toxicity (DLT) is seen, subsequent patients will be treated at the next dose level. If one DLT is seen, an additional three patients will be accrued at that dose level. If two or more DLTs are seen at one dose level, then the previous dose level will be chosen for phase IIA. If two DLT's are seen at dose level 1, the trial will end. The standard 5-azacitidine dose is 75mg/m2/day for 7 days. If no DLT is seen at dose level 3, then we will proceed with the phase IIA portion of the study. | Drug: Bevacizumab<br>* First treatment: 10 milligram per kilograms (MG/KG) intravenously (IV) on Day 1every two weeks over 90 minutes. Second treatment: 10 MG/KG IV on Day 1 every two weeks over 60 minutes. Third and subsequent treatments: 10 MG/KG IV on Day 1 every two weeks over 30 minutes (minimum of two cycles).<br>* Other names: Avastin;Drug: Azacitidine<br>* Dose level 1: 35 mg/m2/day for 7 days. Dose level 2: 55 mg/m2/day for 7 days. Dose level 3: 75 mg/m2/day for 7 days. mg/m2/day = dose based on height and weight<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities by Dose Level | Toxicities determined using Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | 3 to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | The time to progression was measured using time from the first day of treatment to the first day of an evaluation of progressive disease or the date of death for any cause. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney cancer, renal cell