Sirolimus and Bevacizumab in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Sirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab and sirolimus may also stop the growth of liver cancer by blocking blood flow to the tumor. Giving sirolimus together with bevacizumab may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of sirolimus when given together with bevacizumab in treating patients with liver cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of sirolimus used in combination with bevacizumab in patients with unresectable hepatocellular carcinoma. Determine the toxicity profile of this regimen in these patients. Secondary Determine the clinical activity of this regimen in these patients. Determine the pharmacokinetics of sirolimus in these patients. Determine the biologically active dose range of sirolimus in these patients. Correlate phosphorylated p70S6K activity with clinical response in patients treated with this regimen. Correlate PTEN, 4EBP-1, phosphorylated p70S6K, CD31, and vascular endothelial growth factor expression with clinical response in patients treated with this regimen. Correlate the degree of angiogenesis (as measured by DCE-CT scan) with drug levels and clinical response. OUTLINE: This is a dose-escalation study of sirolimus. Patients receive bevacizumab IV over 30-90 minutes once every 2 weeks and oral sirolimus once daily. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of sirolimus 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. Six additional patients receive treatment at the MTD. Blood samples are collected from healthy participants to measure p70S6 kinase activity. Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetic and p70S6K activity assessment. Samples are also analyzed by high-performance liquid chromatography and tandem mass spectrophotometry to determine peak drug concentrations. Patients without archived tumor samples undergo tumor tissue biopsy at baseline. Samples are analyzed for PTEN, 4E-BP1, vascular endothelial growth factor, epidermal growth factor, p70S6K, and CD31 by immunohistochemistry. Patients also undergo DCE-CT scan at baseline and on day 29 to assess angiogenesis. After completion of study treatment, patients are followed for 52 weeks. PROJECTED ACCRUAL: A total of 36 patients and 5 healthy participants will be accrued for this study.

Official Title
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A Phase I Study of Rapamycin in Combination With Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma

Conditions
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Liver Cancer

Intervention / Treatment
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* Drug: Rapamycin
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Meets 1 of the following criteria: Histologically confirmed unresectable hepatocellular carcinoma, meeting all of the following criteria: Failed 0-2 lines of chemotherapy Child-Pugh class A or B for liver cirrhosis Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm with conventional techniques or ≥ 10 mm with spiral CT scan No known brain metastases Bone metastases allowed provided other measurable disease is present Healthy participant PATIENT CHARACTERISTICS: ECOG performance status (PS) 0-2 or Karnofsky PS 70-100% Life expectancy > 3 months WBC ≥ 3,000/mm³ Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 3 times upper limit of normal (ULN) AST and ALT ≤ 5 times ULN Creatinine normal PTT < 1.5 times ULN Fasting serum cholesterol ≤ 350 mg/dL Triglycerides ≤ 300 mg/dL Proteinuria < 2+ by urine dipstick OR urine protein ≤ 1 g by 24-hour urine collection No history of allergic reactions to compounds of similar chemical or biologic composition to sirolimus or bevacizumab No prior thromboembolic disease that may result in bleeding or clotting problems related to use of bevacizumab including, but not limited to, the following: Esophageal varices Bleeding disorders Deep vein thromboses No history of hematemesis or hemoptysis No other uncontrolled illness including, but not limited to, the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that would preclude study participation No HIV positivity Able to take oral medications Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception prior to and during the course of study treatment PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 28 days since prior surgery and recovered No other concurrent investigational agents No other concurrent anticancer therapy No concurrent traditional Chinese medicine(s) No concurrent long term anticoagulation with heparin or warfarin Concurrent prophylactic low-dose acetylsalicylic acid for patients at risk of an arterial thromboembolic event allowed Hepatitis B carriers must be on lamivudine during and for 6 months after completion of study treatment

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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Accepts Healthy Volunteers

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: Phase I study of rapamycin and bevacizumab<br>Rapamycin (available as 1mg per tablet; Wyeth) will be given orally once in the morning before meal. The starting dose of rapamycin will be 1mg administered once daily. All doses of rapamycin will be preceded by an oral loading dose three times the maintenance dose on day 1. The dose of rapamycin will be increased at each dose level. Bevacizumab (100mg/4ml; Roche) will start concurrently with rapamycin. It will be diluted in a total of 100ml of 0.9% sodium chloride given via intravenous injection. The first dose will be infused over 90 minutes. If the first infusion is tolerated without any adverse infusion-related events (fever and/or chills), the second infusion may be delivered over 60 minutes. If the 60- minute infusion is well tolerated, the subsequent doses may be delivered over 30 minutes. | Drug: Rapamycin<br> <br> Drug: Bevacizumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity |  | 3 years | 
| Maximum tolerated dose |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (complete and partial response and stable disease) |  | 3 years | 
| Progression-free survival |  | 3 years | 
| Overall survival |  | 3 years | 
| Distribution of p70S6K activity in peripheral blood mononuclear cells |  | 3 years | 
| Correlation of p70S6K with tumor response |  | 3 years | 
| Expression of tumor tissue biomarkers (PTEN, 4EBP-1, CD31, p70S6K, and vascular endothelial growth factor) |  | 3 years | 
| Correlation of tumor biomarkers with response |  | 3 years | 
| Best overall response (complete and partial response; stable and progressive disease) |  | 3 years | 
| Change in DCE-CT scan assessment of angiogenesis |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult primary hepatocellular carcinoma, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer, advanced adult primary liver cancer