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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00467194
Recruitment Status : Completed
First Posted : April 27, 2007
Last Update Posted : June 17, 2013
Information provided by (Responsible Party):
Choo Su Pin, National Cancer Centre, Singapore

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Liver Cancer Drug: Rapamycin Drug: Bevacizumab Phase 1

Detailed Description:



  • 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.


  • 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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Rapamycin in Combination With Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma
Study Start Date : December 2006
Actual Primary Completion Date : May 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Liver Cancer
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Phase I study of rapamycin and bevacizumab

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 Drug: Bevacizumab

Primary Outcome Measures :
  1. Dose-limiting toxicity [ Time Frame: 3 years ]
  2. Maximum tolerated dose [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Response rate (complete and partial response and stable disease) [ Time Frame: 3 years ]
  2. Progression-free survival [ Time Frame: 3 years ]
  3. Overall survival [ Time Frame: 3 years ]
  4. Distribution of p70S6K activity in peripheral blood mononuclear cells [ Time Frame: 3 years ]
  5. Correlation of p70S6K with tumor response [ Time Frame: 3 years ]
  6. Expression of tumor tissue biomarkers (PTEN, 4EBP-1, CD31, p70S6K, and vascular endothelial growth factor) [ Time Frame: 3 years ]
  7. Correlation of tumor biomarkers with response [ Time Frame: 3 years ]
  8. Best overall response (complete and partial response; stable and progressive disease) [ Time Frame: 3 years ]
  9. Change in DCE-CT scan assessment of angiogenesis [ Time Frame: 3 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes


  • 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


  • 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


  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00467194

National Cancer Centre - Singapore
Singapore, Singapore, 169610
Johns Hopkins Singapore International Medical Centre
Singapore, Singapore, 308433
Sponsors and Collaborators
National Cancer Centre, Singapore
Principal Investigator: Choo Su Pin, MD National Cancer Centre, Singapore
Principal Investigator: Toh Han Chong, MD, MBBS, MRCP National Cancer Centre, Singapore

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Choo Su Pin, Senior Consultant, National Cancer Centre, Singapore Identifier: NCT00467194     History of Changes
Other Study ID Numbers: CDR0000540163
First Posted: April 27, 2007    Key Record Dates
Last Update Posted: June 17, 2013
Last Verified: June 2013

Keywords provided by Choo Su Pin, National Cancer Centre, Singapore:
adult primary hepatocellular carcinoma
localized unresectable adult primary liver cancer
recurrent adult primary liver cancer
advanced adult primary liver cancer

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Liver Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors