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

June 14, 2013 updated by: Choo Su Pin, National Cancer Centre, Singapore

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

27

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Singapore
      • Singapore, Singapore, 169610
        • National Cancer Centre - Singapore
      • Singapore, Singapore, 308433
        • Johns Hopkins Singapore International Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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: Bevacizumab
Drug: Rapamycin

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Centre, Singapore

Investigators

  • Principal Investigator: Choo Su Pin, MD, National Cancer Centre, Singapore
  • Principal Investigator: Toh Han Chong, MD, MBBS, MRCP, National Cancer Centre, Singapore

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2006

Primary Completion (Actual)

May 1, 2011

Study Registration Dates

First Submitted

April 25, 2007

First Submitted That Met QC Criteria

April 25, 2007

First Posted (Estimate)

April 27, 2007

Study Record Updates

Last Update Posted (Estimate)

June 17, 2013

Last Update Submitted That Met QC Criteria

June 14, 2013

Last Verified

June 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000540163
  • SINGAPORE-06-17-HEP

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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