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AzTrials

Liver CancerPhase 1NCT00467194

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

A Phase 1 study testing Rapamycin and Bevacizumab in people with Liver Cancer, run by National Cancer Centre, Singapore at 2 sites in Singapore.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for
Liver Cancer
What is being tested?
Rapamycin and Bevacizumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
27 participants
Where
2 sitesSingapore
Study dates
Dec 2006to May 2011
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

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

Trial locations and contacts

2 sites in 1 country.

Singapore2 sites

  • National Cancer Centre - Singapore

    Singapore, 169610

  • Johns Hopkins Singapore International Medical Centre

    Singapore, 308433

Other trials in Singapore

About this study

Official title: 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.

Read the 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.

Conditions
Liver Cancer
Being tested
Rapamycin, Bevacizumab
Keywords
adult primary hepatocellular carcinoma, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer, advanced adult primary liver cancer
Medical subject headings
Liver Neoplasms, Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT00467194
Study groupRoleWhat they receive
Phase I study of rapamycin and bevacizumabExperimentalRapamycin (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.
Receives: Drug: Rapamycin; Drug: Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Dose-limiting toxicity

    Measured: 3 years

  2. Maximum tolerated dose

    Measured: 3 years

Secondary outcomes (9)

  1. Response rate (complete and partial response and stable disease)

    Measured: 3 years

  2. Progression-free survival

    Measured: 3 years

  3. Overall survival

    Measured: 3 years

  4. Distribution of p70S6K activity in peripheral blood mononuclear cells

    Measured: 3 years

  5. Correlation of p70S6K with tumor response

    Measured: 3 years

  6. Expression of tumor tissue biomarkers (PTEN, 4EBP-1, CD31, p70S6K, and vascular endothelial growth factor)

    Measured: 3 years

  7. Correlation of tumor biomarkers with response

    Measured: 3 years

  8. Best overall response (complete and partial response; stable and progressive disease)

    Measured: 3 years

  9. Change in DCE-CT scan assessment of angiogenesis

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Apr 2007 (estimated)
  2. Study startDec 2006
  3. Primary completionMay 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
27 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00467194
Sponsor's protocol ID
CDR0000540163
Other IDs
SINGAPORE-06-17-HEP
Status last verified
Jun 2013
First submitted
25 Apr 2007
Last updated
17 Jun 2013
Results posted
No

Publications

  • Treiber G. mTOR inhibitors for hepatocellular cancer: a forward-moving target. Expert Rev Anticancer Ther. 2009 Feb;9(2):247-61. doi: 10.1586/14737140.9.2.247.

    PubMed 19192962

  • Choo SP, Chowbay B, Ng QS, Thng CH, Lim C, Hartono S, Koh TS, Huynh H, Poon D, Ang MK, Chang S, Toh HC. A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2013 Mar;49(5):999-1008. doi: 10.1016/j.ejca.2012.11.008. Epub 2012 Dec 19.

    PubMed 23265712

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Rapamycin and Bevacizumab in people with Liver Cancer, run by National Cancer Centre, Singapore at 2 sites in Singapore.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 17 Jun 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Dose-limiting toxicity (time frame: 3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00467194, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jun 2013.

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