A Phase I Study of Rapamycin in Combination With Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma
- 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
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
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
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Choo Su Pin, MD
National Cancer Centre, Singapore
Singapore: Health Sciences Authority