Pharmacodynamic-Guided Dose Finding Study of Rapamycin (Rapamune®, Sirolimus) in Adult Patients With Solid Tumors
- Determine the pharmacodynamic optimal dose of sirolimus, by evaluating p70^s6 kinase
inhibition in peripheral blood mononuclear cells (PBMC) and normal skin, in patients
with metastatic or unresectable solid tumors.
- Correlate target inhibition in tumor tissue with PBMC and normal skin target inhibition
in patients whose tumors are amenable to sequential tumor biopsies.
- Characterize the pharmacokinetics of sirolimus in these patients
- Determine the pharmacodynamic effects of sirolimus on tumor, normal skin, and normal
oral mucosa of these patients
- Correlate the pharmacodynamic effects of sirolimus with pharmacokinetics and clinical
- Correlate the Akt signaling pathway with pharmacodynamic endpoints.
- Explore pharmacokinetic-pharmacodynamic and toxicodynamic relationships of sirolimus in
- Quantify the toxicity of sirolimus in these patients.
- Evaluate, preliminarily, the activity of sirolimus in these patients.
OUTLINE: This is a prospective, dose-escalation study.
Patients receive oral sirolimus once daily on days 1-28. Courses repeat every 28 days 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. The pharmacodynamic optimal dose is
considered the dose at which 10 patients are treated without requiring further dose
Patients undergo blood collection, tumor tissue and normal skin biopsies, and oral mucosal
smears periodically for pharmacodynamic, pharmacokinetic, and biomarker correlative studies.
After completion of study treatment, patients are followed at 4 weeks.
PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.
Primary Purpose: Treatment
Pharmacodynamic optimal dose of sirolimus by evaluation of p70s6 kinase inhibition in peripheral blood mononuclear cells (PBMC) and normal skin
Manuel Hidalgo, MD, PhD
Sidney Kimmel Comprehensive Cancer Center
United States: Federal Government
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins||Baltimore, Maryland 21231-2410|