Sirolimus in Treating Patients With Metastatic or Unresectable Solid Tumors
RATIONALE: Sirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PURPOSE: This phase I trial is studying the side effects and best dose of sirolimus in treating patients with metastatic or unresectable solid tumors.
|Unspecified Adult Solid Tumor, Protocol Specific||Drug: sirolimus Other: laboratory biomarker analysis Other: pharmacological study Procedure: biopsy||Phase 1|
|Study Design:||Primary Purpose: Treatment|
|Official Title:||Pharmacodynamic-Guided Dose Finding Study of Rapamycin (Rapamune®, Sirolimus) in Adult Patients With Solid Tumors|
- Pharmacodynamic optimal dose of sirolimus by evaluation of p70s6 kinase inhibition in peripheral blood mononuclear cells (PBMC) and normal skin
- Correlation of target tissue inhibition in tumor tissue with PMBCs and normal skin
- Pharmacodynamic effects of sirolimus on tumor, normal skin, and normal oral mucosa
- Correlation of pharmacodynamic effects of sirolimus with pharmacokinetics and clinical effects
- Pharmacokinetic-pharmacodynamic and toxicodynamic relationships
- Correlation of activation of the mTOR pathway in tumor tissue with the antitumor effects of sirolimus
- Toxicity by NCI Common Toxicity Criteria Version 3.0
- Activity of sirolimus
- Response rate by RECIST criteria
- Overall survival and progression-free survival by Kaplan-Meier method at 6 and 12 months
|Study Start Date:||December 2004|
|Study Completion Date:||June 2009|
|Primary Completion Date:||June 2009 (Final data collection date for primary outcome measure)|
- 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 effects.
- Correlate the Akt signaling pathway with pharmacodynamic endpoints.
- Explore pharmacokinetic-pharmacodynamic and toxicodynamic relationships of sirolimus in these patients.
- 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 escalation.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00368914
|United States, Maryland|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins|
|Baltimore, Maryland, United States, 21231-2410|
|Principal Investigator:||Manuel Hidalgo, MD, PhD||Sidney Kimmel Comprehensive Cancer Center|