NCT00368914CompletedPhase 1
Pharmacodynamic-Guided Dose Finding Study of Rapamycin (Rapamune®, Sirolimus) in Adult Patients With Solid Tumors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins1 site in 1 country30 target enrollmentStarted: December 1, 2004Last updated:
Conditions
Drugs
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Pharmacodynamic optimal dose of sirolimus by evaluation of p70s6 kinase inhibition in peripheral blood mononuclear cells (PBMC) and normal skin
Study Overview
Brief Summary
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.
Detailed Description
OBJECTIVES:
Primary
- 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.
Secondary
- 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.
Study Design
- Study Type
- Interventional
- Primary Purpose
- Treatment
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •DISEASE CHARACTERISTICS:
- •Histologically confirmed solid tumor malignancy
- •Metastatic or inoperable disease
- •Failed curative or standard palliative therapy OR no such therapy exists
- •Evaluable or measurable disease
- •Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
- •Tumor amenable to serial biopsies
- •No known brain metastases
- •PATIENT CHARACTERISTICS:
- •Life expectancy ≥ 3 months
- •WBC > 3,500/mm³
- •Absolute neutrophil count > 1,500/mm³
- •Hemoglobin > 9 g/dL
- •Creatinine ≤ 2.0 mg/dL
- •Bilirubin ≤ 2 mg/dL
- •ALT and AST ≤ 5 times upper limit of normal (ULN)
- •Alkaline phosphatase ≤ 5 times ULN
- •Triglycerides < 2 times ULN
- •Total cholesterol < 2 times ULN
- •Willing to undergo serial tumor biopsies and normal skin biopsies
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •No immunodeficiency
- •No gastrointestinal tract disease resulting in an inability to take oral medication
- •No requirement for IV alimentation
- •No active peptic ulcer disease
- •No active infections
- •No other uncontrolled medical conditions that could potentially increase the risk of toxicities or complications of this therapy
- •No concurrent or second malignancy within the past 5 years
- •No clinically significant cardiovascular disease, including any of the following:
- •Myocardial infarction within the past 12 months
- •Unstable angina
- •Peripheral vascular disease ≥ grade 2
- •Uncontrolled congestive heart failure
- •Uncontrolled hypertension (i.e., systolic blood pressure [BP] > 170 mm Hg, diastolic BP > 95 mm Hg)
- •PRIOR CONCURRENT THERAPY:
- •Recovered from prior anticancer therapy
- •No unresolved chronic toxicity > CTC grade 2
- •No prior surgical procedures affecting absorption
- •More than 4 weeks since prior surgery except minor procedures (e.g., dental work or skin biopsy)
- •More than 1 month since prior participation in an investigational drug trial
- •More than 1 month since prior chemotherapy
- •No concurrent use of any of the following:
- •Phenytoin
- •Carbamazepine
- •Barbiturates
- •Phenobarbital
- •Cyclosporine
- •Clarithromycin
- +9 more not shown
Exclusion Criteria
- Not provided
Outcomes
Primary Outcomes
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
Secondary Outcomes
- Pharmacokinetics
- 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
Investigators
Study Sites (1)
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