Sirolimus in Treating Patients With Metastatic or Unresectable Solid Tumors

Study Overview
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Brief Summary
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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
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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. 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.

Official Title
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Pharmacodynamic-Guided Dose Finding Study of Rapamycin (Rapamune®, Sirolimus) in Adult Patients With Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: sirolimus
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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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: ECOG 0-1 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 Rifampin Phenobarbital Cyclosporine Clarithromycin Diltiazen Clotrimazole Ketoconazole Fluconazole Hypericum perforatum (St. John's wort) Cimetidine Grapefruit juice No concurrent immunosuppressants No other concurrent investigational or commercial agents or therapies for this malignancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: sirolimus|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|
|Procedure: biopsy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific