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

Phase 1
18 Years
Not Enrolling
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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
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

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.

Inclusion Criteria


- 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


- 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)


- 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

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

Pharmacodynamic optimal dose of sirolimus by evaluation of p70s6 kinase inhibition in peripheral blood mononuclear cells (PBMC) and normal skin

Safety Issue:


Principal Investigator

Manuel Hidalgo, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center


United States: Federal Government

Study ID:

JHOC-J0402, CDR0000491204



Start Date:

December 2004

Completion Date:

June 2009

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • Neoplasms



Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland  21231-2410