Sirolimus in Treating Patients With Metastatic or Unresectable Solid Tumors

Johns Hopkins Medicine

Status and phase: Completed; Phase 1

Conditions: Unspecified Adult Solid Tumor, Protocol Specific

Treatments: Procedure: biopsy; Other: laboratory biomarker analysis; Other: pharmacological study; Drug: sirolimus

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00368914

P30CA006973 (U.S. NIH Grant/Contract)

JHOC-J0402

R21CA112919 (U.S. NIH Grant/Contract)

JHOC-J0402, CDR0000491204

JHOC-04032602

Details and patient eligibility

About

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.

Full 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.

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.

Enrollment: 30 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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:

• 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