Sirolimus in Treating Patients With Metastatic or Unresectable Solid Tumors

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00368914
First received: August 24, 2006
Last updated: August 5, 2010
Last verified: August 2010
  Purpose

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.


Condition Intervention Phase
Unspecified Adult Solid Tumor, Protocol Specific
Drug: sirolimus
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: biopsy
Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: Pharmacodynamic-Guided Dose Finding Study of Rapamycin (Rapamune®, Sirolimus) in Adult Patients With Solid Tumors

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • Pharmacodynamic optimal dose of sirolimus by evaluation of p70s6 kinase inhibition in peripheral blood mononuclear cells (PBMC) and normal skin [ Designated as safety issue: No ]
  • Correlation of target tissue inhibition in tumor tissue with PMBCs and normal skin [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacokinetics [ Designated as safety issue: No ]
  • Pharmacodynamic effects of sirolimus on tumor, normal skin, and normal oral mucosa [ Designated as safety issue: No ]
  • Correlation of pharmacodynamic effects of sirolimus with pharmacokinetics and clinical effects [ Designated as safety issue: No ]
  • Pharmacokinetic-pharmacodynamic and toxicodynamic relationships [ Designated as safety issue: Yes ]
  • Correlation of activation of the mTOR pathway in tumor tissue with the antitumor effects of sirolimus [ Designated as safety issue: No ]
  • Toxicity by NCI Common Toxicity Criteria Version 3.0 [ Designated as safety issue: Yes ]
  • Activity of sirolimus [ Designated as safety issue: No ]
  • Response rate by RECIST criteria [ Designated as safety issue: No ]
  • Overall survival and progression-free survival by Kaplan-Meier method at 6 and 12 months [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: December 2004
Study Completion Date: June 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00368914

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Principal Investigator: Manuel Hidalgo, MD, PhD Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00368914     History of Changes
Other Study ID Numbers: JHOC-J0402, CDR0000491204, R21CA112919, P30CA006973, JHOC-J0402, JHOC-04032602
Study First Received: August 24, 2006
Last Updated: August 5, 2010
Health Authority: United States: Federal Government

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
unspecified adult solid tumor, protocol specific

Additional relevant MeSH terms:
Neoplasms
Sirolimus
Everolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 28, 2014