Clinical trial NCT00311623: Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer
Official title: A Pharmacodynamic Study of Pre-Prostatectomy Rapamycin in Men With Advanced Localized Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Prostate Cancer
Keywords: stage III prostate cancer
stage I prostate cancer
stage IIB prostate cancer
stage IIA prostate cancer
adenocarcinoma of the prostate
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-04-06
Enrollment: 32
Sex: MALE
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as sirolimus, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This clinical trial is studying the best dose of sirolimus and to see how well it works before surgery in treating patients with advanced localized prostate cancer.

Detailed description: OBJECTIVES:

Primary

* Determine the pharmacodynamically optimal dose (POD) of continuous daily oral sirolimus (rapamycin) in patients with advanced localized prostate cancer when given prior to radical prostatectomy, as measured by tumor S6 kinase inhibition by immunohistochemistry (IHC).
* Determine the proportion of men with downstream target inhibition in prostate tumor tissue at the POD using paired tumor biopsies from before and after rapamycin administration.
* Correlate tumor pharmacodynamic (PD) efficacy with a surrogate marker of tumor PD efficacy, peripheral blood mononuclear cell (PBMC) S6 kinase activity inhibition.

Secondary

* Characterize the serum and prostate tissue pharmacokinetics of daily oral rapamycin at 2 dose levels.
* Determine the relationship of PD target inhibition of S6 kinase activity with pretreatment Akt activity and PTEN loss by IHC in prostate cancer.
* Describe the relationship between PD inhibition with the mTOR inhibitor rapamycin and pretreatment prostate biopsy Gleason sum, Ki-67 index of proliferation, Akt activity, p27 IHC, and PTEN.
* Correlate PD efficacy as measured by downstream S6 kinase activity inhibition with markers of increased apoptosis (activated caspase 3) and reduction in markers of proliferation (change in Ki-67) in prostate tumor specimens.
* Quantify and characterize the toxicity of daily continuous rapamycin at 2 dose levels in generally healthy men with prostate cancer prior to surgery.
* Evaluate the activity of rapamycin in prostate cancer as measured in prostate specific antigen response prior to surgery.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive oral sirolimus (rapamycin) once daily on days 1-14 in the absence of unacceptable toxicity.

Cohorts of 12-21 patients receive escalating doses of rapamycin until the pharmacodynamically optimal dose is determined.

Patients undergo radical prostatectomy on day 15.

Patients undergo blood collection and tumor biopsies periodically during study for pharmacologic and correlative biomarker studies.

After completion of study treatment, patients are followed at 30 and 90 days.

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically determined adenocarcinoma of the prostate

  * Stage T1c-T3b disease
  * No evidence of disease that has spread beyond the prostate or seminal vesicles
* No metastatic prostate cancer, including bone, visceral, brain, and lymph node metastases
* Tumor Gleason score sum of 7-10 (4+3 and 3+4 allowed) with tumor involving at least 2 discrete core biopsy sections
* Scheduled to undergo radical prostatectomy
* No other subtypes of prostate cancer, including any of the following:

  * Sarcoma
  * Neuroendocrine tumors
  * Small cell cancer
  * Ductal cancer
  * Lymphoma

PATIENT CHARACTERISTICS:

* ECOG performance status 0-1
* WBC \> 3,500/mm\^3
* Absolute neutrophil count \> 1,500/mm\^3
* Platelet count \> 100,000/mm\^3
* Hemoglobin \> 9 g/dL
* Creatinine \< 2.0 mg/dL
* Bilirubin \< 2 mg/dL
* ALT and AST \< 2 times upper limit of normal (ULN)
* Alkaline phosphatase \< 2 times ULN
* Triglycerides and total cholesterol \< 2 times ULN
* No history of allergy to sirolimus (rapamycin) or its derivatives
* No uncontrolled medical condition that would increase risk or limit compliance with study requirements, including the following:

  * Immunodeficiency
  * Gastrointestinal disease that would limit ability to swallow, take oral medications, or absorb them
* No active infections
* No other concurrent malignancy

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior chemotherapy, biologic therapy, radiotherapy, or immunotherapy for prostate cancer
* No concurrent chronic treatment with immunosuppressants or medications that interfere with the metabolism of sirolimus (rapamycin)
* No concurrent medication or agents that would interfere with the metabolism or excretion of rapamycin or its derivatives, including any of the following:

  * Phenytoin
  * Carbamazepine
  * Cyclosporine
  * Clarithromycin
  * Clotrimazole
  * Erythromycin
  * Amiodarone
  * Protease inhibitors used to treated HIV infection
  * Cisapride
  * Grapefruit juice
  * Diltiazem
  * Tacrolimus
  * Hypericum perforatum (St. John's wort)
  * Barbiturates
  * Rifampin
  * Phenobarbital
  * Rifabutin
  * Efavirenz
  * Nevirapine
* At least 7 days since prior herbal medicines and medications, including any of the following:

  * Hydrastis canadensis (goldenseal)
  * Uncaria tomentosa (cat's claw)
  * Echinacea angustifolia roots
  * Trifolium pretense (wild cherry)
  * Chamomile
  * Glycyrrhiza glabra (licorice)
  * Dillapiol
  * Naringenin
  * Norfloxacin
  * Atorvastatin
  * Pravastatin
  * Cimetidine
  * Fluconazole

Primary outcomes:
measure: Pharmocodynamically Optimal Dose (POD) of Rapamycin as Determined by Number of Participants With Greater Than or Equal to 60% Tumor S6 Kinase Inhibition by Immunohistochemistry (IHC).
timeFrame: Day 15 post-intervention
measure: Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD
timeFrame: Change from baseline to 15 days post-intervention
measure: Pharmacodynamic Response as Assessed by Median Post-treatment S6 Activity H-score
timeFrame: Change from baseline to 15 days post-intervention
Secondary outcomes:
measure: Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis
timeFrame: Change from baseline to 15 days post-intervention
measure: Pharmacokinetic Response of Rapamycin 6mg as Assessed by Whole Blood Analysis
timeFrame: Change from baseline to 15 days post-intervention
measure: Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC)
timeFrame: Change from baseline to 15 days post-intervention
measure: PTEN Loss as Measured by Immunohistochemistry (IHC)
timeFrame: Change from baseline to 15 days post-intervention
measure: p27 as Measured by Immunohistochemistry (IHC)
timeFrame: Change from baseline to 15 days post-intervention
measure: Change in Gleason Sum
timeFrame: Change from baseline to 15 days post-intervention
measure: Increased Apoptosis as Measured by Activated Caspase 3
timeFrame: Baseline, 14 days post-intervention, 90-days post-operative
measure: Reduction in Proliferation as Measured by Decrease in Ki-67
timeFrame: Baseline, 14 days post-intervention, 90-days post-operative
measure: Toxicity as Per National Cancer Institute Common Toxicity Criteria v3.0
timeFrame: Baseline, 14 days post-intervention, 90-days post-operative
measure: Activity of Rapamycin as Measured by Prostate Specific Antigen (PSA) Response Prior to Surgery
timeFrame: Change from baseline to Day 14
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Michael A. Carducci, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Armstrong AJ, Netto GJ, Rudek MA, Halabi S, Wood DP, Creel PA, Mundy K, Davis SL, Wang T, Albadine R, Schultz L, Partin AW, Jimeno A, Fedor H, Febbo PG, George DJ, Gurganus R, De Marzo AM, Carducci MA. A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer. Clin Cancer Res. 2010 Jun 1;16(11):3057-66. doi: 10.1158/1078-0432.CCR-10-0124. Epub 2010 May 25.