Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer

Prostate Cancer Clinical Trial

Official title:

A Pharmacodynamic Study of Pre-Prostatectomy Rapamycin in Men With Advanced Localized Prostate Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00311623
• Other study ID #: J0576
• Secondary ID: P30CA006973CDR00
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: August 2006
• Est. completion date: June 2010

Study information

• Verified date: February 2019
• Source: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: June 2010
• Est. primary completion date: January 2008
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Rapamycin 3mg
Rapamycin 3mg (Wyeth Pharmaceuticals, 1mg tablets) PO once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15).
• Rapamycin 6mg
Rapamycin 6mg (Wyeth Pharmaceuticals, 2mg tablets) PO once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15).

Procedure:
• Radical prostatectomy
Radical prostatectomy performed on Day 15

Locations

Country	Name	City	State
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Duke Comprehensive Cancer Center	Durham	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 inte — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).		Day 15 post-intervention
Primary	Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD		Change from baseline to 15 days post-intervention
Primary	Pharmacodynamic Response as Assessed by Median Post-treatment S6 Activity H-score	Pharmocodynamic response was taken as =60% decrease in the H-score for S6 phosphorylation in the radical prostatectomy tumor tissue compared with the pretreatment (baseline) biopsy tumor tissue. The H-score is a semiquantitative measure of the percentage of cells scoring positive (0-100) multiplied by the intensity of staining (0-3).	Change from baseline to 15 days post-intervention
Secondary	Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis	Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.	Change from baseline to 15 days post-intervention
Secondary	Pharmacokinetic Response of Rapamycin 6mg as Assessed by Whole Blood Analysis	Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.	Change from baseline to 15 days post-intervention
Secondary	Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC)	Number of participants with change (increased, decreased or no change) in Akt phosphorylation as measured by immunohistochemistry (IHC)	Change from baseline to 15 days post-intervention
Secondary	PTEN Loss as Measured by Immunohistochemistry (IHC)	Determine the relationship of PD target inhibition of S6 kinase activity with pretreatment PTEN loss by IHC in prostate cancer.	Change from baseline to 15 days post-intervention
Secondary	p27 as Measured by Immunohistochemistry (IHC)	p27 by IHC in prostate cancer.	Change from baseline to 15 days post-intervention
Secondary	Change in Gleason Sum	pretreatment biopsy compared to post-treatment radical prostatectomy specimen	Change from baseline to 15 days post-intervention
Secondary	Increased Apoptosis as Measured by Activated Caspase 3	Correlate PD efficacy as measured by downstream S6 kinase activity inhibition with markers of increased apoptosis (activated caspase 3) in prostate tumor specimens.	Baseline, 14 days post-intervention, 90-days post-operative
Secondary	Reduction in Proliferation as Measured by Decrease in Ki-67	Correlate PD efficacy as measured by downstream S6 kinase activity inhibition with markers of reduction in markers of proliferation (change in Ki-67) in prostate tumor specimens.	Baseline, 14 days post-intervention, 90-days post-operative
Secondary	Toxicity as Per National Cancer Institute Common Toxicity Criteria v3.0	Dose-limiting toxicity was defined as grade 3/4 neutropenia with fever lasting >7 days, platelets of <100,000/mm3 or associated with bleeding, grade =3 non-hematologic toxicity, or irreversible grade 2 toxicity related to rapamycine.	Baseline, 14 days post-intervention, 90-days post-operative
Secondary	Activity of Rapamycin as Measured by Prostate Specific Antigen (PSA) Response Prior to Surgery	PSA response to daily rapamycin	Change from baseline to Day 14