Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer

NCT ID: NCT00311623

Last Updated: 2019-02-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-08-31
• Study Completion Date: 2010-06-30

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.

Conditions

Prostate Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Control group

Men >18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy.

Receive no intervention on Days 1-14. Surgery performed on Day 15.

Group Type: ACTIVE_COMPARATOR

Radical prostatectomy

Intervention Type: PROCEDURE

Radical prostatectomy performed on Day 15

Low-dose Rapamycin (3mg)

Men >18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy.

Must have adequate hepatic, renal and bone marrow function, no allergy to rapamycins, avoid medications interfering with rapamycin metabolism, no active infection, no prior therapies for prostate cancer.

Will receive rapamycin 3mg (Wyeth Pharmaceuticals, 1mg tablets) oral (PO) once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15).

Group Type: EXPERIMENTAL

Rapamycin 3mg

Intervention Type: DRUG

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).

Radical prostatectomy

Intervention Type: PROCEDURE

Radical prostatectomy performed on Day 15

High-dose Rapamycin (6mg)

Men >18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy.

Must have adequate hepatic, renal and bone marrow function, no allergy to rapamycins, avoid medications interfering with rapamycin metabolism, no active infection, no prior therapies for prostate cancer.

Will receive rapamycin 6mg (Wyeth Pharmaceuticals, 2mg tablets) oral (PO) once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15).

Group Type: EXPERIMENTAL

Rapamycin 6mg

Intervention Type: DRUG

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).

Radical prostatectomy

Intervention Type: PROCEDURE

Radical prostatectomy performed on Day 15

Interventions

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).

Intervention Type: DRUG

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).

Intervention Type: DRUG

Radical prostatectomy

Radical prostatectomy performed on Day 15

Intervention Type: PROCEDURE

Other Intervention Names

sirolimus; sirolimus

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael A. Carducci, MD

Role: PRINCIPAL_INVESTIGATOR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Locations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

Duke Comprehensive Cancer Center

Durham, North Carolina, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 20501622 (View on PubMed)

Other Identifiers

P30CA006973

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000468942

Identifier Type: OTHER

Identifier Source: secondary_id

NA_00001011

Identifier Type: OTHER

Identifier Source: secondary_id

J0576

Identifier Type: -

Identifier Source: org_study_id