Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer

Johns Hopkins Medicine

Status and phase: Completed; Phase 2; Phase 1

Conditions: Prostate Cancer

Treatments: Drug: Rapamycin 6mg; Drug: Rapamycin 3mg; Procedure: Radical prostatectomy

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00311623

J0576

P30CA006973 (U.S. NIH Grant/Contract)

NA_00001011 (Other Identifier)

CDR0000468942 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 32 patients

Sex: Male

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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32 participants in 3 patient groups

Control group

Active Comparator group

Description:

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.

Treatment:

Procedure: Radical prostatectomy

Low-dose Rapamycin (3mg)

Experimental group

Description:

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).

Treatment:

Drug: Rapamycin 3mg

Procedure: Radical prostatectomy

High-dose Rapamycin (6mg)

Experimental group

Description:

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).

Treatment:

Procedure: Radical prostatectomy

Drug: Rapamycin 6mg