Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer

• ClinicalTrials.gov Identifier: NCT00311623
• Recruitment Status: Completed
• First Posted: April 6, 2006
• Results First Posted: February 22, 2019
• Last Update Posted: February 22, 2019
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Prostate Cancer	Drug: Rapamycin 3mg; Drug: Rapamycin 6mg; Procedure: Radical prostatectomy	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pharmacodynamic Study of Pre-Prostatectomy Rapamycin in Men With Advanced Localized Prostate Cancer
• Actual Study Start Date: August 2006
• Actual Primary Completion Date: January 2008
• Actual Study Completion Date: June 2010

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 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.	Procedure: Radical prostatectomy; Radical prostatectomy performed on Day 15
Experimental: 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).	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).; Other Name: sirolimus; Procedure: Radical prostatectomy; Radical prostatectomy performed on Day 15
Experimental: 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).	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).; Other Name: sirolimus; Procedure: Radical prostatectomy; Radical prostatectomy performed on Day 15

Outcome Measures

Primary Outcome Measures :

1. 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). [ Time Frame: Day 15 post-intervention ]
2. Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD [ Time Frame: Change from baseline to 15 days post-intervention ]
3. Pharmacodynamic Response as Assessed by Median Post-treatment S6 Activity H-score [ Time Frame: Change from baseline to 15 days post-intervention ]
   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).

Secondary Outcome Measures :

1. Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis [ Time Frame: Change from baseline to 15 days post-intervention ]
   Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.
2. Pharmacokinetic Response of Rapamycin 6mg as Assessed by Whole Blood Analysis [ Time Frame: Change from baseline to 15 days post-intervention ]
   Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.
3. Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) [ Time Frame: Change from baseline to 15 days post-intervention ]
   Number of participants with change (increased, decreased or no change) in Akt phosphorylation as measured by immunohistochemistry (IHC)
4. PTEN Loss as Measured by Immunohistochemistry (IHC) [ Time Frame: Change from baseline to 15 days post-intervention ]
   Determine the relationship of PD target inhibition of S6 kinase activity with pretreatment PTEN loss by IHC in prostate cancer.
5. p27 as Measured by Immunohistochemistry (IHC) [ Time Frame: Change from baseline to 15 days post-intervention ]
   p27 by IHC in prostate cancer.
6. Change in Gleason Sum [ Time Frame: Change from baseline to 15 days post-intervention ]
   pretreatment biopsy compared to post-treatment radical prostatectomy specimen
7. Increased Apoptosis as Measured by Activated Caspase 3 [ Time Frame: Baseline, 14 days post-intervention, 90-days post-operative ]
   Correlate PD efficacy as measured by downstream S6 kinase activity inhibition with markers of increased apoptosis (activated caspase 3) in prostate tumor specimens.
8. Reduction in Proliferation as Measured by Decrease in Ki-67 [ Time Frame: Baseline, 14 days post-intervention, 90-days post-operative ]
   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.
9. Toxicity as Per National Cancer Institute Common Toxicity Criteria v3.0 [ Time Frame: Baseline, 14 days post-intervention, 90-days post-operative ]
   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.
10. Activity of Rapamycin as Measured by Prostate Specific Antigen (PSA) Response Prior to Surgery [ Time Frame: Change from baseline to Day 14 ]
    PSA response to daily rapamycin

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 120 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States, 21231

United States, Michigan

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States, 48109-0942

United States, North Carolina

Duke Comprehensive Cancer Center

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Michael A. Carducci, MD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

More Information

Publications of Results:

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.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00311623
• Other Study ID Numbers: J0576; P30CA006973 ( U.S. NIH Grant/Contract ); CDR0000468942 ( Other Identifier: other ); NA_00001011 ( Other Identifier: JHM IRB )
• First Posted: April 6, 2006
• Results First Posted: February 22, 2019
• Last Update Posted: February 22, 2019
• Last Verified: February 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:

stage III prostate cancer; stage I prostate cancer; stage IIB prostate cancer; stage IIA prostate cancer; adenocarcinoma of the prostate

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Prostatic Diseases; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs