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Prostate CancerPhase 1/2NCT00311623

Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer

A Phase 1/2 study testing Rapamycin 3mg, Rapamycin 6mg and Radical prostatectomy in people with Prostate Cancer, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 18 to 120 years, men only
Conditions the study is for
Prostate Cancer
What is being tested?
Rapamycin 3mg, Rapamycin 6mg and Radical prostatectomy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
32 participants
Where
3 sitesUnited States
Study dates
Aug 2006to Jun 2010
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 120 years
  • Men only
  • No healthy volunteers
  • Adult, Older adult

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 locations and contacts

3 sites in 1 country.

United States3 sites

  • University of Michigan Comprehensive Cancer Center

    Ann Arbor, Michigan, 48109-0942

  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

    Baltimore, Maryland, 21231

  • Duke Comprehensive Cancer Center

    Durham, North Carolina, 27710

Other trials in United States

About this study

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

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.

Read the 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
Being tested
Rapamycin 3mg, Rapamycin 6mg, Radical prostatectomy
Keywords
stage III prostate cancer, stage I prostate cancer, stage IIB prostate cancer, stage IIA prostate cancer, adenocarcinoma of the prostate
Medical subject headings
Prostatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Rapamycin 3mgDrug

    Also called sirolimus

    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 6mgDrug

    Also called sirolimus

    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 prostatectomyProcedure or surgery

    Radical prostatectomy performed on Day 15

Study groups in NCT00311623
Study groupRoleWhat they receive
Control groupActive comparatorMen >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.
Receives: Procedure: Radical prostatectomy
Low-dose Rapamycin (3mg)ExperimentalMen >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).
Receives: Drug: Rapamycin 3mg; Procedure: Radical prostatectomy
High-dose Rapamycin (6mg)ExperimentalMen >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).
Receives: Drug: Rapamycin 6mg; Procedure: Radical prostatectomy

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

    Measured: Day 15 post-intervention

  2. Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD

    Measured: Change from baseline to 15 days post-intervention

  3. 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).

    Measured: Change from baseline to 15 days post-intervention

Secondary outcomes (10)

  1. Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis

    Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.

    Measured: Change from baseline to 15 days post-intervention

  2. Pharmacokinetic Response of Rapamycin 6mg as Assessed by Whole Blood Analysis

    Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.

    Measured: Change from baseline to 15 days post-intervention

  3. 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)

    Measured: Change from baseline to 15 days post-intervention

  4. 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.

    Measured: Change from baseline to 15 days post-intervention

  5. p27 as Measured by Immunohistochemistry (IHC)

    p27 by IHC in prostate cancer.

    Measured: Change from baseline to 15 days post-intervention

  6. Change in Gleason Sum

    pretreatment biopsy compared to post-treatment radical prostatectomy specimen

    Measured: Change from baseline to 15 days post-intervention

  7. 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.

    Measured: Baseline, 14 days post-intervention, 90-days post-operative

  8. 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.

    Measured: Baseline, 14 days post-intervention, 90-days post-operative

  9. 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.

    Measured: Baseline, 14 days post-intervention, 90-days post-operative

  10. Activity of Rapamycin as Measured by Prostate Specific Antigen (PSA) Response Prior to Surgery

    PSA response to daily rapamycin

    Measured: Change from baseline to Day 14

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Apr 2006 (estimated)
  2. Study startAug 2006
  3. Primary completionJan 2008
  4. Study completionJun 2010

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
32 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00311623
Sponsor's protocol ID
J0576
Other IDs
P30CA006973, CDR0000468942, NA_00001011
Status last verified
Feb 2019
First submitted
5 Apr 2006
Last updated
22 Feb 2019
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 20501622

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Rapamycin 3mg, Rapamycin 6mg and Radical prostatectomy in people with Prostate Cancer, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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). (time frame: Day 15 post-intervention). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00311623, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Feb 2019.

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