Prostate Cancer
Conditions
Keywords
stage III prostate cancer, stage I prostate cancer, stage IIB prostate cancer, stage IIA prostate cancer, adenocarcinoma of the prostate
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.
Interventions
DRUGRapamycin 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).
DRUGRapamycin 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).
PROCEDURERadical prostatectomy
Radical prostatectomy performed on Day 15
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 120 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD | Change from baseline to 15 days post-intervention | — |
| Pharmacodynamic Response as Assessed by Median Post-treatment S6 Activity H-score | 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
| Measure | Time frame | Description |
|---|---|---|
| PTEN Loss as Measured by Immunohistochemistry (IHC) | 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. |
| p27 as Measured by Immunohistochemistry (IHC) | Change from baseline to 15 days post-intervention | p27 by IHC in prostate cancer. |
| Change in Gleason Sum | Change from baseline to 15 days post-intervention | pretreatment biopsy compared to post-treatment radical prostatectomy specimen |
| Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis | Change from baseline to 15 days post-intervention | Snap-frozen prostate tissue was evaluated for tissue rapamycin levels. |
| Reduction in Proliferation as Measured by Decrease in Ki-67 | 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. |
| Toxicity as Per National Cancer Institute Common Toxicity Criteria v3.0 | 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. |
| Activity of Rapamycin as Measured by Prostate Specific Antigen (PSA) Response Prior to Surgery | Change from baseline to Day 14 | PSA response to daily rapamycin |
| Increased Apoptosis as Measured by Activated Caspase 3 | 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. |
| Pharmacokinetic Response of Rapamycin 6mg as Assessed by Whole Blood Analysis | Change from baseline to 15 days post-intervention | Snap-frozen prostate tissue was evaluated for tissue rapamycin levels. |
| Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) | 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) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Radical prostatectomy: Radical prostatectomy performed on Day 15 | 10 |
| 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).
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).
Radical prostatectomy: Radical prostatectomy performed on Day 15 | 20 |
| 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).
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).
Radical prostatectomy: Radical prostatectomy performed on Day 15 | 2 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Control Group | Total | High-dose Rapamycin (6mg) | Low-dose Rapamycin (3mg) |
|---|---|---|---|---|
| Age, Customized | 64 years | 62.5 years | 57.5 years | 61.5 years |
| Any PSA Decline | 1 Participants | 6 Participants | 1 Participants | 4 Participants |
| Biopsy Gleason sum 6 | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Biopsy Gleason sum 7 | 9 Participants | 27 Participants | 1 Participants | 17 Participants |
| Biopsy Gleason sum 8-10 | 1 Participants | 4 Participants | 1 Participants | 2 Participants |
| Body Mass Index | 28.0 kg/m2 STANDARD_DEVIATION 2.31 | 27.83 kg/m2 STANDARD_DEVIATION 4.09 | 28.7 kg/m2 STANDARD_DEVIATION 1.75 | 27.8 kg/m2 STANDARD_DEVIATION 4.95 |
| Pathologic stage T2 | 6 Participants | 18 Participants | 2 Participants | 10 Participants |
| Pathologic stage T3a | 3 Participants | 10 Participants | 0 Participants | 7 Participants |
| Pathologic stage T3b | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Pathologic stage TX N1 | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Preoperative clinical stage T1c | 6 Participants | 21 Participants | 2 Participants | 13 Participants |
| Preoperative clinical stage T2a | 0 Participants | 4 Participants | 0 Participants | 4 Participants |
| Preoperative clinical stage T2b | 3 Participants | 5 Participants | 0 Participants | 2 Participants |
| Preoperative clinical stage T2c | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Preoperative D'Amico risk High | 2 Participants | 5 Participants | 1 Participants | 2 Participants |
| Preoperative D'Amico risk Intermediate | 8 Participants | 26 Participants | 1 Participants | 17 Participants |
| Preoperative D'Amico risk Low | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Preoperative D'Amico risk Undetectable day 90 PSA | 4 Participants | 23 Participants | 2 Participants | 17 Participants |
| Race/Ethnicity, Customized African-American | 0 Participants | 4 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 10 Participants | 28 Participants | 2 Participants | 16 Participants |
| Race/Ethnicity, Customized non-Hispanic | 10 Participants | 32 Participants | 2 Participants | 20 Participants |
| Radical prostatectomy (RP) Gleason sum 6 | 3 Participants | 6 Participants | 0 Participants | 3 Participants |
| Radical prostatectomy (RP) Gleason sum 7 | 6 Participants | 23 Participants | 2 Participants | 15 Participants |
| Radical prostatectomy (RP) Gleason sum 8-10 | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 10 participants | 32 participants | 2 participants | 20 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 32 Participants | 2 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 20 | 0 / 2 |
| other Total, other adverse events | 1 / 10 | 8 / 20 | 2 / 2 |
| serious Total, serious adverse events | 0 / 10 | 0 / 20 | 2 / 2 |
Outcome results
Primary
Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD
Time frame: Change from baseline to 15 days post-intervention
Population: Only 10 participants from the low-dose arm and 8 participants from the control arm had adequate paired tissue for evaluation, due to the lack of availability or inadequacy of either biopsy or radical prostatectomy. The 2 patients from the high-dose arm did not complete due to dose-limiting toxicity.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Group | Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD | 2 percentage of S6 kinase inhibition |
| Low-dose Rapamycin (3mg) | Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD | 58 percentage of S6 kinase inhibition |
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).
Time frame: Change from baseline to 15 days post-intervention
Population: Only 9 participants from the control group and 13 participants in the low-dose arm had evaluable tissue for analysis. Participants in the high dose arm did not complete the study due to serious adverse events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Group | Pharmacodynamic Response as Assessed by Median Post-treatment S6 Activity H-score | 140 score on a scale |
| Low-dose Rapamycin (3mg) | Pharmacodynamic Response as Assessed by Median Post-treatment S6 Activity H-score | 70 score on a scale |
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).
Time frame: Day 15 post-intervention
Population: Only 10 participants from the low-dose arm and 8 participants from the control arm had adequate paired tissue for evaluation, due to the lack of availability or inadequacy of either biopsy or radical prostatectomy. The 2 patients from the high-dose arm did not complete due to dose-limiting toxicity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control Group | 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). | 1 Participants |
| Low-dose Rapamycin (3mg) | 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). | 5 Participants |
Secondary
Activity of Rapamycin as Measured by Prostate Specific Antigen (PSA) Response Prior to Surgery
PSA response to daily rapamycin
Time frame: Change from baseline to Day 14
Population: Data was not collected for this outcome measure
Secondary
Change in Gleason Sum
pretreatment biopsy compared to post-treatment radical prostatectomy specimen
Time frame: Change from baseline to 15 days post-intervention
Population: Data was not collected for this outcome measure
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.
Time frame: Baseline, 14 days post-intervention, 90-days post-operative
Population: Data was not collected for this outcome measure
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)
Time frame: Change from baseline to 15 days post-intervention
Population: Only 7 participants from the control group and 10 participants in the low-dose arm had adequate paired tissue for analysis. Participants in the high dose arm did not complete the study due to serious adverse events.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Control Group | Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) | increased AKT phosphorylation | 3 Participants |
| Control Group | Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) | decreased AKT phosphorylation | 3 Participants |
| Control Group | Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) | no change in AKT phosphorylation | 1 Participants |
| Low-dose Rapamycin (3mg) | Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) | increased AKT phosphorylation | 4 Participants |
| Low-dose Rapamycin (3mg) | Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) | decreased AKT phosphorylation | 4 Participants |
| Low-dose Rapamycin (3mg) | Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) | no change in AKT phosphorylation | 2 Participants |
Secondary
p27 as Measured by Immunohistochemistry (IHC)
p27 by IHC in prostate cancer.
Time frame: Change from baseline to 15 days post-intervention
Population: Data was not collected for this outcome measure
Secondary
Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis
Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.
Time frame: Change from baseline to 15 days post-intervention
Population: Data was not collected for this outcome measure
Secondary
Pharmacokinetic Response of Rapamycin 6mg as Assessed by Whole Blood Analysis
Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.
Time frame: Change from baseline to 15 days post-intervention
Population: 0/2 participants tolerated this dose. Therefore, data for this outcome measure was not collected.
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.
Time frame: Change from baseline to 15 days post-intervention
Population: Data was not collected for this outcome measure
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.
Time frame: Baseline, 14 days post-intervention, 90-days post-operative
Population: Data was not collected for this outcome measure
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.
Time frame: Baseline, 14 days post-intervention, 90-days post-operative
Population: Data was not collected for this outcome measure