Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage I prostate cancer, stage II prostate cancer, stage III prostate cancer
Brief summary
RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving everolimus before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This randomized phase II trial is studying the side effects and how well everolimus works in treating patients with newly diagnosed localized prostate cancer.
Detailed description
OBJECTIVES: Primary * To determine the clinical effects of everolimus, in terms of pathologic response (i.e., histologic P0, margin status, or capsular penetration) and surgical outcome, in patients with newly diagnosed localized prostate cancer treated with two different doses of everolimus prior to radical prostatectomy. * To evaluate the safety and tolerability of this drug in these patients. Secondary * To determine the effect of this drug on prostate-specific antigen (PSA) levels in these patients. * To determine the effect of this drug on levels of expression of PTEN, Akt, phospho-mTOR (i.e., Se2448), phospho-p70 S6 kinase (i.e., Thre389), phospho-Smad3 (i.e., Ser433/435), phospho-Smads 1/5 (i.e., Ser463/465), AR, and TUNEL in these patients. OUTLINE: Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive low-dose oral everolimus once daily for up to 8 weeks in the absence of unacceptable toxicity. * Arm II: Patients receive high-dose oral everolimus once daily for up to 8 weeks in the absence of unacceptable toxicity. Within 7 days after the last dose of everolimus, all patients undergo radical prostatectomy with bilateral pelvic lymphadenectomy. Tumor biopsy specimens acquired prior to treatment and prostate tumor tissue acquired at the time of radical prostatectomy are evaluated for biomarker correlative studies. Tissue samples are assessed by immunohistochemistry (IHC) and tissue microarray analysis for expression of cellular and molecular biomarkers (i.e., p-S6, p-4E-BP1, and p-Akt) that correlate with response. Prostatectomy specimens are also assessed by pathologic analysis for histopathologic response (i.e., pathologic stage, Gleason score, margin status, and tumor size). After completion of study therapy, patients are followed at 6 weeks.
Interventions
DRUGEverolimus
Patients will receive arm-specific dosage of Everolimus daily continuously for 8 week
PROCEDUREconventional surgery
Radical prostatectomy with bilateral pelvic lymphadenectomy will be performed within 10 days of the completion of week 8 on RAD-001 (Everolimus).
Sponsors
National Cancer Institute (NCI)
Jorge A. Garcia, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed newly diagnosed, localized adenocarcinoma of the prostate, meeting any of the following criteria: * Clinical stage T2a, T2b, T2c, or T3 disease (any grade or PSA) * Gleason score 7 (4+3 only) or ≥ 8 (any stage or PSA) * Serum PSA ≥ 10 ng/dL (any grade or stage) * Any stage, PSA, or Gleason score AND ≥ 35% chance of biochemical failure at 5 years based on Kattan's nomogram * Recommended for radical prostatectomy * Normal testosterone level * No pure neuroendocrine or small cell prostate cancer * No metastatic disease by CT scan, MRI, bone scan, or X-ray * No clinical evidence of CNS metastases PATIENT CHARACTERISTICS: Inclusion criteria: * ECOG performance status (PS) 0-1 or Karnofsky PS 70-100% * ANC ≥ 1,500/μL * Platelet count ≥ 100,000/μL * Hemoglobin ≥ 8 g/dL * AST and ALT ≤ 1.5 times upper limit of normal (ULN) * Bilirubin ≤ 1.5 times ULN * Creatinine ≤ 1.5 times ULN * PT/PTT normal (no anticoagulants) * No active unresolved infection * No known HIV positivity * Fertile patients must use effective contraception during and for 6 months after completion of study therapy
Exclusion criteria
* Known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus or temsirolimus) or to its excipients * Gastrointestinal (GI) disease, condition, or symptoms that may significantly impair GI function and alter the absorption of everolimus, including any of the following: * Ulcerative disease * Uncontrolled nausea * Vomiting * Diarrhea * Malabsorption syndrome * Other active malignancy or malignancy at ≥ 30% risk for relapse after completion of therapy, except nonmelanoma skin cancer * Uncontrolled concurrent illness including, but not limited to, any of the following: * Ongoing or active infection (e.g., bacterial, viral or fungal) * Severely impaired lung function * Uncontrolled diabetes (fasting serum glucose \> 1.5 times ULN) * Liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis) * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness or social situation that would limit study compliance * Any underlying medical condition which, in the principal investigator's opinion, will make the administration of everolimus hazardous OR obscure the interpretation of adverse events PRIOR CONCURRENT THERAPY: * More than 4 weeks since major surgery * More than 3 months since finasteride * No prior or concurrent radiotherapy to the prostate gland or pelvis * No prior hormones (e.g., luteinizing hormone-releasing hormone \[LHRH\] agonists, LHRH antagonists, or antiandrogens \[e.g., bicalutamide, flutamide, or nilutamide\]) and/or PC-SPES (or PC-x product) or estrogen-containing nutraceuticals * No prior rapamycin mTOR inhibitor * No prior small bowel resection that may significantly impair GI function and alter the absorption of everolimus * No prior or concurrent immunotherapy, chemotherapy, or other investigational therapy for prostate cancer * No other concurrent investigational or commercial agents * No other concurrent anticancer agents * No concurrent, chronic treatment with systemic steroids (except inhaled or topical steroids) or another immunosuppressive agent * No concurrent live vaccines * No concurrent strong inhibitors or inducers of the isoenzyme CYP3A administered as systemic therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Are P0 (i.e., no Clinically Detectable Tumor in the Pathologic Specimen) at Surgery | After 8 weeks of therapy at the time of prostatectomy | Specimens are fixed in formalin for 24 hours.Specimens are the cut at 3 mm intervals perpendicular to the rectal surface and the sections are examined grossly and microscopically on routine Hematoxylin and Eosin stain (H&E) (pathologic complete response or P0) will be defined as responders. |
| Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity) | at daily dose for 8 weeks | Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 3.0 (CTCAEv3.0) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in PSA | Up to 16 weeks after start of study | Time-to-event data, such as change in PSA will be summarized using the method of Kaplan and Meier. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Effect of Treatment on Biological and Molecular Markers | After 8 weeks of therapy | Immunohistochemical Staining of Cellular and Molecular Markers in Prostate Tumor Tissue |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low-dose Cohort Patients will receive 5.0mg P.O. daily continuously for 8 weeks
everolimus: Low-dose Cohort: Patients will receive 5.0mg P.O. daily continuously for 8 weeks; High-dose Cohort: Patients will receive 10mg P.O. daily continuously for 8 weeks
conventional surgery: Radical prostatectomy with bilateral pelvic lymphadenectomy will be performed within 10 days of the completion of week 8 on RAD-001 (Everolimus). | 8 |
| High-dose Cohort Patients will receive 10mg P.O. daily continuously for 8 weeks
everolimus: Low-dose Cohort: Patients will receive 5.0mg P.O. daily continuously for 8 weeks; High-dose Cohort: Patients will receive 10mg P.O. daily continuously for 8 weeks
conventional surgery: Radical prostatectomy with bilateral pelvic lymphadenectomy will be performed within 10 days of the completion of week 8 on RAD-001 (Everolimus). | 9 |
| Total | 17 |
Baseline characteristics
| Characteristic | Total | Low-dose Cohort | High-dose Cohort |
|---|---|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 6.2 | 58 years STANDARD_DEVIATION 7.9 | 59 years STANDARD_DEVIATION 4.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 8 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 7 Participants | 9 Participants |
| Region of Enrollment United States | 17 participants | 8 participants | 9 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 17 Participants | 8 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 9 / 9 |
| serious Total, serious adverse events | 1 / 8 | 0 / 9 |
Outcome results
Primary
Proportion of Patients Who Are P0 (i.e., no Clinically Detectable Tumor in the Pathologic Specimen) at Surgery
Specimens are fixed in formalin for 24 hours.Specimens are the cut at 3 mm intervals perpendicular to the rectal surface and the sections are examined grossly and microscopically on routine Hematoxylin and Eosin stain (H&E) (pathologic complete response or P0) will be defined as responders.
Time frame: After 8 weeks of therapy at the time of prostatectomy
Population: Intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Cohort | Proportion of Patients Who Are P0 (i.e., no Clinically Detectable Tumor in the Pathologic Specimen) at Surgery | 0 participants |
| High-dose Cohort | Proportion of Patients Who Are P0 (i.e., no Clinically Detectable Tumor in the Pathologic Specimen) at Surgery | 0 participants |
Primary
Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity)
Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 3.0 (CTCAEv3.0)
Time frame: at daily dose for 8 weeks
Population: intention to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low-dose Cohort | Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity) | Patients with Grade 3 toxicity | 2 participants |
| Low-dose Cohort | Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity) | Patients with Grade 4 toxicity | 0 participants |
| High-dose Cohort | Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity) | Patients with Grade 3 toxicity | 1 participants |
| High-dose Cohort | Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity) | Patients with Grade 4 toxicity | 0 participants |
Secondary
Change in PSA
Time-to-event data, such as change in PSA will be summarized using the method of Kaplan and Meier.
Time frame: Up to 16 weeks after start of study
Population: One patient in the high dose cohort was not analyzed for change in PSA because they withdrew early due to progressive disease
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low-dose Cohort | Change in PSA | 3.5 ng/mL |
| High-dose Cohort | Change in PSA | 3.04 ng/mL |
Other Pre-specified
Effect of Treatment on Biological and Molecular Markers
Immunohistochemical Staining of Cellular and Molecular Markers in Prostate Tumor Tissue
Time frame: After 8 weeks of therapy