Androgen Deprivation Therapy and Vorinostat Followed by Radical Prostatectomy in Treating Patients With Localized Prostate Cancer
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Purpose
This phase II trial is studying how well giving androgen deprivation therapy together with vorinostat followed by radical prostatectomy works in treating patients with localized prostate cancer. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as bicalutamide, goserelin, and leuprolide, may lessen the amount of androgens made by the body. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving androgen deprivation therapy and vorinostat before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed
| Condition | Intervention | Phase |
|---|---|---|
|
Adenocarcinoma of the Prostate Stage I Prostate Cancer Stage IIA Prostate Cancer Stage IIB Prostate Cancer Stage III Prostate Cancer |
Drug: goserelin acetate Drug: leuprolide acetate Drug: vorinostat Drug: bicalutamide Procedure: therapeutic conventional surgery Other: laboratory biomarker analysis Genetic: microarray analysis |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Neoadjuvant Androgen Depletion in Combination With Vorinostat Followed by Radical Prostatectomy for Localized Prostate Cancer: Total Androgen-Receptor Gene Expression Targeted Therapy (TARGET) |
- Pathologic complete response at the time of surgery [ Time Frame: At 12 weeks ] [ Designated as safety issue: No ]A Simon 2-stage optimal design that differentiates between response probabilities of 0.05 and 0.20 will be used in the analysis of the pathological complete response at the time of surgery (Type I error 10% and power 90%).
- Pre- and post-treatment levels of PSA, testosterone, DHT, DHEA, and DHEA-S in blood and radical prostatectomy specimens [ Time Frame: At baseline, days 1 and 15 of course 1, then days 1 of each 4-week course, and up to 1 year after surgery ] [ Designated as safety issue: No ]
- Pre- and post-treatment levels of testosterone, androstenedione, androstenediol, DHT, DHEA, and DHEA-S in prostate tissue [ Time Frame: At baseline (tumor biopsy) and post-treatment radical prostatectomy tissue ] [ Designated as safety issue: No ]
- Gene and protein expression analysis including AR target genes, PSA and TMPRSS2 (transmembrane protease, serine 2) [ Time Frame: At baseline (tumor biopsy) and post-treatment radical prostatectomy tissue ] [ Designated as safety issue: No ]Estimates and 95% confidence intervals for the proportion of patients with nondetectable levels of PSA and TMPRSS2 will be computed.
- Safety and tolerability of androgen depletion therapy in combination with vorinostat (SAHA) as assessed by physical examinations, adverse events, and laboratory assessments [ Time Frame: At days 1 and 15 of courses 1 and 2, prior to surgery, and up to 1 year ] [ Designated as safety issue: Yes ]Adverse events will be monitored at each scheduled visit and throughout the study. Toxicity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
| Estimated Enrollment: | 38 |
| Study Start Date: | November 2007 |
| Estimated Primary Completion Date: | January 2100 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (Antihormone therapy and enzyme inhibitor therapy)
Patients receive bicalutamide PO once daily for 1 month and leuprolide acetate IM or goserelin SC once a month until surgery. Patients also receive SAHA PO once daily beginning on the first day of androgen depletion therapy and continuing for up to 8 weeks or until the day of surgery. Patients then undergo an open or laparoscopic radical prostatectomy. Patients with positive surgical margins undergo immediate adjuvant external beam radiotherapy to the prostatic fossa, based on the judgment of the treating physician.
|
Drug: goserelin acetate
Given SC
Other Names:
Drug: leuprolide acetate
Given IM
Other Names:
Drug: vorinostat
Given PO
Other Names:
Drug: bicalutamide
Given PO
Other Names:
Procedure: therapeutic conventional surgery
Undergo radical prostatectomy
Other: laboratory biomarker analysis
Correlative studies
Genetic: microarray analysis
Optional correlative studies
Other Name: gene expression profiling
|
Detailed Description:
PRIMARY OBJECTIVES:
I. Determine the rate of pathologic complete response in patients with localized prostate cancer treated with androgen depletion therapy (ADT) and vorinostat (SAHA) before radical prostatectomy.
SECONDARY OBJECTIVES:
I. Determine and evaluate pre- and post-treatment levels of PSA, testosterone, DHT, DHEA, and DHEA-S in blood.
II. Determine and evaluate pre- and post-treatment levels of testosterone, androstenedione, androstenediol, DHT, DHEA, and DHEA-S in prostate tissue.
III. Determine and evaluate gene and protein expression analysis including AR target genes, PSA and TMPRSS2 (transmembrane protease, serine 2), in pre-treatment biopsy and post-treatment radical prostatectomy specimens.
IV. Perform exploratory gene microarray analysis. V. Determine and evaluate the safety and tolerability of ADT in combination with vorinostat as assessed by physical examinations, adverse events, and laboratory assessments.
OUTLINE: This is a multicenter study. Patients receive bicalutamide orally (PO) once daily for 1 month and leuprolide acetate intramuscularly (IM) or goserelin subcutaneously (SC) once a month until surgery. Patients also receive vorinostat (SAHA) PO once daily beginning on the first day of androgen depletion therapy and continuing for up to 8 weeks or until the day of surgery. Patients then undergo an open or laparoscopic radical prostatectomy. Patients with positive surgical margins undergo immediate adjuvant external beam radiotherapy to the prostatic fossa, based on the judgment of the treating physician.
Patients undergo tissue sample collection at baseline and during surgery for laboratory correlative studies. Biomarker expression analysis is performed on the samples by quantitative real time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) for HDAC-regulated target genes, AR and AR-regulated genes, PSA and TMPRSS2. If adequate material is available, fresh frozen tissue is analyzed by microarray analysis for predictors of response and resistance to therapy. Hormonal levels are also measured in these tissue samples. Patients also undergo blood sample collection periodically to measure hormone and PSA levels.
After completion of study therapy, patients are followed every 3 months for up to 1 year.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Male |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Histologically confirmed adenocarcinoma of the prostate
- At least 3 biopsy cores positive for cancer, of which at least 1 core demonstrates > 30% involvement with tumor
- Confirmation of localized disease by MRI with endorectal probe, if available
- Serum PSA < 100 ng/mL
- Candidate for radical prostatectomy
- No evidence of small cell, transitional cell, or neuroendocrine pathologic features
- No evidence of distant disease on CT scan or MRI of the abdomen and pelvis and on radionuclide bone scan (with plain film or MRI confirmation as clinically indicated)
- Karnofsky performance status 80-100%
- WBC > 3,000/µL
- Platelet count > 150,000/µL
- Creatinine < 2 mg/dL
- Bilirubin < 1.5 times upper limit of normal (ULN)
- AST/ALT < 2 times ULN
Adequate cardiac function (evidence of cardiac disease should be evaluated to determine appropriateness of patient as a surgical candidate)
- May have a history of deep vein thrombosis, pulmonary embolism, and/or cerebrovascular accident, if otherwise deemed to be suitable for radical prostatectomy
- Must use adequate contraceptive methods during and for at least 3 months after completion of study therapy
- No history of allergic reactions attributed to compounds of similar chemical or biological composition to vorinostat (SAHA)
- No concurrent uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
- No psychiatric illness/social situation that would compromise compliance with study requirements
- No currently active secondary malignancy (as determined by the treating physician) other than nonmelanoma skin cancer
- No prior hormonal therapy (e.g., 5-alpha-reductase inhibitors, gonadotropin hormone releasing analogs, steroids, megestrol acetate, or nonstudy-related antiandrogens) with the intent to treat the malignancy
- No prior chemotherapy or herbal medications administered with the intent to treat the malignancy
- At least 2 weeks since prior valproic acid
- No concurrent valproic acid to treat prostate cancer
- No other concurrent antineoplastic therapy
- Concurrent systemic anticoagulation allowed
Contacts and Locations| United States, New York | |
| Memorial Sloan Kettering Cancer Center | |
| New York, New York, United States, 10065 | |
| Principal Investigator: | Susan Slovin | Memorial Sloan-Kettering Cancer Center |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT00589472 History of Changes |
| Other Study ID Numbers: | NCI-2009-00238, 06-160, CDR0000579559, N01CM62206, N01CM62205 |
| Study First Received: | December 20, 2007 |
| Last Updated: | September 12, 2012 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Adenocarcinoma Prostatic Neoplasms Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Genital Neoplasms, Male Urogenital Neoplasms Neoplasms by Site Genital Diseases, Male Prostatic Diseases Androgens Leuprolide Goserelin Bicalutamide |
Vorinostat Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Pharmacologic Actions Antineoplastic Agents, Hormonal Antineoplastic Agents Therapeutic Uses Fertility Agents, Female Fertility Agents Reproductive Control Agents Androgen Antagonists Hormone Antagonists Histone Deacetylase Inhibitors Enzyme Inhibitors |
ClinicalTrials.gov processed this record on October 17, 2012
