Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer (ARS)
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Purpose
This is a phase II multi-center study to determine the clinical impact of using a patient-specific genomic expression signature of androgen receptor (AR) activity to determine therapy for patients with castration-resistant metastatic prostate cancer (CRPC). After patient eligibility is determined, the genomic signature will be applied to fresh frozen tissue harvested from a metastatic lesion during image-guided biopsy. After assessing for androgen receptor activity, the investigators will select patients for either continued androgen manipulation with nilutamide (high AR activity) or targeted therapy with dasatinib (low AR activity). Once patients develop a first progression on either arm, patients will receive combination therapy with dasatinib and nilutamide. The primary aim is to estimate the median progression free survival in men with CRPC treated according to tumor AR activity. The investigators hypothesize that by treating men based upon AR activity, median progression free survival (PFS) will improve from a historical median of 3.0 months to 6.0 months.
| Condition | Intervention | Phase |
|---|---|---|
|
Prostate Cancer |
Drug: Nilutamide Drug: Dasatinib |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Phase II Trial of Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer |
- Progression free survival [ Time Frame: 3 - 6 months ] [ Designated as safety issue: No ]
- Toxicity of nilutamide in men with high AR activity [ Time Frame: 3 - 6 months ] [ Designated as safety issue: Yes ]
- Toxicity of dasatinib in men with low AR activity [ Time Frame: 3 - 6 months ] [ Designated as safety issue: Yes ]
- Toxicity of the combination of nilutamide and dasatinib in men progressing on monotherapy [ Time Frame: 3 - 6 months ] [ Designated as safety issue: Yes ]
- Overall response rate (based on symptoms, prostate specific antigen (PSA), soft tissue, as defined by the PCWG2 recommendations) [ Time Frame: 3 - 6 months ] [ Designated as safety issue: No ]
- PSA response rate (Greater than 30% decline in PSA from baseline confirmed by a second PSA separated by 3-4 weeks) [ Time Frame: 3 - 6 months ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 60 |
| Study Start Date: | May 2009 |
| Primary Completion Date: | February 2012 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: 1
High Androgen Receptor (AR) activity
|
Drug: Nilutamide
Nilutamide 150mg orally each day for 28 days per cycle. After first progression, Nilutamide 150mg orally each day in combination with Dasatinib 100mg orally each day for 28 days per cycle.
Other Name: Nilandron
|
|
Active Comparator: 2
Low Androgen Receptor (AR) activity
|
Drug: Dasatinib
Dasatinib 100mg orally daily x 28 days per cycle. After first progression, Dasatinib 100mg orally each day in combination with Nilutamide 150mg orally each day for 28 days per cycle.
Other Name: Sprycel
|
Detailed Description:
Prostate cancer is the most commonly diagnosed non-cutaneous malignancy of men in the United States and remains the second leading cause of cancer-related mortality among men. Novel approaches are necessary to personalize and improve treatment. The androgen receptor (AR) plays a critical role in the normal development and function of the prostate and promotes growth in most prostate cancers. Most patients with advanced prostate cancer have cancer that will initially respond to androgen-targeting therapy (focusing on decreasing the circulating levels of testosterone which is the primary source of ligand for the AR receptor). However, castrate resistance usually develops within 18 to 24 months and the median survival of men with castration resistant prostate cancer (CRPC) ranges between 12 to 18 months. Current options are limited including: secondary hormonal manipulations, radiopharmaceuticals, and chemotherapy and only docetaxel, a taxane that targets microtubules, has been proven to prolong survival.
Importantly, it has become clear that for some patients with CRPC, the prostate tumors remain dependent on AR activity. This has been supported by studies demonstrating different genetic and metabolic mechanisms by which prostate cancer cells maintain AR activity despite low levels of circulating androgen. An assay detecting AR activity that more comprehensively reflects the variety of mechanisms by which AR activity is preserved has the potential to accurately differentiate between men who have tumors still dependent on AR activity from those that are truly independent of AR activity. The identification of patients with continued AR activity has the potential to improve response to secondary hormonal manipulations; men with tumors having low levels of AR activity are likely to require alternative approaches.
We have developed a transcriptional "signature" for AR activity with the goal of identifying the true status of AR in tumors of men with CRPC. After validating the AR signature on in vitro and human prostate samples to ensure that it accurately and reproducibly detects AR activity, we applied the AR signature to several independent datasets to determine the distribution of CRPC tumors with preserved AR activity. Interestingly, there is consistent heterogeneity with respect to predicted AR activity. While overall AR activity decreases in CRPC, there is a subgroup of patients with persistently elevated AR activity. In tumors with low AR activity, we observed that the probability of AR activity was negatively correlated with predicted SRC activity in localized prostate cancer and CRPC.
Patients with persistently high AR activity will be treated with nilutamide, an approved oral agent used in metastatic CRPC to target the AR. Patients with tumors having low AR activity will be treated with dasatinib (an oral drug known to target the SRC family kinases). As there is compelling pre-clinical evidence of interactions between the SRC pathway and AR signaling, patients failing either single agent treatment will be treated with the combination of nilutamide and dasatinib and followed again for progression.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Male |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Confirmed diagnosis of adenocarcinoma of the prostate.
- Radiographic evidence of metastatic disease amenable to image-guided biopsy.
- Testosterone <50ng/dL on androgen deprivation therapy (ADT). ADT must continue while on study.
- The patient must have discontinued antiandrogens 30 days prior to baseline PSA unless the patient did not respond to anti-androgen therapy or experienced a decline in PSA lasting < 3 months after starting antiandrogen therapy.
- Evidence of disease progression on ADT.
Patients must have adequate organ and marrow function as defined below:
- Hemoglobin >9.0g/dL (without transfusion of PRBC)
- ANC/AGC >1,500/μl
- Platelets >75,000/μl
- Total bilirubin < 2.0 times the institutional ULN
- Creatinine <1.5 times the institutional ULN
- PT or INR and aPTT < 1.5 times the institutional ULN
- AST and ALT <2.5 x ULN
- Age > 18 years
- Ability to take oral medications (pills must be swallowed whole)
- ECOG performance status 0-2
Concomitant Medications:
- Patient agrees to discontinue and not to initiate taking St. Johns Wort while receiving dasatinib therapy (discontinue St. Johns Wort at least 5 days before starting dasatinib)
- Patient agrees not to initiate IV bisphosphonates while on dasatinib. Patients on IV bisphosphonates for > 4 weeks prior to dasatinib will continue on therapy
- Men of reproductive potential who have not had a radical prostatectomy must agree to use an effective contraceptive method. Patients who have had a prostatectomy are sterile and do not need to use contraception
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have received prior treatment with nilutamide or dasatinib
- Patients who have not recovered to Grade 1 or Grade 0 from the toxic effects of prior investigational therapy, biologic therapy, hormonal therapy (other than ADT), immunotherapy, or chemotherapy
- Medical contraindications to stopping aspirin or coumadin for 1 week prior to image-guided tumor biopsy AND while on dasatinib treatment.
History of the following cardiac related conditions:
- Uncontrolled angina, congestive heart failure or MI within (6 months)
- Diagnosed congenital long QT syndrome
- Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
- Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
- Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration
- History of significant bleeding disorder unrelated to cancer.
- Concomitant use of Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (These medications can be stopped while the patient is on the protocol and the patient needs to be off the drugs for at least 7 days prior to starting dasatinib)
- Patients who have a history of amiodarone use.
- Clinically significant pericardial or pleural effusion or severe respiratory insufficiency
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (requiring antifungal, antibiotic or antiviral therapy), symptomatic congestive heart failure (NYHC II or greater, unstable angina pectoris, cardiac arrhythmia (uncontrolled SVT or any VT), or psychiatric illness/social situations that would limit compliance with study requirements.
- Patients with a medical contraindication to image-guided biopsies
Contacts and Locations| United States, North Carolina | |
| Duke University Medical Center | |
| Durham, North Carolina, United States, 27710 | |
| United States, Oregon | |
| Oregon Health and Science University | |
| Portland, Oregon, United States, 97239 | |
| United States, Washington | |
| University of Washington/Seattle Cancer Care Alliance | |
| Seattle, Washington, United States, 98109 | |
| Principal Investigator: | Phillip G. Febbo, MD | Duke University |
More Information
Publications:
| Responsible Party: | Duke University |
| ClinicalTrials.gov Identifier: | NCT00918385 History of Changes |
| Other Study ID Numbers: | Pro00012159, CA180-263 |
| Study First Received: | June 10, 2009 |
| Last Updated: | March 26, 2013 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Duke University:
|
hormone resistant prostate cancer castration resistant prostate cancer hormone refractory prostate cancer metastatic prostate cancer hormonal therapy antiandrogen therapy androgen receptor |
nilutamide dasatinib genomics genomic signature genomic predictor genomic analysis genomic expression profile |
Additional relevant MeSH terms:
|
Prostatic Neoplasms Genital Neoplasms, Male Urogenital Neoplasms Neoplasms by Site Neoplasms Genital Diseases, Male Prostatic Diseases Nilutamide Dasatinib Androgen Antagonists |
Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Pharmacologic Actions Antineoplastic Agents Therapeutic Uses Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
ClinicalTrials.gov processed this record on May 22, 2013