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Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer (ARS)

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ClinicalTrials.gov Identifier: NCT00918385
Recruitment Status : Terminated (Permanent closure of trial to further accrual based on IDE disapproval)
First Posted : June 11, 2009
Results First Posted : October 29, 2014
Last Update Posted : October 29, 2014
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Duke University

Tracking Information
First Submitted Date  ICMJE June 10, 2009
First Posted Date  ICMJE June 11, 2009
Results First Submitted Date  ICMJE September 11, 2014
Results First Posted Date  ICMJE October 29, 2014
Last Update Posted Date October 29, 2014
Study Start Date  ICMJE May 2009
Actual Primary Completion Date February 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 28, 2014)
Progression Free Survival (PFS) [ Time Frame: During monotherapy ( at least 12 weeks) ]
PFS is the interval from start of monotherapy until first disease progression or death, whichever occurred first.
Original Primary Outcome Measures  ICMJE
 (submitted: June 10, 2009)
Progression free survival [ Time Frame: 3 - 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2014)
  • Overall Response Rate of Men With High AR Activity [ Time Frame: During monotherapy (at least 12 weeks) ]
    Tumor response was based on Response Criteria in Solid Tumors (RECIST). Complete response (CR) is defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
  • Overall Response Rate of Men With Low AR Activity [ Time Frame: During dasatinib monotherapy ( at least 12 weeks) ]
    Tumor response is based on Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2009)
  • Toxicity of nilutamide in men with high AR activity [ Time Frame: 3 - 6 months ]
  • Toxicity of dasatinib in men with low AR activity [ Time Frame: 3 - 6 months ]
  • Toxicity of the combination of nilutamide and dasatinib in men progressing on monotherapy [ Time Frame: 3 - 6 months ]
  • Overall response rate (based on symptoms, PSA, soft tissue, as defined by the PCWG2 recommendations) [ Time Frame: 3 - 6 months ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer
Official Title  ICMJE A Phase II Trial of Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Prostate Cancer
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • Active Comparator: 1
    High Androgen Receptor (AR) activity
    Intervention: Drug: Nilutamide
  • Active Comparator: 2
    Low Androgen Receptor (AR) activity
    Intervention: Drug: Dasatinib
Publications * Mendiratta P, Mostaghel E, Guinney J, Tewari AK, Porrello A, Barry WT, Nelson PS, Febbo PG. Genomic strategy for targeting therapy in castration-resistant prostate cancer. J Clin Oncol. 2009 Apr 20;27(12):2022-9. doi: 10.1200/JCO.2008.17.2882. Epub 2009 Mar 16.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 28, 2014)
57
Original Estimated Enrollment  ICMJE
 (submitted: June 10, 2009)
60
Actual Study Completion Date  ICMJE August 2013
Actual Primary Completion Date February 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Confirmed diagnosis of adenocarcinoma of the prostate.
  2. Radiographic evidence of metastatic disease amenable to image-guided biopsy.
  3. Testosterone <50ng/dL on androgen deprivation therapy (ADT). ADT must continue while on study.
  4. 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.
  5. Evidence of disease progression on ADT.
  6. 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
  7. Age > 18 years
  8. Ability to take oral medications (pills must be swallowed whole)
  9. ECOG performance status 0-2
  10. 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
  11. 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
  12. Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  1. Patients who have received prior treatment with nilutamide or dasatinib
  2. 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
  3. Medical contraindications to stopping aspirin or coumadin for 1 week prior to image-guided tumor biopsy AND while on dasatinib treatment.
  4. 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
  5. History of significant bleeding disorder unrelated to cancer.
  6. 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)
  7. Patients who have a history of amiodarone use.
  8. Clinically significant pericardial or pleural effusion or severe respiratory insufficiency
  9. 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.
  10. Patients with a medical contraindication to image-guided biopsies
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00918385
Other Study ID Numbers  ICMJE Pro00012159
CA180-263
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Duke University
Study Sponsor  ICMJE Duke University
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Daniel George, MD Duke University
PRS Account Duke University
Verification Date September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP