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A Phase II Trial of Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer

Phase 2
18 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

A Phase II Trial of Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer

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.

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

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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival

Outcome Time Frame:

3 - 6 months

Safety Issue:


Principal Investigator

Phillip G. Febbo, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Institutional Review Board

Study ID:




Start Date:

May 2009

Completion Date:

Related Keywords:

  • Prostate Cancer
  • 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
  • Prostatic Neoplasms



Duke University Medical Center Durham, North Carolina  27710
Oregon Health and Science University Portland, Oregon  97201
University of Washington/Seattle Cancer Care Alliance Seattle, Washington  98109