Prostate CancerPhase 2ARSNCT00918385
Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer
A Phase 2 study testing Nilutamide and Dasatinib in people with Prostate Cancer, run by Duke University at 3 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older, men only
- Conditions the study is for
- Prostate Cancer
- What is being tested?
- Nilutamide and Dasatinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 57 participants
- Where
- 3 sitesUnited States
- Study dates
- May 2009to Aug 2013
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Duke University Medical Center
Durham, North Carolina, 27710
Oregon Health and Science University
Portland, Oregon, 97239
University of Washington/Seattle Cancer Care Alliance
Seattle, Washington, 98109
About this study
Official title: A Phase II Trial of Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer
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.
Read the 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.
- Conditions
- Prostate Cancer
- Being tested
- Nilutamide, Dasatinib
- Keywords
- 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
- Medical subject headings
- Prostatic Neoplasms, Bulbo-Spinal Atrophy, X-Linked
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NilutamideDrug
Also called Nilandron
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.
DasatinibDrug
Also called Sprycel
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.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | High Androgen Receptor (AR) activity Receives: Drug: Nilutamide |
| 2 | Active comparator | Low Androgen Receptor (AR) activity Receives: Drug: Dasatinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival (PFS)
PFS is the interval from start of monotherapy until first disease progression or death, whichever occurred first.
Measured: During monotherapy ( at least 12 weeks)
Secondary outcomes (2)
Overall Response Rate of Men With High AR Activity
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.
Measured: During monotherapy (at least 12 weeks)
Overall Response Rate of Men With Low AR Activity
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.
Measured: During dasatinib monotherapy ( at least 12 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jun 2009 (estimated)
- Study startMay 2009
- Primary completionFeb 2012
- Study completionAug 2013
Why it stopped: Permanent closure of trial to further accrual based on IDE disapproval
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Prostate CancerStudies of the same condition, open and under way.
- More trials run by Duke UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 57 participants (actual)
Sponsor and investigators
- Lead sponsor
- Duke University
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Sponsor
- Investigators
- Daniel George, MD, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00918385
- Sponsor's protocol ID
- Pro00012159
- Other IDs
- CA180-263
- Acronym
- ARS
- Status last verified
- Sep 2014
- First submitted
- 10 Jun 2009
- Last updated
- 29 Oct 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
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.
PubMed 19289629
Study at a glance
From the registry record, last updated by the sponsor on 29 Oct 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Trial of Genomic Guided Therapy With Dasatinib or Nilutamide in Metastatic Castration-Resistant Prostate Cancer
- ClinicalTrials.gov ID
- NCT00918385
- Acronym / sponsor ID
- ARS / Pro00012159
- Conditions
- Prostate Cancer
- Keywords
- hormone resistant prostate cancer, castration resistant prostate cancer, hormone refractory prostate cancer, metastatic prostate cancer, hormonal therapy, antiandrogen therapy, androgen receptor, nilutamide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Permanent closure of trial to further accrual based on IDE disapproval
- Enrolment
- 57 participants (actual)
- Lead sponsor
- Duke UniversityUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- May 2009
- Primary completion
- Feb 2012 (actual)
- Study completion
- Aug 2013 (actual)
- First posted
- 11 Jun 2009 (estimated)
- Results
- Posted 29 Oct 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Drug: NilutamideHigh Androgen Receptor (AR) activity |
| 2 | Active comparator | Drug: DasatinibLow Androgen Receptor (AR) activity |
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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.
Key exclusion criteria (15 listed)
- 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:
- History of significant bleeding disorder unrelated to cancer.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NilutamideAlso: NilandronNilutamide 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. | Drug | 1 |
| DasatinibAlso: SprycelDasatinib 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. | Drug | 2 |
Primary outcome
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.
2 secondary outcomes
Overall Response Rate of Men With High AR Activity
Time frame: During monotherapy (at least 12 weeks)
Overall Response Rate of Men With Low AR Activity
Time frame: During dasatinib monotherapy ( at least 12 weeks)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Oct 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19289629Mendiratta 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Daniel George, MD principal investigator
Duke University
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nilutamide and Dasatinib in people with Prostate Cancer, run by Duke University at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 Oct 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Oct 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression Free Survival (PFS) (time frame: During monotherapy ( at least 12 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00918385, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2014.