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Molecular Features and Pathways in Predicting Drug Resistance in Patients With Metastatic Castration-Resistant Prostate Cancer Receiving Enzalutamide

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02228265
Recruitment Status : Active, not recruiting
First Posted : August 29, 2014
Last Update Posted : September 23, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Tom Beer, OHSU Knight Cancer Institute

Brief Summary:
This research trial studies molecular features and pathways in predicting drug resistance in patients with castration-resistant prostate cancer that has spread to other parts of the body and who are receiving enzalutamide. Studying samples of blood and tissue in the laboratory from patients receiving enzalutamide may help doctors learn more about molecular features and pathways that may cause prostate cancer to be resistant to the drug.

Condition or disease Intervention/treatment
Castration Levels of Testosterone Castration-Resistant Prostate Carcinoma Prostate Adenocarcinoma PSA Progression Recurrent Prostate Carcinoma Stage IV Prostate Cancer Other: Cytology Specimen Collection Procedure Drug: Enzalutamide Other: Laboratory Biomarker Analysis

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the correlations between baseline molecular features and pathways and prostate-specific antigen (PSA) response (</>= 50% decline) at 12 weeks versus (vs.) baseline.

SECONDARY OBJECTIVES:

I. To assess the correlations between the baseline molecular features and pathways and progression-free survival (defined as time from day 1 of study drug treatment to date of radiographic progression or clinical progression), disease-specific survival (defined as the time from day 1 of study drug to date of death from prostate cancer), and overall survival (defined as time from day 1 of study drug treatment to date of death from any cause).

II. To assess the correlations between the baseline molecular features and pathways and time to PSA progression.

III. To identify molecular features and cellular pathways present in tumors from men with metastatic castrate-resistant prostate cancer (CRPC) that are progressing despite enzalutamide treatment.

IV. To explore correlation between baseline molecular features and pathways and objective response.

V. To assess the correlations between the baseline molecular features and pathways and degree of PSA decline at 12 weeks and maximal PSA decline observed while on study.

VI. To assess the correlations between the baseline molecular features and time on treatment.

TERTIARY OBJECTIVES:

I. To assess correlations between cell-free deoxyribonucleic acid (cfDNA) molecular features from blood and molecular features and pathways from the biopsy samples.

II. To assess correlations between cfDNA molecular features and endpoints in the primary and secondary objectives listed above.

III. To explore correlations with baseline molecular features and tissue histology.

IV. To explore correlations with baseline tissue histology and PSA change, time to PSA progression, time on treatment, progression-free survival, and overall survival.

OUTLINE:

Patients undergo collection of blood and tissue samples at baseline, during administration of enzalutamide, and after the time of disease progression for analysis via immunohistochemistry, comparative genome hybridization, and sequencing.

After completion of study, patients are followed up every 12 weeks.

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Study Type : Observational
Actual Enrollment : 65 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Identifying Mechanisms of Resistance to Enzalutamide (MDV3100) Treatment in Men With Castration-Resistant Prostate Cancer
Actual Study Start Date : March 12, 2013
Estimated Primary Completion Date : October 1, 2019
Estimated Study Completion Date : October 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Group/Cohort Intervention/treatment
Ancillary-Correlative (genetic analysis)
Patients undergo collection of blood and tissue samples at baseline, during administration of enzalutamide and after the time of disease progression for analysis via immunohistochemistry, comparative genome hybridization, and sequencing.
Other: Cytology Specimen Collection Procedure
Undergo blood and tissue collection
Other Name: Cytologic Sampling

Drug: Enzalutamide
Given PO
Other Names:
  • ASP9785
  • MDV3100
  • Xtandi

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. PSA response, a binary variable indicating whether the PSA level has declined >= 50% within 12 weeks of beginning enzalutamide treatment [ Time Frame: Within 12 weeks ]
    Will be reported with 95% exact confidence interval.


Secondary Outcome Measures :
  1. Degree of PSA decline [ Time Frame: 12 weeks ]
    Simple linear regression will be used to assess the association between molecular biomarker predictors and the continuous endpoints. Logarithm transformation or other forms of transformation may be conducted to the continuous endpoints to address the skewedness of the distributions if necessary.

  2. Disease-specific survival [ Time Frame: Time from day 1 of the study drug to date of death from prostate cancer, assessed up to 4 years ]
    Will be graphically illustrated using Kaplan-Meier plots of estimated survival distribution for patients (</>= 50%) PSA decline at 12 weeks. Log-rank test will be fitted to determine whether the estimated survival distribution of each time-to-event endpoint differs for patients with PSA decline >= 50% versus patients with PSA decline < 50%. Cox regression models will be fitted to obtain the estimated hazard ratio for each time-to-event endpoints for patients who had >= 50% PSA decline at 12 weeks versus those who had not.

  3. Maximal PSA decline observed while on study [ Time Frame: Up to 4 years ]
    Simple linear regression will be used to assess the association between molecular biomarker predictors and the continuous endpoints. Logarithm transformation or other forms of transformation may be conducted to the continuous endpoints to address the skewedness of the distributions if necessary.

  4. Molecular features [ Time Frame: Up to 4 years ]
    Will assess correlations between the baseline molecular features and time on treatment.

  5. Objective response [ Time Frame: Up to 4 years ]
    Will be summarized using the estimated proportion and 95% confidence interval. Simple logistic regression model will be used to assess the association between molecular biomarker predictors and these binary secondary endpoints.

  6. Overall survival [ Time Frame: Time from day 1 of study drug treatment to date of death from any cause, assessed up to 4 years ]
    Will be graphically illustrated using Kaplan-Meier plots of estimated survival distribution for patients (</>= 50%) PSA decline at 12 weeks. Log-rank test will be fitted to determine whether the estimated survival distribution of each time-to-event endpoint differs for patients with PSA decline >= 50% versus patients with PSA decline < 50%. Cox regression models will be fitted to obtain the estimated hazard ratio for each time-to-event endpoints for patients who had >= 50% PSA decline at 12 weeks versus those who had not.

  7. Progression for a subgroup of patients who have metastatic castration resistant prostate cancer and have received enzalutamide treatment [ Time Frame: Up to 4 years ]
    Will be summarized using the estimated proportion and 95% confidence interval. Simple logistic regression model will be used to assess the association between molecular biomarker predictors and these binary secondary endpoints.

  8. Progression-free survival [ Time Frame: Time from day 1 of study drug treatment to date of first documented radiographic progression or clinical progression, assessed up to 4 years ]
    Will be graphically illustrated using Kaplan-Meier plots of estimated survival distribution for patients (</>= 50%) PSA decline at 12 weeks. Log-rank test will be fitted to determine whether the estimated survival distribution of each time-to-event endpoint differs for patients with PSA decline >= 50% versus patients with PSA decline < 50%. Cox regression models will be fitted to obtain the estimated hazard ratio for each time-to-event endpoints for patients who had >= 50% PSA decline at 12 weeks versus those who had not.

  9. Time to PSA progression [ Time Frame: Up to 4 years ]
    Will be graphically illustrated using Kaplan-Meier plots of estimated survival distribution for patients (</>= 50%) PSA decline at 12 weeks. Log-rank test will be fitted to determine whether the estimated survival distribution of each time-to-event endpoint differs for patients with PSA decline >= 50% versus patients with PSA decline < 50%. Cox regression models will be fitted to obtain the estimated hazard ratio for each time-to-event endpoints for patients who had >= 50% PSA decline at 12 weeks versus those who had not.


Biospecimen Retention:   Samples With DNA
Tissue and blood


Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with prostate cancer treated at Oregon Health and Science University Knight Cancer Institute
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
  • Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical castration); for patients who have not had an orchiectomy, there must be a plan to maintain effective GnRH-analogue therapy for the duration of the trial
  • Radiographic evidence of regional or distant metastases with suspected tumor in an area that is safe to biopsy
  • Willingness to undergo a tumor biopsy at baseline and at disease progression
  • Serum testosterone level < 50 ng/dL at screening
  • Progressive disease by PSA or imaging in the setting of medical or surgical castration; disease progression for study entry is defined as one or more of the following three criteria:

    • PSA progression defined by a minimum of three rising PSA levels with an interval of >= 1 week between each determination; the PSA value at screening should be >= 2 ug/L (2 ng/ml)
    • Soft tissue disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
    • Bone disease progression defined by two or more new lesions on bone scan
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Clinically able, in the opinion of the investigator, to receive MDV3100 (enzalutamide)
  • Willing and able to give informed consent
  • A minimum of 4 weeks elapsed off of anti-androgen therapy prior to enrollment for flutamide and 6 weeks for bicalutamide and nilutamide without evidence of an anti-androgen withdrawal response; patients who NEVER HAD A PSA decline with the most recent anti-androgen therapy or in whom the response to the most recent anti-androgen was for < 3 months require only a 2 week washout period prior to first dose of study drug

Exclusion Criteria:

  • Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, would make the patient inappropriate for enrollment
  • Metastases in the brain or active epidural disease (NOTE: patients with treated epidural disease are allowed)
  • Platelet count < 75,000/uL
  • Prothrombin time (PT) or international normalized ratio (INR) and a partial thromboplastin time PTT > 1.5 times the institutional upper limit of normal (ULN)
  • Structurally unstable bone lesions suggesting impending fracture
  • Previous treatment with MDV3100, ARN-509, or BMS-641988
  • Medical contraindications to stopping aspirin, Coumadin or other anticoagulants for 1 week prior to image-guided tumor biopsies
  • Plans to initiate treatment with an investigational agent while on study prior to discontinuation of MDV3100 treatment
  • A second active malignancy except adequately treated non-melanoma skin cancer or other non-invasive or in situ neoplasm

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02228265


Locations
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United States, California
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States, 90095
UCSF Medical Center-Mount Zion
San Francisco, California, United States, 94115
United States, Oregon
OHSU Knight Cancer Institute
Portland, Oregon, United States, 97239
Sponsors and Collaborators
OHSU Knight Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Joshi Alumkal OHSU Knight Cancer Institute

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Responsible Party: Tom Beer, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT02228265    
Other Study ID Numbers: IRB00009259
NCI-2014-01438 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MR00046920
IRB00009259 ( Other Identifier: OHSU Knight Cancer Institute )
P30CA069533 ( U.S. NIH Grant/Contract )
First Posted: August 29, 2014    Key Record Dates
Last Update Posted: September 23, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Carcinoma
Prostatic Neoplasms
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases