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Castration-Resistant Prostate CarcinomaPhase 2NCT02099864

Genetic and Molecular Mechanisms in Assessing Response in Patients With Prostate Cancer Receiving Enzalutamide Therapy

A Phase 2 study testing Enzalutamide in people with Castration-Resistant Prostate Carcinoma and Metastatic Malignant Neoplasm in the Bone, run by OHSU Knight Cancer Institute at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This phase II trial studies genetic and molecular mechanisms in assessing response in patients with prostate cancer receiving enzalutamide therapy. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as enzalutamide, may lessen the amount of androgens made by the body. Read more about this study

Who is it for?
Ages 18 years and older, men only
What is being tested?
Enzalutamide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
2 sitesUnited States
Study dates
5 Feb 2014to 8 Jul 2024
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

  • Histologically or cytologically confirmed adenocarcinoma of the prostate without pure small cell carcinoma; patients without histologically confirmed adenocarcinoma may be eligible if both the treating physician and the study principal investigator (PI) agree that the patient's history is unambiguously indicative of advanced adenocarcinoma
  • Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical castration); patients who have not had an orchiectomy must 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:
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  • PSA evidence for progressive prostate cancer which consists of a PSA level of at least 2 ng/ml which has risen on at least 2 successive occasions, at least 1 week apart; if the confirmatory PSA value is less than the screening value, then an additional PSA value greater than #2 will be required to document progression of >= 1 week
  • PSA values to be obtained >= 1 week apart
  • 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
  • Patient's physician has already recommended enzalutamide for treatment of progression
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Willing and able to give informed consent
  • Estimated life expectancy >= 6 months
  • Subjects who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 1 week after last study drug administration
  • 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
  • A minimum of 4 weeks from prior systemic anti-cancer therapies or 3 weeks for radiation treatment prior to enrollment is required

Who cannot join

  • Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, would make the patient inappropriate for enrollment
  • Previous treatment with docetaxel for metastatic prostate cancer
  • Known metastases in the brain or active epidural disease (NOTE: patients with treated epidural disease are allowed)
  • Absolute neutrophil count < 1,000/uL
  • Platelet count < 75,000/uL
  • Hemoglobin < 9 g/dL at the screening visit; (NOTE: subject may not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at the screening visit)
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  • Total bilirubin (TBL) > 2.5 times the upper limit of normal at the screening visit
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at the screening visit
  • Creatinine (Cr) > 2 mg/dL at the screening visit
  • Prothrombin time (PT) or international normalized ratio (INR) and a partial thromboplastin time (PTT) > 1.5 times the upper limit of normal
  • Previous treatment with an agent that blocks adrenal androgen synthesis (e.g. abiraterone acetate, TAK-700, TOK-001, ketoconazole) or second generation androgen receptor (AR) antagonists (e.g., BMS 641988, ARN-509,TOK-001)
  • Systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4 weeks of study drug administration are prohibited
  • Structurally unstable bone lesions suggesting impending fracture
  • Previous treatment with enzalutamide (MDV3100)
  • Medical contraindications to stopping aspirin, Coumadin or other anticoagulants prior to image-guided tumor biopsies; follow institutional guidelines when determining drugs to avoid and length of washout
  • Plans to initiate treatment with an investigational agent during the study
  • History of seizure or condition that may predispose to seizure; also, history of loss of consciousness or transient ischemic attack within 12 months of (day 1 visit)
  • Concomitant use of the strong CYP2C8 inhibitors gemfibrozil or trimethoprim (Bactrim)
  • History of known malabsorption syndrome or prior surgery(ies) that may lead to malabsorption
  • Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) within 4 weeks of study drug administration (day 1)
  • Use of the following drugs within 4 weeks of study drug administration: 5 alpha-reductase inhibitors (finasteride, dutasteride), estrogens, Cyproterone acetate, biologic, or other agents with anti-tumor activity against prostate cancer, and androgens (testosterone, dihydroepiandrosterone [DHEA], etc.)
  • A second active malignancy except adequately treated non-melanoma skin cancer or other non-invasive or in situ neoplasm

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • OHSU Knight Cancer Institute

    Portland, Oregon, 97239

  • UCSF Medical Center-Mount Zion

    San Francisco, California, 94115

Other trials in United States

About this study

Official title: Molecular Mechanisms Underlying Tumor Progression Despite Enzalutamide Treatment

This phase II trial studies genetic and molecular mechanisms in assessing response in patients with prostate cancer receiving enzalutamide therapy. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as enzalutamide, may lessen the amount of androgens made by the body. Studying samples of tissue and blood in the laboratory from patients with prostate cancer may help doctors better understand castration-resistant prostate cancer. It may also help doctors make improvements in prostate cancer treatment.

Read the detailed description

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

  1. To measure PSA change at 12 weeks and at each study visit vs. baseline after enzalutamide treatment.

II. To measure objective response after enzalutamide treatment. III. To assess the correlations between the baseline molecular features and pathways and progression-free survival, disease-specific survival, and overall survival.

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

  1. 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.

VI. To explore correlation between baseline molecular features and pathways and changes in circulating tumor cells (CTCs) counts.

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

VIII. 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.

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

EXPLORATORY OBJECTIVES:

  1. To assess correlations between cell-free deoxyribonucleic acid (DNA) (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 assess correlations between cell-free DNA and tumor molecular features and changes in PSA after discontinuing enzalutamide.

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

  1. 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 receive enzalutamide orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients undergo a tumor biopsy of a metastatic site at study entry (prior to initiation of enzalutamide) and after the time of progression. Patients may continue treatment beyond progression at the investigator's discretion.

After completion of study treatment, patients are followed up at 2-3 or 6 weeks and then every 12 weeks thereafter.

Being tested
Enzalutamide
Medical subject headings
Prostatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EnzalutamideDrug

    Also called ASP9785, MDV3100, Xtandi

    Given PO

Study groups in NCT02099864
Study groupRoleWhat they receive
Treatment (Enzalutamide)ExperimentalPatients receive enzalutamide PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo a tumor biopsy of a metastatic site at study entry (prior to initiation of enzalutamide) and after the time of progression. Per the investigator, patients may continue treatment beyond progression.
Receives: Drug: Enzalutamide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With a >= 50% Decline in Prostate-specific Antigen (PSA) Value

    The percentage of participants with a >= 50% decline in PSA values will be reported with 95% exact confidence interval. For each participant, percentage decline in PSA values are calculated as 100% times the difference between PSA values taken at baseline and 12 weeks divided by PSA values at baseline. Percentage of participants determined as 100% times the number of participants with >= 50% decline divided by overall number of participants.

    Measured: Baseline to 12 weeks

  2. Percentage of Participants With Tumor Protein 53 Gene (TP53) Copy Number Alterations and Mutations

    Evaluate the association between PSA response at 12 weeks after initiating therapy, and TP53 copy number alterations and mutations at baseline. Simple Logistic regression was planned but due to sample size we used Fisher's Exact test. Percentage of patients in each arm with TP53 copy number alterations and mutations will be reported and odds ratio with two-sided 95% confidence interval will be calculated.

    Measured: Baseline to 12 weeks

  3. Percentage of Participants With Phosphatase and Tensin Homologue Gene (PTEN) Copy Number Alterations and Mutations

    Evaluate the association between PSA response at 12 weeks after initiating therapy, and PTEN copy number alterations and mutations at baseline. Simple Logistic regression was planned but due to sample size we used Fisher's Exact test. Percentage of patients in each arm with PTEN copy number alterations and mutations will be reported and odds ratio with two-sided 95% confidence interval will be calculated.

    Measured: Baseline to 12 weeks

  4. Percentage of Participants With Retinoblastoma Gene (RB1) Copy Number Alterations and Mutations

    Evaluate the association between PSA response at 12 weeks after initiating therapy, and RB1 copy number alterations and mutations at baseline. Simple Logistic regression was planned but due to sample size we used Fisher's Exact test. Percentage of patients in each arm with RB1 copy number alterations and mutations will be reported and odds ratio with two-sided 95% confidence interval will be calculated.

    Measured: Baseline to 12 weeks

  5. Androgen Receptor (AR) Messenger RNA (mRNA) Expression

    Median AR mRNA expression between responders and non-responders.

    Measured: Baseline to 12 weeks

  6. Androgen Receptor Variant 7 (AR-V7) Expression

    Median AR-V7 expression between responders and non-responders.

    Measured: Baseline to 12 weeks

  7. Percentage of Participants With Androgen Receptor (AR) Copy Number Alterations and Mutations

    Evaluate the association between PSA response at 12 weeks after initiating therapy, and AR copy number alterations and mutations at baseline. Simple Logistic regression was planned but due to sample size we used Fisher's Exact test. Percentage of patients in each arm with AR copy number alterations and mutations will be reported and odds ratio with two-sided 95% confidence interval will be calculated.

    Measured: Baseline to 12 weeks

  8. Number of Participants With Protein Expression of AR

    The number of participants, responders and non-responders, that were found to have protein expression of AR.

    Measured: Baseline to 12 weeks

  9. Androgen Receptor (AR) Activity Level

    Median Normalized Enrichment Score (NES) AR activity levels of responders and non-responders. Gene Set Enrichment Analysis (GSEA) is used to interpret gene expression data. GSEA enrichment score (ES) reflects the degree to which a gene set (GS) is overrepresented at the top or bottom of a ranked list of genes. ES is calculated by walking down the list, increasing a running-sum statistic when a gene is in the GS and decreasing when it's not. Magnitude of increment depends on correlation of the gene with the phenotype. ES is the max deviation from zero encountered in walking the list. Positive ES indicates GS enrichment at the top of the list; negative indicates GS enrichment at the bottom. GSEA calculates NES as actual ES divided by mean (ESs against all permutations of the dataset). Low AR activity has been linked to stemness and lineage plasticity that are recognized as a cause of acquired resistance to AR-targeting therapies.

    Measured: Baseline to 12 weeks

Secondary outcomes (11)

  1. Prostate-specific Antigen (PSA) Changes

    Number of patients who achieved a 50% or greater PSA decline any time after 12 weeks post-baseline.

    Measured: Baseline to up to 5 years

  2. Percentage of Participants With an Objective Response

    The percentage of participants with an objective response will be reported with 95% exact confidence interval. Objective radiographic response is evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. For each participant, objective response is calculated as 100% times the difference between the sum of measurable target lesions at baseline and the smallest sum of measurable target lesions achieved after the initiation of therapy, divided by the sum of target lesions at baseline.

    Measured: Baseline to date of first documented radiographic objective response, assessed up to 1 year

  3. Progression-free Survival (PFS)

    Correlations between baseline molecular features and pathways and PFS will be assessed using cox regression model. In addition, Kaplan-Meier plots will be used to graphically illustrate the survival distributions across the strata of categorical molecular predictors.

    Measured: Time from day 1 of study drug treatment to date of first documented radiographic progression or clinical progression, assessed up to 5 years

  4. Disease-specific Survival (DSS)

    Correlations between baseline molecular features and pathways and DSS will be assessed using cox regression model. In addition, Kaplan-Meier plots will be used to graphically illustrate the survival distributions across the strata of categorical molecular predictors.

    Measured: Time from day 1 of study drug treatment to date of death from prostate cancer, assessed up to 5 years

  5. Overall Survival (OS)

    Correlations between baseline molecular features and pathways and OS will be assessed using cox regression model. In addition, Kaplan-Meier plots will be used to graphically illustrate the survival distributions across the strata of categorical molecular predictors.

    Measured: Time from day 1 of study drug treatment to date of death from any cause, assessed up to 5 years

  6. Time to Prostate-specific Antigen (PSA) Progression

    Correlations between baseline molecular features and pathways and time to PSA progression will be assessed.

    Measured: Up to 5 years

  7. Molecular Features and Cellular Pathways Present in Tumors That Are Progressing Despite Treatment With Enzalutamide

    Random Forests classification will be used to identify molecular features and pathways present in patients with disease progression or who discontinue Enzalutamide treatment.

    Measured: Up to 5 years

  8. Changes in Circulating Tumor Cell (CTC) Counts

    Linear regression model will be used to assess the association for changes in CTC counts from baseline and maximal prostate-specific antigen (PSA) observed while on study.

    Measured: Baseline to up to 5 years

  9. Degree of Prostate-specific Antigen (PSA) Decline

    Degree of prostate-specific antigen (PSA) change from baseline to 12 weeks. PSA at week 12 minus PSA at baseline divided by PSA at baseline and multiplied by 100%. Decline shown as negative percent and incline shown as positive percent.

    Measured: At 12 weeks

  10. Maximal Prostate-specific Antigen (PSA) Decline Observed

    Correlations between baseline molecular features and pathways and maximal PSA decline observed will be assessed. Linear regression model will be used to assess the association for changes in circulating tumor cells (CTC) counts from baseline and maximal PSA observed while on study.

    Measured: Up to 5 years

  11. Time on Treatment

    The association between molecular predictors and survival outcomes (e.g., progression-free survival [PFS], disease-free survival [DSS] and overall survival [OS]) and time on treatment will be assessed using cox regression model.

    Measured: Up to 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Mar 2014 (estimated)
  2. Study start5 Feb 2014
  3. Primary completion1 Oct 2019
  4. Study completion8 Jul 2024

Resources

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
36 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02099864
Sponsor's protocol ID
IRB00010241
Other IDs
NCI-2014-00417, IIT000800, MR00045569, IRB00010241
Status last verified
Sep 2024
First submitted
26 Mar 2014
Last updated
19 Sep 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Enzalutamide in people with Castration-Resistant Prostate Carcinoma and Metastatic Malignant Neoplasm in the Bone, run by OHSU Knight Cancer Institute at 2 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 17 inclusion and 22 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: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 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 13 Jan 2021). 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?

Percentage of Participants With a >= 50% Decline in Prostate-specific Antigen (PSA) Value (time frame: Baseline to 12 weeks). The study lists 9 primary outcomes in all. 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 NCT02099864.

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 19 Sep 2024.

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