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

NCT02099864 | Completed Phase 2 Results DMC FDA Drug

• 4 other identifiers: IRB00010241NCI-2014-00417IIT000800MR00045569
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 2

Brief 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. 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.

Conditions

Castration-Resistant Prostate Carcinoma; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Prostate Adenocarcinoma; Recurrent Prostate Carcinoma; Stage III Prostate Adenocarcinoma AJCC v7; Stage IV Prostate Adenocarcinoma AJCC v7

Outcome Measures

Primary Outcomes (9)

• 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.

  Baseline to 12 weeks

• 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.

  Baseline to 12 weeks

• 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.

  Baseline to 12 weeks

• 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.

  Baseline to 12 weeks

• Androgen Receptor (AR) Messenger RNA (mRNA) Expression

  Median AR mRNA expression between responders and non-responders.

  Baseline to 12 weeks

• Androgen Receptor Variant 7 (AR-V7) Expression

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

  Baseline to 12 weeks

• 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.

  Baseline to 12 weeks

• 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.

  Baseline to 12 weeks

• 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.

  Baseline to 12 weeks

Secondary Outcomes (11)

• Prostate-specific Antigen (PSA) Changes

  Baseline to up to 5 years

• Percentage of Participants With an Objective Response

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

• Progression-free Survival (PFS)

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

• Disease-specific Survival (DSS)

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

• Overall Survival (OS)

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

Study Arms (1)

Treatment (Enzalutamide)

EXPERIMENTAL

Patients 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.

Drug: Enzalutamide

Interventions

Enzalutamide DRUG

Given PO

Also known as: ASP9785, MDV3100, Xtandi

Treatment (Enzalutamide)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• OHSU Knight Cancer Institute: lead
• Astellas Pharma US, Inc.: collaborator
• Oregon Health and Science University: collaborator

Study Sites (2)

UCSF Medical Center-Mount Zion

San Francisco, California, 94115, United States

Location

OHSU Knight Cancer Institute

Portland, Oregon, 97239, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

enzalutamide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Results Point of Contact

• Title: Dr. Alexandra Sokolova, M.D.
• Organization: Oregon Health & Science University

sokolova@ohsu.edu

(503) 494-4396

Study Officials

• Alexandra Sokolova, M.D.

  OHSU Knight Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 26, 2014
• First Posted: March 31, 2014
• Study Start: February 5, 2014
• Primary Completion: October 1, 2019
• Study Completion: July 8, 2024
• Last Updated: September 19, 2024
• Results First Posted: January 13, 2021

Record last verified: 2024-09

Locations

US (2)