Molecular Mechanisms Underlying Tumor Progression Despite Enzalutamide Treatment
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 36
- 试验地点
- 2
- 主要终点
- Percentage of Participants With a >= 50% Decline in Prostate-specific Antigen (PSA) Value
研究概览
简要总结
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.
详细描述
PRIMARY OBJECTIVE:
I. 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:
I. 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- •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
- •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
研究组 & 干预措施
Treatment (Enzalutamide)
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.
干预措施: Enzalutamide (Drug)
结局指标
主要结局
Percentage of Participants With a >= 50% Decline in Prostate-specific Antigen (PSA) Value
时间窗: Baseline to 12 weeks
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.
Percentage of Participants With Tumor Protein 53 Gene (TP53) Copy Number Alterations and Mutations
时间窗: Baseline to 12 weeks
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.
Percentage of Participants With Phosphatase and Tensin Homologue Gene (PTEN) Copy Number Alterations and Mutations
时间窗: Baseline to 12 weeks
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.
Percentage of Participants With Retinoblastoma Gene (RB1) Copy Number Alterations and Mutations
时间窗: Baseline to 12 weeks
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.
Androgen Receptor (AR) Messenger RNA (mRNA) Expression
时间窗: Baseline to 12 weeks
Median AR mRNA expression between responders and non-responders.
Androgen Receptor Variant 7 (AR-V7) Expression
时间窗: Baseline to 12 weeks
Median AR-V7 expression between responders and non-responders.
Number of Participants With Protein Expression of AR
时间窗: Baseline to 12 weeks
The number of participants, responders and non-responders, that were found to have protein expression of AR.
Androgen Receptor (AR) Activity Level
时间窗: Baseline to 12 weeks
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.
Percentage of Participants With Androgen Receptor (AR) Copy Number Alterations and Mutations
时间窗: Baseline to 12 weeks
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.
次要结局
- 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)
- Time to Prostate-specific Antigen (PSA) Progression(Up to 5 years)
- Molecular Features and Cellular Pathways Present in Tumors That Are Progressing Despite Treatment With Enzalutamide(Up to 5 years)
- Changes in Circulating Tumor Cell (CTC) Counts(Baseline to up to 5 years)
- Degree of Prostate-specific Antigen (PSA) Decline(At 12 weeks)
- Maximal Prostate-specific Antigen (PSA) Decline Observed(Up to 5 years)
- Time on Treatment(Up to 5 years)
研究者
Alexandra Sokolova, M.D.
Principal Investigator
OHSU Knight Cancer Institute