A Pharmacodynamic Study of Vismodegib in Men With Metastatic Castration-resistant Prostate Cancer (mCRPC) With Accessible Metastatic Lesions for Tumor Biopsy
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- The Proportion of mCRPC Patients Treated With Vismodegib Who Achieve a Pharmacodynamic (PD) Response in Tumor Biopsies
研究概览
简要总结
This is a single-arm pharmacodynamic study with mandatory metastatic tumor biopsies in men with castration-resistant prostate cancer.
The trial will evaluate the effect of vismodegib on tumor tissue in men with metastatic CRPC by obtaining tumor biopsies at baseline and after 4 weeks of treatment with vismodegib.
详细描述
The study will enroll 10 evaluable patients. Patients will receive a 30-day supply of 150 mg of vismodegib on day one of each cycle daily by mouth, beginning on Day 1, and continuously until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib or withdrawal from the study.
Tumor biopsies (nodal or visceral), skin biopsies, and CTCs will be obtained at baseline and after 4 weeks of treatment. PSA evaluations will be conducted every 4 weeks, imaging assessments (CT and Bone scan) will be conducted every 12 weeks and routine labs (blood counts and chemistry panel) will be conducted every 4 weeks.
The investigator's intent is to examine the fold change in GLI1 expression in each man following exposure to drug (comparing pre-treatment and on-treatment core biopsy samples). As secondary endpoints, the investigator will also explore clinical response (PSA responses, progression-free survival [PFS], radiographic responses), safety, and will examine changes from baseline in Gli2, PTCH1, and AKT1 mRNA levels by qRT-PCR, in situ GLI1 expression in tissue sections by mRNA in situ hybridization, and GLI1 expression in isolated circulating tumor cells (CTCs).
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
- •Men with metastatic castration-resistant prostate cancer (mCRPC), with accessible metastatic soft-tissue lesions for tumor biopsy
- •Greater than 18 years of age
- •Evidence of disease progression (PSA progression, or radiographic/clinical progression [PCWG2])
- •PSA progression is defined as at least two consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, and each value ≥ 2.0 ng/mL.
- •Radiographic progression is defined for soft tissue lesions using RECIST criteria, i.e. an increase greater than 20% in the sum of the longest diameter of all target lesions based on the smallest sum longest diameter since treatment started or the appearance of one of more new lesions with a confirmatory scan 6 or more weeks later. Radiographic progression will be defined for bone lesions as the appearance of two new lesions with a confirmatory scan performed 6 or more weeks later that shows at least 2 or more additional new lesions.
- •Presence of ≥1 metastatic site (nodal, visceral) that is amenable to core biopsy
- •Castrate serum testosterone (<50 ng/dL)
- •Prior anti-androgens are permitted but not required (2 week washout from anti-androgens)
- •Prior abiraterone and enzalutamide are permitted (2 week washout for both agents)
- •Prior immunotherapy (e.g. sipuleucel-T), and chemotherapy are permitted (4 week washout period from chemotherapy)
- •Bisphosphonates and denosumab are permitted, if on a stable dose for ≥4 weeks
- •Life expectancy ≥12 months
- •Adequate renal, liver, and bone marrow function with the following acceptable initial laboratory values:
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤ 2.5 x the upper limit of normal (ULN).
- •Total bilirubin must be ≤ 1.5 x ULN.
- •Estimated creatinine clearance using the Cockcroft-Gault formula must be > 40 mL/minute (See section 12.2 for formula)
- •Absolute neutrophil count (ANC) must be ≥ 1500/μL
- •Platelet count must be ≥ 100,000/μL
- •Willing and able to provide written informed consent and HIPAA authorization for the release of personal health information.
- •NOTE: HIPAA authorization may be either included in the informed consent or obtained separately.
- •Karnofsky Performance status/ECOG Performance Status ≥70/2 (Appendix A: Performance Status Criteria)
- •Male patients must use condoms at all times, even after a vasectomy, during sexual intercourse with female partners of reproductive potential during treatment with vismodegib and for 2 months after the last dose to avoid exposing a pregnant partner and unborn fetus to vismodegib.
排除标准
- •Current use of systemic corticosteroids (>5 mg prednisone)
- •Known brain metastases, or untreated meningeal/dural disease
- •Receiving any other investigational agents or receipt of another investigational agent within 4 weeks of study entry
- •Patients taking anticoagulants or with a history of a bleeding diathesis (due to need for visceral biopsy)
- •Use of any prohibited concomitant medications (washout period of 1 week)
- •Insufficient time from last prior regimen or radiation exposure (washout period of 4 weeks)
- •Grade > 2 treatment-related toxicity from prior therapy
- •Any other condition which, in the opinion of the Investigator, would preclude participation in this trial
研究组 & 干预措施
Vismodegib
Vismodegib Treatment arm will receive Vismodegib by mouth 150 mg daily up to 1 year.
干预措施: Vismodegib (Drug)
结局指标
主要结局
The Proportion of mCRPC Patients Treated With Vismodegib Who Achieve a Pharmacodynamic (PD) Response in Tumor Biopsies
时间窗: Up to 1 year
The primary endpoint is the proportion of mCRPC patients treated with vismodegib who achieve a pharmacodynamic (PD) response in tumor biopsies, defined as both a decrease in GLI1 mRNA greater than 1.2 times the standard deviation (SD) of the baseline values and a ≥50% (≥2-fold) reduction in GLI1 messenger ribonucleic acid (mRNA) expression in metastatic tumor biopsies after 4 weeks of treatment when comparing post-treatment biopsy to pre-treatment biopsy in the same patient.
次要结局
- The Effect of Vismodegib on PSA Responses(Up to 1 Year)
- Progression-free Survival (PFS)(Up to 1 Year)
- GLI1 Expression(Up to 1 Year)
- AKT1 Expression in Tumor Biopsies(Up to 1 Year)