A Phase 0 Study of AZD1775 in Preoperative Glioblastoma Multiforme (GBM) Patients Scheduled for Resection to Evaluate for Central Nervous System (CNS) Penetration
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Plasma concentration of AZD1775 following single dose of AZD1775
研究概览
简要总结
This study would test how much of the new drug, AZD1775, is present in tumor, blood, and skin after one dose of the drug.
The purpose of the study is not to treat the tumor, but to see if the drug actually gets into the tumor cells. This study does not replace routine cancer treatment.
详细描述
Patients will be administered one dose of AZD1775 prior to surgical resection of their tumor. There will be 2 portions of this trial, referred to as Part 1 and Part 2. Part 1 will involve a dose escalation strategy where 3 separate doses (100, 200, and 400mg) will be evaluated. Each dose cohort will involve 4 patients. Surgery, with tissue harvest for determination of both tissue drug level and biomarker evaluation, will occur at 8 hrs post drug administration.
Part 2 will determine the potential tumor drug level and PD effects at various time intervals after drug administration of a single select drug dose. Currently, we are planning to use a dose (200 mg) that has been deemed safe when used in combination with cytotoxic therapy. However, if results from Part 1 suggest an alternate dose may be preferable, we will consider using that alternate dose in Part 2. Dosing will be followed by surgical resection at 2-4 hrs and at 22-26 hrs post dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with 1 prior resection of histologically-diagnosed de novo GBM
- •Patient must have MRI evidence of disease recurrence
- •Patients must have Eastern Cooperative Oncology Group (ECOG) performance status ≤2
- •Patients ≥ 18 years of age
- •Adequate hematologic, renal, and hepatic function
- •Patients must not have co-morbid condition(s) that, at the opinion of the investigator, prevent safe surgical treatment
- •Patients must not have active infection or fever > 38.5°C
- •Patients must not be pregnant or nursing
- •Patients must have archival tumor tissue block available for research use
- •Ability to understand and the willingness to sign a written informed consent document.
- •Patient has voluntarily agreed to participate by giving written informed consent.
排除标准
- •Less than 18 years of age
- •Diagnosis of anything other than first-recurrence GBM
- •GBM tissue from first-resection not available
- •Previous treatment with AZD1775
- •Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Patient has known hypersensitivity to the components of potential study therapy or its analogs.
- •Patient has had prescription or non-prescription drugs or other products known to be metabolized by cytochrome P450 3A4 (CYP3A4), or to inhibit or induce CYP3A4, which cannot be discontinued prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study medication (inhibitors generally for 5 half-lives). Medications of particular concern are the following inhibitors of CYP3A4: azole antifungals (ketoconazole itraconazole, fluconazole and voriconazole), macrolide antibiotics (erythromycin, clarithromycin), cimetidine, HIV protease inhibitors, nefazodone and the following inducers of CYP3A4: phenytoin, barbiturates and rifampicin. Substrates of CYP3A4 include statins (lovastatin, simvastatin), midazolam, terfenadine, astemizole, and cisapride. CYP3A
- •Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.
- •Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse.
- •Patients expecting to reproduce within the projected duration of the study (estimated to be 1 year), and women who are pregnant or breastfeeding.
- •Patient is known to be suffering from Acquired Immune Deficiency Syndrome (AIDS).
- •Patient has known history of Hepatitis B or C.
- •Patient has symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions is eligible.
- •Patient has a clinical history suggestive of Li-Fraumeni Syndrome.
结局指标
主要结局
Plasma concentration of AZD1775 following single dose of AZD1775
时间窗: at baseline, 2-4, 8-12, and 22-26 hours following single dose of AZD1775
Will be summarized using descriptive statistics
Intratumoral concentration of AZD1775
时间窗: up to day of surgery
Will be summarized using descriptive statistics
次要结局
- Presence of double-strand DNA damage (γH2AX).(at baseline and up to 26 hours post dose AZD1775)
- Degree of CDC2 (Tyr15) phosphorylation in tissue(at baseline and up to 26 hours post dosing)
- Number of GBM cells in M-phase of cell cycle (PH3)(at baseline and up to 26 hours post dose AZD1775)