A Phase I Trial of Chlorpromazine Together With Standard of Care in New Diagnosis of Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Recommended phase II dose of chlorpromazine in combination with the standard treatment protocol for glioblastoma
研究概览
简要总结
This is a phase 1 study investigating the re-purposing of chlorpromazine, combined with temozolomide and radiation in the treatment of newly diagnosed glioblastoma multiforme.
详细描述
The purpose of the study is to determine the safety and acute toxicity of chlorpromazine (CPZ) when administered throughout the standard treatment protocol for glioblastoma multiforme, as well as determine progression free survival.
Chlorpromazine (25 mg daily for the first 3 patients then dose escalate to 50 mg if no DLT) will be added to a standard of care regimen which includes radiation and adjuvant Temozolomide. Chlorpromazine treatment will continue for up to 6 cycles or until criteria for removal is met. Temozolomide is administered following standard practice adopted at the University of Iowa Hospitals and Clinics (UIHC).
Subject will have several MRI scans for disease assessment throughout the treatment. There will be 3 phases of treatment for each patient:
Concomitant Chlorpromazine- Start 7 days prior to day 1 of concurrent Temozolomide and radiation. Will continue with Chlorpromazine through radiation therapy (temozolomide will cease after 49 days)
Interim Phase- When radiation has ended, subject will take Chlorpromazine for 28 days- no Temozolomide
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
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have newly diagnosed (i.e., within 5 weeks from recent surgery), histologically or cytologically or molecularly confirmed glioblastoma, gliosarcoma, or diffuse midline glioma.
- •Diagnosis must be made by surgical biopsy or excision.
- •Therapy must begin ≤ 5 weeks after most recent surgery.
- •Age ≥ 18 years
- •ECOG performance status 0-2 (Karnofsky > 50%, see Appendix B).
- •A complete blood count and differential must be obtained within 21 days prior to radiation fraction 1, with adequate bone marrow functions as defined below:
- •Absolute neutrophil count (ANC) ≥ 1500 cells per mm^3
- •Platelets ≥ 100,000 per mm^3
- •Hemoglobin ≥ 8 g/dL
- •Plasma blood chemistries within 21 days of radiation fraction 1, as defined below:
- •Creatinine ≤ 2.0 mg/dL
- •Total bilirubin ≤ 1.5 mg/dL
- •ALT ≤ 3 times the institutional upper limit of normal
- •AST ≤ 3 times the institutional upper limit of normal
- •Patient or patient's legally authorized representative's ability to understand and willingness to sign a written informed consent document.
排除标准
- •Recurrent high-grade glioma.
- •Significant abnormalities on ECG at screening. QTcF > 450 msec for males or > 470 msec for females at screening.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or chlorpromazine.
- •Significant co-morbid central nervous system disease, including but not limited to, multiple sclerosis, Parkinson's disease, history of myasthenia gravis, or dementia.
- •Patients with prior malignancies of the same or different tumor type and patients with concurrent malignancies of the same or different tumor type whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational drug.
- •Patients who have received prior chemotherapy (including Gliadel wafers) for the current glioma
- •Prior radiation therapy to the head or neck, which would result in overlap of radiation therapy fields.
- •Patients may not be receiving any other investigational agents. Use of tumor treating fields (TTF) in adjuvant phase is permitted as per standard of care.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, hypoparathyroidism, or psychiatric illness/social situations that would limit compliance with study requirements. Uncontrolled seizures despite being on maximal anti-seizure therapy.
- •Pregnant women are excluded from this study because ionizing radiation is a known teratogen, and temozolomide is a Class D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide, breastfeeding should be discontinued if the mother is treated with temozolomide.
研究组 & 干预措施
Chlorpromazine with standard of care chemoradiation
Each patient will undergo 3 phases of treatment.
Concurrent Phase: includes concurrent radiation Monday - Friday (60 Gy total radiation dose in 2 Gy fractions), oral temozolomide (75 mg/m2/day) daily for a maximum 49 days starting Day 1 of radiation, and oral chlorpromazine (25 mg for first 3 patients, then escalate to 50 mg if no DLT) daily starting 7 days prior to radiation start.
Interim Phase: Continue oral chlorpromazine daily dose post-radiation and prior to beginning adjuvant temozolomide.
Adjuvant Phase: 28 days after radiation fini (+/- 5 business days), Start oral temozolomide (starting dose 150 mg/m2/day and escalated to 200 mg/m2/day if no treatment related adverse events noted) once daily for 5 consecutive days of a 28 day cycle, and continue oral daily chlorpromazine seven days a week per cycle. The adjuvant phase treatment will continue for up to 6 cycles. Cycle length is 28 days.
干预措施: Chlorpromazine (Drug)
Chlorpromazine with standard of care chemoradiation
Each patient will undergo 3 phases of treatment.
Concurrent Phase: includes concurrent radiation Monday - Friday (60 Gy total radiation dose in 2 Gy fractions), oral temozolomide (75 mg/m2/day) daily for a maximum 49 days starting Day 1 of radiation, and oral chlorpromazine (25 mg for first 3 patients, then escalate to 50 mg if no DLT) daily starting 7 days prior to radiation start.
Interim Phase: Continue oral chlorpromazine daily dose post-radiation and prior to beginning adjuvant temozolomide.
Adjuvant Phase: 28 days after radiation fini (+/- 5 business days), Start oral temozolomide (starting dose 150 mg/m2/day and escalated to 200 mg/m2/day if no treatment related adverse events noted) once daily for 5 consecutive days of a 28 day cycle, and continue oral daily chlorpromazine seven days a week per cycle. The adjuvant phase treatment will continue for up to 6 cycles. Cycle length is 28 days.
干预措施: Temozolomide (Drug)
Chlorpromazine with standard of care chemoradiation
Each patient will undergo 3 phases of treatment.
Concurrent Phase: includes concurrent radiation Monday - Friday (60 Gy total radiation dose in 2 Gy fractions), oral temozolomide (75 mg/m2/day) daily for a maximum 49 days starting Day 1 of radiation, and oral chlorpromazine (25 mg for first 3 patients, then escalate to 50 mg if no DLT) daily starting 7 days prior to radiation start.
Interim Phase: Continue oral chlorpromazine daily dose post-radiation and prior to beginning adjuvant temozolomide.
Adjuvant Phase: 28 days after radiation fini (+/- 5 business days), Start oral temozolomide (starting dose 150 mg/m2/day and escalated to 200 mg/m2/day if no treatment related adverse events noted) once daily for 5 consecutive days of a 28 day cycle, and continue oral daily chlorpromazine seven days a week per cycle. The adjuvant phase treatment will continue for up to 6 cycles. Cycle length is 28 days.
干预措施: Radiation Therapy (Radiation)
结局指标
主要结局
Recommended phase II dose of chlorpromazine in combination with the standard treatment protocol for glioblastoma
时间窗: 4 weeks
The study will utilize a 3+3 design, and up to 6 patients will be treated at each dose level. The recommended Phase II dose will be defined as the highest dose level for which at most 1 of 6 patients experience a dose limiting toxicity (DLT).
Safety and acute toxicity of chlorpromazine (CPZ) when administered throughout the standard treatment for glioblastoma multiforme (GBM) will be graded per NCI's Common Terminology Criteria for Adverse Events v 5.0 (CTCAE v5.0)
时间窗: First treatment through 30 days post last dose of study drug
The incidence of treatment-emergent adverse events will be summarized by system organ class and/or preferred term, type of adverse event, and severity (based on NCI CTCAE v5.0 grades)
次要结局
- Progression free survival of patients with newly diagnosed GBM treated with CPZ and standard chemoradiation 6 months from the date of surgery(2 years)
- 2-year overall survival of patients with newly diagnosed GBM treated with CPZ and standard chemoradiation 6 months from the date of surgery(2 years)
研究者
Mohammed Milhem
Clinical Professor
University of Iowa