NCT01752491已完成1 期
A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme
Joseph J. Cullen, MD, FACS1 个研究点 分布在 1 个国家目标入组 13 人开始时间: 2013年4月1日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Number of grade 3, 4, & 5 adverse events
研究概览
简要总结
This is a phase 1 (first in man) study testing the safety of adding high dose ascorbate (vitamin C) to standard radiation and chemotherapy for initial treatment of glioblastoma multiforme (GBM).
详细描述
This phase 1 study will test the safety of adding high dose ascorbate (vitamin C) to standard chemoradiation and, after the radiation is completed, during 6 cycles of temozolomide.
Standard treatment for glioblastoma multiforme (GBM) involves surgery followed by radiation combined with temozolomide (a chemotherapy). After radiation, patients receive cycles of temozolomide (adjuvant chemotherapy)
Participants will:
- receive high doses of intravenous (IV) ascorbate three times a week during chemoradiation
- receive high doses of intravenous (IV) ascorbate twice a week during adjuvant chemotherapy (after radiation)
This is a phase 1 study will evaluate the side effects of adding this drug to the standard therapy. The dose given to a participant will be determined by how well other participants have tolerated the drug.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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), histologically or cytologically confirmed glioblastoma multiforme.
- •Diagnosis must be made by surgical biopsy or excision.
- •Therapy must begin ≤ 5 weeks after surgery.
- •Age ≥ 18 years
- •ECOG performance status 0-2 (Karnofsky > 50%).
- •A complete blood count and differential must be obtained within 21 days prior to the first dose of radiation, with adequate bone marrow functions as defined below:
- •Absolute neutrophil count (ANC) ≥ 1500 cells per mm3
- •Platelets ≥ 100,000 per mm3
- •Hemoglobin ≥ 8 g/dL
- •Serum blood chemistries within 21 days before the first day of radiation, as defined below:
- •Creatinine ≤ 2.0 mg
- •Total bilirubin ≤ 1.5 mg/dL
- •ALT (Alanine Aminotransferase)≤ 3 times the institutional upper limit of normal
- •AST (Aspartate Aminotransferase) ≤ 3 times the institutional upper limit of normal
- •Tolerate one text dose (15g) of ascorbate
- •Not pregnant
- •Ability to understand and willingness to sign a written informed consent document
排除标准
- •Recurrent high grade glioma
- •G6PD (glucose-6-phosphate dehydrogenase) deficiency
- •Patients actively receiving insulin unless approved by the study medical monitor, study sponsor, and the study principal investigator.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide.
- •Significant co-morbid central nervous system disease, including but not limited to, multiple sclerosis.
- •Patients who are on the following drugs and cannot have a drug substitution: flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs.
- •Prior invasive malignancies (except non-melanomatous skin cancers and carcinoma in situ of the cervix or bladder) unless disease free for ≥ 5 years.
- •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.
- •Uncontrolled intercurrent 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.
- •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.
- •Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 (an enzyme pathway) inducer, which results in lower serum levels of antiretroviral drugs
研究组 & 干预措施
15g Ascorbate
Experimental
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gray / fraction / day), 5 days/week, for approximately 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once daily, every day, until radiation is completed.
- Ascorbate: 15 g administered by IV three times a week until 1 month after radiation is completed (approximately 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Ascorbate (Drug)
15g Ascorbate
Experimental
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gray / fraction / day), 5 days/week, for approximately 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once daily, every day, until radiation is completed.
- Ascorbate: 15 g administered by IV three times a week until 1 month after radiation is completed (approximately 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Temozolomide (Drug)
15g Ascorbate
Experimental
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gray / fraction / day), 5 days/week, for approximately 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once daily, every day, until radiation is completed.
- Ascorbate: 15 g administered by IV three times a week until 1 month after radiation is completed (approximately 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Radiation therapy (Radiation)
25g Ascorbate
Experimental
If the 15g arm is tolerated, the study opens the 25g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 25 g administered by IV three times/wk until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Ascorbate (Drug)
25g Ascorbate
Experimental
If the 15g arm is tolerated, the study opens the 25g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 25 g administered by IV three times/wk until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Temozolomide (Drug)
25g Ascorbate
Experimental
If the 15g arm is tolerated, the study opens the 25g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 25 g administered by IV three times/wk until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Radiation therapy (Radiation)
50g arm
Experimental
If the 25g arm is tolerated, the study opens the 50g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 50 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Ascorbate (Drug)
50g arm
Experimental
If the 25g arm is tolerated, the study opens the 50g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 50 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Temozolomide (Drug)
50g arm
Experimental
If the 25g arm is tolerated, the study opens the 50g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 50 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Radiation therapy (Radiation)
62.5g
Experimental
If the 50g arm is tolerated, the study opens the 62.5g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 62.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Ascorbate (Drug)
62.5g
Experimental
If the 50g arm is tolerated, the study opens the 62.5g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 62.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Temozolomide (Drug)
62.5g
Experimental
If the 50g arm is tolerated, the study opens the 62.5g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 62.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Radiation therapy (Radiation)
75g Ascorbate
Experimental
If the 62.5g arm is tolerated, the study opens the 75g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 75 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Ascorbate (Drug)
75g Ascorbate
Experimental
If the 62.5g arm is tolerated, the study opens the 75g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 75 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Temozolomide (Drug)
75g Ascorbate
Experimental
If the 62.5g arm is tolerated, the study opens the 75g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 75 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Radiation therapy (Radiation)
87.5g Ascorbate
Experimental
If the 75g arm is tolerated, the study opens the 87.5g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 87.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Ascorbate (Drug)
87.5g Ascorbate
Experimental
If the 75g arm is tolerated, the study opens the 87.5g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 87.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Temozolomide (Drug)
87.5g Ascorbate
Experimental
If the 75g arm is tolerated, the study opens the 87.5g arm.
During radiation therapy:
- Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks.
- Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed.
- Ascorbate: 87.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks).
After radiation therapy:
- Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles.
- Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
干预措施: Radiation therapy (Radiation)
结局指标
主要结局
Number of grade 3, 4, & 5 adverse events
时间窗: Weekly during therapy for up to 10 months
Assess grade 3 and higher adverse events. Evaluate the frequency and severity against the published literature to determine the likely causality between ascorbate and the adverse event(s).
次要结局
- Time to progression(monthly up to 5 years post treatment)
- Overall survival(Up to 5 years)
研究者
John M. Buatti
Professor and Chair, Department of Radiation Oncology
University of Iowa
研究点 (1)
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