NCT00555399终止1 期
Phase I / II Adaptive Randomized Trial of Vorinostat, Isotretinoin and Temozolomide in Adults With Recurrent Glioblastoma Multiforme
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 55
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
The goal of this clinical research study is to learn if vorinostat when given with isotretinoin and temozolomide can help to control glioblastoma or gliosarcoma. The safety of these drug combinations will also be studied.
详细描述
Study Groups:
If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 3 groups. If you are on of the first 30 participants in the study, you will be randomly assigned to a group. If you are enrolled after the first 30 participants, you will be more likely to be enrolled in the group that is showing better results.
- If you are in Group 1, you will take vorinostat and isotretinoin.
- If you are in Group 2, you will take isotretinoin and temozolomide.
- If you are in Group 3, you will take vorinostat, isotretinoin and temozolomide.
Study Drug Administration:
Each study cycle is 28 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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 with histologically proven supratentorial WHO grade IV glioma (glioblastoma or gliosarcoma) will be eligible for the study.
- •Patients must have shown unequivocal evidence for tumor recurrence or progression by MRI scan and should have failed radiation therapy. The scan done prior to study entry documenting progression will be reviewed by the treating physician to document changes in tumor dimension to confirm recurrence. Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis.
- •continued) Patients with prior therapy that included interstitial brachytherapy, Gliadel wafers or stereotactic radiosurgical procedures must have confirmation of true progressive disease rather than radiation necrosis. Such confirmation may be using advanced imaging studies (e.g. PET scans, diffusion-perfusion MRI, SPECT etc) or if available, surgical sampling and histological confirmation (surgery is not required).
- •Patients may have had up to 2 prior relapses.
- •All patients must sign an IRB approved informed consent indicating their awareness of the investigational nature of this study. Patients must have signed an authorization for the release of their protected health information.
- •The baseline on-study MRI should be performed within 14 days (+ 3 working days) prior to registration and on a steroid dosage that has been stable or decreasing for at least 5 days. If the steroid dose is increased between the date of imaging and the initiation of therapy (or at that time), a new baseline MRI is required. The same type of scan, i.e., MRI, must be used throughout the period of protocol treatment for tumor measurement.
- •Patients who have undergone recent resection of recurrent or progressive tumor will be eligible as long as they have recovered from the effects of surgery. Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual measurable disease post-operatively, a MRI should be done no later than 96 hours in the immediate post-operative period or 4-6 weeks post-operatively.
- •Patients must be 18 years old or older.
- •Patients must have a Karnofsky performance status equal or greater than
- •Patients must have recovered from the toxic effects of prior therapy to < grade 2 non hematological or grade 2 or lesser hematological toxicity per CTC ver 4 (except deep vein thrombosis): 4 weeks from prior cytotoxic therapy and/or at least two weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, cis-retinoic acid, etc. (radiosensitizer does not count). Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study
- •continued) (such as presurgically for obtaining pharmacology data for the agent) will be eligible to enter the study provided they have recovered from the toxic effects of the agent if any. Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
- •Patients must have adequate bone marrow function (ANC = or > 1,500/mm^3 and platelet count of = or > 100,000/mm^3), adequate liver function (SGPT = or < 3 times upper limit of normal and alkaline phosphatase = or < 2 times upper limit of normal, bilirubin = or <1.5 mg/dl), adequate renal function (BUN and creatinine = or <1.5 times upper limit of normal) and normal serum amylase and lipase prior to starting therapy. Elevated cholesterol and triglycerides are not a contraindication to study enrollment, but should be managed as clinically appropriate by the treating physician.
- •Patients must be willing and able to comply with the FDA mandated iPLEDGE program for treatment with isotretinoin (cRA). Patients must sign specific informed consents for treatment with cRA, as mandated by iPLEDGE guidelines. Women of childbearing potential must not be pregnant, must not be breast-feeding and must practice adequate contraception during and one month after participation in the study. Male and Female patients on treatment with vorinostat must agree to use an adequate method of contraception for the duration of the study, and for 30 days after the last dose of study medication.
- •Prior treatment with dose dense regimens of temozolomide is not allowed (e.g, 7 days on/7 days off, 21 day/28 day and daily low dose continuous dosing). However, prior treatment with standard day 1-5 dosing in the adjuvant setting and low dose daily dosing as part of chemoradiation therapy are allowed
- •Prior treatment with isotretinoin is allowed because the trial is based on the hypothesis that HDAC inhibition will potentially overcome resistance to retinoids.
排除标准
- •Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix or bladder), unless in complete remission and off of all therapy for that disease for a minimum of 3 years.
- •Patients must not have: a) active infection; b) disease that will obscure toxicity or dangerously alter drug metabolism, especially liver disease; c) serious intercurrent medical illness; d) prior treatment with HDAC inhibitors. However, patients who have received anticancer agents for non-therapeutic purposes (for eg., as part of a pharmacology study without therapeutic intent) will remain eligible for enrollment into the study.
- •Prior treatment with bevacizumab is not allowed.
- •Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor properties, will be excluded, unless they are switched to an alternative agent prior to treatment initiation. No wash out period is required.
- •Patients on previous treatment with carboplatin.
- •Patients with a known allergy to any component of vorinostat, or a known allergy to temozolomide and/or isotretinoin.
- •Patient must be able to tolerate the procedures required in this study including periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study. Inability to comply with protocol or study procedures (for example, an inability to swallow tablets) will be an exclusion criterion.
- •Patients receiving treatment with other antiepileptic medications will not be excluded. Vorinostat is not metabolized by cytochrome P450 3A4 (CYP 3A4). However, vorinostat may potentially suppress CYP 3A4 activity. Therefore, patients should preferably be treated with non-enzyme inducing anti-epileptic medications to avoid any potential interactions with vorinostat.
- •continued) However, the use of non-enzyme inducing anti-epileptic medications is not mandatory. If enzyme-inducing antiepileptic drugs are used, monitoring of drug levels should be considered, as considered clinically appropriate by the treating physician.
研究组 & 干预措施
Ph I: Arm 1
Experimental
Vorinostat plus isotretinoin
干预措施: Vorinostat (Drug)
Ph I: Arm 3
Experimental
Vorinostat plus isotretinoin plus temozolomide
干预措施: Vorinostat (Drug)
Ph I: Arm 1
Experimental
Vorinostat plus isotretinoin
干预措施: Isotretinoin (Drug)
Ph I: Arm 2
Experimental
Temozolomide plus isotretinoin
干预措施: Isotretinoin (Drug)
Ph I: Arm 2
Experimental
Temozolomide plus isotretinoin
干预措施: Temozolomide (Drug)
Ph I: Arm 3
Experimental
Vorinostat plus isotretinoin plus temozolomide
干预措施: Isotretinoin (Drug)
Ph I: Arm 3
Experimental
Vorinostat plus isotretinoin plus temozolomide
干预措施: Temozolomide (Drug)
Ph II: Arm 2
Other
Surgical Arm
干预措施: Surgical Resection (Procedure)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: 62 months
To determine the maximum tolerated dose (MTD) of vorinostat + isotretinoin (cRA), carboplatin (CBT) + cRA, and vorinostat + cRA + CBT combinations in adult patients with recurrent glioblastoma multiforme (GBM) and anaplastic gliomas. The units of measurement for the drug dose were either mg/day \[VOR and cRA\] or AUC \[CBT\]. In the outcome measure data table below we have provided the cohort number for each arm at which MTD was declared.
Phase II: To Determine the Efficacy of Vorinostat + cRA, Versus CBT + cRA, Versus Vorinostat + cRA + CBT in Patients With Recurrent Glioblastoma Multiforme as Determined by Time to Progression (TTP) Using an Adaptive Randomization Phase II Trial Design.
时间窗: two patients withdrew consents and one pt chose not to proceed with treatment
Phase II of the trial has never opened d/t Sponsor's withdrawal of the funding
次要结局
未报告次要终点
研究者
研究点 (1)
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