Phase I / II Adaptive Randomized Trial of Vorinostat, Erlotinib and Temozolomide in Adults With Recurrent Glioblastoma Multiforme
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Vorinostat in Combination With Escalating Doses of Erlotinib and Temozolomide
研究概览
简要总结
Phase I Objectives:
-To determine the maximum tolerated dose (MTD) of vorinostat + erlotinib versus vorinostat + erlotinib + temozolomide in adult patients with recurrent glioblastoma multiforme (GBM) and anaplastic gliomas.
Phase II Objectives:
Primary: To determine the efficacy of vorinostat + erlotinib versus vorinostat + erlotinib + temozolomide in patients with recurrent glioblastoma multiforme as progression free survival using a two arm adaptive randomization phase II trial design.
Secondary: To determine the radiological response, progression free survival (PFS) at 6 months, overall survival and unexpected toxicity in the two treatment arms; and to obtain exploratory data regarding histone 3 and 4 acetylation, treatment related changes in the epidermal growth factor receptor (EGFR) pathway proteins, and changes in e-cadherin and vimentin expression (mRNA /protein) levels in tumor tissue and peripheral monocytes in a subset of surgical patients.
详细描述
Phase I:
The Study Drugs:
Vorinostat is designed to cause chemical changes in different groups of proteins that are attached to DNA (the genetic material of cells), which may slow the growth of cancer cells or cause the cancer cells to die.
Erlotinib is designed to block the activity of a protein found on the surface of many tumor cells that may control tumor growth and survival. This may stop tumors from growing.
Temozolomide is designed to kill cancer cells by damaging DNA (the genetic material of cells). The damaged DNA may cause tumor cell death.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 with histologically proven glioblastoma multiforme, gliosarcoma or anaplastic glioma will be eligible for the Phase I component. Anaplastic gliomas include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), or malignant glioma not otherwise specified (NOS). Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made. Only patients with histologically proven supratentorial glioblastoma multiforme or gliosarcoma will be eligible for the Phase II component.
- •Patients must have shown unequivocal evidence for tumor recurrence or progression by MRI scan and should have failed radiation therapy. Patients should have completed radiation therapy at least 3 months prior to entry into the study. 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.
- •continued) Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have reasonable confirmation of true progressive disease rather than radiation necrosis as determined by the treating physician and neuro-radiologist; for example, through MRI, magnetic resonance (MR) spectroscopy, or PET scan of the brain.
- •For the Phase I component, any number of prior relapses is allowed, provided the patient fulfills all other eligibility criteria particularly that of the functional status. For the phase II component, patients may have had up to 2 prior relapses
- •All patients must sign an informed consent indicating their awareness of the investigational nature of this study in keeping with the policies of this hospital.
- •The baseline on-study MRI should be performed within 14 days (+/- 3 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 having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: a) They have recovered from the effects of surgery. b) Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study. c) 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 (KPS) equal or greater than 60
- •Patients must have recovered from the toxic effects of prior therapy to grade 1 non hematological or </= grade 2 hematological toxicity (except deep vein thrombosis): 4 weeks from prior cytotoxic therapy or bevacizumab 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).
- •continued) Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study (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>/= 1,500/mm^3 and platelet count of >/= 100,000/mm^3), adequate liver function (SGPT </= 3 times normal and alkaline phosphatase </= 2 times normal, bilirubin </= 1.5 mg/dl), adequate renal function (BUN and creatinine </= 1.5 times institutional normal) prior to registration.
- •Women of childbearing potential on treatment must not be pregnant, must not be breast-feeding and must practice adequate contraception. Male 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.
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 are ineligible.
- •Patients must not have: a) active infection b) disease that will obscure toxicity or dangerously alter drug metabolism, especially liver disease including cirrhosis or hepatic dysfunction c) serious intercurrent medical illness
- •Patients who are currently on active treatment for AIDS or hepatitis will be excluded due to the potential for adverse interaction with ongoing treatment agents and for unknown toxicity.
- •Patients receiving valproic acid (VPA), an anticonvulsant drug with histone deacetylase (HDAC) inhibitor properties, will be excluded, unless they are switched to an alternative agent prior to treatment initiation. A 5 day wash out period is required.
- •Prior treatment with EGFR inhibitors or temozolomide on a standard day 1-5 dosing and low dose daily dosing as part of chemoradiation therapy is allowed because the trial is based on the hypothesis that the combination of agents used will be synergistic in their effects, and that HDAC inhibition will potentially overcome resistance to EGFR inhibitors and temozolomide. However, prior treatment with dose dense regimens of temozolomide (7 days on/ 7 days off, 21 days/28 days or continuous low dose daily dosing not with chemoradiation) and HDAC inhibitors other than valproic acid (such as depsipeptide, LBH-589 or vorinostat) are not permitted.
- •Patients with a known allergy to any component of vorinostat, or a known allergy to Temozolomide or erlotinib will be excluded.
- •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 criteria.
- •This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender.
- •No exclusion to this study will be based on race. The malignant glioma patient population treated at MD Anderson Cancer Center (MDACC) over the past year is as follows: American Indian or Alaskan Native - 0; Asian or Pacific Islander - <2%; Black, not of Hispanic Origin - 3%; Hispanic - 6%; White, not of Hispanic Origin - 88%; Other or Unknown - 2%; Total-100%.
研究组 & 干预措施
Phase I Group 1: Vorinostat + Erlotinib + Temozolomide
Phase I 3-Drug Combination Vorinostat with Erlotinib + Temozolomide
Starting doses Vorinostat 200 mg orally twice daily on Days 1-7 and 15-21 of every cycle; Erlotinib 200 mg orally once daily on Days 1-21; Temozolomide 125 mg/m^2 orally once daily on Days 1-7 and 15-21.
干预措施: Vorinostat (Drug)
Phase I Group 1: Vorinostat + Erlotinib + Temozolomide
Phase I 3-Drug Combination Vorinostat with Erlotinib + Temozolomide
Starting doses Vorinostat 200 mg orally twice daily on Days 1-7 and 15-21 of every cycle; Erlotinib 200 mg orally once daily on Days 1-21; Temozolomide 125 mg/m^2 orally once daily on Days 1-7 and 15-21.
干预措施: Erlotinib (Drug)
Phase I Group 1: Vorinostat + Erlotinib + Temozolomide
Phase I 3-Drug Combination Vorinostat with Erlotinib + Temozolomide
Starting doses Vorinostat 200 mg orally twice daily on Days 1-7 and 15-21 of every cycle; Erlotinib 200 mg orally once daily on Days 1-21; Temozolomide 125 mg/m^2 orally once daily on Days 1-7 and 15-21.
干预措施: Temozolomide (Drug)
Phase I Group 2: Vorinostat + Erlotinib
This Phase I arm to be activated only after completion of Part A of the Phase II trial of the 3-Drug combination. If part A of the Phase II trial shows lack of efficacy, trial will be terminated.
Vorinostat orally twice daily, Days 1-14; and Erlotinib orally once daily Days 1-21 of every cycle.
干预措施: Vorinostat (Drug)
Phase I Group 2: Vorinostat + Erlotinib
This Phase I arm to be activated only after completion of Part A of the Phase II trial of the 3-Drug combination. If part A of the Phase II trial shows lack of efficacy, trial will be terminated.
Vorinostat orally twice daily, Days 1-14; and Erlotinib orally once daily Days 1-21 of every cycle.
干预措施: Erlotinib (Drug)
Phase II Part A 3-Drug Combination
Vorinostat+Erlotinib+Temozolomide where drug dosing based on the MTD identified in the Phase I portion of the study.
Vorinostat 200 mg orally twice daily on Days 1-7 and 15-21 of every cycle; Erlotinib 200 mg orally once daily on Days 1-21; Temozolomide 100 mg/m^2 orally once daily on Days 1-7 and 15-21.
干预措施: Vorinostat (Drug)
Phase II Part A 3-Drug Combination
Vorinostat+Erlotinib+Temozolomide where drug dosing based on the MTD identified in the Phase I portion of the study.
Vorinostat 200 mg orally twice daily on Days 1-7 and 15-21 of every cycle; Erlotinib 200 mg orally once daily on Days 1-21; Temozolomide 100 mg/m^2 orally once daily on Days 1-7 and 15-21.
干预措施: Erlotinib (Drug)
Phase II Part A 3-Drug Combination
Vorinostat+Erlotinib+Temozolomide where drug dosing based on the MTD identified in the Phase I portion of the study.
Vorinostat 200 mg orally twice daily on Days 1-7 and 15-21 of every cycle; Erlotinib 200 mg orally once daily on Days 1-21; Temozolomide 100 mg/m^2 orally once daily on Days 1-7 and 15-21.
干预措施: Temozolomide (Drug)
Phase II Part B 2-Drug Combination
This Phase II Part B arm to be activated only after completion of Part A of the Phase I and II Part A trial of the 3-Drug combination. If part A of the Phase II trial shows lack of efficacy, trial will be terminated.
Vorinostat orally twice daily, Days 1-14; and Erlotinib orally once daily Days 1-21 of every cycle.
干预措施: Vorinostat (Drug)
Phase II Part B 2-Drug Combination
This Phase II Part B arm to be activated only after completion of Part A of the Phase I and II Part A trial of the 3-Drug combination. If part A of the Phase II trial shows lack of efficacy, trial will be terminated.
Vorinostat orally twice daily, Days 1-14; and Erlotinib orally once daily Days 1-21 of every cycle.
干预措施: Erlotinib (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Vorinostat in Combination With Escalating Doses of Erlotinib and Temozolomide
时间窗: Evaluated with each 28 day (+2 days) cycle, up to 24 weeks
Phase I assessment MTD Vorinostat in combination with escalating doses of Erlotinib and Temozolomide using conventional phase I design where 3 enrolled into first dose level, monitored for 3 weeks and if no dose-limiting toxicity (DLT) seen, 3 more enrolled at next dosage level. If 2/6 participants experience DLT, the previous (lower) dosage level declared MTD of vorinostat in combination with Erlotinib and Temozolomide. A maximum of 4 dosage levels utilized with deescalation by 2 dose levels if DLT is seen at the starting dose level. If no DLT noted after dose escalation to Level 4, these doses utilized as MTD for phase II.
次要结局
- Progression Free Survival (PFS)(6 months)