NCT01119599已完成1 期
Phase 1 Trial of RO4929097 in Combination With Standard Radiotherapy and Temozolomide for Newly Diagnosed Malignant Glioma: A Pharmacokinetic and Pharmacodynamic Study
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- Maximum-tolerated dose defined as the highest dose studied for which the incidence of dose limiting toxicity is less than 33% using National Cancer Institute Common Toxicity Criteria
研究概览
简要总结
This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) when given together with temozolomide and radiation therapy in treating patients with newly diagnosed malignant glioma. Enzyme inhibitors, such as gamma-secretase/Notch signalling pathway inhibitor RO4929097, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 together with temozolomide and radiation therapy may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. To establish the maximum tolerated dose/recommended phase II dose of RO4929097 in combination with temozolomide and radiotherapy in patients with glioblastoma or malignant gliomas.
SECONDARY OBJECTIVES:
I. To evaluate the pharmacokinetics of RO4929097 when given in combination with temozolomide (correlative study C1).
II. To evaluate brain and tumor penetration of RO4929097 when given in recommended phase II single agent schedule and when given at the maximum tolerated dose (MTD) for the combination with radiotherapy and temozolomide (correlative study C2).
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
- 19 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 glioblastoma, anaplastic astrocytoma, gliosarcoma or other malignant gliomas with the exception of pure anaplastic oligodendroglioma; note: patients with presumed malignant glioma based on radiographic assessment may be enrolled onto Arm A of the study without histological confirmation provided they meet the following additional eligibility criteria:
- •The MRI of the brain shows typical findings of a malignant glioma or glioblastoma (single ring-enhancing mass with necrotic portions)
- •To exclude brain abscess, diffusion-weighted MRI must show absence of restricted diffusion corresponding to the necrotic center of the lesion
- •To confirm the diagnosis of neoplastic disease, MR perfusion must show that the lesion has increased perfusion
- •To exclude pilocytic astrocytoma, the patient's age must be over 25
- •To exclude brain metastasis, a computed tomography (CT) of the chest, abdomen and pelvis must demonstrate absence of other malignancy
- •The principal investigator must review MRI and CT findings and agree with diagnosis of presumed malignant glioma
- •Note: If after the on-protocol surgery the patient is found not to meet histological criteria described (diagnosis of glioblastoma, anaplastic astrocytoma, gliosarcoma or other malignant gliomas with the exception of pure anaplastic oligodendroglioma), the patient will be removed from the study and replaced
- •ARM A ONLY: Patients must have an indication for additional debulking surgery as part of their initial treatment
- •Life expectancy of greater than 2 months
- •Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%)
- •Hemoglobin >= 9 g/dL
- •Leukocytes > 3,000/mcL
- •Absolute neutrophil count > 1,500/mcL
- •Platelets > 100,000/mcL
- •Total bilirubin < 1.5 X institutional upper limit of normal
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal
- •Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- •Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 12 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately
- •Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of RO4929097; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
- •Female patients of childbearing potential are defined as follows:
- •Patients with regular menses
- •Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
- •Women who have had tubal ligation
- •Female patients may be considered to NOT be of childbearing potential for the following reasons:
- •The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy
- •The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive months
- •Pre-pubertal females; the parent or guardian of young female patients who have not yet started menstruation should verify that menstruation has not begun. If a young female patient reaches menarche during the study, then she is to be considered as a woman of childbearing potential from that time forward
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Prior chemotherapy, radiotherapy, biological or experimental therapy for glioma
- •Prior history of radiotherapy to the brain, head or neck
- •Patients may not be receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 or other agents used in the study
- •Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
- •Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study
- •Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
- •Patients with known history of hepatitis B or C, or who have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible; (hepatitis B and C serology should be obtained as part of pre-treatment evaluation but are not required for eligibility)
- •Patients with uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, and hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, history of torsades de pointes or other significant cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with RO4929097 or temozolomide; these potential risks may also apply to other agents used in this study
- •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
- •A corrected QT (QTc) > 450 msec in males and a QTc > 470 msec in females
- •Patients who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study
- •ARM A ONLY: Patients with contraindication to a brain surgical procedure
- •A requirement for antiarrhythmics or other medications known to prolong QTc
研究组 & 干预措施
Treatment (RO4929097, surgery, radiation therapy)
Experimental
See Detailed Description.
干预措施: Therapeutic Conventional Surgery (Procedure)
Treatment (RO4929097, surgery, radiation therapy)
Experimental
See Detailed Description.
干预措施: 3-Dimensional Conformal Radiation Therapy (Radiation)
Treatment (RO4929097, surgery, radiation therapy)
Experimental
See Detailed Description.
干预措施: Gamma-Secretase Inhibitor RO4929097 (Drug)
Treatment (RO4929097, surgery, radiation therapy)
Experimental
See Detailed Description.
干预措施: Intensity-Modulated Radiation Therapy (Radiation)
Treatment (RO4929097, surgery, radiation therapy)
Experimental
See Detailed Description.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (RO4929097, surgery, radiation therapy)
Experimental
See Detailed Description.
干预措施: Pharmacological Study (Other)
Treatment (RO4929097, surgery, radiation therapy)
Experimental
See Detailed Description.
干预措施: Temozolomide (Drug)
结局指标
主要结局
Maximum-tolerated dose defined as the highest dose studied for which the incidence of dose limiting toxicity is less than 33% using National Cancer Institute Common Toxicity Criteria
时间窗: 28 days
The percentage of patients who experience toxicity at each dose level will be calculated, with a 95% confidence interval.
次要结局
- Changes in MRI parameters(Baseline to up to 4 years)
- Percent changes in serum YKL-40 levels and hair follicle HES1 levels(Baseline to up to 4 years)
- Pharmacokinetic (PK) parameters of gamma-secretase/Notch signalling pathway inhibitor RO4929097(Pre-dose, 30 minutes, 1, 2, 4, 6, and 8 hours)
研究者
研究点 (2)
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