Phase I, Dose Finding Trial of the Combination of Panobinostat and Stereotactic Radiation in the Treatment of Brain Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 17
- 试验地点
- 1
- 主要终点
- Maximum tolerated does (MTD) of panobinostat, defined as one level below at which 2 of 6 patients experience a dose-limiting toxicity (DLT)
研究概览
简要总结
This is an open label phase I clinical trial with two arms, representing single and fractionated radiation therapy (Figure 4.1). Within each arm the radiation dose is pre-determined and not escalated. Panobinostat will be administered orally 3 times a week for 2 weeks. Panobinostat will be dose-escalated independently in each arm. There is no intra-patient dose escalation.
Recurrent gliomas (Arm A) will be treated according to the Jefferson protocol for re-irradiation, 10 fractions each of 3.5Gy delivered over 2 weeks. Panobinostat will be administered orally three times a week for 2 weeks, starting on day 1 or 2 of radiation therapy. High-grade meningiomas (Arm A) will be treated with 6 weeks/30 fractions of fractionated radiation therapy, to a total dose of between 54 Gy and 60 Gy in fractions of either 1.8Gy or 2Gy. Panobinostat will be administered orally three times a week for 2 weeks, starting on the day of 1st fraction of radiation.
Large brain metastases (Arm B) will be treated with a single fraction of radiosurgery. Panobinostat will be administered orally three times a week for 2 weeks, starting on the day of radiation. The radiosurgery may be delivered by either LINAC, gamma-knife, cyber-knife or tomotherapy technology.
详细描述
Brain tumors, both primary and metastatic present a therapeutic challenge. Radiation therapy plays a major role in management of both entities. Nonetheless, local control remains sub-optimal in a large proportion of patients. Over the previous decade there has been a great deal of progress regarding 1) precision in the localization and targeting of brain lesions with radiation, 2) increased use of single/hypofractionation schedules and 3) combining fractionated conformal radiation with targeted agents. This trial utilizes a novel approach - the combination of an HDAC inhibitor (Panobinostat) with stereotactic radiosurgery. The combination blends the advantages of extreme high precision radiation with a potent targeted agent - promising enhanced efficacy with minimal toxicity. The investigators will examine the combination in three settings, in all of which current standard of care is sub-optimal:
- Recurrent glioma
- High grade meningioma
- Large brain metastases from solid malignancies
Histone deacetylase (HDAC) inhibitors, including Panobinostat, radiosensitize tumor cells both in vitro and in vivo. HDAC inhibitors modify the expression of approximately 8% of the transcriptome83. In particular, they have been shown to down regulate expression of the DNA repair enzyme rad51, possibly explaining their radiosensitization properties. It is thought that Panobinostat radiosensitizes through an epigenetic mechanism. Since the target of HDAC inhibitors includes many proteins beyond histones, many prefer the name "deacetylase inhibitors", (DAC).
There are several lines of evidence suggesting HDAC inhibitors cross the BBB. The anticonvulsant valproic acid, a member of the short chain fatty acid class of HDAC inhibitors, has a well-recognized capacity to cross the BBB. HDAC inhibitors are also being studied in Huntington's disease. Panobinostat is able to cross the blood-brain-barrier and influence gene expression in rodents.
When combining radiation therapy with systemic agents it is generally considered important that there is a high concentration of drug present at, or just before, the time of irradiation. The goal is to use panobinostat as a radiosensitizer, not a single systemic agent. The investigators will administer oral panobinostat 3 times weekly for 2 weeks. This is an open label phase I clinical trial with two arms, representing single and fractionated radiation therapy (Figure 4.1). Within each arm the radiation dose is pre-determined and not escalated. Panobinostat will be administered orally 3 times a week for 2 weeks. Panobinostat will be dose-escalated independently in each arm. There is no intra-patient dose escalation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Patient age is > or = 18 years
- •Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of < or = 2
- •Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
- •Patients must meet the following laboratory criteria:
- •Hematology:
- •Neutrophil count of > 1500/mm3
- •Platelet count of > 100,000/mm3L
- •Hemoglobin > or = 9 g/dL
- •Biochemistry:
- •AST/SGOT and ALT/SGPT < or = 2.5 x upper limit of normal (ULN) or < or = 5.0 x ULN if the transaminase elevation is due to disease involvement
- •Serum bilirubin < or = 1.5 x ULN
- •Serum creatinine < or = 1.5 x ULN or 24-hour creatinine clearance > or = 50 ml/min
- •Total serum calcium (corrected for serum albumin) or ionized calcium > or = LLN
- •Serum potassium > or = LLN
- •Serum sodium > or = LLN
- •Serum albumin > or = LLN or 3g/dl
- •Patients with any elevated Alkaline Phosphatase due to bone metastasis can be enrolled
- •Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
- •Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of study treatment. and must be willing to use two methods of contraception one of them being a barrier method during the study and for 3 months after last study drug administration
- •Pathologic diagnosis and other conditions relating to the different arms of the study:
- •Arm A Recurrent glioma: Pathological diagnosis of glioma (grade 2-4) is required. All patients are required to have initially undergone fractionated radiation therapy, to between 55 Gy to 70 Gy in fractions of 1.8-2 Gy as part of 'first line therapy'. The diagnosis of 'recurrence' is to be made by the treating physician on the basis of radiological and clinical data. Measurable disease is not required.
- •Arm A High-grade meningioma: Pathological diagnosis of high-grade meningioma, as defined by WHO grade 2 or 3 (also known as atypical and anaplastic/malignant meningioma). WHO grade 1 meningiomas with an elevated Ki67 proliferation rate of > or = 8% are also considered high-grade for the purposes of this trial, due to their poor prognosis32, 86-
- •The meningioma may be treated in the scenario of either adjuvant treatment (radiation therapy following complete / sub-total / biopsy only resection) or recurrent disease (re-growth following surgery alone). Measurable disease is not required.
- •Arm B Large brain metastases: Pathological diagnosis of malignancy is required, from either the primary tumor or a metastasis. A radiological diagnosis (CT or MRI scan) of one of more brain metastases is required. At least one of the brain metastases to be treated as part of this study must be 2.5cm or larger in maximal diameter. The brain metastasis/es to be treated may not be more than 4cm in maximal diameter, as assessed by CT or MRI scan. The brain metastasis may either be un-resected or partially resected, provided that the target lesion (which may include a resection cavity) remains between 2.5 and 4cm in diameter, as defined in section
- •Whole brain radiation therapy may or may-not have been delivered prior to entering this protocol.
排除标准
- •Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer
- •Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
- •Impaired cardiac function including any one of the following:
- •History or presence of sustained ventricular tachyarrhythmia.
- •Any history of ventricular fibrillation or torsade de pointes
- •Bradycardia defined as HR < 50 bpm. Patients with pacemakers are eligible if HR > or = 50 bpm.
- •Screening ECG with a QTc > 450 msec
- •Right bundle branch block + left anterior hemiblock (bifascicular block)
- •Patients with myocardial infarction or unstable angina < or = 6 months prior to starting study drug
- •Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
- •Uncontrolled hypertension
- •Concomitant use of drugs with a risk of causing torsades de pointes
- •Patients with unresolved diarrhea > or = grade 2
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
- •Other concurrent severe and/or uncontrolled medical conditions
- •Patients who have received chemotherapy, any investigational drug or undergone major surgery < 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
- •Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and 3 months after the end of treatment. One of these methods of contraception must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of oral panobinostat.
- •Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom
- •Patients with a history of another primary malignancy within 5 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin
- •Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
- •Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
- •Allergy to MRI contrast agent.
- •Any anti-cancer treatment within 2 weeks of initiating treatment as part of this trial, including cytotoxic chemotherapy (e.g. temozolomide), radiation therapy (single fraction or fractionated), and biological therapies (e.g. mono-clonal antibodies, tyrosine kinase inhibitors, interferon). Hormonal therapies (e.g. in breast and prostate cancer) are allowed both prior to and during treatment.
- •Exclusion criteria specific to arms of the trial:
- •Arm A Recurrent glioma: The subject has received more than one prior course of radiation therapy within the target volume to be treated as part of this protocol. Additional courses of radiation therapy (single fraction or fractionated) are permitted if outside of the volume to be treated.
- •Arm A High-grade meningioma: The subject has received a prior course of radiation therapy within the target volume to be treated as part of this protocol.
- •Arm B Large brain metastases: The subject has received a prior course of radiation therapy within the target volume to be treated as part of this protocol, aside from whole brain radiation.
研究组 & 干预措施
Arm A (panobinostat, multiple fractions of SBRT)
Patients receive panobinostat PO thrice weekly for 2 weeks and undergo 10 fractions of SBRT over 2 weeks (recurrent gliomas) OR 30 fractions of SBRT over 6 weeks (high grade meningiomas).
干预措施: Panobinostat (Drug)
Arm A (panobinostat, multiple fractions of SBRT)
Patients receive panobinostat PO thrice weekly for 2 weeks and undergo 10 fractions of SBRT over 2 weeks (recurrent gliomas) OR 30 fractions of SBRT over 6 weeks (high grade meningiomas).
干预措施: Stereotactic body radiation therapy (Radiation)
Arm A (panobinostat, multiple fractions of SBRT)
Patients receive panobinostat PO thrice weekly for 2 weeks and undergo 10 fractions of SBRT over 2 weeks (recurrent gliomas) OR 30 fractions of SBRT over 6 weeks (high grade meningiomas).
干预措施: Quality-of-life assessment (Procedure)
Arm B (panobinostat, stereotactic radiosurgery)
Patients receive panobinostat as in Arm A and undergo a single fraction of stereotactic radiosurgery on day 1 of week 1.
干预措施: Panobinostat (Drug)
Arm B (panobinostat, stereotactic radiosurgery)
Patients receive panobinostat as in Arm A and undergo a single fraction of stereotactic radiosurgery on day 1 of week 1.
干预措施: Quality-of-life assessment (Procedure)
Arm B (panobinostat, stereotactic radiosurgery)
Patients receive panobinostat as in Arm A and undergo a single fraction of stereotactic radiosurgery on day 1 of week 1.
干预措施: Stereotactic radiosurgery (Radiation)
结局指标
主要结局
Maximum tolerated does (MTD) of panobinostat, defined as one level below at which 2 of 6 patients experience a dose-limiting toxicity (DLT)
时间窗: Up to 30 days after the completion of study treatment
Assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Dose-limiting toxicities as defined by the NCI CTCAE version 4.0
时间窗: Up to 30 days after the completion of study treatment
Overall survival
时间窗: Assessed up to 2 years
Analyzed using Kaplan-Meier estimates
Progression free survival (PFS)
时间窗: Assessed up to 2 years
Analyzed using Kaplan-Meier estimates
Response as defined by RECIST criteria
时间窗: Assessed up to 2 years
A 2-sided exact 95% confidence interval will be computed.
次要结局
未报告次要终点