Pivotal, Open-label, Randomized Study of Radiosurgery With or Without Tumor Treating Fields (TTFields) for 1-10 Brain Metastases From Non-small Cell Lung Cancer (NSCLC).
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 298
- 试验地点
- 252
- 主要终点
- Time to intracranial progression
研究概览
简要总结
The study is a prospective, randomized controlled phase III trial, to test the efficacy, safety and neurocognitive outcomes of advanced NSCLC patients, following stereotactic radiosurgery (SRS) for 1 inoperable brain metastasis or 2-10 brain metastases, treated with NovoTTF-200M and supportive treatment compared to supportive treatment alone. The device is an experimental, portable, battery operated device for chronic administration of alternating electric fields (termed TTFields or TTF) to the region of the malignant tumor, by means of surface, insulated electrode arrays.
详细描述
PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:
The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in vitro and in vivo NSCLC pre-clinical models both as a single modality treatment and in combination with chemotherapies. TTFields have also shown to inhibit metastatic spread of malignant melanoma in in vivo experiment.
In a pilot study, 42 patients with advanced NSCLC who had tumor progression after at least one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz) applied to the chest and upper abdomen until disease progression (Pless M., et al., Lung Cancer 2011). Efficacy endpoints were remarkably high compared to historical data for pemetrexed alone.
In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active chemotherapy in extending survival, associated with minimal toxicity, good quality of life, and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a phase III trial of Optune® combined with maintenance temozolomide compared to maintenance temozolomide alone has shown that combined therapy led to a significant improvement in both progression free survival and overall survival in patients with newly diagnosed glioblastoma without the addition of high grade toxicity and without decline in quality of life (Stupp R., et al., JAMA 2015).
Applying TTFields at 150 kHz to the brain for the treatment of 1-5 brain metastasis from NSCLC using the NovoTTF-100M device has been demonstrated to be safe in a pilot study, where patients were randomized after local therapy of their brain metastasis by neurosurgery and/or stereotactic radiosurgery to receive either NovoTTF-100M treatment or supportive care alone. Eighteen (18) patients have been enrolled in the study. There have been no device-related serious adverse events (SAE) reported to date (Brozova H., et al., Neuro Oncol 2016).
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
- •18 years of age and older
- •Life expectancy of ≥ 3 months
- •New diagnosis of brain metastases from a histologically or cytologically confirmed primary or metastatic NSCLC tumor within 5 years of registration on the study. If the original histological proof of malignancy is greater than 5 years, then pathological confirmation is required (i.e.: from extra-cranial or intracranial disease).
- •5. 1 inoperable brain metastasis or 2- 10 brain lesions per screening MRI, confirmed by contrast enhanced MRI amenable to SRS according to the following criteria:
- •a. largest tumor volume < 10 cc b. longest tumor diameter < 3 cm c. Cumulative volume of all tumors ≤ 15 cc
- •At least one measurable disease per study protocol
- •Patients must be receiving optimal therapy for their extracranial disease according to local practice at each center. Patients may continue on systemic therapy while receiving TTFields.
- •8. Able to operate the NovoTTF-200M device independently or with the help of a caregiver
- •Clinical trials prior to enrollment are allowed, as long as no brain directed therapy was included (current treatment trials are exclusionary)
排除标准
- •Patients who are known to have somatic tumor mutations in the following genes, for which targeted agents are available that directly affect the treatment of brain metastasis: Anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ROS-1 proto- oncogene, and proto-oncogene B-RAF
- •Patients who have a single, operable brain metastasis
- •Patients with significant edema leading to risk of brain herniation
- •Patients with midline shift > 10mm
- •Patients with intractable seizures
- •Leptomeningeal metastases
- •Recurrent brain metastases
- •Prior WBRT for newly diagnosed brain metastases
- •Severe comorbidities:
- •Clinically-significant inadequate hematological, hepatic and renal function, defined as: Neutrophil count < 1.5 x 10 9/L and platelet count < 100 x 10^9/L; bilirubin > 1.5 x upper limit of normal (ULN); aspartate transaminase (AST) and/or alanine aminotransferase (ALT) > 2.5 x ULN or > 5 x ULN if patient has documented liver metastases; and serum creatinine > 1.5 x ULN
- •History of significant cardiovascular disease unless the disease is well controlled. Significant cardiac disease includes second/ third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary activity results in fatigue, palpitation or dyspnea).
- •History of arrhythmia that is symptomatic or requires treatment. Patients with atrial fibrillation or flutter controlled by medication are not excluded from participation in the study.
- •History of cerebrovascular accident (CVA) within 6 months prior to randomization or that is not stable
- •Active infection or serious underlying medical condition that would impair the ability of the patient to received protocol therapy
- •History of any psychiatric condition that might impair patient's ability to understand or comply with the requirements of the study or to provide consent
- •Implantable electronic medical devices in the brain
- •Known allergies to medical adhesives or hydrogel
- •Currently pregnant or breastfeeding
- •Planned concurrent brain directed therapy (beyond SRS and NovoTTF-200M as per protocol)
结局指标
主要结局
Time to intracranial progression
时间窗: 3 years
次要结局
- Radiological response in the brain following study treatments(3 years)
- Time to second intracranial progression(3 years)
- Time to intracranial progression, measured from the date of first SRS treatment to intracranial progression (per modified RECIST 1.1 Criteria) or neurological death, whichever occurs first.(3 years)
- Rate of decline in cognitive function as measured by HVLT-R free recall, delayed recall and delayed recognition, COWAT and TMT Parts A and B at 2, 4, 6, 8, 10, 12 months follow-up.(3 years)
- Time to neurocognitive failure(3 years)
- Overall survival(3 years)
- Time to first and second intracranial progression evaluated in two cohorts of patients, 1-4 brain metastases and 5-10 brain metastases.(3 years)
- Rate of intracranial progression at 2, 4, 6, 8, 10, 12 months after first SRS treatment(3 years)
- Time to distant progression, as measured from the date of first SRS treatment to a new intracranial lesion(3 years)
- Neurocognitive failure-free survival(3 years)
- Quality of Life using the EORTC QLQ C30 with BN20 addendum(3 years)
- Toxicity during NovoTTF-200M treatment based on incidence and severity of treatment emergent adverse events as evaluated using the CTCAE version 4.0(3 years)