A Multicenter Randomized Phase III Study for Recurrent Glioblastoma Comparing Bevacizumab Alone With Dose-dense Temozolomide Followed by Bevacizumab (JCOG1308C, RE-GEND-pIII)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 146
- 试验地点
- 37
- 主要终点
- Overall survival
研究概览
简要总结
The aim of this Phase III study is to evaluate the superiority of dose-dense temozolomide (ddTMZ) followed by bevacizumab at ddTMZ failure for glioblastoma at first recurrence or progression, comparing to bevacizumab alone.
详细描述
Glioblastoma (GBM), the most frequent malignant primary brain tumor, has yet been incurable despite recent progress on its standard of care using TMZ as the main trunk of initial therapy in the newly diagnosed setting. One of the main reasons accounting for the dismal prognosis would attribute to lack of active therapeutic regimens at recurrence.
Bevacizumab, a humanized monoclonal antibody against cardinal angiogenic factor vascular endothelial growth factor (VEGF), has recently shown efficacy for recurrent GBM, and has been approved in Japan, thereby being a standard care for recurrent GBM. Since there is no effective drugs or regimens developed at bevacizumab failure, insertion of another active drug prior to bevacizumab induction would enhance survival time for patients with recurrent GBM.
In Japan, there are currently only few chemotherapeutic agents approved and available for GBM. Among them rechallenge with alternating dosing of TMZ have shown certain efficacy with acceptable toxicities for patients with TMZ-pretreated recurrent GBM, thus being a good candidate for the regimen used prior to bevacizumab at recurrence.
The present proposal of sequential administration of dose dense TMZ (7/14d) followed by bevacizumab wishes to define a new standard of care for recurrent disease and hopes to identify the subgroups of patients with progressive or recurrent glioblastoma that respond particularly well to dose-dense temozolomide regimens.
This study is carried out as a JCOG Brain Tumor Study Group multicenter randomized phase III trial under approval by Advanced Medical Care B system, Ministry of Health, Labour and Welfare, Japan.
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
- 20 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically proven diagnosis of glioblastoma (including giant cell glioblastoma and gliosarcoma) by WHO2007 criteria.
- •For patients who did not undergo surgery for recurrent disease; pre-registration contrast MRI should confirm; (i)progressive or recurrent glioblastoma; (ii)no evidence of acute or subacute cerebral hemorrhage at enrolment; (iii)presence of a measurable lesion.
- •For patients who underwent surgery for recurrent disease; (i)progressive or recurrent glioblastoma must be confirmed on contrast MRI before reoperation; (ii)glioblastoma or anaplastic astrocytoma must be histologically identified in the tissue resected at reoperation; (iii)presence of measurable lesions is not mandatory on pre-registration contrast MRI (more than 4 days after reoperation); (iv)no MRI evidence of aggravating cerebral hemorrhage.
- •No evidence of tumors in the cerebellum, brain stem, optic nerve, olfactory nerve, and pituitary gland.
- •No evidence of meningeal dissemination or gliomatosis cerebri.
- •Prior treatment for newly-diagnosed glioblastoma (or diffuse astrocytoma (Grade II) or anaplastic astrocytoma (Grade III)) with postoperative TMZ administered concomitantly with radiotherapy (>=54 Gy for <=69 years old; >=30 Gy for >=70 years old) and at least for two cycles (5/28d) as an adjuvant treatment have been given.
- •No history of prior treatment with stereotactic radiotherapy (ex. Gamma-knife/Cyberknife), proton beam irradiation, neutron capture therapy, and chemotherapies except standard dose TMZ and immunotherapy (vaccines, immune checkpoint inhibitors, antibodies etc.), bevacizumab (12 weeks or more after termination of prior upfront bevacizumab use) that were combined with TMZ, and intraoperative placement of carmustine wafers, for glioblastoma (including diffuse astrocytoma (Grade II) and anaplastic astrocytoma (Grade III) at onset) diagnosed with WHO2007 criteria.
- •Time periods required from the last day of the prior treatment indicated at registration.
- •①Peptide vaccination, immune checkpoint inhibitors, antibodies: 4 weeks.
- •②Bevacizumab: 12 weeks.
- •More than 90 days after completion of radiotherapy. For those who underwent reoperation, between 21 and 28 days postoperatively.
- •Age between 20 and 75 years at enrolment.
- •Karnofsky Performance Status >= 60 within 14 days before enrolment.
- •No prior treatment with chemotherapy, molecular targeted therapy, or radiotherapy to head and neck area for other malignancies.
- •Adequate organ function.
- •Written informed consent.
排除标准
- •Synchronous or metachronous (within 5 years) malignancy, except for carcinoma in situ or mucosal tumors curatively treated with local therapy
- •Active infection requiring systemic therapy
- •Body temperature >= 38 degrees Celsius at registration
- •Women during pregnancy, possible pregnancy, within 28 days after delivery, or breast-feeding
- •Psychosis or with psychotic symptom
- •Continuous systemic use of immunosuppressant except for steroid
- •Uncontrolled diabetes mellitus
- •Unstable angina within 3 weeks, with a history of myocardial infarction within 6 months, or New York Heart Association (NYHA) class II or greater congestive heart failure
- •Inadequately controlled hypertension (cannot be controlled to a systolic pressure of >= 150 mmHg and a diastolic pressure of >= 100 mmHg)
- •History of symptomatic cerebrovascular disorder (including subarachnoid hemorrhage, cerebral infarction and transient ischemic attack) within 6 months or history of vascular disorder requiring intervention (including venous/arterial thrombosis or embolism and aortic aneurysm) within 6 moths
- •History of grade >= 2 hemoptysis within 28 days
- •History of hemorrhagic tendency (e.g., coagulation disorder) or any grade >= 3 hemorrhage within 28 days
- •History of gastrointestinal perforation, fistula, abdominal abscess or uncontrolled peptic ulcer within 6 months
- •Interstitial pneumonia, pulmonary fibrosis, or severe lung emphysema
- •Severe non-healing wound or traumatic fracture at enrolment
- •Hypersensitivity to Chinese Hamster Ovary-derived drugs or other recombinant antibodies
- •Gadolinium allergy
- •Positive HIV antibody
- •Positive Hepatitis B (HB)s antigen
研究组 & 干预措施
Bevacizumab (BEV) alone
Bevacizumab 10 mg/kg, day 1 div, every 2 weeks
干预措施: Bevacizumab (Drug)
Dose Dense Temozolomide Followed by BEV
Temozolomide (120 mg/m2, po, 7 days on/7 days off, every 2 weeks per cycle) up to 48 cycles. The dose will be escalated to 150 mg/m2 at 3rd cycle if the defined conditions are met throughout the first 2 cycles. At recurrence or progression, bevacizumab alone(10 mg/kg, day 1 div, every 2 weeks)
干预措施: Temozolomide (Drug)
Dose Dense Temozolomide Followed by BEV
Temozolomide (120 mg/m2, po, 7 days on/7 days off, every 2 weeks per cycle) up to 48 cycles. The dose will be escalated to 150 mg/m2 at 3rd cycle if the defined conditions are met throughout the first 2 cycles. At recurrence or progression, bevacizumab alone(10 mg/kg, day 1 div, every 2 weeks)
干预措施: Bevacizumab (Drug)
结局指标
主要结局
Overall survival
时间窗: Time to event. Up to 2 years from the last patient in.
Overall survival will be measured from registration until death for any reason. If the patient is alive at last follow-up, the patient will be censored at the last time of confirmation of survival.
次要结局
- Serious adverse events(Up to 1 year after completion/termination of the protocol treatment.)
- Progression-free survival (PFS)(Time to event. Up to 2 years from the last patient in.)
- 6-month progression-free survival (6m-PFS)(6 months from registration)
- Response rate(Through study completion, an average of 1 year)
- 6-month progression-free survival (6m-PFS) after initiation of bevacizumab (BEV) (Experimental Arm Only)(6 months from initiation of BEV)
- Overall survival after initiation of bevacizumab (BEV)(Time to event from initiation of BEV. Up to 2 years from the last patient in.)
- Adverse events(Up to 1 year after completion/termination of the protocol treatment.)
- Progression-free survival (PFS) from bevacizumab (BEV) initiation(Time to event from initiation of BEV. Up to 2 years from the last patient in.)
- Complete response rate(Through study completion, an average of 1 year)
- MMSE non-deterioration rate(MMSE non-deterioration rates will be calculated at 8 and 24 weeks after initiation of protocol treatment)
- KPS non-deterioration rate(KPS non-deterioration rates will be calculated at 8 and 24 weeks after initiation of protocol treatment)