Phase III Trial of Temozolomide/Lomustine (TMZ/LOM) Combination Therapy vs. Standard TMZ Therapy for Newly Diagnosed MGMT Promoter Methylated Glioblastoma (IDHwt) Patients +/- Tumor Treating Fields (Optune)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 200
- 试验地点
- 20
- 主要终点
- overall survival
研究概览
简要总结
Background: Glioblastoma (GBM) is notoriously difficult to treat, with current therapies often extending life by only a few months. The standard treatment involves surgery followed by radiation and chemotherapy with Temozolomide (TMZ). The efficacy of TMZ, however, is significantly enhanced when the tumor's o6-methylguanine-DNA-methyltransferase (MGMT) gene is methylated. Recent studies, such as the NOA-09 trial, have suggested that adding Lomustine (LOM) to TMZ could improve outcomes for patients with this specific tumor profile.
Hypothesis: The investigators hypothesize that the addition of LOM to the TMZ regimen will lead to significantly improved survival rates among patients with newly diagnosed glioblastoma who have a methylated MGMT promoter compared to those receiving only TMZ.
Treatment Plans: The study will randomly assign participants to two groups:
- Control Group: Standard treatment with TMZ during and after radiation therapy.
- Experimental Group: TMZ combined with LOM, starting on the first day of radiation therapy.
Outcome Measures: The primary outcome measure will be survival. Other outcomes will include progression-free survival (time from randomization until tumor progression or death), safety profiles (adverse effects of the treatments), and quality of life measures as well as neurocognitive outcomes.
详细描述
Current evidence:
In this section the investigators highlight the evidence behind the current standard fo care, and the emerging data supporting our approach. The RCT of Stupp showed that radiotherapy (RT) together with concomitant and adjuvant TMZ prolong survival. The NORDIC trial investigated the role of TMZ compared to RT for the subgroup of elderly patients, showing that survival was superior with TMZ, especially for those with mMGMT. LOM has been used for treatment of glioma for many decades, often used in combination with procarbazine and vincristine (PCV), but in recent years it is used in patients with glioblastoma as 2nd line therapy after failure of TMZ.
A phase 3 trial with Tumor Treating Fields (TTF, alternating low intensity electromagnetic fields) showed prolonged survival in patients with glioblastoma, but it is not universally applied/approved. Despite full multimodal treatment with surgery, RT, TMZ and TTFields, the median survival is <2 years. There is an unmet medical need to further improve treatments for these patients.
One RCT (NOA-09) provided preliminary data to exploit the specific vulnerability of mMGMT in glioblastoma (although no use of TTF in this trial). The overall tolerability of TMZ-LOM in combination was acceptable, as most adverse events (AE) were moderate and transient. Furthermore, health-related quality of life (HRQoL) and neurocognition did not differ between groups.
Estimated sample size and power:
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed glioblastoma/gliosarcoma, IDH wild type
- •Methylated MGMT promoter
- •World Health Organization performance status 0-2
- •Age 18-70
排除标准
- •Previous malignancy within 3 y or malignancy treated non-curatively
- •Previous chemotherapy or radiotherapy involving the head
- •Off-protocol tumor-specific treatment
- •Serious comorbidity
研究组 & 干预措施
treatment arm
arm with temozolomide (TMZ) plus lomustine (LOM) treatment.
6 cycles of LOM/TMZ Start day 1 of RT. Cycle length of 42 days. Duration 9 months.
干预措施: Temozolomide (Drug)
treatment arm
arm with temozolomide (TMZ) plus lomustine (LOM) treatment.
6 cycles of LOM/TMZ Start day 1 of RT. Cycle length of 42 days. Duration 9 months.
干预措施: Lomustine (Drug)
standard arm
arm with standard of care treatment with temozolomide only.
Oral TMZ 75 mg/m2 daily during RT and with start day 1 of RT. This is followed by 6 cycles of TMZ with start 4 weeks after the end of RT. Cycle length 28 days. Duration 8,5 months.
干预措施: Temozolomide (Drug)
结局指标
主要结局
overall survival
时间窗: Assessed from day of randomization to event or last day of follow-up (FU). Aanlyzed 36 months after last inclusion ensures that all patients have a potential of minimum 36 months FU
visualized with Kaplan-Meier plot, tested with log-rank test
次要结局
- progression free survival (PFS)(Assessed from day of randomization to event or last day of follow-up (FU). Aanlyzed 36 months after last inclusion ensures that all patients have a potential of minimum 36 months FU)
- quality of life (QoL)(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- neurocognition - verbal memory(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- neurocognition - visual memory(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- neurocognition - motor speed and fine motor control(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- neurocognition - cognitive speed(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- neurocognition - simple and complex reaction time, inhibition/disinhibition, mental flexibility, and focused attention.(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- neurocognition - attention(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- neurocognition - attention, vigilance, and reaction time(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- neurocognition - Perception(done at baseline after informed consent, before randomisation and start of treatment, week 6 from start of treatment= end of radiotherapy, and every 24 weeks from start of treatment and for max 36 months.)
- Adverse events (AE)(assessed from day of randomization to death or 36 months FU)