一项关于XRT、RRx-001和替莫唑胺的多中心1期剂量递增临床试验（G-FORCE-1），随后对新诊断的胶质母细胞瘤患者使用替莫唑胺并加用或不加用RRx-001。
A multicenter, phase 1, dose escalation clinical trial (G-FORCE-1) of XRT, RRx-001 and temozolomide followed by temozolomide +/- RRx-001 in newly diagnosed glioblastoma.
作者信息
Fine Howard, Reid Tony, Caroen Scott, Oronsky Bryan, Abrouk Nacer, Butowski Nicholas
机构信息
Department of Neuro-oncology, Brain Tumor Center at New York-Presbyterian Weill Cornell Medical Center, New York, NY, United States.
Department of Oncology, EpicentRx, Torrey Pines, CA, United States.
出版信息
Front Oncol. 2023 Jun 5;13:1176448. doi: 10.3389/fonc.2023.1176448. eCollection 2023.
INTRODUCTION
The current standard of care for newly diagnosed glioblastoma (GBM) is maximum surgical resection followed by concurrent treatment with temozolomide (TMZ) and radiotherapy (RT) and then six to twelve cycles of maintenance TMZ. RRx-001, an NLRP3 inhibitor and nitric oxide (NO) donor with chemoradiosensitizing, vascular normalizing and macrophage repolarizing properties, is currently in a Phase III trial for small cell lung cancer (SCLC). The purpose of this non-randomized trial was to establish the safety and look for a signal of clinical activity of RRx-001 as an add-on to RT and TMZ in patients with newly diagnosed glioblastoma.
METHODS
In this non-randomized, open-label, two part trial called G-FORCE-1 (NCT02871843), the first four cohorts of adult patients with histologically confirmed high grade gliomas received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and escalating doses of once weekly RRx-001 from 0.5 mg to 4 mg according to a 3+3 design followed by a 6 week no treatment interval and then standard maintenance TMZ (150 mg/m2 Cycle 1 and 200 mg/m2 in subsequent cycles) until disease progression. The second two cohorts of patients received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and once weekly RRx-001 4 mg followed by a 6 week no treatment interval and then two different maintenance schedules until disease progression according to the same 3+ 3 design: 1. 0.5 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapy; 2. 4 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapyThe primary endpoint was the recommended dose/maximally tolerated dose of the combination of RRx-001, TMZ and RT. Secondary endpoints were overall survival, progression free survival, objective response rate, duration of response and clinical benefit response.
RESULTS
A total of 16 newly diagnosed glioblastoma patients were enrolled. No dose limiting toxicities were observed and no MTD was reached. The recommended dose is 4 mg. After 24 months of follow up the median OS was 21.9 months (95% CI: 11.7 - NA). PFS median was 8 months (95% CI: 5 - NA). The overall response rate was 18.8% (3 PR out of 16) and the disease control rate was 68.8% (3 PR, 8 SD out of 16).
CONCLUSIONS
The addition of RRx-001 to TMZ and RT and to TMZ during maintenance was safe and well-tolerated and deserves further study.
引言
新诊断的胶质母细胞瘤（GBM）目前的标准治疗方案是最大程度的手术切除，随后同步进行替莫唑胺（TMZ）和放疗（RT），然后进行6至12个周期的维持性TMZ治疗。RRx-001是一种NLRP3抑制剂和一氧化氮（NO）供体，具有化学放射增敏、血管正常化和巨噬细胞重极化特性，目前正在进行小细胞肺癌（SCLC）的III期试验。这项非随机试验的目的是确定RRx-001作为新诊断胶质母细胞瘤患者RT和TMZ的附加治疗的安全性，并寻找临床活性信号。
方法
在这项名为G-FORCE-1（NCT02871843）的非随机、开放标签的两部分试验中，前四个队列的经组织学证实的高级别胶质瘤成年患者接受了分割放疗（6周内30次分割，共60 Gy）、每日75 mg/m²替莫唑胺以及根据3+3设计从0.5 mg至4 mg每周一次递增剂量的RRx-001，随后有6周的无治疗间隔，然后是标准的维持性TMZ（第1周期150 mg/m²，后续周期200 mg/m²），直至疾病进展。后两个队列的患者接受分割放疗（6周内30次分割，共60 Gy）、每日75 mg/m²替莫唑胺以及每周一次4 mg的RRx-001，随后有6周的无治疗间隔，然后根据相同的3+3设计采用两种不同的维持方案直至疾病进展：1. 每周一次0.5 mg RRx-001 + 每周5天100 mg/m² TMZ，最多6个治疗周期；2. 每周一次4 mg RRx-001 + 每周5天100 mg/m² TMZ，最多6个治疗周期。主要终点是RRx-001、TMZ和RT联合使用的推荐剂量/最大耐受剂量。次要终点是总生存期、无进展生存期、客观缓解率、缓解持续时间和临床获益反应。
结果
共纳入16例新诊断的胶质母细胞瘤患者。未观察到剂量限制性毒性，也未达到最大耐受剂量。推荐剂量为4 mg。随访24个月后，中位总生存期为21.9个月（95%置信区间：11.7 - 无可用值）。中位无进展生存期为8个月（95%置信区间：5 - 无可用值）。总缓解率为18.8%（16例中有3例部分缓解），疾病控制率为68.8%（16例中有3例部分缓解，8例疾病稳定）。
结论
在TMZ和RT中以及维持治疗期间添加RRx-001是安全且耐受性良好的，值得进一步研究。
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