A Phase 1, Two-Part, Accelerated Dose Titration Trial of CT-179 as Monotherapy in the Treatment of Recurrent Glioblastoma and in Combination With Radiation Therapy in the Treatment of Newly Diagnosed MGMT-Unmethylated Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 54
- 试验地点
- 2
- 主要终点
- Determine Maximum Tolerated Dose (MTD) in TA1 in patients with rGBM
研究概览
简要总结
This is a first-in-human Phase 1 two-part, open-label, multi-center, dose escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and maximum tolerated dose (MTD) of CT-179 in patients with recurrent glioblastoma and newly diagnosed MGMT-unmethylated glioblastoma who are eligible to receive radiation therapy following surgery, and to establish the recommended Phase 2 dose.
详细描述
The OPAL trial is a Phase 1, multi-center, open-label study designed to evaluate the safety and tolerability of CT-179. CT-179 is an orally administered small molecule that modulates the oligodendrocyte transcription factor 2 (OLIG2). The study will enroll up to 54 adult patients with isocitrate dehydrogenase (IDH)-wild type Glioblastoma (GBM).
To evaluate the drug across different stages of the disease, the trial is structured into distinct treatment groups:
- Treatment Arm 1 (Recurrent GBM): In Treatment Arm 1, patients will receive a daily oral dose of CT-179 for a 28-day Dose-Limiting Toxicity (DLT) assessment period. Dose escalation begins at 0.65 mg/kg and may proceed up to 10.4 mg/kg across six planned cohorts. The first three cohorts will use an Accelerated Titration design (one patient per cohort) before reverting to a standard 3+3 dose-escalation design if specific moderate or dose-limiting toxicities are observed.
- Treatment Arm 2 (Newly Diagnosed MGMT-Unmethylated GBM):
Enrollment in Arm 2 will only begin after the sixth cohort in Arm 1 successfully clears its 28-day DLT period. These patients will receive CT-179 for a one-week lead-in, followed by six weeks of CT-179 administered concurrently with standard radiation therapy (60 Gy). The DLT observation period for this arm lasts up to 12 weeks and uses a standard 3+3 dose-escalation design.
- Intra-Tumoral Drug Concentration (IDC) Sub-Study: Once the Maximum Tolerated Dose (MTD) is established in Arm 1, a sub-study will evaluate how well CT-179 penetrates tumor tissue. Patients will receive CT-179 for 7 to 14 days before their scheduled tumor resection so that intra-tumoral drug concentrations can be measured from the resected tissue.
- Study Objectives: The primary objective across all cohorts is to determine the MTD and the Recommended Phase 2 Dose (RP2D) for CT-179. Secondary and exploratory measures include tracking pharmacokinetics (PK), assessing preliminary efficacy via Overall Response Rate (ORR) and Progression-Free Survival (PFS) using RANO 2.0 criteria, and evaluating changes in tumor metabolism via FET-PET imaging.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female aged ≥ 18 years at the time of signing informed consent
- •Supratentorial, histologically confirmed diagnosis of primary GBM that meets the current diagnostic classification: 2021 WHO Classification of Tumors of the Central Nervous System
- •KPS score ≥ 70
- •Adequate organ function
- •Contraception during study participation, as applicable
- •Able to swallow tablets
排除标准
- •Treatment with an investigational agent within the last 30 days excluding 5- aminolevulinic acid (5-ALA)
- •Placement of Gliadel wafers or similar local therapy at time of surgery
- •Receive bevacizumab
- •Evidence of intracranial or intra-tumoral hemorrhage
- •Significant concomitant disorder or serious intercurrent illness
- •History of prior malignancy, except adequately treated non-melanoma skin cancer, carcinoma in-situ of the cervix, or disease-free for more than 5 years
- •Treatment for HIV, hepatitis B, or hepatitis C
- •Any gastrointestinal disorder that could result in reduced absorption of CT-179
- •Any psychiatric illness or social situation that would limit compliance with study requirements
- •Dose of dexamethasone higher than 4 mg/day within 1 week of the first dose of study medication
研究组 & 干预措施
Treatment Arm 1 (TA1) (recurrent GBM)
Dose Escalation Study drug CT-179 at multiple dose levels
干预措施: CT-179 (Drug)
Treatment Arm 2 (TA2) (newly diagnosed MGMT-unmethylated GBM)
Dose Escalation Study drug CT-179 at two dose levels
干预措施: CT-179 (Drug)
结局指标
主要结局
Determine Maximum Tolerated Dose (MTD) in TA1 in patients with rGBM
时间窗: From first dose of CT-179 through the end of the 28-day DLT assessment period (Day 28) for each cohort.
The MTD will be the highest tested dose of CT-179 at which protocol specified number of patients experience a DLT or the MAD at the highest administered dose in the absence of a DLT.
Determine MTD/RP2D in TA2 in patients with newly diagnosed MGMT-unmethylated GBM
时间窗: From first dose of CT-179 through 4 weeks after completion of radiotherapy (up to 12 weeks).
The MTD will be the highest dose of CT-179 at which protocol specified number of patients experience a DLT or the MAD at the highest administered dose in the absence of a DLT.
次要结局
- Incidence of Adverse Events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0(From first dose of CT-179 through 28 days after the last dose of study treatment, assessed for up to 24 months.)
- Pharmacokinetic parameters Tmax(From first dose of CT-179 through the end of treatment, assessed for up to 24 months.)
- Overall response rate (ORR)(From first dose of CT-179 until documented disease progression or withdrawal, assessed for up to 24 months.)
- Progression-Free Survival (PFS)(From first dose of CT-179 to first documented disease progression, assessed for up to 24 months.)
- Pharmacokinetic parameters Cmax(From first dose of CT-179 through the end of treatment, assessed for up to 24 months.)
- Pharmacokinetic parameters T1/2(From first dose of CT-179 through the end of treatment, assessed for up to 24 months.)
- Pharmacokinetic parameters AUC(From first dose of CT-179 through the end of treatment, assessed for up to 24 months.)