OLIG2 Inhibitor CT-179 for Recurrent and Newly-diagnosed Glioblastoma

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.

Inclusion criteria

• 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

Exclusion criteria

• 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