Newly Diagnosed MGMT Unmethylated Glioblastoma, Recurrent Glioblastoma
Conditions
Keywords
Glioblastoma, Brain Tumour, OLIG2
Brief summary
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.
Detailed description
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.
Interventions
DRUGCT-179
Daily administration of CT-179
Sponsors
Olivia Newton-John Cancer Research Institute
Curtana Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1 dose escalation cohorts
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine Maximum Tolerated Dose (MTD) in TA1 in patients with rGBM | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Rate of patients reporting adverse events or serious adverse events |
| Pharmacokinetic parameters Tmax | From first dose of CT-179 through the end of treatment, assessed for up to 24 months. | Time to maximum concentration (Tmax) |
| Overall response rate (ORR) | From first dose of CT-179 until documented disease progression or withdrawal, assessed for up to 24 months. | Per RANO 2.0 (Response Assessment in Neuro-Oncology) |
| Progression-Free Survival (PFS) | From first dose of CT-179 to first documented disease progression, assessed for up to 24 months. | Per RANO 2.0 (Response Assessment in Neuro-Oncology) |
| Pharmacokinetic parameters Cmax | From first dose of CT-179 through the end of treatment, assessed for up to 24 months. | Peak Plasma Concentration (Cmax) |
| Pharmacokinetic parameters T1/2 | From first dose of CT-179 through the end of treatment, assessed for up to 24 months. | Terminal elimination half-life (T1/2) |
| Pharmacokinetic parameters AUC | From first dose of CT-179 through the end of treatment, assessed for up to 24 months. | Area under the plasma concentration versus time curve (AUC) |
Countries
Australia
Contacts
CONTACTAlexandra Romano
Outcome results
None listed