Phase 1 safety and dose-finding of GLIX1 for adults with recurrent or progressive high-grade glioma

An Open-Label Phase 1 Safety and Dose Finding Study of Orally Administered GLIX1 in Adults With Recurrent or Progressive High-grade Glioma

This trial will test whether taking oral GLIX1 daily is safe, tolerable, and shows early anti-tumor activity in adults with recurrent or progressive high-grade glioma.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Tetragon Biosciences Ltd (Industry-sponsored)
• Drugs / interventions: denosumab, radiation, prednisone
• Locations: 3 sites (Tampa, Florida and 2 other locations)
• Trial ID: NCT07464925 on ClinicalTrials.gov

What this trial studies

This open-label, multicenter Phase 1 dose-escalation and expansion trial gives adults with recurrent or progressive grade 3–4 glioma daily oral GLIX1 until disease progression or unacceptable toxicity. The dose-escalation phase will identify the optimal tolerable dose using safety, tolerability, pharmacokinetics, and preliminary clinical activity, followed by a dose-expansion cohort. GLIX1 is a small-molecule TET2 agonist that increases DNA oxidation at 5-methylcytosine, producing clustered single-strand breaks that can convert to lethal double-strand breaks in cancer cells. Enrollment requires predefined washout periods and recovery from prior treatment toxicities, with treatment continuing until progression or intolerable side effects.

Who should consider this trial

Good fit: Ideal candidates are adults (≥18) with histologically confirmed grade 3 or 4 glioma that has recurred or progressed after up to two prior treatment lines and who have recovered from prior treatment toxicities.

Not a fit: Patients with more than two prior systemic treatment lines, recent radiotherapy or systemic therapy within the required washout periods, significant uncontrolled medical issues, or unstable corticosteroid/seizure control are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, GLIX1 could provide a new oral therapy that selectively induces lethal DNA damage in glioma cells and may slow tumor progression for patients with limited options.

How similar studies have performed: Clinical experience directly targeting TET2 in glioma is limited and the approach is largely novel, though other epigenetic-targeting agents in brain tumors have shown mixed results.

Eligibility criteria

Main Inclusion Criteria:

* Adult patients aged ≥18 years at the time of informed consent
* Participants must have histologically confirmed Grade 3 or Grade 4 glioma
* Recurrent or progressive disease
* A maximum of two prior treatment lines
* Interval of at least 3 months since the last day off of radiotherapy, unless tumor progression and index lesion is outside the prior radiation field.
* Interval since last dose of systemic therapy and Baseline MRI of ≥28 days, except:

  * for nitrosoureas (e.g., lomustine, carmustine, fotemustine): 42 days (6 weeks)
  * for monoclonal antibodies: 42 days (6 weeks)
  * for small molecules, 4 weeks or at least 5 half-lives (whatever is longer)
* Recovered from all toxicities from prior treatments to Grade 1 or less by NCI CTCAE v6.0:
* Participants receiving corticosteroids must be on a stable or decreasing dose of ≤6 mg daily dexamethasone (or ≤40 mg prednisone) for the 7 days prior to the start of study treatment.
* Participants with seizures must be adequately controlled on a stable regimen of anti-epileptic drugs.
* Adequate performance status: Eastern Cooperative Oncology Group (ECOG) 0 or 1.
* Ability to swallow tablets or capsules.
* Adequate hematological, liver and renal function.
* Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to first dosing. Women must use a highly effective form of contraception (with Pearl Index \<1%) for the duration of the study and for at least 3 months after the last dose of study medication.
* Men with partners of childbearing potential must be willing to use condoms in combination with a second effective method of contraception by the partner during the study and for at least 3 months after the last dose of study medication.

Main Exclusion Criteria:

* Known contraindication for gadolinium (Gd) based, contrast-enhanced MRI
* Prior history of another invasive malignancy unless a complete remission was achieved at least 3 years prior to enrolment AND no additional therapy is required during the study period, except for anti-estrogen or androgen therapy and/or bisphosphonates or denosumab.
* Participants with known active or uncontrolled infection, and/or unexplained fever \>38°C in the 3 days prior to the start of study treatment.
* Major non-tumor related surgical procedure or significant traumatic injury within 28 days prior to signing of consent.
* Receiving any investigational products (defined as treatment for which there is currently no regulatory authority-approved indication) within 4 weeks or 5 half-lives (whichever is the longest) prior to Baseline MRI.

Where this trial is running

Tampa, Florida and 2 other locations

• Moffitt Cancer Center — Tampa, Florida, United States (Not_yet_recruiting)
• Northwestern Medicine — Chicago, Illinois, United States (Not_yet_recruiting)
• NYU Langone Health — New York, New York, United States (Recruiting)

Conditions Glioblastoma Multiforme of Brain; Glioma; Glioblastoma; GLIX1; GBM; TET2