A Phase 1 Safety and Dose Finding Study of GLIX1 in Adults With Recurrent or Progressive High-grade Glioma

Official title

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

Overview

This is an open-label, multicenter dose-escalation study to be followed by a dose expansion to define the optimal dose of GLIX1 as monotherapy by reviewing safety and tolerability, disease characteristics and pharmacokinetic profiles and preliminary clinical activity in participants with a high grade diffuse glioma that progressed during or recurred after prior standard of care therapies or investigational therapies as clinically indicated. Patients will be treated daily with GLIX1 capsules until disease progression or unacceptable safety.

Detailed description

Glioblastomas (GBMs) are the most common and aggressive primary malignant tumors in adult central nervous system. High-grade glioma almost always recur and/or progress, and upon progression treatment options are very limited with no universal standard therapy established.

GLIX1 is a small molecule administered PO (per os, i.e., orally), that targets the deoxyribonucleic acid (DNA) damage repair mechanism by enhancing Tet methylcytosine dioxygenase 2 (TET2) activity. Increasing the activity of the TET2 enzyme increases DNA oxidation at 5-methylcytosine residues. Such oxidation is normally processed by base excision repair. During base excision repair, a single stranded DNA break is formed. These single strand DNA breaks are well tolerated in normal cells. In cancer, alterations in DNA methylation are common and TET2 activity is inhibited, giving rise to increased DNA methylation in close genomic proximity. When GLIX1 agonizes TET2 activity in cancer cells, excessive base excision repair results in numerous single strand DNA breaks in close proximity, which ultimately converge to form double strand DNA breaks that overwhelm the repair capacity of these cancer cells, resulting in apoptotic cell death.

High-grade glioma have some of the lowest levels of genomic 5-hydroxymethylcytosine. Thus, enhancing the activity of the TET2 enzyme in these cells is likely to have the greatest effect in terms of treating cancers.

Indeed, GLIX1 has been shown to cross the blood brain barrier in rodents and has shown significant activity in various in vitro and in vivo GBM and glioma tumor models.

Interventions

• Drug GLIX1
  Administered orally, once daily, in cycles of 28 days

Primary outcome measures

• Safety Profile of GLIX1 (%Participants with Treatment-emergent Adverse Events) [Time frame: From first administration of GLIX1 (Cycle 1 Day 1) until 30 days following last dose administration]
• Maximal Tolerated Dose and/or Recommended Dose [Time frame: From first administration of GLIX1 (Cycle 1 Day 1) until one cycle of 28 days is complete]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• Moffitt Cancer Center — Tampa
• Northwestern Medicine — Chicago
• NYU Langone Health — New York

Identifiers

NCT: NCT07464925 · GLIX1-C101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗