A Study of AB-218 in Patients With IDH1 Mutated Low Grade Glioma

Study Overview
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Brief Summary
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The aim of this clinical trial is to evaluate the feasibility of undertaking a Phase 0 surgical study in patients with diagnosis of a IDH1 mutated Low Grade Glioma (LGG) who have not received prior radiation or chemotherapy and are planned to undergo surgical resection.

Detailed Description
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This is a single arm, open label Phase 0 trial to assess the feasibility, pharmacokinetics and pharmacodynamics of treatment with AB-218 following biopsy and prior to resection in patients with IDH1 mutated glioma. Participants will receive treatment in 2 parts: Part A: Biopsy followed by 1 cycle (28 days) of AB-218, an orally available, small molecular inhibitor of mutated IDH1, then safe maximal resection of the tumour. Part B: Following recovery from surgery, patients will receive up to 12 cycles of AB-218. It is expected that 10 patients will take part in this study. It is anticipated this research study will enable investigators to objectively measure the biological activity of AB-218 in patients with IDH1 mutated LGG. Anti-tumour activity will be assessed by RANO response criteria. The investigators have previous experience in pre-treating patients with GBM prior to surgery with systemic therapies and collecting tumour, peri-tumour and normal brain tissues for PK, PD and biomarker evaluation

Official Title
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A Phase 0/2 Study of AB-218 in Patients With IDH1 Mutated Low Grade Glioma

Conditions
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Glioma

Intervention / Treatment
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* Procedure: Biopsy
* Drug: Part A: AB-218
* Procedure: Surgery (maximal resection)
* Drug: Part B: AB-218


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will have a radiological diagnosis of LGG or a previously confirmed LGG and be planned for elective, non-urgent resection of the tumour Patients who do not require urgent resection for mass effect, cerebral oedema or hydrocephalus in the opinion of the treating neurosurgeon Tumour size 2 - 5 cm Measurable and/or evaluable disease as per LGG-RANO criteria Willing to undergo planned surgical procedures Routine trial inclusion criteria Adults ≥ 18 < 40 years of age ECOG performance score 0 - 1 Life expectancy of at least 24 months Haematological and renal function as prescribed Hepatic function with prescribed limits Reproductive and contraception criteria as prescribed Exclusion Criteria: Patients who meet any of the following criteria will be excluded from participation in the study: Patients who require urgent resection due to degree of mass effect, oedema, hydrocephalus or symptoms Patients who have received chemotherapy or radiation for the diagnosis of LGG Tumour involves cerebellum or brainstem Routine trial exclusion criteria Any significant Intracranial bleeding in the opinion of the principal investigator Prior malignancy Significant co-morbidity ECG abnormalities Recent surgery Known allergy or sensitivity to any of the excipients in the investigational product

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase 0 'window of opportunity'/perioperative (Part A) followed by Phase 2 adjuvant treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AB-218<br>Part A: Peri-operative treatment (Phase 0); Part B: Post operative adjuvant therapy (phase 2) | Procedure: Biopsy<br>* Patients will undergo stereotactic biopsy by craniotomy or burr hole.<br>Drug: Part A: AB-218<br>* Part A: AB-218 orally 250 mg BID for 28 days.<br>Procedure: Surgery (maximal resection)<br>* Surgery: Maximal safe resection, within 24 hours of last dose of AB-218.<br>Drug: Part B: AB-218<br>* Part B: AB-218 orally 250 mg BID for 28 days for up to 12 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 0: Feasibility of Phase 0 study in patient population | Number of patients to complete all planned investigations and procedures | 14 months | 
| Phase 0: pharmacokinetic analysis of tumour tissue | Total and unbound AB-218 in tumour tissue | 4 weeks | 
| Phase 0: pharmacokinetic analysis of cerebrospinal fluid (CSF) | Total and unbound AB-218 in CSF | 4 weeks | 
| Phase 2: Number of Adverse events | Number of adverse events (AEs) according to NCI CTCAE v 5 | up to 30 days after last study dose | 
| Phase 2: Incidence of drug related adverse events | Drug related adverse events | up to 30 days after last study dose | 
| Phase 2: Incidence of dose limiting toxicity | Dose limiting toxicity events | up to 30 days after last study dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 0: Incidence of treatment emergent Adverse events | Treatment emergent adverse events (AEs) according to NCI CTCAE v 5 | during 1 cycle of AB-128, prior to maximal resection (4 weeks) | 
| Phase 0: Safety of planned craniotomy and resection after stereotactic biopsy and treatment with AB-218 | 30-day morbidity and mortality post surgery | 30 days after maximal resection | 
| Phase 0: Pharmacodynamic (PD) analysis of AB-218 in tumour | Changes in 2-hydroxyglutarate (2-HG) levels in tumour | after maximal resection (4 weeks), at progression (optional) | 
| Phase 0: Pharmacodynamic (PD) analysis of AB-218 in cerebrospinal fluid (CSF) | Changes in 2-hydroxyglutarate (2-HG) levels in cerebrospinal fluid (CSF) | after maximal resection (4 weeks), at progression (optional) | 
| Phase 0: Pharmacodynamic (PD) analysis of AB-218 in plasma | Changes in 2-hydroxyglutarate (2-HG) levels in plasma | after maximal resection (4 weeks), monthly during treatment, at progression (optional) | 
| Phase 0: anti-tumour activity | Objective response (LGG RANO assessment) | 4 weeks | 
| Phase 2: anti-tumour activity | Objective response (LGG RANO assessment) | 8 weekly until progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IDH1, Diffuse Astrocytoma, oligodendroglioma, phase 0, perioperative