A Study of AB-218 in Patients With IDH1 Mutated Low Grade Glioma (AB-218-IIT-201)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioma
• Intervention / Treatment: Procedure: Biopsy; Drug: Part A: Safusidenib Erbumine; Procedure: Surgery (maximal resection); Drug: Part B: Safusidenib Erbumine

Detailed Description

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 Safusidenib Erbumine (formerly 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 at least 12 cycles of Safusidenib, subject to ongoing documented evidence of clinical benefit, until disease progression or unacceptable toxicity.

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 Safusidenib 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

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Kate Drummond, Prof; Phone Number: +61 3 9345 2767; Email: AnHeart@wehi.edu.au

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia
      • Royal Melbourne Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 38 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically confirmed LGG or new diagnosis of LGG based on MRI
2. Tumours suitable for biopsy and safe for maximal resection in the opinion of the treating neurosurgeon
3. Patients who in the consensus of the treating neurosurgeon require resection of the brain tumour.
4. Patients who do not require immediate definitive resection of the brain tumour in the opinion of the treating neurosurgeon
5. Measurable and/or evaluable disease as per LGG-RANO criteria
6. Age ≥ 18 years of age.
7. ECOG performance score 0-1
8. Life expectancy of at least 24 months, in the opinion of the investigator
9. Adequate haematological, renal and hepatic function
10. Reproductive and contraception criteria as prescribed

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from participation in the study:

1. Patients who require immediate definitive resection due to degree of mass effect or symptoms
2. Multicentric / multifocal tumour
3. Tumour involves cerebellum or brainstem
4. Patients who have undergone surgery for glioma within 24 months of study enrolment
5. Patients who have received prior chemotherapy and / or radiation for a diagnosis of glioma
6. Patients with contraindications to MRI or unwilling to undergo MRI
7. History of central nervous system bleeding as defined by stroke within 6 months before enrolment
8. Evidence of acute intracranial / intra-tumoural haemorrhage, except for participants with stable grade 1 haemorrhage

9. Other general criteria including:

   i) ECG abnormalities ii) significant comorbidity or infection iii) Prior malignancy iv) Recent surgery v) Known allergy or sensitivity to any of the excipients in the investigational product vi) no contraindicated concomitant medications

10. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator would pose a risk to participant safety or interfere with the study evaluation, procedures or completion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Safusidenib Erbumine (AB-218); Part A: Peri-operative treatment (Phase 0); Part B: Post operative adjuvant therapy (phase 2)

Procedure: Biopsy; Patients will undergo stereotactic biopsy by craniotomy or burr hole.; Drug: Part A: Safusidenib Erbumine; Part A: Safusidenib Erbumine orally 250 mg BID for 28 days.; Procedure: Surgery (maximal resection); Surgery: Maximal safe resection, within 24 hours of last dose of Safusidenib Erbumine.; Drug: Part B: Safusidenib Erbumine; Part B: Safusidenib Erbumine orally 250 mg BID for 28 days for a minimum of 12, 28-day cycles subject to ongoing documented evidence of clinical benefit, until disease progression or unacceptable toxicity.

What is the study measuring?

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 0: Identify factors that can improve the patient experience quality of the service provided to participants using Research Participant Perception Survey short form (RPPS)	Understanding the patients' perspective on the peri-operative design and satisfaction with study procedures	4 months post op
Phase 2: Identify factors that can improve the patient experience quality of the service provided to participants using Research Participant Perception Survey short form (RPPS)	Understanding the patients' perspective on the peri-operative design and satisfaction with study procedures	4 months post op
Phase 2: anti-tumour activity	Objective response (LGG RANO assessment)	12 weekly until progression

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: Survival	Progression free survival (PFS)	30 days after last study dose
Phase 2: Survival	Overall survival (OS)	30 days after last study dose
Phase 2: Survival	Time to treatment failure (TTF)	30 days after last study dose
Phase 0: Change in tumour volume in response to Safusidenib	Volumetric analysis of post biopsy and pre-op MRI images	4 weeks
Phase 2: Change in tumour volume in response to Safusidenib	Volumetric analysis of MRI images during adjuvant treatment	12 weekly until progression

Collaborators and Investigators

• Sponsor: Melbourne Health
• Collaborators: AnHeart Therapeutics Inc.; Walter and Eliza Hall Institute of Medical Research
• Investigators: Principal Investigator: Kate Drummond, Prof, Melbourne Health

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: September 19, 2022
• First Submitted That Met QC Criteria: October 11, 2022
• First Posted (Actual): October 13, 2022

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: IDH1; perioperative; oligodendroglioma; Diffuse Astrocytoma; phase 0
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: 2022.003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No