Lay Summary

Brain cancers are the deadliest of all childhood cancer and the leading cause of disease associated death in children. Diffuse intrinsic pontine glioma (DIPG), and diffuse midline glioma (DMG) remain the most aggressive childhood cancers and the only available treatments for this group of brain cancers are palliative.

Our group has made the ground-breaking discovery that the polyamine pathway is a critical driver of DIPG/DMG and represents a novel therapeutic target. We have shown that dual targeting of the polyamine pathway is the most effective drug treatment strategy published to date in orthotopic animal models of childhood brainstem gliomas.

This project translates this preclinical work into a clinical trial to make this promising treatment available to children with DIPG. The combination of AMXT 1501 and DFMO potently inhibits the polyamine pathway and represents an exciting new treatment strategy for DIPG/DMG. Since DFMO is clinically available and the combination of AMXT 1501 and DFMO is currently being tested in adult patients in an open clinical trial, this combination can be rapidly translated to children with these aggressive, incurable brain tumours. Furthermore, this clinical trial will open through the international collaborative network, CONNECT, which will allow it to be open in at least 18 children’s hospitals around the world with access for children internationally.

Executive Summary

Background.   

Childhood brain tumours are the most common childhood solid tumor and remain the single largest disease entity causing death in children[1]. Despite dedicated preclinical and clinical research in this area, including many clinical trials delivering conventional and novel treatment strategies to children, improvements in survival for children with aggressive brain tumours have been negligible[1]. DIPG/DMG is the most aggressive of all childhood cancers accounting for up to 80% of pediatric brainstem tumors[2, 3]. Devastatingly, DIPG/DMG is an incurable brain cancer for which the median survival is a dismal 11 months[4]. These tumors are located in crucial midline structures of the brain and thus, surgical removal is not feasible. Additional treatment with radiation temporarily slows tumour growth and chemotherapy has largely been ineffective in DIPG/DMG[3-5]. 

Many barriers have been identified to the development of successful treatment strategies for aggressive childhood brain tumours, such as DIPG/DMG. These include the poor penetration of the blood-brain-barrier to many conventional and novel agents and the molecular heterogeneity and clonal evolution of brain tumors[6].  The majority of novel clinical trials for DIPG/DMG have used single therapeutic agents and those with published results have to date not shown any improvement in survival[5, 7]. Therefore, novel and, ideally, combinatorial treatment approaches are required for this aggressive tumour type with a devastating prognosis.

Our clinical trial will be a first-in-child study of the novel agent AMXT 1501 in combination with DFMO, targeting the polyamine pathway that we have shown to be critical for DIPG tumorigenesis. This study represents the translation of the highly promising pre-clinical work in DIPG/DMG to allow children around the world access this treatment.

Elevated polyamines are known to induce tumorigenesis and survival by activation of the rate-limiting polyamine pathway enzyme ODC1 (Ornithine Decarboxylase 1) and upregulation of polyamine transport into the cancer cell in childhood and adult malignancies[8-11]. DFMO, an ODC1 inhibitor, crosses the blood brain barrier (BBB) and potently blocks proliferation of DIPG neurospheres and colony formation[10]. However, it has only minimal single agent clinical activity against a variety of tumor types[11-14]. We have shown that the polyamine pathway is upregulated in DIPG/DMG. These tumours display both overexpression of ODC1 and reduced expression of catalytic enzymes in the polyamine pathway[15]. DFMO had modest single agent activity in DIPG neurosphere cultures at clinically achievable concentrations. Importantly, we discovered a critical mechanism of resistance, in that treatment with DFMO led to increased expression of the polyamine transporter SLC3A2 as a compensatory mechanism[15].

AMXT 1501 is a novel polyamine transport inhibitor that specifically targets SLC3A2. WE have shown that treatment with AMXT 1501 leads to effective blockade of SLC3A2 with a significant impact on the intracellular polyamine pool in DIPG cells[15]. Treatment with AMXT 1501 synergistically increases DFMO cytotoxicity, reduces DIPG cell proliferation, colony formation and enhances apoptosis in vitro. Testing in three aggressive DIPG in vivo orthotopic models, SU-DIPG-VI, HSJD-DIPG007 and RA055, showed that the combination of DFMO and AMXT 1501 was highly potent, with significant inhibition of tumor growth and profoundly improved survival. This indicates that DIPG cells are sensitive to pharmacological inhibition of the polyamine pathway and represents a novel, potentially effective, combination therapeutic strategy for DIPG/DMG. Importantly, we have found that the target of AMXT 1501 (the polyamine transporter SLC3A2) is potently upregulated in patient DMG/DIPG tumour samples, with much higher levels than in other high risk paediatric cancers.

This early phase clinical trial using AMXT 1501 in combination with DFMO will represent the rapid translation of our pre-clinical work from ‘bench to bedside’ to test the safety and efficacy of this potent new combinatorial treatment strategy. Comprehensive biology studies built into the trial will inform further optimization of combination therapy, identification of predictive and pharmacodynamic biomarkers, and facilitate clinical translation for direct benefit of children with DIPG and other aggressive brain tumors. There is extensive data on the safety and tolerability of DFMO in the pediatric population. Given the in vivo results demonstrated with DIPG, there is strong scientific rationale for proceeding with this combination trial of AMXT1501 and DFMO in this patient population. Ex vivo exploratory PD biomarkers will be used to assess AMXT 1501 target engagement. As this combination is under study in a phase I adult clinical trial that is near completion and given the strong support of Aminex Therapeutics to provide drug for this trial, this is a unique opportunity to translate to this treatment to the pediatric population.

Hypothesis.     We propose that the combination of AMXT 1501 and DFMO will be a safe, tolerable, and active combination treatment strategy for children with DIPG/DMG.

Design and Methods.

Our clinical trial is a phase I/II combination dose-escalation trial using continuous oral dosing of DFMO and AMXT 1501. The study is designed to rapidly ascertain the recommended phase II dose (RP2D) in children of the combination with the view to then allow it to test its efficacy in patients with DIPG/DMG at different stages of their disease course. This approach will allow the assessment of the treatment strategy for patients with DIPG/DMG patients who are either newly diagnosed or relapsed/refractory.   

This clinical trial has been designed in consultation with the leadership team of CONNECT, and consists of two parts:

1. The phase I dose-finding cohort A to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of AMXT 1501 in combination with DFMO, in children with recurrent or refractory CNS tumors.

2. Once the RP2D has been determined, the phase II component will be comprised of two cohorts which will be assessed separately:

• • Phase II Cohort B: patients with newly-diagnosed DIPG/DMG can be enrolled on study up to 31 days after the completion of radiation therapy (standard of care)

• • Phase II Cohort C: patients with recurrent, progressive, or refractory DIPG/DMG who can be enrolled on study following disease progression or recurrence.

Clinical Significance: This clinical trial will allow rapid translation of our highly promising pre-clinical work seen in DIPG/DMG, using the combination of DFMO and AMXT 1501, to directly benefit patients with DIPG/DMG. Through the CONNECT international clinical trial consortium, children around the world will have access to this promising combinatorial approach and we will more rapidly be able to ascertain signal of efficacy so that this combination can be further optimised to benefit a wider patient base. In addition, ex vivo testing, PK and PD analysis will allow us to derive further biological correlates for this combination to take forward into the next phase of clinical trials to benefit this vulnerable patient population. The open adult phase I trial using this combination and the supportive industry partner (Aminex Therapeutics) will allow drug supply and the establishment of paediatric doses to be feasible.  

Description of Research Proposal

Budget

Collaborations and Conflicts of Interest