FivepHusion, an advanced clinical-stage biotechnology company, is pleased to announce the commencement of the investigator-initiated phase 1b/2a Deflexifol™ at Relapse Trial (DART) in paediatric brain cancer patients. This study is supported by the Kids with Cancer Foundation.
  • Deflexifol™ is an optimised all-in-one formulation of the chemotherapeutic agent 5-fluorouracil (5-FU) and its biomodulator leucovorin (LV), a drug that potentiates 5-FU anti-tumour activity, for the treatment of solid tumours.
  • Ependymoma is the third most common brain tumour in children. There are no drugs approved for its treatment. Currently, surgical resection and radiation therapy are the only available options. Up to half of all patients will relapse, and most of these patients will die from the disease.
  • Independent pre-clinical and clinical data has demonstrated promising 5-FU activity against ependymoma. However, until the development of Deflexifol™, it has not been possible to co-administer therapeutically effective doses of 5-FU and LV in a safe and tolerable manner.
  • The DART phase 1b/2a clinical study is designed with two parts:
    • Part A, to determine Deflexifol™ safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in paediatric patients with refractory or recurrent central nervous system (CNS) tumours, or newly diagnosed diffuse intrinsic pontine glioma (DIPG) / diffuse midline glioma (DMG) who have completed radiotherapy.
    • Part B, a phase 2 study at the RP2D to evaluate Deflexifol™ anti-tumour activity in patients with refractory or recurrent ependymoma. Response rate, progression free survival and overall survival will be assessed.
  • The DART study is led by Professor David Ziegler and Dr Marion Mateos at the Kids Cancer Centre and coordinated by the Sydney Children’s Hospital, Randwick, with support from the Cancer Institute NSW. The study is being run at paediatric oncology centres throughout Australia and is sponsored by the Australian and New Zealand Children’s Haematology / Oncology Group (ANZCHOG) with support from the Robert Connor Dawes Foundation.

FivepHusion is developing Deflexifol™, an optimised all-in-one physiological pH formulation of the chemotherapeutic agent 5-FU and its biomodulator LV – a drug that potentiates 5-FU anti-tumour activity1 – for the treatment of solid tumours. Deflexifol™ is specifically formulated to facilitate the simultaneous administration of both agents, for the first time. Deflexifol™ has demonstrated superior safety and tolerability at standard and higher equivalent doses of 5-FU across two clinical trials2,3 in end-stage adult cancer patients with a variety of heavily pre-treated chemo-resistant solid tumours. Disease control was reported in the majority of patients even though they had typically previously failed multiple 5-FU treatment regimens2. The most recently completed clinical trial, FP101A3, declared an MTD for Deflexifol™ at a 525 mg/m2 bolus + 3400 mg/m2 infusional dose when administered to mimic the standard of care (SOC) ‘modified de Gramont’ regimen. The MTD for Deflexifol™ tolerably delivered the equivalent of ~40% more 5-FU than is typically administered in clinical practice4; it has previously been demonstrated that higher 5-FU doses correlate with improved response and better survival5. Additionally, multiple independent phase 2 studies have reported that investigational co-administration of 5-FU and LV, as is achieved with Deflexifol™, leads to higher response rates and better survival compared with SOC serial administration of these agents6-10. Deflexifol™ is therefore expected to provide superior anti-tumour efficacy.

Ependymomas are rare central nervous system tumours (~4 per million) originating from the ependymal cells that line the ventricles of the brain and central canal of the spinal cord. Tumours can manifest at any age, with peak incidence in young children (0-4 years) and older adults11,12. The current SOC treatment for ependymoma is surgery and radiotherapy, though relapse occurs in approximately half of all paediatric patients and is associated with a poor prognosis13,14. Currently there are no drugs approved for the treatment of ependymoma, presenting a significant unmet medical need for safe and efficacious new treatments.

Previously, independent laboratories reported that 5-FU possesses selective cytotoxicity against ependymoma cells both in vitro and in vivo15,16. In rodent models, intravenous 5-FU was demonstrated to significantly reduce tumour growth and prolong survival15. A St Jude Children’s Research Hospital phase 1 trial of 5-FU monotherapy in 23 patients aged ≤22 years with recurrent intracranial or spinal ependymoma reported partial responses (n=5) or stable disease (n=6) in 48% of patients17. 5-FU was administered as a bolus only, and dose limiting toxicities restricted its use and dose. Whilst the clinical potential for standard formulations of 5-FU in ependymoma showed promise, it ultimately demonstrated limited clinical utility.

Deflexifol™ is a promising new candidate for the treatment of ependymoma. Due to the improved safety, tolerability, and potentially superior anti-tumour efficacy of Deflexifol™, the drug offers the exciting opportunity of addressing the limitations of standard formulations of 5-FU to treat ependymoma and potentially other brain tumours. The higher equivalent 5-FU MTD of Deflexifol™ together with the simultaneous delivery of LV is expected to facilitate greater drug concentrations in the brain and at the tumour, leading to enhanced efficacy.

The investigator-initiated DART study is led by Professor David Ziegler and Dr Marion Mateos at the Kids Cancer Centre and coordinated by the Sydney Children’s Hospital, Randwick, with support from the Cancer Institute NSW. Professor Ziegler is the Director of the Kids Cancer Alliance. The trial will be run at all major paediatric oncology centres around Australia and is sponsored by ANZCHOG with major funding support from the Kids with Cancer Foundation and the Robert Connor Dawes Foundation. Deflexifol™ will be supplied by FivepHusion.

The DART study is designed in two sequential parts. Part A will investigate safety, including the dose-limiting toxicities, tolerability, pharmacokinetics, MTD and RP2D of Deflexifol™ in children and young adults with relapsed CNS tumours and newly diagnosed DIPG/DMG tumours that have completed radiotherapy. Part B will evaluate the anti-tumour activity, progression free survival and overall survival associated with Deflexifol™ monotherapy at the RP2D in patients with refractory or recurrent ependymoma.

Dr Christian Toouli, CEO and Managing Director of FivepHusion commented, “We are excited to collaborate with Professor Ziegler, Dr Mateos and other participating clinicians, their teams and organisations, and are very grateful of the generous charity funding support enabling the investigation of Deflexifol™ as a promising new treatment for paediatric brain cancer patients.”

1Longley et al. 2003, Nat Rev Cancer, 3(5):330.

2Clingan et al. 2019, Asia-Pac J Clin Oncol., 15(3):151.

3FP101A (ACTRN12619001533189).

4www.eviq.org.au

5Saif et al. 2009, J Natl Cancer Inst., 101(22):1543.

6Ardalan et al. 1991, J Clin Oncol., 9(4):625.

7Yeh et al. 1997, Anticancer Res., 17(5B):3867.

8Yang et al. 1999, Cancer, 85(9):192.

9Bleiberg et al. 2012, Acta Gastroenterol Belg., 75(1):14.

10Romano et al. 2021, Oncotarget, 12(3):221.

11Ostrom et al. 2022, Neuro Oncol., 24(supp 5):v1.

12Villano et al. 2013, Br J Cancer, 108(11):2367.

13Ritzmann et al. 2020, Pediatr Blood Cancer, 67(9):e28426.

14Marinoff et al. 2017, J Neurooncol., 135(1):201.

15Atkinson et al. 2011, Cancer Cell, 20(3):384.

16Donson et al. 2018, Mol Cancer Ther., 17(9):1984.

17Wright et al. 2015, Neuro Oncol., 17(12):1620.

About FivepHusion

FivepHusion (www.fivephusion.com) is an advanced clinical-stage, globally focused biotechnology company whose purpose is to optimise chemotherapy to improve patient treatment outcomes and quality of life.

FivepHusion is developing Deflexifol™, a proprietary, novel, and optimised physiological pH formulation to co-administer the chemotherapeutic agent 5-fluorouracil (5-FU) and its biomodulator leucovorin (LV), a drug that enhances 5-FU anti-cancer activity. These drugs are commonly used globally to treat various solid tumours including colorectal, pancreatic, gastric and breast cancers. However, due to their chemical incompatibility, current formulations of 5-FU and LV suffer from limitations in their safety, tolerability, effectiveness and pharmacological compatibility. These disadvantages contribute to limited treatment response rates, unpleasant side effects and toxicities, and a reduced quality of life experienced by cancer patients. Deflexifol™ has been designed to address these limitations through co-administration of the two agents with clinically demonstrated improvements in safety and tolerability and the potential to offer superior anti-tumour efficacy, better quality of life, and overall enhanced clinical benefit for cancer patients.

FivepHusion is developing Deflexifol™ via the FDA 505(b)(2) and EMA Article 10b regulatory pathways as a bioequivalent, chemotherapy replacement of sub-optimal standard of care formulations of 5-FU and LV for the treatment of metastatic colorectal cancer, and other tumours with a projected global incidence of greater than 6 million patients. Deflexifol™ is also being developed as a new therapy for cancers with high unmet medical need, including paediatric ependymoma; a rare and deadly brain cancer which afflicts very young children.

Deflexifol™ is a trademark of FivepHusion.

Forward-Looking Statements
This announcement (and any attachments) may contain certain forward-looking statements that are based on any number of assumptions and estimates which may prove incorrect and relate to circumstances and events that may not take place. Forward-looking statements involve known and unknown risks, uncertainties, and other factors (such as significant business, economic and competitive uncertainties and contingencies, and regulatory and clinical development risks and uncertainties) which may cause the actual future plans, results or the performance of FivepHusion and its drug Deflexifol™ to differ materially from the plans, results or performance expressed or implied by such forward-looking statements. Past performance is not a reliable indicator of future performance. There can be no assurance that any forward-looking statements will be realised. FivepHusion does not make any representation or give any warranty as to the likelihood of achievement or reasonableness of any forward-looking statements.