Race Oncology Ltd (ASX:RAC) has received research governance office approval from the Calvary Mater Newcastle Hospital for its open label clinical trial of Zantrene® (bisantrene dihydrochloride) in patients with extramedullary acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS).
According to the company, this will be the first clinical trial in the world to investigate the targeting of the FTO protein – a fat mass and obesity-associated gene expression – as a potential cancer therapy using an AML and MDS population.
Kick-off meeting on horizon
Representatives of the Race Oncology clinical team, the contract research organisation Paraxel and associated clinical teams of the Calvary Mater Hospital are scheduled to meet for site initiation and training on May 31.
Human ethics approval for the trial has been ticked off and the first patient will be recruited once site training is complete.
The open-label Phase 1 trial with a dose expansion Phase 2 stage will recruit up to 60 patients with extramedullary AML or MDS using a two-stratum (arm) design at trial sites in Australia and Europe.
What is extramedullary AML
Extramedullary AML occurs when the leukaemia spreads from the bone marrow and forms solid tumours in tissues such as the skin, breast, kidney, brain and elsewhere.
A 2020 prospective positron imaging trial found that up to 22% of AML patients have the extramedullary form.
Extramedullary AML patients have no clinically approved treatments and limited experimental treatment options, with many clinical trials explicitly excluding this difficult-to-treat form of AML.
Myelodysplastic (MDS) syndromes are a group of blood cancers that affect the production of normal blood cells in the bone marrow.
There is a one-in-three risk of a MDS patient’s illness progressing to AML – indeed, high-risk MDS is considered to be an earlier stage of AML.
The annual rate of MDS is 40 to 50 clinical cases per million people, which is approximately half the case rate of AML.
Clinical trial design
This open label Phase 1 trial with a Phase 2 dose expansion phase will recruit up to 60 patients with confirmed extramedullary AML at up to 10 clinical sites in Australia and Europe using a two-stratum (arm) design.
The first stratum will use Zantrene as a high-dose, single-agent treatment over seven days in patients with extramedullary AML who are able to tolerate high-intensity chemotherapy, followed by one or more cycles of consolidation treatment using Zantrene in combination with Ara-C, a standard of care AML drug.
The second stratum will use Zantrene as a low dose FTO-targeted agent in combination with the oral hypomethylating agent, ASTX727, for MDS or AML patients unwilling or unable to tolerate high-intensity chemotherapy.
Data reveals FTO inhibition synergies
Published preclinical data from the City of Hope Hospital/Beckman Research Institute by Professor Chen’s Laboratory identified that FTO inhibition synergised with decitabine in leukaemic cells.
Subsequent preclinical work by Race in collaboration with the Verrill’s Laboratory validated these findings in vivo setting, using a mouse model of the disease.
Associate Professor Verrills demonstrated that optimal dosing of decitabine and Zantrene is able to synergistically target extramedullary AML tumours as well as AML lesions in the bone marrow and spleen.
Trial targets complete response
The trial primary endpoint will be complete response, and complete response with incomplete haematological recovery, with the clinical aim of bridging the patient to an allogeneic hematopoietic stem cell transplant (Stratum 1), and safety and tolerability of the decitabine/Zantrene regimen (Stratum 2).
Key secondary endpoints include safety and tolerability of Zantrene, overall and event-free survival, and the correlation of FTO expression or other biomarkers with response to treatment.
Indicative timelines and reporting
The trial is expected to take 36 to 40 months, with patient recruitment taking roughly 18 months.
Because this is an open label trial, patient outcome results will be obtained soon after patients are treated, and the company intends to release progress updates on a regular basis.