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Clinical trial for high-risk MDS tests new drug combination 

A Phase I investigator-driven clinical trial, which is ready to recruit its first participant, gives Australian patients with high-risk MDS access to two new oral drugs.

Professor John Pimanda
Professor John Pimanda, Director, Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales

Professor John Pimanda, Head, Stem Cell Laboratory, Lowy Cancer Research Centre, University of NSW, is leading the study into a compound that is related to the current standard of care, azacitidine (Vidaza®).

Prof. Pimanda said pre-clinical research, co-funded through a Translational Research Grant from the Leukemia & Lymphoma Society in the U.S., and Snowdome Foundation and Leukaemia Foundation in Australia, had made this clinical trial possible.

In a bid to improve treatment for high-risk MDS, this new study is looking at the safety of Inqovi®, also called ASTX727, when combined with another drug, defactinib. An added convenience for patients is that both drugs are tablets, rather than injections that are given in hospital. 

ASTX727 is an oral form of decitabine, (which is in the same class of hypomethylation agents as azacitidine) combined with another drug, cedazuridine that slows the breakdown of the drug in the liver so more of the drug is available to act on the body’s tissues. 

ASTX727 has received both U.S. Food & Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) approval for high-risk MDS and was listed on the Pharmaceutical Benefits Scheme (PBS) on 1 October 2022.

Prof. Pimanda, who also is a consultant haematologist at the Prince of Wales Hospital (Sydney) said the objective of the ASTX727/defactinib combination trial goes back to fundamental research done in his laboratory “that was useful in understanding drug failures”. 

Azacitidine has been available on Australia’s Pharmaceutical Benefits Scheme (PBS) for the treatment of high-risk MDS since 2011, however, less than 50% of people will respond to this treatment.

“Work we did some years ago showed the reason some patients were responding to azacitidine, and others weren’t, was related to whether the blood stem cells were proliferating [multiplying] or not,” he said. 

“You need the blood stem cells to enter the cell cycle* and multiply, to incorporate this drug.

“If they aren’t increasing in number, they don’t incorporate the drug, and the drug won’t have an effect. 

“Another question we hope to answer is, what does the drug do when it’s incorporated?” said Prof. Pimanda.

This trial, called CELESTIAL-MDS: Combined evaluation of epigenetic and sensitising therapy in AML and MDS is based on preliminary results that show one reason patients are not responding is because the blood stem cells are highly confined to the surrounding bone marrow environment cells, where they don’t multiply.

“If we interrupt that interaction between the stem cells and the environment, the cells start cycling… they start multiplying, and then we hope they will incorporate more of the drug.

“We have evidence, from our laboratory data, that when you combine azacitidine and defactinib together, the ability of the blood stem cells to multiply and make blood increases. Now we need to demonstrate that this happens in patients,” said Prof. Pimanda.

This trial will investigate whether the combination of ASTX727 and defactinib is tolerated by patients and also, does this drug combination see an increase in blood production? 

Defactinib, which has been used in solid organ cancers, is a focal adhesion kinase (FAK) inhibitor and it blocks interactions between the blood stem cells and the environment.

“By combining ASTX727 with a second drug, we expect we will get better drug absorption in those patients that are not absorbing the drug and, as a consequence, that they will have a better response,” Prof. Pimanda explained.  

“I think the combination will be more effective, especially in that subgroup of patients who are failing treatment because they’re not absorbing the drug enough. We’re not talking about absorbing it in the gut, it’s the blood stem cells themselves taking it up, and they need to be proliferating. That is the key.”

The trial is being coordinated by Canberra Hospital haematologist and clinical triallist, Professor Mark Polizzotto and his team at the Clinical Hub in Interventional Research (CHOIR) at the Australian National University. 

In the trial design, patients will get only one drug in the first cycle, then in the second and subsequent cycles, they’ll get both trial drugs.

“We will measure whether the amount of drug that’s being incorporated increases when you give the two drugs together,” said Prof. Pimanda.

“The hope is that you do get increased drug absorption in the blood stem cells, and that also then translates to increased blood production.” 

The Phase I trial will be run over 12 months in New South Wales, at Prince of Wales, Concord, Nepean, and Royal Prince Alfred hospitals, and extended to other sites in NSW and the Australian Capital Territory. Depending on the results, the investigators would like to see the trial extended to Victoria and perhaps South Australia and Queensland in a Phase II study.

“Phase I will give us real world data about whether the drug combination will improve drug absorption, and that will answer a very important question,” said Prof. Pimanda.

“Then we’ll do a dose expansion study over another two years and if that proves effective, hopefully we can run a Phase II study,” he said.

The study is funded by the Medical Research Future Fund with each drug being supplied by the manufacturer.

Prof. Pimanda said one of the issues with investigator-driven trials such as this, “is the need for enthusiasm from the manufacturer”.

“Even though we’re paying for the trial and running it, we need the companies to supply the drug. To do that, they need to see potential for their compound to be registered for use following large multi-centre trials.

“These are the challenges around investigator initiated early-phase trials. You need to demonstrate safety, you need to show evidence of efficacy, and you need commercial interest to progress drug development for a particular clinical indication,” said Prof. Pimanda.

The two experimental drugs for this trial are being provided at no cost by the manufacturers; Inqovi (ASTX727) by Astex Pharmaceuticals/Otsuka Pharmaceutical, and defactinib by Verastem Oncology. 

“From a pragmatic point of view, when we run these trials, the patient gets on a trial and if they do respond, then they are assured a supply of the drug. That is a benefit for the patients.

“Our hope is that the response rates are going to be better, but also that they will be more sustained because this is not a curative treatment. 

“Data from such trials could feed into decisions by a manufacturer whether to continue drug development or not,” he said.

The cell cycle is a sequence of events that occur in a cell in preparation for cell division.

People with high-risk MDS who are interested in this trial should speak to their haematologist. The CELESTIAL-MDS trial will be listed on the ClinTrial Refer App.

Last updated on January 3rd, 2023

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