Avasopasem produces significant improvement of severe oral mucositis in head and neck patients

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Published: 4 Jun 2022
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Dr Carryn Anderson - University of Texas Medical Branch, Texas, USA

Dr Carryn Anderson speaks to ecancer about the results of a randomised Phase 3 trial of avasopasem manganese (GC4419), known as ROMAN, for severe oral mucositis (SOM) in patients receiving chemoradiotherapy (CRT) for locally advanced, nonmetastatic head and neck cancer (LAHNC), which indicated that patients with high-risk renal cell carcinoma, who took the drug everolimus daily for up to one year after surgery lived longer without their disease returning. 

In relation to the methodology of the trial, it was a double-blind, PBO-controlled trial; patients receiving 60-72 Gy of IMRT plus cisplatin were randomised 3:2 to AVA 90 mg vs PBO by 60-minute IV infusion, M-F before each RT fraction.

She notes that avasopasem manganese showed significant benefit in decreasing the incidence and duration of SOM and showed a decrease in severity of the SOM for patients. Importantly, the tumour outcomes at 1 and 2 years were not significantly impacted and were equally good to the placebo arm.

Dr Anderson concludes by discussing the next steps in the investigation, which involves moving forward with an FDA submission.

 

I’m presenting the ROMAN trial, a randomised phase III trial testing avasopasem manganese against
placebo in patients who are receiving concurrent cisplatin and IMRT for their head and neck cancer
with the goal of decreasing severe oral mucositis. Some brief background information as to the clinical
setting for this drug – severe oral mucositis is a very common side effect in patients who are receiving
radiation and concurrent chemotherapy for their head and neck cancer. It is debilitating and painful
and it’s a difficult side effect for us as clinicians to manage. It can result in patients needing a feeding
tube placed; sometimes they need to be hospitalised or get treatment breaks and, of course, that can
impact their cancer outcomes. Unfortunately there aren’t any FDA approved drugs to mitigate this
side effect and so we’re excited that this drug, avasopasem manganese, is showing significant
promise.

It was tested in a phase II trial and those results are previously published in JCO in 2019. The drug
showed significant benefit in decreasing the incidence and duration of severe oral mucositis and
showed a decrease in severity of the oral mucositis as well. Importantly, the tumour outcomes at one
and two years were not significantly impacted and were equally good to the placebo arm.

I’d like to tell you a little bit more about the drug itself. The mechanism of the drug is such that it
rapidly converts radiation induced superoxide to hydrogen peroxide. This is important because
superoxide is what causes the downstream events that result in the development of oral mucositis. In
the basic science studies, and now in several clinical trials, we have shown that the mechanism of this
drug protects normal tissues from the radiation effects but does not spare cancer cells from the
damaging effects of radiation. This drug was tested in a randomised placebo controlled trial at two
dose levels, 30mg and 90mg, against placebo. The important outcomes of that trial were that the
severe oral mucositis was significantly decreased in duration as well as incidence. The severity of the
oral mucositis was also decreased and the benefit was greatest in the higher dose of the drug, the
90mg arm. So that was brought forward for phase III testing and that is what is being tested here in
the ROMAN trial.

The design of the ROMAN trial is such that oral cavity and oropharynx patients that were otherwise
going to be receiving concurrent cisplatin and IMRT were enrolled and the drug was delivered as a 60
minute IV infusion prior to each radiation treatment. The patients were stratified by their surgical
status as well as the dose of cisplatin that they received. Ultimately we enrolled 455 patients on the
trial. The data that we presented today was the intention to treat analysis of 407 patients. The patient
characteristics were such that the characteristics were well distributed between the two arms. The
most common patient presentation was a p16 positive oropharynx patient receiving definitive
chemoradiation on the weekly cisplatin schedule.

Importantly, every patient enrolled on this trial was required to receive 50Gy or more radiation to two
oral cavity sites. If we look at the patients that were enrolled, 50% of these patients actually received
that dose or more to five or more oral cavity sites. So we were really expecting a lot of mucositis in
this patient cohort.


We’re pleased to announce that the trial met its primary endpoint of severe oral mucositis incidence
by the end of IMRT. The avasopasem arm significantly decreased the incidence from 64% down to
54%, this was a p-value of 0.045. Importantly, the drug also statistically and significantly decreased
other important clinical endpoints like the duration of severe oral mucositis. It impressively decreased
the duration from 18 days down to only 8 days, this is a relative decrease of 56%, and also decreased
the incidence of grade 4 mucositis and the duration of grade 4 mucositis, though those did not quite
meet statistical significance. The active arm also delayed the onset of severe oral mucositis during the
treatment course from 38 days in the placebo arm to 49 arms in the avasopasem arm.

As we looked at the drug against placebo as far as adverse effects, the adverse effects incidence
were similar to what we otherwise expect in cisplatin and radiation patients. There is a known mild
side effect, grade 1-2 nausea and vomiting, with the active drug but this was self-limiting and resolved
on its own within a few hours after the infusion completed. This did not translate to an increased
incidence of grade 3 nausea or vomiting compared to placebo.

So we’re excited to present today that this is a positive trial, that the primary endpoint of severe oral
mucositis incidence was statistically and clinically meaningfully reduced with avasopasem 90mg. We
also decreased the duration of severe oral mucositis, decreased the incidence of grade 4 mucositis
and delayed onset of severe oral mucositis. Thankfully, the safety profile of the drug is very similar to
that of placebo. The results that we presented today were very similar to the results already published
by the phase II trial, results in JCO 2019. We look forward to following these patients for their one-
and two-year tumour outcomes and we’ll subsequently report that data as it comes available.

We’re also exploring whether or not the drug may mitigate cisplatin induced kidney injury and we’re
excited because the company is moving forward with the FDA submission. So we hope to hear more
about that later this year as well.

This will have a significant impact on our patients’ quality of life. If we can decrease the severity of the
ulcers that develop in their mouths and throats during the treatment course that may decrease how
many doses of the narcotics they need to take; it may decrease the incidence of having a feeding
tube placed. They may return to a normal diet faster and may return to a normal life faster if we can
decrease this awful side effect from radiation.

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