Peter Younis is the eighth patient in the world to try new monotherapy drug Zanubrutinib for Waldenstroms Macroglobulinemia.

Melbourne Physician helps to develop a potential new line of treatment for Waldenstroms Macroglobulinemia

by Mackenzie Gignac

Five years ago Peter Younis became the eighth human patient in the world to receive the experimental drug BGB-3111. Peter was first diagnosed with Waldenstroms Macroglobulinemia in 2004, however, he was able to get by on his condition until 2007 when his paraprotein levels began to rapidly increase.

Listening to his doctor’s advice Peter underwent four cycles of intensive chemotherapy. Following chemotherapy Peter’s bone marrow biopsy suggested there were very few malignant cells left in his bone marrow, and he was able to go back to living a normal life with no treatment.

Seven years later in 2014, Peter’s paraprotein levels began to rise again. At that time, Haematologist and disease group lead at Peter Mac Constantine Tam offered Peter the chance to enroll in a phase I clinical trial for BGB-3111. The drug was so new that when Peter was approached by Professor Tam about enrolling in the trial, the right dosage amount was still being tested.

Prof Tam says that for his trial Zanubrutinib (BGB-3111) dose started as 40mg daily and then went up to 80mg, which is what Peter started with. Thanks to the study Peter participated in, we now know that the drug is most effective at a dose of 160mg twice daily.

Peter said that the decision to try BGB-3111 to treat his condition was more of a rational decision for him than one out of courage. ‘I wasn’t going to die next week. I figured I had some time,’ recalls Peter.

Another factor that Peter took into account was the similarity of Ibrutinib, the current drug used to treat Waldenstroms, and the new drug he was going to be using. ‘The new drug I was given was a new molecule of a BTK inhibitor, so it was likely going to have some effect,’ says Peter.

Additionally, Peter says that he was interested in the trial as a way to help those in the scientific community. ‘That probably made me choose this decision,’ recalls Peter. ‘I was contributing to the greater scientific good.’

Prof Tam says that the staging of clinical trials usually follows a similar format. ‘Phase I is about determining the right dose and side effect profile of the drug,’ says Tam.

After the correct dose is determined, phase II focuses on getting more experience with the drug. If there is enough evidence to progress then it goes to phase III.

This phase is focused on licensing the drug by going head-to-head with the world’s best-determined treatment option for the medical condition in focus. Prof Tam says by this point, ‘we know the drug, we know the dose, but how does it compare with the best of the best?’

Phase III involves an international randomised study where patients are randomly assigned the new drug or the previous best standard of care to see in a direct comparison which one is better. ‘It makes it a fair comparison because there is no bias,’ says Prof Tam.

Thanks to Peter’s courage to partake in the clinical trial, Zanubrutinib has made its way through phase III and is on its way to seek approval from the FDA to treat the blood disease Waldenstroms Macroglobulinemia.

Phase III of the Zanubrutinib study is called ASPEN and compares this drug to the current standard drug treatment, Ibrutinib. Prof Tam recently revealed his ASPEN findings at the American Society of Clinical Oncology Conference.

ASPEN compares the two drugs head-to-head. Zanubrutinib and Ibrutinib are similar. They come from the same class of drugs and hit the same target, the BTK inhibitor.

Another similarity is their side effect profile which includes high blood pressure, bleeding and heart arrhythmia. Although both these drugs are very similar Prof Tam suggests that Zanubrutinib is like a cleaner version of Ibrutinib, meaning it has the potential for less side-effects.

They are both similar in terms of effectiveness, however, the side effects that patients faced when on Zanubrutinib are much less significant. ‘The most prominent side effect was the heart going out of rhythm which 18% with Ibrutinib and only 3% with Zanubrutinib, so a six-fold difference in the rate of the heart going out of rhythm,’ says Prof Tam.

Prof Tam says that his key finding throughout the ASPEN study was the difference in side effect rate in favor of Zanubrutinib. ‘Because of fewer side effects, patients were able to take the drug for longer and therefore had a better quality of life,’ says Prof Tam.

The world’s first 25 patients were treated with this drug received the treatment in Melbourne under the supervision of Prof Tam and his colleagues. Prof Tam expresses great personal satisfaction in seeing Zanubrutinib progress throughout its whole life cycle. ‘We took it from a chemical, designed the first study, gave it to the first humans, and now see the drug successfully complete phase III testing. The type of success is every cancer researcher’s dream.’

Prof Tam says he credits this breakthrough to those like Peter who take a leap of faith to enroll in these clinical studies. ‘It’s because of patients like Peter who put their lives and bodies on the line that we can get to where we are today.’

Currently, Peter is still taking an oral dose of Zanubrutinib every day and has seen virtually no side effects. His cancer continues to remain in remission.