rAd-IFNα/Syn3 Phase 3 Trial NMIBC [2022]
rAd-IFNα/Syn3 Bladder Cancer Trial
It’s an honor to be asked to speak about this medication, which is a very exciting new development for many patients with non muscle-invasive bladder cancer. So RAD interferon alpha CIN 3 is a compound that links. The adenoviral vector RAD alpha interferon to an excipient CIN 3, which helps transduction of the adenovirus into bladder cancer cells. So it is a new compound. It was developed in conjunction by Dr. Colin Denney from MD Anderson with FKD Therapeutics, a company in Finland. And it was, as we’ll talk about, tested progressively through development trials in phase 1, phase II (randomized study), and then now the most recent phase 3 study (rAd-IFNα/Syn3).
Current Standard of Care For Bladder Cancer
So the current standard of care for patients with high risk, non muscle invasive bladder cancer is rith resection followed by BCG therapy (Bacillus Calmette-Guerin), which is a type of intravesical immunotherapy. Unfortunately, many patients will experience disease recurrence after BCG and ultimately be rendered what we have now turned BCG unresponsive. Meaning a disease state in which additional treatment (not initial treatment) with BCG is unlikely to be efficacious and likely to put the patient at risk for developing continued disease recurrence and progression.
The current standard of care for patients with BCG unresponsive, non muscle invasive bladder cancer is radical cystectomy, or surgical removal of the bladder. Unfortunately, bladder cancer often affects patients who are elderly and unable to undergo such a surgical procedure, and at the same time, bladder cancer surgery can impact patients’ quality of life such that there are patients who are unwilling to undergo this type of surgical procedure, therefore developing new therapeutics. Agents for the treatment of patients with BCG. Unresponsive, non muscle invasive bladder cancer represents a significant unmet need to enhance future patient outcomes. The medication was chosen here because of evidence in the past that interferon as a protein when put inside the bladder, does have activity against bladder cancer.
One of the issues with interferon as a protein is the dwell time or exposure. The (initial) treatment of the bladder mucosa is limited. The concept, therefore, with this gene therapy is to turn the bladder into a interferon producing bioreactor. So introduce an adenoviral gene therapy into the bladder, can into the bladder, allow it to transduce into bladder cells, and allow the cells themselves to produce sustained high levels of the interferon protein, which will then have the biologic activity against the bladder.
What Is The rAd-IFNα/Syn3 Trial Design?
So the rAd-IFNα/Syn3 trial was designed in a unique collaboration between a pharmaceutical company, FKD Pharma, and the Society of Urologic Oncology Clinical Trials Consortium, or SUCT. Which is a research network of institutions that facilitates clinical trial enrollment. The trial was also designed in close collaboration with the FDA and in that advice was designed as a single armed phase 3 rAd-IFNα/Syn3trial designed to test the efficacy of the RAD interferon medication for patients with BCG (Bacillus Calmette-Guerin) unresponsive non muscle invasive disease. (rAd-IFNα for patients with NMIBC).
Why Is The rAd-IFNα/Syn3 Trial Set Up This Way?
So the trial was set up as a single armed phase 3 trial because, short of radical cystectomy, there has not remained a gold standard or fair comparative therapy for testing new medications in patients with BCG responsive disease. And so in collaboration with FDA guidance, the trial was designed as a single armed study to test the efficacy of the RAD interferon medication. Primarily, I would say for the primary outcome metric of patients with BCG unresponsive carcinoma in situ.
What Are The Inclusions And Exclusions?
So the specific inclusion criteria for the rAd-IFNα/Syn3 trial are (rAd-IFNα for) patients with BCG unresponsive, non muscle invasive bladder cancer. Now, the term “BCG unresponsive” is defined by several different criteria. The first one is a patient who has received what’s considered to be adequate BCG therapy and has high grade TA or T1 disease (high grade Bacillus Calmette-Guerin) within 6 months of their last exposure to the BCG.
The second criteria is a patient who has received what’s considered to be adequate BCG therapy. Has carcinoma insight you within 12 months of their last exposure to BCG. Adequate BCG is defined as either two prior induction courses of BCG, which is a six week course, or one prior induction course and one maintenance cycle of BCG.
The single exception to those criteria is patients who have high grade T1 (high grade Bacillus Calmette-Guerin). At their first evaluation after a single induction course of BCG, those patients are also considered to be BCG unresponsive. So that’s the critical inclusion criteria for this trial. It’s BCG (Bacillus Calmette-Guerin) unresponsive noninvasive bladder cancer. The exclusion criteria for the trial are therefore patients with muscle invasive bladder cancer, patients who have non-US invasive disease but also have hydronephrosis, and patients who have upper track urothelial carcinoma. Or disease in the prosthetic urethra as well as patients on active immunosuppressives.
The Primary Endpoint Of The rAd-IFNα/Syn3 Clinical Trial
So the primary endpoint of the rAd-IFNα/Syn3 trial is the most exciting data that came out of this trial. So the primary endpoint of the trial was the complete response rate at any time after the first installation of (initial) treatment for patients with BCG unresponsive carcinoma in situ. There were 107 patients that were included in the study that had this BCG unresponsive carcinoma insight, and of those, 53.4% achieved a complete recovery.
All of those were identified within the first three months after the first installation. So that was very exciting. The data that came out of the trial for its primary endpoint and that it met the trial’s primary endpoint.
Secondary Outcomes For The rAd-IFNα/Syn3 Trial
So a variety of different secondary outcome measures were outlined on the outside of the rAd-IFNα/Syn3 trial (rAd-IFNα for patients with NMIBC). One of them was to look at the duration of the complete response among those patients who achieved a complete response with BCG (Bacillus Calmette-Guerin) on response of carcinoma in situ.
And as we mentioned for patients in terms of the primary study objective, 53.4. Of patients achieved a complete response and a response, and of those 45% maintained that complete response at 12 months after first installation. A second secondary endpoint of the trial was to look at high grade (Bacillus Calmette-Guerin) recurrence free survival among patients with BCG unresponsive TA or T1 (efficacy and safety analyses).
Non muscle-invasive bladder cancer, so papillary disease. And what we found was that 73% of those patients were high grade recurrence free at three months. And of those who achieved high grade (Bacillus Calmette-Guerin) recurrence free survival at three months, 60% maintained that at 12 months. So again, demonstrated promising efficacy data (efficacy and safety analyses) in the papillary BCG (Bacillus Calmette-Guerin) unresponsive cohort.
Another one of the trials’ secondary endpoints was cystectomy free survival. As we talked about, the gold standard for BCG on responsive non muscle invasive bladder cancer is removal of the bladder. One of the goals of medical therapy or bladder sparing therapy would be to avoid surgery. And we found that the two year cystectomy free survival in this patient cohort was 64 points, or 64%, which again, was very demonstrated promising (for the efficacy and safety analyses and demonstrated promising efficacy) efficacy.
And a final secondary endpoint from the trial was overall survival, and we found the two year overall survival here was 92.
How Are These Clinical Outcomes Significant?
So these are significant outcomes for patients with bladder cancer because they offer us the promise that there is going to be an alternative to radical cystectomy that would avoid the morbidity of that surgery that would allow maintenance of their quality of life.
One of the other important things that was studied in this trial was the safety profile of the treatment. Did any patient discontinued treatment? And what was demonstrated in the trial was that it was overall very well tolerated as a medication by far and away. The vast majority of adverse events were irritative lower urinary tract symptoms.
Only 2% of patients experienced serious treatment related adverse events, and only 2% of patient discontinued (treatment because an adverse event) therapy because of an adverse event. So I think as this therapy develops further, this really offers a window of promise for the future of patients with PCG unresponsive non muscle invasive disease.
What Was Your Journey To Study Bladder Cancer?
I would say that my journey both as a doctor and my interest in bladder cancer came from mentorship. My first mentor that I can credit from a urology standpoint is my dad, who was a urologist and who inspired me to go into the field as a urologic oncologist.
I worked with Dr. Douglas Scherr at Weill Cornell Medical Center, New York Hospital. And he has a particular interest and expertise in bladder cancer, and that got me inspired to further pursue bladder cancer, both clinically and from a research standpoint. And then, as my career evolved a bit, a third mentor, specifically for this trial, was Dr. Colin Dinney at MD Anderson Cancer Center, who engaged me very early on in phase II randomized study. He advised me throughout, mentored me as the principal investigator for this phase 3 study as well, and was just a tremendous resource and source of guidance and advice at all points through this.
And so I really would say that I’ve come to this as a beneficiary of excellent mentorship at different points in my own life.
Final Thoughts
I’d say that there’s lots of excitement in the field of BCG and responsive non muscle invasive disease. It was static for decades.
And now we have, with these trial results and other ongoing studies, a window of promise that we’re going to have a lot more to offer our patients going forward. And I would offer continued encouragement to the urologic and oncologic communities to support clinical trials and continue to enroll patients in the ongoing and plan trials in this disease space so that we may further refine. What’s going to be the optimal treatment for the future of patients with BCG on responsive, noninvasive.
Stephen Boorjian, MD – About The Author, Credentials, and Affiliations
Dr. Boorjian’s research focuses on the intracellular signaling systems that help bladder and prostate cancers in clinical oncology. His research is mostly about the androgen receptor in these cancers’ steroid hormone receptor pathways. Targeting The molecular pathways implicated in different stages of cancer, in this case the androgen receptor, may permit the creation of innovative treatments for people with these illnesses.
He also does clinical research on the outlook for people with cancers of the prostate, bladder, and kidneys. He focuses on people with high-risk prostate cancer and advanced renal cell carcinoma. In these areas, he uses the huge research databases at the Mayo Clinic, which have information on thousands of people who have been treated for different diseases.