Phase II Trial Evaluates New Gene Therapy for Non–Muscle Invasive Bladder Cancer After BCG

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A novel approach using intravesical gene therapy showed promising activity in a phase II trial that enrolled patients with bacillus Calmette-Guérin (BCG)-refractory or -relapsed nonmuscle invasive bladder cancer.1

The rate of high-grade relapse-free survival at 12 months was 35% in patients treated with rAd-interferon-alpha/Syn3 (Instiladrin). The rate of relapse-free survival was even higher in patients with papillary bladder cancer only: 50% at 12 months were free of relapse.

The treatment has an acceptable side-effect profile. It is well tolerated and not absorbed systemically. Assays show it is delivered only to the bladder and with undetectable DNA levels in the blood of treated patients.
— Stephen Boorjian, MD

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The new treatment approach utilizes an adenoviral vector to deliver the interferon alpha gene to the bladder, thereby stimulating the bladder to produce interferon alpha and creating enhanced antitumor activity, explained lead author Stephen Boorjian, MD, Carl Rosen Professor of Urology; Vice Chair of Research in the Department of Urology; and Director of Urology Oncology Fellowships, Mayo Clinic, Rochester, Minnesota.

“These response rates showing 35% of all patients free of recurrence at 1 year and 50% recurrence-free survival in papillary tumors were observed in heavily pretreated patients. The treatment has an acceptable side-effect profile. It is well tolerated and not absorbed systemically. Assays show it is delivered only to the bladder and with undetectable DNA levels in the blood of treated patients,” revealed Dr. Boorjian.

The next step is a phase III multicenter open-label trial in what is now termed patients with “BCG-unresponsive” disease, Dr. Boorjian told attendees. “The phase III trial is now open and accruing patients,” he added.

The phase II study was the first trial to be conducted entirely through the Society of Urologic Oncology-Clinical Trials Consortium (SUO-CTC). “We hope this partnership with the SUO-CTC will lead to further studies of therapies for urologic cancers,” Dr. Boorjian noted.

Novel Treatment for Invasive Bladder Cancer

  • Treatment of bacillus Calmette-Guérin (BCG)-refractory or -relapsed bladder cancer represents an unmet need.
  • A novel approach using intravesical therapy to deliver the interferon-alpha gene shows promise in a phase II trial.
  • A phase III trial of this agent, which stimulates the bladder to produce interferon, is ongoing.

As background to the study, Dr. ­Boorjian said that better treatment for high-grade nonmuscle invasive bladder cancer represents an unmet need. Valrubicin (Valstar) is the only drug approved for this indication, and 1-year disease-free survival is only 10% with valrubicin, he explained. Other agents have been studied, but they have been hampered by small size and disappointing results.

Dr. Boorjian pointed out that treatment guidelines for bladder cancer include clinical trial enrollment for patients unwilling or unable to undergo radical cystectomy.

Previous studies of intravesical interferon monotherapy have not shown good efficacy, but this is thought to be related to poor exposure of the bladder to interferon. “The current approach we are studying is to use gene therapy to increase the bladder’s exposure to interferon. Preclinical studies showed that this approach reduced bladder cancer, which led to a small phase I trial with promising results,” he explained.

Key Study Findings

The single-arm phase II trial enrolled 43 patients with BCG-refractory or relapsed nonmuscle invasive bladder cancer.1 Of them, 40 patients received the treatment. Patients who achieved complete response were allowed to be re-dosed at 3-month intervals up to 1 year. The primary endpoint was high-grade disease-free survival at 12 months.

This was a relatively highly pretreated population. A total of 16 patients had at least 3 prior courses of BCG. At enrollment, 75% had some element of carcinoma in situ; 25% had papillary cancer. 

No differences in response were observed based on age, gender, or refractory vs relapsed classification. In a subgroup analysis, patients with papillary cancer alone had a particularly favorable outcome.

Overall, the treatment was well tolerated, with no difference in the rate of grade 3 or higher adverse events based on treatment dose. There were no grade 4 to 5 events, and the majority of adverse events were related to irritative lower urinary tract symptoms (ie, urination urgency, dysuria, and nocturia).

Surrogate studies showed that the gene transfer was effectively delivered to the bladder and not the blood, Dr. Boorjian said.

Additional Commentary

Noah Hahn, MD, Associate Professor of Oncology and Urology at Johns Hopkins University School of Medicine in Baltimore, was encouraged by the study results. “This is an interesting therapy with a clear signal of activity in a phase II study. This is a novel approach that addresses a bladder cancer population with a high unmet need. These phase II results support the conduct of the ongoing phase III trial. We will need to see the final phase III results in order to know if and how this approach could shape future practice,” he said. ■

Disclosure: Dr. Boorjian has served on the advisory board of Astellas Medivation. The study was funded by FKD Therapies, Kuopio, Finland. Dr. Hahn reported no potential conflicts of interest.


1. Boorjian SA, Shore ND, Canter D, et al: Intravesical rad-IFN alpha/Syn3 for patients with high-grade bacillus Calmette-Guérin refractory or relapsed non-muscle invasive bladder cancer. 2017 Genitourinary Cancers Symposium. Abstract 279. Presented February 17, 2017.