In August, the Journal of Clinical Oncology published results from a phase II, open-label, multicenter trial for intravesical recombinant adenovirus interferon alpha with Syn3 (rAd-IFN[alpha]/Syn3) as treatment for high-grade non-muscle invasive bladder cancer (NMIBC) patients who are unresponsive to bacillus Calmette-Guerin (BCG). In the trial, rAd-IFN[alpha]/Syn3-a novel gene therapy-showed three-fold improvement in recurrence-free survival in high-risk, early-stage bladder cancer patients, and it demonstrated acceptable toxicity and a clinically meaningful durable response that has been maintained beyond 36 months in some patients.
In oncology, especially in urologic oncology, there are limited options for patients with high-grade NMIBC. At this time, intravesical immunotherapy with BCG is the frontline therapy. Recurrence and progression are common as patients develop BCG-unresponsive disease, and there remains a critical unmet need for effective salvage therapy for BCG-unresponsive NMIBC to avoid cystectomy and improve disease-specific outcomes. As such, these data are encouraging and hold promise in improving outcomes for this patient group.
In BCG-unresponsive NMIBC, there is a high risk of disease progression. This, coupled with the lack of effective treatment options, often leads patients to surgery to remove the bladder-not always the most desirable choice. An alternative is second-line chemotherapy, but valrubicin, the only FDA-approved drug for BCG-refractory disease, provides a durable, 12-month complete response for only about 8-10 percent of patients.
As an adenovirus gene therapy, rAd-IFN[alpha]/Syn3 contains the gene interferon alfa-2b. It is administered by catheter into the bladder where the virus enters the cells of the bladder wall. Inside the cells, the virus breaks down leaving the active gene to do its work. The cell's internal gene/DNA machinery picks up the gene and translates its DNA sequence, resulting in the cells secreting high quantities of interferon alfa-2b protein, a naturally occurring protein the body uses to fight cancer. This novel gene therapy approach turns the patient's own bladder wall cells into multiple interferon microfactories, enhancing the body's natural defenses against the cancer.
Further, although IFN[alpha] protein is an established anticancer agent, instillation into the bladder has had only limited efficacy against bladder cancer because the drug is cleared from the bladder in a few hours. Interferon-[alpha] gene therapy causes the cells lining the bladder to produce high levels of their own IFN[alpha] for a protracted period of time, up to 3 weeks, resulting in more extended exposure and an enhanced anti-tumor activity.
Trial Design & Results
The study randomized patients equally into two groups to receive intravesical rAd-IFN[alpha]/Syn3 1 x 1011 viral particles (vp)/mL or 3 x 1011 vp/mL. Patients judged to have been cancer-free at follow-up visits conducted at months 3, 6, and 9 were retreated at months 4, 7, and 10.
Results of the primary endpoint analysis showed that at 12 months, 14 (35%) of 40 treated patients were HG recurrence-free. The response rate was comparable in the two dose groups. In comparison, valrubicin has been associated with a 12-month complete response rate of only 8-10 percent.
The data, which are consistent with a previous phase I clinical trial, found three-fold improvement in recurrence-free survival when rAd-IFN[alpha]/Syn3 was compared to valrubicin.
No patients in the phase II study developed a grade 4 or 5 adverse event or discontinued treatment because of a drug-related adverse event. There were 10 grade 3 adverse events considered to be serious, but of these, only one episode of diarrhea and one episode of acute renal failure secondary to a urinary tract infection were judged related to the study drug, and both issues resolved with medical therapy.
Urgency and frequency of micturition were the most common adverse events (40%), but they were generally minor, transient, and could be minimized by pretreatment with anticholinergics.
What's Next
The Society of Urologic Oncology Clinical Trials Consortium, as part of the Society of Urologic Oncology, has now launched a phase III registration trial in patients with BCG-unresponsive NMIBC. The trial, which opened in 2016, is recruiting across the U.S. now and is expected to enroll approximately 135 patients at 35 centers. With a planned duration of 24 months, this trial is designed to repeat treatments at 3-month intervals for responding patients and is analyzing HG recurrence-free survival at a 12-month primary endpoint. Details of the phase III trial can be found at http://ClinicalTrials.gov and on the Bladder Cancer Advocacy Network website (http://clinicaltrials.bcan.org/).
COLIN DINNEY, MD, is Professor and Chair of the Department of Urology, The University of Texas MD Anderson Cancer Center, Houston.