Intravesical rAd-IFNα/Syn3 showed promising response rates, a tolerable treatment schedule, and acceptable toxicity among patients with high-grade, nonmuscle-invasive bladder cancer (NMIBC), refractory or relapsed after bacillus Calmette-Guérin (BCG) therapy, according to an open-label, phase II study presented (abstract 279) at the 2017 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held February 16–18 in Orlando, Florida.
The study found “a 12-month, high-grade, recurrence-free survival rate of 35% in this heavily pretreated population,” reported lead study author Stephan A. Boorjian, MD, Carl Rosen Professor of Urology at Mayo Clinic in Rochester, Minnesota.
Patients with papillary-only (Ta/T1) disease saw a 12-month, high-grade, recurrence-free survival rate of 50%, Boorjian noted. The treatment “was well-tolerated and demonstrated promising efficacy for patients with NMIBC,” he said.
Optimal management of BCG-unresponsive NMIBC “remains to be established,” Boorjian said. Valrubicin has been approved by the US Food and Drug Administration (FDA) for carcinoma in situ, but conveys a modest 1-year disease-free survival rate of 10%. Gemcitabine with and without mitomycin and various taxane therapies have been studied, but these trials had relatively small numbers of participants and “modest efficacy,” he noted.
rAd-IFNα/Syn3 is composed of recombinant adenovirus (rAd)-mediated IFN-α2b protein and Syn3, an excipient that enhances viral transduction of NMIBC urothelial. IFNα protein has multiple antitumor effects, but intravesical IFNα monotherapy does not offer durable responses, probably because of insufficient exposure, Boorjian said.
Preclinical studies have suggested no major toxicities associated with rAd-IFNα/Syn3 and in xenografted mice, it led to regression of human bladder tumors. A phase I trial of 17 patients found that a single rAd-IFNα/Syn3 treatment was safe, with no significant treatment-related adverse events, and no rAd-IFNα–specific DNA detected in patients’ blood. Seven of 17 (41%) patients in the phase I safety trial achieved a complete response at 3 months.
The new phase II trial was an open-label, parallel-arm, multicenter study conducted between 2012 and 2015. Forty-three patients with high-grade NMIBC after BCG therapy (BCG-refractory or BCG-relapsed patients) were randomly assigned to receive either intravesical rAd-IFNα/Syn3 (one dose) vs 3 × 1011 vp/mL. Those patients who maintained complete response were retreated every 3 months for up to a year. Three patients withdrew from the study prior to receiving treatment. Seventy-five percent had “an element of CIS at enrollment,” Boorjian noted.
“Fourteen of 40 patients (35%) were high-grade, recurrence-free at 12 months,” with no statistically significant difference in 12-month, recurrence-free survival between the study-dose arms, reported Boorjian. However, median time to recurrence was longer among patients in the high-dose study group (11.7 months vs 3.5 months for the low-dose group).
“Most  of the 23 patients who were high-grade, recurrence-free at 3 months maintained response to the end of the study,” noted Boorjian. Age, gender, and refractory vs relapsed status were not associated with 12-month, high-grade, recurrence-free survival.
All but one of the patients experienced a treatment-associated adverse event, but 30 of these 39 were grade 1 or 2 events and 9 were grade 3. Dysuria, micturition urgency, and pollakiuria were the most common side effects.
Surrogate markers of efficacy included significant levels of IFNα-2b in urine of patients 2 days after treatment, Boorjian reported. Serum IFNα-2b concentrations were “very low,” with 31 of 40 patients having levels lower than assay quantification, indicating biological safety.