Intravesical rAd-IFNα/Syn3 showed promising response rates, a tolerable treatment schedule, and acceptable toxicity among patients with high-grade, nonmuscle-invasive bladder cancer, refractory or relapsed after bacillus Calmette-Guérin therapy.
Intravesical rAd-IFNÎ±/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-GuÃ©rin (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-IFNÎ±/Syn3 is composed of recombinant adenovirus (rAd)-mediated IFN-Î±2b protein and Syn3, an excipient that enhances viral transduction of NMIBC urothelial. IFNÎ± protein has multiple antitumor effects, but intravesical IFNÎ± monotherapy does not offer durable responses, probably because of insufficient exposure, Boorjian said.
Preclinical studies have suggested no major toxicities associated with rAd-IFNÎ±/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-IFNÎ±/Syn3 treatment was safe, with no significant treatment-related adverse events, and no rAd-IFNÎ±–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-IFNÎ±/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 IFNÎ±-2b in urine of patients 2 days after treatment, Boorjian reported. Serum IFNÎ±-2b concentrations were “very low,” with 31 of 40 patients having levels lower than assay quantification, indicating biological safety.