Dr. Stephen A. Boorjian
Although bacillus Calmette-Guérin (BCG) remains the primary therapy for patients with NMIBC, many patients have disease that is resistant to this treatment or relapses. “Optimal management for patients with what is now considered BCG-unresponsive NMIBC remains to be established,” said Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minnesota, during a General Session on bladder cancer on Feb. 17. Valrubicin is the only approved option for patients who are unresponsive to BCG, but offers only a 10% 1-year disease-free survival rate. Studies on various other therapies have been limited by modest efficacy results, small patient populations, and differing definitions of treatment success, Dr. Boorjian said.
IFN-α protein has pleiotropic antitumor effects, but monotherapy has been disappointing, likely related to insufficient exposure of the protein to the urothelium. Intravesical gene therapy could increase that exposure, and potentially increase efficacy; rAd-IFN-α is a recombinant adenovirus, and Syn 3 is an excipient, which enhances adenoviral transduction. A phase I trial of this agent showed promising efficacy with no dose-limiting toxicities or significant treatment-emergent adverse events.
The new study was open-label, and included a total of 40 patients with high-grade NMIBC who were either BCG refractory or who relapsed after BCG treatment. Patients were randomly assigned to one of two rAd-IFN-α/Syn 3 dose levels; 21 patients received a 1 x 1011 vp/mL dose, and 19 received a 3 x 1011 vp/mL dose. The median patient age was 71 years, most were male (33 patients), and similar numbers had relapsed (19 patients) and refractory (21 patients) disease; this was a heavily pretreated population, with 16 patients having received three or more courses of BCG.
The primary endpoint was 12-month high-grade recurrence-free survival. Fourteen patients (35.0%) achieved this endpoint, with no significant difference between the dosage arms; seven of 21 patients who received the low-dose (33.3%) and seven of 19 patients who received the high-dose (36.8%) were recurrence-free at 12 months (p = 0.55). The median time to high-grade recurrence was longer in the high-dose group, at 11.73 months compared with 3.52 months with the lower dose.
In general, being high-grade recurrence-free soon after the treatment began was an indicator of freedom from recurrence through the 12-month mark. There were 23 patients recurrence-free at 3 months, 17 at 6 and at 9 months, and 14 at 12 months. There were no differences in the outcome based on age or gender.
There were differences in recurrence rates, however, based on tumor stage at entry, although Dr. Boorjian noted these subgroups had small numbers of patients. Patients with papillary tumors (Ta or T1, 10 patients) had a 50% recurrence-free rate at 12 months, while those with carcinoma in situ only (21 patients) had a 29% 12-month recurrence-free rate. Patients with papillary and CIS staging at entry (9 patients) had a 30% rate at 12 months, and patients with any CIS also had a 30% rate at 12 months.
All but one patient experienced at least one treatment-emergent adverse event; 30 of 39 patients had only grade 1 or 2 events, and there were no grade 4 or 5 events. Two serious adverse events were deemed related to the treatment, and both resolved with therapy. The most common treatment-emergent adverse events included micturition urgency (15 patients), dysuria (11 patients), pollakiuria (11 patients), fatigue (9 patients), and nocturia (8 patients).
All patients had significant levels of IFN-α-2b in their urine on day 2 after treatment initiation, which Dr. Boorjian said was evidence of effective gene transfer. Serum IFN-α-2b concentrations were very low—31 of 40 patients had levels below assay quantification—which can be considered an indicator of systemic biosafety.
The success of this phase II study has led to a phase III trial, with a target accrual of 135 patients across 35 sites, using the higher of the two phase II doses based on the longer time to recurrence.
– David Levitan