The FDA voted against approving Qapzola for treatment of some patients with bladder cancer.
In a 14-0 vote, the U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) decided against approving Qapzola (EOquin; apaziquone) for intravesical instillation immediately following transurethral resection in patients with non-muscle invasive bladder cancer.
The panel considered a new drug application for Qapzola based on findings from two phase 3 trials (identified as 611 and 612), which both missed the primary endpoint of a statistically significant reduction in disease recurrence at two years with a single dose of Qapzola versus placebo.
Subsequent to these findings, Spectrum Pharmaceuticals, the developer of Qapzola, further examined the drug through pooling analyses of the two trials that were not part of the initial study designs. The company reported to the panel that these analyses revealed that the impact of Qapzola may be increased based on the timing of the treatment relative to resection.
An ongoing phase 3 trial designed through a special protocol assessment with the FDA is examining the impact of the timing of treatment, as well as the effect of administering a second dose of Qapzola. Spectrum will now await a final decision on Qapzola from the FDA, which is scheduled to be made on or before Dec. 11, 2016, under the Prescription Drug User Fee Act. The FDA usually follows the recommendations of ODAC.
The multicenter, placebo-controlled, double-blind studies 611 and 612 had the same eligibility criteria and basic study design. The trials primarily included patients with Ta grade 1 or 2 nonmuscle invasive bladder cancer by central pathology review.
Patients were randomized to 4 mg of Qapzola in 40 mL diluent or placebo in 40 mL diluent. Treatment was administered within six hours of transurethral resection and retained in the bladder for one hour.
Patient demographics were well balanced between the treatment arms in both trials. The median age was 68 in study 611 and 67 in study 612. Across both trials, over 95 percent of patients were white and approximately 70 percent were male. Over 90 percent of patients in study 611 were from the United States, while 80 percent of patients in study 612 were from other countries.
At baseline, approximately two-thirds of patients with TaG1-2 disease in both arms of study 611 had one lesion, with the remaining patients having two to four lesions. Around eighty percent of patients in each arm had lesions that were all less than 3 cm. In study 612, approximately 60 percent of patients with TaG1-2 disease in both arms had one lesion, with the remainder of patients having two to four lesions. Around 87 percent of patients across the study had lesions that were all less than 3 cm.
In study 611, 38 percent (112/295) of patients with TaG1-2 disease in the Qapzola arm had disease recurrence compared with 44.6 percent (121/271) of patients in the placebo arm. The 6.6 percent difference favoring Qapzola was not statistically significant.
In study 612, 40.4 percent (114/282) of patients with TaG1-2 disease in the Qapzola arm had disease recurrence compared with 46.6 percent (139/298) of patients in the placebo arm. The 6.2 percent difference favoring Qapzola was not statistically significant.
The safety analyses included patients enrolled in the trials across all disease stages, not just TaG1-2. During study 611, there were 11 deaths in the Qapzola arm (406 patients) and 13 deaths in the placebo arm (396 patients). In its FDA briefing, Spectrum reported that none of the deaths seemed to be related to Qapzola treatment.
Discontinuations related to adverse events (AEs) occurred in four patients in the Qapzola cohort and three patients in the placebo group. The incidence of all-grade AEs was 80 percent and 75 percent in the Qapzola and control arms, respectively. This included grade 3/4 AE rates of 19 percent and 21 percent, respectively.
All-grade AEs occurring at higher rates in the Qapzola arm included dysuria (18 percent), urinary tract infection (18 percent), bladder pain/discomfort (9 percent), procedural pain (8 percent) and bladder spasm (7 percent). Serious AEs occurring more frequently in the Qapzola arm included atrial fibrillation (1.5 percent), chest pain (1.2 percent), COPD (1.2 percent) and cellulitis (1.2 percent).
In study 612, there were 14 deaths in both the Qapzola arm (402 patients) and the placebo arm (411 patients). As in the 611 trial, the deaths did not appear to be related to Qapzola treatment.
AE-related discontinuations occurred in four patients in the Qapzola cohort and three patients in the placebo group. The incidence of all-grade AEs was 80 percent and 81 percent in the Qapzola and control arms, respectively. This included grade 3/4 AE rates of 17 percent and 20 percent, respectively.
All-grade AEs occurring at higher rates in the Qapzola arm included dysuria (21 percent), pollakiuria (11 percent) and bladder pain/discomfort (8 percent). Serious AEs occurring more frequently in the Qapzola arm included urinary retention (2.2 percent) and heart failure (2 percent).