Liquid Imiquimod Formulation May Induce Immune Response in Bladder Cancer

TMX-101 (Vesimune), a liquid formulation of the toll-like receptor 7 agonist imiquimod, appeared safe and demonstrated preliminary clinical activity, including the potential to induce an immune response, in patients with non-muscle invasive bladder cancer.

Nicholas M. Donin, MD

TMX-101 (Vesimune), a liquid formulation of the toll-like receptor 7 agonist imiquimod, appeared safe and demonstrated preliminary clinical activity, including the potential to induce an immune response, in patients with non-muscle invasive bladder cancer (NMIBC).1

Four of 10 evaluable patients in the small trial had negative cytology and cystoscopy 6 weeks after intravesical instillation of TMX-101. Comparison of pre- and postoperative urinary cytokine levels showed significant increases (response) in several different molecules, including interleukins.

Adverse events (AEs) were common but for the most part were limited to grade 1/2 events affecting the genitourinary tract, Nicholas M. Donin, MD, a urology fellow at UCLA, reported at the 2016 American Urological Association Annual Meeting.

“These results follow a positive phase I trial of this liquefied form of imiquimod and provide preliminary evidence of activity,” said Donin. “The results also support previous evidence that imiquimod can induce an immune response.”

The drug’s therapeutic niche remains to be determined, he added. The “post-BCG failure” market is fairly crowded, and the drug might have potential clinical application beyond in situ disease.

Topical imiquimod has proven antitumor activity and has FDA approved indications for the treatment of patients with actinic keratosis and superficial basal cell carcinoma. The liquefied formulation was developed for applications other than skin cancer. The ongoing phase II trial reported by Donin and colleagues represented a continuation of the evaluation of imiquimod’s safety and efficacy in NIMBC.

Investigators on the multicenter trial enrolled adults with bladder carcinoma in situ. Patients with concomitant papillary disease were eligible if all papillary lesions had been fully resected.

Treatment consisted of 6 weekly instillations of TMX-101 (0.4%, 200 mg/50 mL). The principal endpoints were rates of AEs, changes in urinary cytokine levels, and response rate 6 weeks after the final treatment.

The safety analysis included 12 patients, all but 2 of whom were eligible for the efficacy evaluation. The patients had a median disease duration of 7.4 months from diagnosis. Treatment history included at least 1 instillation of BCG, a median of 2 prior transurethral resection of the bladder, and 6 of 12 patients had received 2 or more courses of BCG.

All but 1 of the patients had 1 or more AEs. Donin reported that 50 of 51 total AEs were grade 1/2 in severity. The most common AEs were dysuria in 13 patients; fatigue in 8 patients; urinary urgency in 6; and hematuria in 4.

Comparison of pre- and posttreatment urinary cytokine levels revealed significant increases in 5 cytokines: interleukin (IL)-6 (pre- to posttreatment level change, 0.36; P = .0021), IL-18 (0.50; P = .0000), IL-1 beta (0.44; P = .0167), IL-1 receptor antagonist (1.36; P = .0000), and VEGF (0.15; P = .0437).

Although 4 of 10 patients had negative cytology at the 6-week posttreatment follow-up, 2 of the 4 subsequently were found to have positive cytology by central review.

The preceding phase I dose escalation study of TMX-101 included 16 patients with NMIBC.2 The patients were divided equally among 4 dose arms (0.05%, 0.1%, 0.2% or 0.4%) and received 6 weekly instillations of TMX-101. Treatment was initiated 2 weeks after transurethral resection of the bladder tumor.

Across the study, there were 88 successful instillations without serious AEs. There were 118 AEs reported, of which 71% (n = 84) were related to TMX-101. According to the study authors, all toxicities were mild or moderate, and dose level was not correlated with the number or severity of AEs. Seventy percent of the treatment-related AEs were localized in the genitourinary tract and did not require intervention.

Up to dose group 3 (0.2%, 100 mg), there was a dose dependent systemic uptake with low plasma levels. In dose group 4 (0.4%, 200 mg), the maximum plasma concentration was 71.7 ng/ml.

“TMX-101 is safe and well tolerated,” Donin and colleagues concluded in their poster presentation at the AUA meeting. “No patients required dose reductions or treatment discontinuation. Treatment-related adverse events were common, but the majority were grade 1 or 2 and the majority were limited to the genitourinary tract. Clinical activity is suggested by the detectable increases in cytokines following treatment and the small number of responding patients.”


  1. Donin N, Chamie K, Reddy M, et al. A phase 2 study of Vesimune, intravesical imiquimod, for the treatment of carcinoma in situ bladder cancer. Presented at: 2016 American Urological Association Annual Meeting; May 6-10, 2016; San Diego, CA. Abstract LB-S&T-21.
  2. Falke J, Lammers RJ, Arentsen HC, et al. Results of a phase 1 dose escalation study of intravesical TMX-101 in patients with nonmuscle invasive bladder cancer. J Urol. 2013;189(6):2077-2082.


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