The Safety, Tolerability, and Preliminary Efficacy of a Gemcitabine-releasing Intravesical System (TAR-200) in American Urological Association-defined Intermediate-risk Non-muscle-invasive Bladder Cancer Patients: A Phase 1b Study.

Background and objective: Patients with intermediate-risk non-muscle-invasive bladder cancer (IR NMIBC) have a high risk of recurrence and need effective therapies to reduce the risk of disease recurrence or progression. This phase 1b study (NCT02720367) assessed the safety and tolerability of TAR-200, an intravesical drug delivery system, in participants with IR NMIBC. Methods: Participants with recurrent IR NMIBC were eligible. Participants received either two 7-d or two 21-d TAR-200 dosing cycles over a 4-6-wk period in a marker lesion/ablation design. TAR-200 was placed in the window between the cystoscopy showing recurrent papillary disease and the subsequent complete transurethral resection of the bladder tumour. The primary endpoint was TAR-200 safety. The secondary endpoints included TAR-200 tolerability, pharmacokinetics, and preliminary efficacy. Key findings and limitations: Twelve participants received TAR-200 treatment. No TAR-200-related serious or grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred. Nine participants had grade ≤ 2 TAR-200-related TEAEs, with urgency, dysuria, and haematuria being most common. Two participants refused a second dosing cycle due to urinary urgency and frequency. Insertion and removal of TAR-200 was successful in all cases. Plasma gemcitabine concentrations remained below the lower limit of detection. Five participants (42%) had complete response (CR): four had pathological CR and one had CR based on visual assessment. Conclusions and clinical implications: TAR-200 appears to be safe and well tolerated, with encouraging preliminary efficacy in participants with IR NMIBC. This study lays the groundwork for the multiple phase 2 and 3 global studies that are currently on-going for TAR-200. Patient summary: In this study, researchers evaluated the safety of the novel drug delivery system TAR-200 in participants with intermediate-risk non-muscle-invasive bladder cancer. They concluded that TAR-200 was safe and well tolerated with promising antitumour activity.

Safety, Tolerability, and Preliminary Efficacy of TAR-200 in Patients With Muscle-invasive Bladder Cancer Who Refused or Were Unfit for Curative-intent Therapy: A Phase 1 Study.

PURPOSE: Half of patients with muscle-invasive bladder cancer worldwide may not receive curative-intent therapy. Elderly or frail patients are most affected by this unmet need. TAR-200 is a novel, intravesical drug delivery system that provides sustained, local release of gemcitabine into the bladder over a 21-day dosing cycle. The phase 1 TAR-200-103 study evaluated the safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who either refused or were unfit for curative-intent therapy. MATERIALS AND METHODS: Eligible patients had cT2-cT3bN0M0 urothelial carcinoma of the bladder. TAR-200 was inserted for 4 consecutive 21-day cycles over 84 days. The primary end points were safety and tolerability at 84 days. Secondary end points included rates of clinical complete response and partial response as determined by cystoscopy, biopsy, and imaging; duration of response; and overall survival. RESULTS: Median age of the 35 enrolled patients was 84 years, and most were male (24/35, 68.6%). Treatment-emergent adverse events related to TAR-200 occurred in 15 patients. Two patients experienced treatment-emergent adverse events leading to removal of TAR-200. At 3 months, complete response and partial response rates were 31.4% (11/35) and 8.6% (3/35), respectively, yielding an overall response rate of 40.0% (14/35; 95% CI 23.9-57.9). Median overall survival and duration of response were 27.3 months (95% CI 10.1-not estimable) and 14 months (95% CI 10.6-22.7), respectively. Progression-free rate at 12 months was 70.5%. CONCLUSIONS: TAR-200 was generally safe, well tolerated, and had beneficial preliminary efficacy in this elderly and frail cohort with limited treatment options.

The safety, tolerability, and efficacy of a neoadjuvant gemcitabine intravesical drug delivery system (TAR-200) in muscle-invasive bladder cancer patients: a phase I trial.

OBJECTIVES: Neoadjuvant chemotherapy and radical cystectomy (RC) are underutilized standards of care for the treatment of muscle-invasive bladder cancer (MIBC) due to high patient burden from systemic toxicities and postoperative complications, respectively. TAR-200 is a novel intravesical drug delivery system developed to release gemcitabine into the bladder urine continuously, resulting in distribution of drug into stromal layers of the bladder. The primary aim of the TAR-200-101 study was to evaluate the safety of TAR-200 in patients with MIBC prior to RC (NCT02722538). METHODS AND MATERIALS: This phase I, open-label study was conducted across 6 US and European sites. Eligible patients were aged ≥18 years with histologically confirmed T2a-T3b N0-N1 M0 urothelial cancer and had refusal or were ineligible to receive cisplatin-based combination chemotherapy. Two arms were enrolled serially. Patients in Arm 1 had residual tumor >3 cm after transurethral resection of bladder tumor (TURBT); those in Arm 2 had undergone maximal TURBT (residual tumor <3 cm). Patients received two 7-day cycles of intravesical gemcitabine delivery via TAR-200 before undergoing RC. Primary outcome was safety; secondary outcomes were tolerability, pharmacokinetics, and preliminary efficacy. RESULTS: Of 23 patients in the intention-to-treat population (11 in Arm 1, 12 in Arm 2), 20 completed both dosing cycles of TAR-200. No patients were classified as intolerant to TAR-200. Ten patients (4 in Arm 1, 6 in Arm 2) experienced ≥1 treatment-emergent adverse events (TEAEs). The most common TAR-200-related TEAEs were pollakiuria (n = 3) and urinary incontinence (n = 2). All TEAEs prior to RC were grade ≤2; 1 patient in Arm 2 experienced a grade 3 non-treatment-related TEAE. Plasma gemcitabine levels were undetectable. In Arm 1, those with residual tumor, 4 of 10 patients exhibited pathologic downstaging; 1 experienced a complete response (CR) and 3 a partial response (PR). In Arm 2, those undergoing maximal TURBT, 6 of 10 patients exhibited downstaging; 3 experienced a CR and 3 a PR. CONCLUSION: Controlled intravesical gemcitabine release via TAR-200 was safe and well tolerated in patients with MIBC.

Development and validation of a 32-gene prognostic index for prostate cancer progression.

The accurate determination of the risk of cancer recurrence is an important unmet need in the management of prostate cancer. Patients and physicians must weigh the benefits of currently available therapies against the potential morbidity of these treatments. Herein we describe the development of a gene expression-based continuous risk index and a validation of this test in an independent, blinded cohort of post-radical prostatectomy (RP) patients. A gene expression signature, prognostic for prostate-specific antigen (PSA) recurrence, was identified through a bioinformatic analysis of the expression of 1,536 genes in malignant prostate tissue from a training cohort of consecutive patients treated with RP. The assay was transferred to a real-time RT-PCR platform, and a continuous risk index model was constructed based on the expression of 32 genes. This 32-gene risk index model was validated in an independent, blinded cohort of 270 RP patients. In multivariate analyses, the risk index was prognostic for risk of PSA recurrence and had added value over standard prognostic markers such as Gleason score, pathologic tumor stage, surgical margin status, and presurgery PSA (hazard ratio, 4.05; 95% confidence interval, 1.50-10.94; P = 0.0057). Furthermore, RP patients could be stratified based on the risk of PSA recurrence and the development of metastatic disease. The 32-gene signature identified here is a robust prognostic marker for disease recurrence. This assay may aid in postoperative treatment selection and has the potential to impact decision making at the biopsy stage.