Single Arm Phase I/II Study of Everolimus and Intravesical Gemcitabine in Patients with Primary or Secondary Carcinoma In Situ of the Bladder who failed Bacillus Calmette Guerin (NCT01259063)

Abstract

Background: Standard treatment for BCG-refractory urothelial cancer is radical cystectomy. Identification of active agents is clearly warranted.Objective: To determine a safe dose of oral everolimus in combination with standard intravesical gemcitabine and to evaluate the efficacy of this combination.Methods: Patients with carcinoma in situ refractory to intravesical bacillus Calmette-Guérin and refusing cystectomy were eligible. Patients in the phase I part of the trial received one of three dose levels of oral everolimus. Patients also received a fixed dose of intravesical gemcitabine. Maintenance everolimus was given for 12 months in patients achieving a complete response confirmed by cystoscopy and cytology. Patients in phase II received continuous everolimus administered at 10 mg daily with intravesical gemcitabine followed by everolimus maintenance for 12 months of total therapy. The enrollment goal for the phase II was 33 patients.Results: 14 patients were enrolled in phase I of the trial. 23 patients were enrolled in phase II of the trial and 19 were evaluable for primary and secondary endpoints. Four patients withdrew consent prior to treatment initiation. Of the 19 patients evaluable for response, 3 (16%, 95% confidence interval [CI] 3% – 40%) were disease free at 1 yr. The probability of RFS was 20% (95% CI 5% – 42%) at 12 months. Ten patients out of 19 had grade 3 or greater toxicity events. Seven withdrew consent or were taken off study.Conclusions: Many patients withdrew, and enrollment was halted. Continuous oral everolimus plus intravesical gemcitabine was not well tolerated in this patient population where the threshold for tolerability is low.

Novel intravesical therapeutics in the treatment of non-muscle invasive bladder cancer: Horizon scanning

“…Intravesical gemcitabine has also been investigated as a combination therapeutic in early clinical trials, including with everolimus, an mTOR inhibitor which enhances the cytotoxic effect of gemcitabine ( 32 , 33 ). Bi-weekly, intravesical gemcitabine (2000 mg) was administered for six weeks, and daily oral everolimus (10 mg) for 12 months to 19 patients with BCG-refractory NMIBC ( 32 ). Only 16% of patients were disease free at one year, but 53% suffered grade 3 or 4 AEs, leading to early termination of the study.…”

Experimental and New Approaches for Bladder Preservation in Intermediate and High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC)

“…Chemotherapy is another modality that has already proven its role in metastatic and muscle invasive bladder cancer and intravesical administration has been studied for NMIBC (summarized in Table 3 ). Several studies have been carried out with gemcitabine as monotherapy, 13–27 as well as in association with several other medications, such as docetaxel, 28 , 29 cabazitaxel and cisplatin, 30 oral everolimus 31 and mitomycin C (MMC). 32 , 33 …”

“… - The PFS was 43.75%. The OS and CSS were 77.9% (95% CI 58.78%–88.92%) and 80.68% (95% CI 61.49%–90.96%), respectively - The most common mild and moderate adverse events reported were urinary symptoms and fatigue (CDC 1 and 2) Nayan Kumar Mohanty et al, 2018 23 35 Prospective Intravesical Gemcitabine 6 weekly Gemcitabine acts as a deoxycytidine nucleoside analog, thereby inhibiting deoxyribonucleic acid (DNA) synthesis, resulting in cell apoptosis - 21 patients (60%) showed no recurrences - 11 patients (31.4%) had superficial recurrences - 3 patients (8.75%) progressed to muscle invasive Guido Dalbagni et al, 2017 31 56 Phase I/II Everolimus and Gemcitabine One dose of everolimus and gemcitabine / Continuous everolimus daily with gemcitabine followed by everolimus maintenance Everolimus is a rapamycin analog (rapalog), suppress hypoxia induced and increases in hypoxia inducible factor-1α (HIF-1α), and inhibit the response of vascular endothelial cells to stimulation by vascular endothelial growth factor (VEGF)Gemcitabine acts as a deoxycytidine nucleoside analog, thereby inhibiting deoxyribonucleic acid (DNA) synthesis, resulting in cell apoptosis - 16% were disease free at 1 yr (95% - CI: 3%–40%). The probability of RFS was 20% (95% - CI 5%–42%) at 12 months - 4 patients withdrew consent prior to treatment initiation, 10 patients out of 19 had grade 3 or greater toxicity events, 7 withdrew consent or were taken off study (21 patients) - Continuous oral everolimus plus intravesical gemcitabine was not well tolerated in this patient population Niv Milbar et al, 2017 35 33 Retrospective Gemcitabine and Docetaxel 6 weekly Gemcitabine acts as a deoxycytidine nucleoside analog, thereby inhibiting deoxyribonucleic acid (DNA) synthesis, resulting in cell apoptosis.…”

CIS of the Bladder: Significance and Implications for Therapy

“…However, MCNA was not approved by the FDA. Dalbagni et al published a phase II study of combination therapy with intravesical gemcitabine and oral everolimus in patients with BCG-refractory or BCG-intolerant urothelial cancer [47]. The study was terminated early due to increased toxicity and did not demonstrate a benefit compared to the use of gemcitabine alone.…”