Updated results of a phase I/II trial of intravesical CG0070 in patients with superficial bladder cancer after BCG failure.

Abstract

271 Background: Loss of retinoblastoma (Rb) tumor suppressor activity occurs commonly in bladder cancer and leads to upregulation of the E2F-1 transcription factor. CG0070 is a replication competent oncolytic adenovirus genetically modified to express GMCSF under control of the human E2F-1 promoter. Updated results from a phase I/II study of CG0070 in patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG treatment are presented here. Methods: The V-0046 phase I/II study previously reported the safety and evidence of efficacy of single and multiple doses of intravesical CG0070. Efficacy was determined using quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was assessed immunohistochemically in 18 tumors. Results: 35 patients were treated with either a single dose (n=13) of CG0070 ranging from 1x1012 to 3x1013 viral particles (vp) or with weekly x 6 (n=9) or every 4 week x 3 doses (n=13) ranging from 1x1012 to 1x1013 vp per dose. Only one dose limiting toxicity, grade 3 lymphopenia in an every 4 week patient, was observed. The most common adverse events regardless of schedule were flu-like illness, dysuria, hematuria, bladder spasm, and nocturia. Urine GMCSF was detectable in 94% of patients and 58% of patients in the single dose cohort had an increase in CG0070 levels suggesting in-vivo viral replication. The CR rate in the single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose cohorts. Median follow up for all responders is 9.1 months. Of all responders, 11 recurred with a remission duration ranging from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts, remain in remission as of last follow-up with a remission duration ranging from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13 of the 18 (72%) patients evaluated. Nine of these 13 patients (70%) had a CR. All patients (5/5, 100%) with known phosphorylated Rb treated in the weekly cohort experienced a CR. Conclusions: CG0070 was well tolerated with minimal local and systemic toxicities. Complete responses were more frequently observed in the multiple-dose cohorts, including durable CRs in patients with phosphorylated Rb. Further study in Rb inactivated tumors is warranted.