PD10-06: A Phase 1/2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients (pts) With Muscle-Invasive Bladder Cancer (NCT01938573)

Dimitrios Makrakis*, Martine Roudier, Yan Wang, Funda Vakar-Lopez, Jose Garcia, Atreya Dash, Daniel Lin, George Schade, Elahe A Mostaghel, Heather Cheng, Michael T. Schweizer, Sarah K Holt, John L. Gore, Evan Yu, Hung-Ming Lam, Jonathan L. Wright, Bruce Montgomery, Seattle, WA

Introduction: Cisplatin-based neoadjuvant chemotherapy is the standard of care for pts with MIBC; high relapse rates require strategies to improve outcomes. Evidence suggests that tumor microenvironment responses to DNA damage activate a survival pathway dependent on mTOR signaling.  We hypothesized that adding rapamycin, an mTOR inhibitor, to cisplatin-based neoadjuvant chemotherapy would result in improved pathologic complete response (pCR) rates.

Methods: We conducted a phase I/II clinical trial of rapamycin combined with gemcitabine and cisplatin (GC). Patients with pT2-4, cN0-1 urothelial carcinoma were eligible. All pts were treated with 4-cycles of GC (Days 1 & 8) + rapamycin(D2)  followed by cystectomy. Primary objectives were determination of maximum tolerated dose-MTD (phase I) and pCR rates at cystectomy (phase 2). The study followed a 2-stage Simon design; 15 pts would be accrued in the 1st stage; pCR target response rate was 26% (4 of 15 pts) in the 1st and 45% in the 2nd stage.  TURBT and cystectomy specimens were stained for Ki67, mTOR/pmTOR, and downstream markers of mTOR activation (S6, pS6-235/236 and pS6-240/244) via a 3-step immunohistochemistry protocol. Staining validation used a breast cancer positive control sample; tissue was evaluated by a single pathologist in a blinded fashion; both epithelial cells & stroma were assessed; protein expression was quantified via H-score (0-300).  We compared mTOR pathway expression levels between TURBT and cystectomy samples in pairs.

Results: In the phase I portion, six patients were enrolled with one dose limiting toxicity; 5/6 patients had stable/responding disease after a median of 4 cycles.  A weekly dose of 35mg rapamycin was taken to phase II with 15 patients enrolled; 13 had evaluable tissue samples.  Three pts (21%) achieved pCR; six (43%) achieved < pT1, and 50% of participants had down staging. Rate of pCR did not meet the 45% target response for the 2nd stage of the study. Tissue staining in 6 pts demonstrated successful suppression of the mTOR pathway comparing cystectomy to TURBT specimens.

Conclusions: The addition of rapamycin to cisplatin-based therapy was safe and successfully inhibited the mTOR pathway in bladder cancer tissue but did not improve the therapeutic efficacy, as measured by pCR. Further efforts are needed to understand how the tumor microenvironment can influence therapy resistance and whether mTOR blockade may be of utility independent of cisplatin resistance.

Source of Funding: Society of Surgical Oncology