Phase II Study of Docetaxel (D) and Oxaliplatin (O) in Recurrent Metastatic Transitional Cell Carcinoma of the Bladder Davar D1, Appleman LA1, Friedland DM1, 2, Georgiadis M2, Tribble G1, Chatta GS1. 1Division of Hematology-Oncology, University of Pittsburgh. 2U.P.M.C Cancer Centers, Pittsburgh, Pennsylvania. Abstract # 89745 Background Statistical Considerations Table III: Toxicity Data Grade 1 Grade 2 Grade 3/4 Hematological toxicity Anemia Leukopenia Thrombocytopenia Febrile neutropenia 7 3 - 8 1 6 GI toxicity Nausea/vomiting Diarrhea Mucositis Abdominal pain 9 4 2 Constitutional Fatigue 12 Neuropathy 5 Table II: Response Data Cycles completed <2 2-4 5-6 2 13 7 Response (after 2 cycles) PD SD CR/PR 9 3 (all PR) Response (after 6 cycles) 14 3 2 (all PR) Disease stabilization rate (SD + CR + PR) 5/19 (26.3%) First-line regimens for metastatic transitional cell carcinoma (mTCC) of the bladder are MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) and the cisplatinum-gemcitabine doublet with response rates in the 30 to 70% range. There are no approved second-line or salvage options for patients with recurrent disease. Response rates of 10-20% have been associated with the use of single agent D and O in the salvage setting in cisplatin-resistant patients (pts). Since D and O have non-overlapping non-hematological toxicities, the combination may be useful – particularly in elderly patients with impaired renal function in the setting of recurrent mTCC. Primary endpoint – response defined as a 30% or greater reduction in measurable disease (per the RECIST criteria). Secondary endpoints - progression free survival (PFS), overall survival (OS) and safety and tolerance. Sample size of 35 based on Kepner-Chang 2 stage design. Probability of falsely concluding that the proportion of responders exceeds 0.1 is 0.05 and probability of correctly concluding efficacy when the true proportion of responders is 30% or higher is 0.86. Patient Characteristics Inclusion and Exclusion Criteria 22 pts were enrolled of whom 19 were evaluable for response. Median age - 72 years (range 44 – 87). All pts had prior treatment with at least 1 cytotoxic regimen. 8 pts received 2 or more prior regimens. Median number of cycles administered - 3 (range 1 - 6). Histologically confirmed metastatic TCC of the urothelial tract. Prior treatment with standard of care chemotherapy (2 or less prior cytotoxic regimens). Pts with prior oxaliplatin therapy were excluded. No other experimental, cytotoxic or radiation treatment 4 weeks prior to enrollment. Radiologically measurable disease. Age > 18. ECOG performance status of 0-1. Life expectancy of greater than 6 months. Adequate hematologic (WBC > 2500/mm3 or ANC > 1500/mm3, Hb > 9.0 g/dL, platelet count > 100,000/mm3), hepatic (bilirubin < 1.5 mg/dL, ALT/AST < 2x ULN or < 4x ULN if liver metastases present) and renal (Cr < 1.8mg/dL) function. Responses Conclusions 19 pts evaluable for efficacy. Median number of cycles administered - 3 (range 1 - 6). Objective responses seen in 2 pts (both PR). 3 pts had stable disease. 14 progressed. Overall disease stabilization rate - 26%. Median time to progression (TTP) - 3.0 months (95% CI 0.2- 5.8). Median overall survival (OS) was 7.0 months (95% CI 4.6 to 9.4). Combination of D and O is active in pts with previously treated mTCC. Regimen is well-tolerated with acceptable toxicity. Although the study was not powered to evaluate survival, the presence of stable disease in 26% of patients with a median age of 72 suggests that further evaluation of this combination may be warranted in this challenging setting. Table I: Summary of Demographic Data Number of patients Enrolled Evaluable 22 19 Median age 72 (range 44-87) Sex (%) M - 13(61) F - 9(39) Prior cytotoxic therapies (%) 1 2 or more 14 (64) 8 (36) Toxicity References Toxicity, evaluable in all 22 patients, was relatively mild. Grade 3-4 diarrhea occurred in 4 pts (4 events) and 3-4 nausea/vomiting in 3 pts (3 events). Grade 3-4 hematological toxicity occurred in 4 pts (7 events) and grade 3-4 fatigue in 1 pt (3 events). No grade 3-4 neuropathy was observed. No grade 5 toxicity was observed. No patients were admitted with febrile neutropenia. No transfusions were required in any patient. No toxic deaths were noted. The median follow-up period was 7.0 months (95% CI 4.5 to 9.5). Vaughn DJ, et al. Recent developments in chemotherapy for bladder cancer. Oncology (Williston Park). 2001 Jun;15(6):763-71, 775; discussion 775-6, 779-80. Sternberg CN, et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol, 139: 461-469, 1988. de Wit R, et al. Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in non-chemotherapy-pretreated patients. Br J Cancer, 78: 1342-1345, 1998. von der Maase H, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol, 18: 3068-3077, 2000. Iqbal S, et al. Phase I Trial of Oxaliplatin (O) in Combination with Taxotere (T). Proc Am Soc Clin Oncol 20: 2001 (abstr 2108). Kitamura H, et al. Paclitaxel, ifosfamide, and nedaplatin as second-line treatment for patients with metastatic urothelial carcinoma: a phase II study of the SUOC group. Cancer Sci. 2011 Jun;102(6):1171-5. Kuono T, et al. Weekly paclitaxel and carboplatin against advanced transitional cell cancer after failure of a platinum-based regimen. Eur Urol. 2007 Oct;52(4):1115-22. Study Design Non-randomized phase II trial of D and O in mTCC of the urothelial tract. Prior phase I trials had established a recommended phase II dose (RP2D) for D and O. RP2D of the combination is D 60 mg/m2 and O 80- 130 mg/m2. D 60 mg/m2 followed by O 110 mg/m2 administered every 3 weeks. Pts evaluated for response every 2 cycles with imaging. Pts were treated either till disease progression, unacceptable toxicity, patient refusal, or treatment delay > 3 weeks. In the absence of progression, pts were treated with a maximum of six cycles of D and O.