1. 1 Phase II trial of sequential gemcitabine and carboplatin followed by paclitaxel as first-line treatment of advanced urothelial carcinoma Presented by Celine BOUTROS Hotel-Dieu de France

2. 2 Background Bladder cancer is the 4 th cancer in men, the 9 th in women Bladder cancer is the 4 th cancer in men, the 9 th in women 69,000 new cases diagnosed in the US in 2008 69,000 new cases diagnosed in the US in 2008 Transitional Cell Carcinoma (TCC): most frequent histological subtype Transitional Cell Carcinoma (TCC): most frequent histological subtype The standard first-line regimen in advanced TCC: The standard first-line regimen in advanced TCC: - 1989-2000: Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC) 1 - 1989-2000: Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC) 1 - > 2000: Gemcitabine plus Cisplatin 2 : similar activity, less toxicity - > 2000: Gemcitabine plus Cisplatin 2 : similar activity, less toxicity 1 Sternberg CN et al. Cancer 1989;64:2448-2458. 2 Von der Maase H et al. J Clin Oncol 2000;18:3068-3077.

3. 3 Objectives of the study Explore the activity of Gemcitabine plus Carboplatin (GC) followed sequentially with Paclitaxel in advanced TCC Explore the activity of Gemcitabine plus Carboplatin (GC) followed sequentially with Paclitaxel in advanced TCC Secondary objective Assess the toxicity profile of the regimen Assess the toxicity profile of the regimen Primary objective

4. 4 Materials and Methods eligibility Eligibility Criteria: At least one dimensionally measurable disease At least one dimensionally measurable disease Locally advanced or metastatic disease Locally advanced or metastatic disease Histological infiltrative urothelial cancer Histological infiltrative urothelial cancer No prior chemotherapy unless given in more than one year free- interval No prior chemotherapy unless given in more than one year free- interval No prior radiation therapy No prior radiation therapy Performance status (PS) ≤ 2 Performance status (PS) ≤ 2 Adequate blood counts and chemistries Adequate blood counts and chemistries Normal organ function Normal organ function Eligibility Criteria: At least one dimensionally measurable disease At least one dimensionally measurable disease Locally advanced or metastatic disease Locally advanced or metastatic disease Histological infiltrative urothelial cancer Histological infiltrative urothelial cancer No prior chemotherapy unless given in more than one year free- interval No prior chemotherapy unless given in more than one year free- interval No prior radiation therapy No prior radiation therapy Performance status (PS) ≤ 2 Performance status (PS) ≤ 2 Adequate blood counts and chemistries Adequate blood counts and chemistries Normal organ function Normal organ function Single-Arm, Multicenter, Phase II trial, from September 2004 to September 2007

5. 5 Materials and Methods treatment schedule Evaluation (RECIST) Evaluation (RECIST) Gemcitabine 800mg/m 2 (D1, D8) + Carboplatin AUC 2 (D1, D8) Every 3 weeks for 4 cycles Gemcitabine 800mg/m 2 (D1, D8) + Carboplatin AUC 2 (D1, D8) Every 3 weeks for 4 cycles Paclitaxel 60 mg/m 2 weekly for 12 weeks weekly for 12 weeks Paclitaxel 60 mg/m 2 weekly for 12 weeks weekly for 12 weeks Evaluation (RECIST) Evaluation (RECIST)

6. 6 Results Patient Characteristics n% Mean age (years) 68 Male / Female 22 / 5 81/18 ECOG PS ≤ 2 27100 Prior radical cystectomy 1244 Prior chemotherapy 00 Distant metastases 1140 Locoregional disease with only positive lymph nodes 1660 Patients included Patients included27

7. 7 Results Drug delivery GC sequence Paclitaxel sequence Mean number of cycles administered 3.57 Number of patients removed - progression - progression - personal request - personal request 761606 Dose reduction for myelosuppression 22 Assessment of drug delivery for GC and Paclitaxel sequences

8. 8 Results Treatment efficacy GC sequence End of therapy Overall response rate CR PR 41% (1) 110 43% (2) 33 SD34 PD114 Response Assessment to GC and Paclitaxel sequences Response Assessment to GC and Paclitaxel sequences (1)8 responses of 11 achieved in locally advanced TCC without distant metastases (2)Responses achieved in locally advanced TCC without distant metastases (same patients)

9. Results follow-up Median response duration: 6 months Median response duration: 6 months Median follow-up: 7 months Median follow-up: 7 months - 21 patients died - 21 patients died - 6 remained alive ---> 2 CR - 6 remained alive ---> 2 CR ---> 1 PR ---> 1 PR 9

10. 10 Results treatment-related toxicities (grade 3/4) GC sequence End of treatment Neutropenia20 Anemia31 Thrombocytopenia20 Nausea/emesis10 Diarrhea01

11. 11 Results Myelosuppression-related complications GC sequence End of treatment Febrile neutropenia 10 Platelet transfusion 10 RBC transfusion 110 Bleeding episodes 00

12. Conclusion Well tolerated regimen Well tolerated regimen ORR is in agreement with the results of previous regimens ORR is in agreement with the results of previous regimens Limited number of patients Limited number of patients Relatively short follow-up (7 months) Relatively short follow-up (7 months) 12