19 CSPOR CRC/2009.8.8-9 2009 8 8 ( ) - CSPOR CRC SEMINAR- twatanab@oncoloplan.com http://www.oncoloplan.com - Toru Watanabe MD - 2 Phase I: Dose Finding trial Phase II : Efficacy and Safety trial Phase III: Comparative Treatment Efficacy trial Phase I: Dose Finding trial 3-5 Maximum Tolerated Dose Dose Limiting Toxicity 3 4 Phase I Phase I: Dose Finding trial Phase II : Efficacy and Safety trial Phase III: Comparative Treatment Efficacy trial 5 6 1
19 CSPOR CRC/2009.8.8-9 Phase II: Efficacy and Safety trial RECIST phase I CTC-AE 7 8 CONSORT diagram (330 ) (138 ) 1500 mg / (69 ) 500 mg 1 2 (69 ) Gomez, H. L. et al. J Clin Oncol; 26:2999-3005 2008 Phase II trial ( randomized phase II 9 3 (4%) 66 (96%) 4 (6%) 0 2 (3%) 50 (72%) 2 (3%) 3 (4%) 5 (7%) Gomez, H. L. et al. J Clin Oncol; 26:2999-3005 2008 4 (6%) 65 (94%) 6 (9%) 4 (6%) 1 (1%) 41 (59%) 4 (6%) 3 (4%) 6 (9%) CONSORT randomized controlled triall: RCT RCT CONSORT Consolidated Standards of Reporting Trials flow diagram 2
19 CSPOR CRC/2009.8.8-9 Fig 2. Progression-free survival. qd, once daily; bid, twice daily Gomez, H. L. et al. J Clin Oncol; 26:2999-3005 2008 Copyright American Society of Clinical Oncology Phase I: Dose Finding trial Phase II : Efficacy and Safety trial Phase III: Comparative Treatment Efficacy trial Phase III Comparative Treatment Efficacy trial (+) (-),, QOL 15 16 (AC) (Taxanes) Hortobagyi G New Engl J Med 339; 974 1998 17 ( FU ) Hortobagyi G New Engl J Med 339; 974 1998 3
19 CSPOR CRC/2009.8.8-9 - - - - (AC) (Taxanes) (oral FU) (oral FU) + New Drug (oral FU) (oral FU) + New Drug + 19 20 Phase III trial 21 -EQUIPOISE( ) - A B C Clinical Equipoise (random sampling) random sampling biased sampling 4
19 CSPOR CRC/2009.8.8-9 random allocation Phase III 26 Phase III trial 27 28 324 163 16 136 145 49 PD 72 PD Geyer CE et al. N Engl J Med 2006;355:2733-2743 5
19 CSPOR CRC/2009.8.8-9 Efficacy End Points in the Intention-to-Treat Population Geyer CE et al. N Engl J Med 2006;355:2733-2743 Disease Progression free Survival Overall Survival Progression Free Survival Overall Survival hazard ratio 0.51 (95% CI, 0.35 to 0.74) P<0.001 2004 3 292005 11 15 2006 3 20 capecitabine lapatinib lapatinib lapatinib capecitabine Geyer CE et al. N Engl J Med 2006;355:2733-2743 Geyer CE et al. N Engl J Med 2006;355:2733-2743 Adverse Events 6
19 CSPOR CRC/2009.8.8-9 Schema of trial design CONSORT Diagram Copyright American Society of Clinical Oncology Copyright American Society of Clinical Oncology (A) Relapse-free survival (B) overall survival of the total patients treated with UFT or CMF Results of subset analysis ( UFT vs. CMF): recurrence Impact of CMFand UFT on QOL Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: A pooled analysis of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) Y. Ohashi 1, T. Watanabe 2, M Sano 3, H. Koyama 4, H. Inaji 4, T. Suzuki 4 1. University of Tokyo, 2. Hamamatsu Oncology Center, 3. Niigata Cancer Center Hospital, 4. Osaka Medical Center for Cancer and Cardiovascular Diseases. 7
19 CSPOR CRC/2009.8.8-9 CUBC Diagnosis Stage I-IIIA Invasive Breast cancer, Histological positive axillary node (1-9), Mastectomy, Age:20-65 years Central Randomization Minimization: Tumor classification(t1, T2, T3), Age (-50, 51-), No. of lymph-node meta (1-3, 4-6, 7-9), ER (+, -, unknown) Diagnosis Stage I-IIIA Invasive Breast cancer, Histological negative axillary node, Nuclear grade2 or 3, Age 18-75 years Central Randomization Minimization: Tumor size (<3.0cm/ >-3.0cm),Age (-50, 51-), ER/PgR (-/-, other), Surgical procedure, Radiotherapy, Institutions CMF+TAM CPA: 65mg/m 2, days 1-14 MTX: 40mg/m 2, days 1, 8 FU: 500mg/m 2, days 1,8 q28 days x 6cycles TAM: 20mg/body/day for 2 years UFT+TAM UFT: 300mg/m 2 /days for 2 years TAM: 20mg/body/day for 2 years Patient enrollment: September 1996 - July 2000 CMF(+TAM)* CPA: 100mg po days 1-14 MTX: 40mg/m 2, days 1, 8 FU: 500mg/m 2, days 1,8 q28 days x 6cycles UFT(+TAM)* 300mg/m 2 /day for 2 years *Patients whose tumors were positive for ER, PgR or both received tamoxifen for 5 years in both arm Patient enrollment: October 1996 - April 2001 CUBC 377 women enrolled N SAS BC-01 733 women enrolled Hazard Ratio No. of 95% Cl Patients All Patients 1.04(0.78 to 1.40) 1057 Risk Reduction In Favor of UFT In Favor of CMF Test for Interaction 367 randomized to CMF vs UFT 10 ineligible 725 randomized to CMF vs UFT 7 ineligible 1 withdrew consent Age, years 50 50 Pathological tumor size 3cm 3cm 1.56(0.99 to 2.46) 0.82(0.56 to 1.20) 1.11(0.76 to 1.63) 0.99(0.64 to 1.54) 416 641 740 317 0.03 0.70 14 declined protocol therapy 3 lost to follow-up 18 declined protocol therapy Lymph nodes 0-3 4-1.15(0.84 to 1.58) 0.66(0.32 to 1.37) 980 77 0.17 1057 in combined analysis Histological Classification Invasive ductal ca. Others ER negative positive 1.03(0.76 to 1.39) 1.39(0.49 to 3.97) 1.30(0.86 to 1.98) 0.79(0.52 to 1.20) 975 82 479 534 0.59 0.10 528 assessed in CMF arm 529 assessed in UFT arm PgR negative positive 1.12(0.74 to 1.69) 0.81(0.52 to 1.27) 501 485 0.0 1.0 2.0 3.0 4.0 Hazard Ratio and 95% CI 0.30 Probability (%) Probability (%) ER- / <50 100 90 CMF 80 70 UFT 60 50 40 30 UFT (n=100) 76.5% 20 CMF (n=95) 85.3% 10 HR:1.735 (0.880-3.422) 0 0 1 2 3 4 5 6 7 8 9 Years ER+ / <50 100 90 CMF 80 UFT 70 60 50 40 30 UFT (n=99) 81.3% 20 CMF (n=104) 84.8% 10 HR:1.254 (0.638-2.463) 0 0 1 2 3 4 5 6 7 8 9 Years Probability (%) Probability (%) ER- / 50=< 100 90 CMF 80 70 UFT 60 50 40 30 UFT (n=140) 83.2% 20 CMF (n=144) 82.2% 10 HR:1.072 (0.619-1.855) 0 0 1 2 3 4 5 6 7 8 9 Years ER+ / 50=< 100 90 UFT 80 70 CMF 60 50 40 30 UFT (n=166) 88.1% 20 CMF (n=165) 83.6% 10 HR:0.582 (0.335-1.013) 0 0 1 2 3 4 5 6 7 8 9 Years UFT is non-inferior to CMF in terms of inhibiting relapse of ER-positive early breast cancer. In particular, UFT may be more effective in patients with ER-positive tumors who are 50 years or older. 8
19 CSPOR CRC/2009.8.8-9 1 2 1 A B A B C A B A B 2 CONSORT QOL 51 9