ACRIN Gynecologic Committee - PDF Free Download

ACRIN Gynecologic Committee Fall Meeting 2010 ACRIN Abdominal Committee

Biomarkers & Endpoints in Ovarian Cancer Trials Robert L. Coleman, MD Professor and Vice Chair, Clinical Research Department of Gynecologic Oncology M. D. Anderson Cancer Center

First line Therapy: Standard Treatment Options

100% % progression free survival % overall survival 75% 50% 25% 0 mm 1 10 mm > 10 mm 0% 0 12 24 36 48 60 72 84 96 108 120 132 144 10 0 % 75% 50% 25% HR (95%CI) 1 10 mm vs. 0 mm: 2.52 (2.26;2.81) >10 mm vs. 1 10 mm: 1.36 (1.24;1.50) log rank: p<0.0001 HR (95%CI) 1 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs. 1 10 mm: 1.34 (1.21; 1.49) log rank: p<0.0001 0 mm 1 10 mm > 10 mm What is optimal debulking? Generated from 3 prospective Phase III trials (OVAR 3, 5 & 7) N = 3126 pts Currently Distribution: Optimal (macro): 75% No visible: 30% of optimal Suboptimal: 25% 0% 0 12 24 36 48 60 72 84 96 108 120 132 144 Du Bois, Cancer (2009)115:1234

Current Standards

Ovarian Cancer: IP Chemotherapy

GOG 172 Survival IV: 18 mos IP: 24 mos HR: 0.80, P= 0.05 IV: 50 mos IP: 66 mos HR: 0.75, P= 0.03 Armstrong. N Engl J Med. 354:34, 2006

Current Standards

Ovarian Cancer: GOG 111 Suboptimal (>1 cm) Cytoreduction EOC R A N D O M I Z E Cyclophosphamide 1 gm/m 2 q 21 days x 6 Cisplatin 75 mg/m 2 Paclitaxel 135 mg/m 2 24 hour q 21 days x 6 Cisplatin 75 mg/m 2

GOG 111: Results Parameter Response Clinical CR Grossly Disease-Free CP 60% 31% 24% TP 73%* 51%* 40%* McGuire WP, et.al N Engl J Med 334:1, 1996

Ovarian Cancer: GOG 158 EOC Stage III Residual <1 cm N = 840 (798 evaluable) R A N D O M I Z E Taxol (24 hour) 135 mg/m 2 q 21 d x 6 Cisplatin 75 mg/m 2 q 21 d x 6 Taxol (3 hour) 175 mg/m 2 q 21 d x 6 Carboplatin AUC = 7.5 q 21 d x 6 Taxol (96 hour) 120 mg/m 2 q 21 d x 6 Cisplatin 75 mg/m 2 q 21 d x 6 SLL No SLL SLL No SLL Ozols R, J Clin Oncol 2003

GOG 158: PFS and OS by Treatment Group 1.0 0.9 0.8 0.7 RR Death : 0.86 (0.71 1.04) RR Death 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 RR Progression : 0.88 (0.75 1.03) RR Progression Treatment Cisplatin + Paclitaxel Carboplatin + Paclitaxel Median DFS (mos) 19.4 20.7 Median Survival (mos) 48.8 56.7 12 24 36 48 60 Months on Study Ozols R, J Clin Oncol 2003

Ovarian Cancer: SCOTROC Trial Scottish Study Group Trial EOC (Stage IC IV) All Strata R A N D O M I Z E Docetaxel (1 hour) 75 mg/m 2 q 21 d x 6 Carboplatin AUC = 5.0 q 21 d x 6 Paclitaxel (3 hour) 175 mg/m 2 q 21 d x 6 Carboplatin AUC = 5.0 q 21 d x 6 N = 1077 Accrual completed 4/2000 Primary endpoint: 25% superiority Docetaxel Vasey J Natl Cancer Inst, 2004

SCOTROC: Outcomes PFS P = NS OS P = NS Vasey J Natl Cancer Inst, 2004

Current Standards

Dose Dense: Weekly Therapy Ovarian Ovarian Epithelial, PP, PP, FT FT FIGO FIGO Stage Stage II-IV II-IV IV Stratification; Residual disease: <1cm, > 1cm FIGO Stage II vs. III vs. IV Histology clear cell/mucinous vs serous/others Paclitaxel 180mg/m 2 Carboplatin AUC 6.0 q 21 days (6-9 9 cycles) Dose density: 60 mg/m 2 /wk R Paclitaxel 80mg/m 2, days 1, 8, 15 Carboplatin AUC 6.0, day 1 q 21 days (6-9 9 cycles) Dose density: 80 mg/m 2 /wk (+33%) Katsumata, Lancet 2009

Progression Free Survival (Iº) Treatment n Event Median PFS P value HR 95%CI c-tc 319 200 17.2 mos. dd-tc 312 160 28.0 mos. 0.0015 0.714 0.581-0.879 Katsumata, Lancet 2009

Overall Survival Katsumata, Lancet 2009

GOG 160/170 Series: Performance Comparison Bevacizumab PFS 6 (%) Temsirolimus Sorafenib Imatinib Gefitinib Mifepristone Trastuzumab Enzastaurin Lapatinib Vorinostat Response Rate (%)

Front line Trials: GOG GOG-218 N = 1873 patients Survival, PFS primary endpoints Biologic & QOL endpoints EOC, PP, FT cancer Primary Treatment Phase Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Maintenance Phase Placebo X 15 mos Placebo X 15 mos Bevacizumab X 15 mos PI: Burger

GOG 218: ASCO 2010 Median: 10.3 vs 11.2 vs 14.1 mos

Summary of End Points for Regular Approval of Oncology Drug Marketing Applications Total 57 Survival 18 RR 26 RR alone 10 RR decreased tumor specific symptoms 9 RR TTP 7 Decreased tumor specific symptoms 4 PFS 2 TTP 1 Recurrence of malignant pleural effusion 2 Occurrence of breast cancer 2 Decreased impairment of creatinine clearance 1 Decreased xerostomia 1 J Clin Oncol 21:1404-1411.

Hazard Ratios of PFS vs. OS: Data from Platinum based Ov Ca Chemotherapy Trials Linear Regression lnhr os =1.01*lnHR PFS -0.006 R 2 =0.91 Courtesy of E. Eisenhaurer ASCO 2010

Hazard Ratios of PFS vs. OS: Data from RCTs of Bevacizumab in Other Solid Tumors Line of identity Linear Regression lnhr os =0.67*lnHR PFS +0.09 R 2 =0.61 Courtesy of E. Eisenhaurer ASCO 2010

GOG 218: PFS vs. OS

Biomarker studies: Why? Patient selection for protocol continuation Early assessment of efficacy Who does or does not benefit? (plasma VEGF A, HTN, etc) Early assessment of toxicity Patient assessment for treatment allocation Intrinsic biology: molecular and histological subgroups Correlative pharmacodynamics vs. non invasive imaging Understanding tumor biology at progression

Biomarkers in Ovarian Cancer Serum Based: CA125 HE4 Lots and lots and lots (prognostic and unvalidated) Tissue Based: P53 expression Cyclin E Lots and lots and lots (prognostic and unvalidated) Novel: Genomic expression Pathway activation Target specific and dynamic

Biomarkers in Ovarian Cancer CA125 Elevated in most advanced serous epithelial tumors Not elevated in 50% early stage cases and mucinous tumors May dissociated with response to biological agents Elevated in non gyn tumors, as well as pathological and normal conditions (endometriosis, peritonitis, pregnancy)

CA125 and Assessment of Progression CA 125 Doubling Median = 1.5 mos CA 125 lead time : 3 mos Rustin J Clin Oncol 19:4054, 2001

Biomarkers in Ovarian Cancer Serum Based: CA125 HE4 Lots and lots and lots (prognostic and unvalidated) Tissue Based: P53 expression Cyclin E validated in GOG 111 samples Lots and lots and lots (prognostic and unvalidated) Novel: Genomic expression Pathway activation Target specific and dynamic

Pathway Activation Model for Therapy Initial Diagnosis and Surgery Platinum Response? No Yes Treat Platinum-based therapy plus Targeted Pathway Specific Drugs Predict Best Response To Alternative Chemotherapy Treat with Microarray-directed Chemotherapy plus Targeted Pathway Specific Drugs Predict Response to Pathway Specific Drug(s)

Dynamic Assessment of Efficacy Imaging Assessment Anatomical Morphological Functional

Biomarker Development in Ovarian Ca All contemporary studies will be powered for OS whether or not it is the primary endpoint Registration discussions with regulatory authorities will define acceptable surrogates (if any) Investigative environment is suitable to explore dynamic tumor assessment Recurrent disease more likely fruitful

Thanks ACRIN Abdominal Committee

Advanced Ovarian Cancer: Phase III 1981 052 CAP vs CP 093 32 P (IP) vs Obs (Path CR) 097 Cisplatin Dose Intensity (DI) 104 Intraperitoneal (IP) Cisplatin 111 Cisplatin Paclitaxel vs Cyclophosphamide 114 Cisplatin (IP) and Carboplatin (AUC 9, IV) 132 Sequential Single Agent vs Combination 152 Interval Cytoreduction 158 Carboplatin vs Cisplatin and 3 h vs 24 h Paclitaxel ICON Carbo vs carb paclitaxel 162 24 h vs 96 h Paclitaxel 164 ABMT Consolidation Probably Yes 172 Cisplatin (IP) and Paclitaxel (IP) OVAR 3, 5, 7 178 Paclitaxel Consolidation 182 Gemcitabine, Topotecan, PEG Lipo Dox (MITO) JGOG Dose dense/intense paclitaxel Are we approaching the ceiling for improved benefit from combination chemotherapy? 2010

Relationship of PFS to OS in GOG Trials Mark Brady PhD Adopted from M Brady PhD

Relationship of PFS to OS in GOG Trials GOG 182 GOG 218 JGOG Mark Brady PhD Adopted from M Brady PhD