“Taking Care of Tomorrows Patient Better than Today”… the Future is Now Set A1 – Title Slide David O’Malley, M.D.

Describe the Collaborative Trials (GOG) Past Present Future Discuss Ovarian Cancer Research at The James Cancer Center – OSU Set A1 – Content Slide

Have we made improvements? Are we doing any good? Set A1 – Content Slide Salani, et al. Overview of epithelial ovarian cancer and updates in management strategies, Expert Rev. Obstet. Gynecol. (2009)

Talking the same language Ovarian Carcinoma - Talking the same language Staging Primary cytoreduction Interval Cytoreduction Secondary Diagnosis Progression Death Symptoms Chemotherapy #1 Chemo #2 Chemo #3+ Consolidation Set A1 – Content Slide Cure Supportive Care

Gynecologic Oncology Group (GOG) Adjuvant/First Line Therapy GOG 218 (NEJM just published) GOG 252 (just completed enrollment) GOG 262 (just completed enrollment) Recurrent Therapy GOG 213 (just completed enrollment, except for surgery question Set A1 – Content Slide

Bevacizumab every 3 wks for 16 cycles GOG 218 Study Scheme Bevacizumab during Treatment and as Maintenance Maintenance n = 1873 Control arm: Carboplatin AUC 6 d1 Paclitaxel 175 mg/m2 d1 Placebo d1 R A N D O M I Z E Placebo x 16 cycles Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV Experimental arm: Carboplatin AUC 6 IV d 1 Paclitaxel 175 mg/m2 IV d 1 Bevacizumab 15 mg/kg d1 Set A1 – Content Slide Experimental arm: Carboplatin AUC 6 IV d 1 Paclitaxel 175 mg/m2 IV d 1 Bevacizumab 15 mg/kg d1 Bevacizumab every 3 wks for 16 cycles Every 21 days x 6 courses Burger RA, NEJM 2012

218 Progression Free Survival Arm I CP + PLA → PLA (n=625) Arm II CP + BEV → PLA (n=625) Arm III CP + BEV → BEV (n=623) Patients with event, n (%) 375(60) 405(67) 363(71) Median PFS, months 10.4 11.5 13.9 HR (stratified) (95% CI) 0.864 (0.759–0.996) 0.726 (0.627–0.840) One-sided log-rank p-value 0.0218* <0.0001a 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Median follow-up: 17.4 months Proportion surviving progression free Median II vs I III vs I 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months since randomization Burger RA, J Clin Oncol 2010;28(18S):

GOG Statistical Manual IV versus IP (different regimens) Bevacizumab during Treatment and as Maintenance Maintenance Paclitaxel 80 mg/m2 IV days 1, 8, 15 Carboplatin AUC 6 IV day 1 Bevacizumab 15 mg/kg IV on day 1 beginning on cycle 2 R A N D O M I Z E Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer Stage II. III optimal Stage III suboptimal (some) Stage IV (some) Paclitaxel 80 mg/m2 IV days 1, 8, 15 Carboplatin AUC 6 IP day 1 Bevacizumab 15 mg/kg IV on day 1 beginning on cycle 2 Bevacizumab x 16 cycles Set A1 – Content Slide Paclitaxel 135 mg/m2 IV on day 1 Cisplatin 75 mg/m2 IP on day 2 Paclitaxel 60 mg/m2 IP on day 8 Bevacizumab 15 mg/kg IV on day 1 beginning on cycle 2 GOG Statistical Manual

OPTIONAL Bevacizumab until PROGRESSION GOG Statistical Manual Different taxol IV schedules *OPTIONAL Bevacizumab during Treatment and as Maintenance Maintenance* Paclitaxel 80 mg/m2 IV days 1, 8,15 Carboplatin AUC 6 IV day 1 *Bevacizumab 15 mg/kg IV on day 1 R A N D O M I Z E Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer Stage II. III optimal suboptimal Stage IV OPTIONAL Bevacizumab until PROGRESSION Set A1 – Content Slide Paclitaxel 175 mg/m2 IV days 1 Carboplatin AUC 6 IV day 1 *Bevacizumab 15 mg/kg IV on day 1 GOG Statistical Manual

Anti VEGF and angiopoietin agent TRINOVA - 3 (AMG 386) Anti VEGF and angiopoietin agent Maintenance n = 2000 Control arm: Carboplatin AUC 5-6 d1 Paclitaxel 175 mg/m2 d1 Placebo weekly R A N D O M I Z E Weekly Placebo x 18 months Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer Post operative Stage III, IV Neoadjuvant 2:1 randomization Set A1 – Content Slide Experimental arm: Carboplatin AUC 5-6 IV d 1 Paclitaxel 175 mg/m2 IV d 1 AMG 386 weekly AMG 386 x 18 months TRINOVA 3 AMGEN PROTOCOL

GOG Statistical Manual NEXT STEP in GOG PARP inhibitors Maintenance Paclitaxel Carboplatin PLACEBO R A N D O M I Z E PLACEBO Paclitaxel Carboplatin PARP Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer Stage II. III optimal Stage III suboptimal Stage IV NEOADJUVANT? Paclitaxel Carboplatin PLACEBO Set A1 – Content Slide PARP Paclitaxel Carboplatin PARP GOG Statistical Manual

Recurrent Cancer Set A1 – Content Slide

Bevacizumab every 3 wks until progression GOG Statistical Manual Bev with treatment UNTIL PROGRESSION Plus Surgery question Surgical candidate? R A N D O M I Z E R A N D O M I Z E Paclitaxel IV Carboplatin IV Surgery Recurrent Ovarian Cancer in patients with a treatment free interval for at least 6 months from primary therapy Yes No Surgery Maintenance Paclitaxel IV Carboplatin IV BEV IV Bevacizumab every 3 wks until progression Set A1 – Content Slide No Every 21 days x 6 courses GOG Statistical Manual

…the Future is Now Set A1 – Content Slide

Novel Agents - Reolysin Reovirus Serotype 3 – naturally occurring human reovirus In nature, reovirus infection is mild Reovirus replicate specifically in and are cytopathic to cells possessing an activated Ras signaling pathway (Cancer cells) Reovirus Serotype 3 Dearing Strain has been demonstrated to be effective against solid tumors when administered IV and IP OSU was the first institution in the world to have treated patients with ovarian cancer Phase I completed Set A1 – Content Slide

Set A1 – Content Slide http://www.oncolyticsbiotech.com/reolysin

Recurrent Ovarian Cancer GOG 186 H Phase II Weekly taxol R A N D O M I Z E Recurrent Ovarian Cancer Weekly taxol + Reolysin daily x 5 Set A1 – Content Slide TRINOVA 3 AMGEN PROTOCOL

Not yet ready for humans… but close Safe, Targeted Antitumor Therapeutics (STAT3 Inhibitors) for Ovarian Cancer NOH moiety (HO-3867 and HO-4200 would function act as an anti-oxidant and it Selectively Target the Cancer cells HO-3867 compound mixed with the animal feed at 3 different levels (25, 50 & 100 ppm). Set A1 – Content Slide

Efficacy of HO-3867 in vivo Untreated 25 ppm 50 ppm 100 ppm Days 200 400 600 800 1000 1200 1 4 7 10 13 17 20 25 30 35 Tumor Growth (mm3) Tumor – N=6 25PPM – N=8 50PPM – N=8 100PPM –N=8 HO-3867 compound mixed with the animal feed at 3 different levels (25, 50 & 100 ppm).

STAT3 in Ovarian Cancer The active form of STAT3 (pSTAT3) has been identified in 60 percent of cancer cells including ovarian cancer. Clin.Cancer Res -2007 STAT3 has attracted much attention as a pharmacologic target HO-3867 Target STAT3, resulting inhibition of cell proliferation and induction of apoptosis In Silico Molecular Modeling pSTAT3 Tyr705 STAT3 Ser727

The antioxidant-conjugated HO-3867 appears to be a safe and effective anticancer agent for ovarian cancer. HO-3867 might target, at least in part, STAT3 activation in the ovarian tumor Set A1 – Content Slide

Survivorship Quality of Life Lance Armstrong Foundation (LAF) Multi-Disciplinary Set A1 – Content Slide

How do we improve? Research Personalized Medicine Behavioral Phase I, II, III trials GOG/NCI Consortium Collaborations Institutional Advocacy Groups Private Personalized Medicine Molecular Genetics Psychosocial Behavioral Set A1 – Content Slide

Why do we do what we do? Set A1 – Content Slide Why are we here?

Survivors! Set A1 – Content Slide

Closing Slide