1. “Taking Care of Tomorrows Patient Better than Today”… the Future is Now
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David O’Malley, M.D.

2. Describe the Collaborative Trials (GOG)
Past
Present
Future
Discuss Ovarian Cancer Research at The James Cancer Center – OSU
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3. Have we made improvements? Are we doing any good?
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Salani, et al. Overview of epithelial ovarian cancer and updates in management strategies, Expert Rev. Obstet. Gynecol. (2009)

4. 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
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Cure
Supportive
Care

5. 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
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6. 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
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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

7. 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
Months since randomization
Burger RA, J Clin Oncol 2010;28(18S):

8. 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
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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

9. 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
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Paclitaxel 175 mg/m2 IV days 1
Carboplatin AUC 6 IV day 1
*Bevacizumab 15 mg/kg IV on day 1
GOG Statistical Manual

10. 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
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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

11. 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
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PARP
Paclitaxel
Carboplatin
PARP
GOG Statistical Manual

12. Recurrent Cancer
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13. 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
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Every 21 days x 6 courses
GOG Statistical Manual

14. …the Future is Now
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16. 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
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17. Set A1 – Content Slide

18. 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

19. 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).
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20. 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).

21. 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

22. 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
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23. Survivorship Quality of Life Lance Armstrong Foundation (LAF)
Multi-Disciplinary
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24. 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
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25. Why do we do what we do?
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Why are we here?

26. Survivors!
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27. Closing Slide