Transcript Local-Research-Update-David

“Taking Care of Tomorrows
Patient Better than Today”…
the Future is Now
David O’Malley, M.D.
• Describe the Collaborative Trials (GOG)
– Past
– Present
– Future
• Discuss Ovarian Cancer Research at The
James Cancer Center – OSU
Have we made improvements?
Are we doing any good?
Salani, et al. Overview of epithelial ovarian cancer and updates
in management strategies, Expert Rev. Obstet. Gynecol. (2009)
Ovarian Carcinoma Talking the same language
Secondary
Cytoreduction
Interval
Cytoreduction
Diagnosis
Symptoms
Chemotherapy #1
Progression
Consolidation
Chemo #2
Death
Chemo #3+
Cure
Staging
Primary cytoreduction
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
GOG 218 Study Scheme
Bevacizumab during Treatment and as Maintenance
Maintenance
n = 1873
Control arm:
Carboplatin AUC 6 d1
Stage III optimal (macroscopic)
Stage III suboptimal
Stage IV
Placebo d1
Experimental arm:
Carboplatin AUC 6 IV d 1
Paclitaxel 175 mg/m2 IV d 1
Bevacizumab 15 mg/kg d1
Paclitaxel 175 mg/m2 IV d 1
Bevacizumab 15 mg/kg d1
Every 21 days x 6 courses
Bevacizumab every 3
wks for 16 cycles
Experimental arm:
Carboplatin AUC 6 IV d 1
Burger RA, NEJM 2012
Placebo x 16 cycles
Previously untreated epithelial
ovarian, primary peritoneal, or
fallopian tube cancer
R
A
N
D
O
M
I
Z
E
Paclitaxel 175 mg/m2 d1
218 Progression Free Survival
Patients with event, n (%)
Median PFS, months
Proportion surviving progression free
1.0
0.9
HR (stratified)
(95% CI)
0.8
One-sided log-rank p-value
Arm I
CP + PLA → PLA
(n=625)
Arm II
CP + BEV → PLA
(n=625)
Arm III
CP + BEV BEV
(n=623)
375(60)
405(67)
363(71)
10.4
11.5
0.864
(0.759–0.996)
0.0218*
13.9
0.726
(0.627–0.840)
<0.0001a
0.7
0.6
Median follow-up: 17.4 months
0.5
0.4
0.3
0.2
0.1
0
2
16
30
4
18
32
6
20
34
8
22
36
Months since randomization
10
24
12
26
14
28
Burger RA, J Clin Oncol 2010;28(18S):
GOG 252
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
Stage II. III optimal
Stage III suboptimal (some)
Stage IV (some)
Bevacizumab 15 mg/kg IV on day 1
beginning on cycle 2
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
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
Bevacizumab x 16 cycles
Previously untreated epithelial ovarian,
primary peritoneal, or fallopian tube
cancer
R
A
N
D
O
M
I
Z
E
GOG 262
Different taxol IV schedules
*OPTIONAL Bevacizumab during Treatment and as Maintenance
Maintenance*
Paclitaxel 80 mg/m2 IV days 1, 8,15
Previously untreated epithelial ovarian,
primary peritoneal, or fallopian tube
cancer
Stage II. III optimal suboptimal
Stage IV
R
A
N
D
O
M
I
Z
E
*Bevacizumab 15 mg/kg IV on day 1
Paclitaxel 175 mg/m2 IV days 1
Carboplatin AUC 6 IV day 1
*Bevacizumab 15 mg/kg IV on day 1
GOG Statistical Manual
OPTIONAL Bevacizumab until PROGRESSION
Carboplatin AUC 6 IV day 1
TRINOVA - 3
(AMG 386)
Anti VEGF and angiopoietin agent
Maintenance
n = 2000
Control arm:
Previously untreated epithelial ovarian,
primary peritoneal, or fallopian tube
cancer
•Post operative Stage III, IV
•Neoadjuvant
Placebo weekly
2:1 randomization
Experimental arm:
Carboplatin AUC 5-6 IV d 1
Paclitaxel 175 mg/m2 IV d 1
AMG 386 weekly
TRINOVA 3 AMGEN PROTOCOL
AMG 386 x 18 months
R
A
N
D
O
M
I
Z
E
Paclitaxel 175 mg/m2 d1
Weekly Placebo
x 18 months
Carboplatin AUC 5-6 d1
NEXT STEP in GOG
PARP inhibitors
Maintenance
Previously untreated epithelial ovarian,
primary peritoneal, or fallopian tube
cancer
GOG Statistical Manual
Paclitaxel
Carboplatin
PARP
Paclitaxel
Carboplatin
PLACEBO
Paclitaxel
Carboplatin
PARP
PARP
Stage II. III optimal
Stage III suboptimal
Stage IV
NEOADJUVANT?
R
A
N
D
O
M
I
Z
E
PLACEBO
Paclitaxel
Carboplatin
PLACEBO
Recurrent Cancer
GOG 213
Bev with treatment UNTIL PROGRESSION
Plus Surgery question
Yes
Paclitaxel IV
Surgery
Carboplatin IV
No
Surgery
No
R
A
N
D
O
M
I
Z
E
Maintenance
Paclitaxel IV
Carboplatin IV
BEV IV
Every 21 days x 6 courses
GOG Statistical Manual
Bevacizumab every 3
wks until progression
Surgical candidate?
Recurrent
Ovarian
Cancer in
patients
with a
treatment
free interval
for at least
6 months
from
primary
therapy
R
A
N
D
O
M
I
Z
E
…the Future is Now
Novel Agents - Reolysin
•
Reovirus Serotype 3 –
–
naturally occurring human reovirus
•
In nature, reovirus infection is mild
•
Reovirus
–
•
Reovirus Serotype 3
–
•
replicate specifically in and are cytopathic to cells possessing an activated Ras
signaling pathway (Cancer cells)
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
http://www.oncolyticsbiotech.com/reolysin
GOG 186 H
Phase II
Recurrent Ovarian Cancer
R
A
N
D
O
M
I
Z
E
TRINOVA 3 AMGEN PROTOCOL
Weekly taxol
Weekly taxol +
Reolysin daily x 5
Not yet ready for humans…
but close
• Safe, Targeted Antitumor
Therapeutics (STAT3
Inhibitors) for Ovarian
HO-3867 compound mixed with the
Cancer animal feed at 3 different levels (25, 50
& 100 ppm).
• NOH moiety (HO-3867
and HO-4200 would
function act as an antioxidant and it Selectively
Target the Cancer cells
Efficacy of HO-3867 in vivo
1200
Tumor – N=6
Tumor Growth (mm3)
1000
25PPM – N=8
800
25 ppm
Untreated
600
50 ppm
100 ppm
50PPM
– N=8
100PPM –N=8
400
200
0
1
4
7
10
13
17
20
25
30
35
Days
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.
• STAT3 has attracted much attention as a
Clin.Cancer Res -2007
pharmacologic target
• HO-3867 Target STAT3, resulting inhibition of cell
proliferation and induction of apoptosis
In Silico Molecular Modeling
pSTAT3
Tyr705
pSTAT3
Ser727
STAT3
•
•
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
Survivorship
• Quality of Life
• Lance Armstrong Foundation (LAF)
• Multi-Disciplinary
How do we improve?
• Research
– Phase I, II, III trials
– GOG/NCI
– Consortium
– Collaborations
– Institutional
– Advocacy Groups
– Private
•Personalized
Medicine
•Molecular
•Genetics
•Psychosocial
•Behavioral
Why do we do what we do?
Why are we here?
Survivors!