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Second-line treatment of ovarian cancer
Second Gynaecological Oncological Update
Leuven May 5, 2007
Outcomes by therapy-free interval
Survival
(days)
1000
800
100
Response
rate (%)
957
80
Overall
survival
600
400
60
•
40
217
200
20
•
9
0
•
0
•
•
33
••
•
•
•
0-3
3-6
•• 90
Pr
393
•
174
6-9
TFI (mos)
•
•
•
•
Response
rate
•
•
9-12
•
60
•
339
Progressionfree survival
12-18
>18
E. Pujade-Lauraine et al.
Second-line
Chemotherapy in platin
sensitive ovarian cancer.
ICON4 - Trial design
Relapsed ovarian or primary
peritoneal (serous type) carcinoma,
requiring chemotherapy
•Previous chemotherapy platinum-based
•Treatment-free interval of >6 months MRC, >12 months IRFMN
Randomize
Platinum-based
chemotherapy
Paclitaxel plus
platinum
ICON 4 Overall survival
Hazard ratio = 0.77
(95% CI 0.64 - 0.93; p = 0.006)
Absolute difference at 2 years = 9%
(50%  59%) 95% CI (3% - 14%)
Events Totals
245
410
Plat
392
Plat & Pac 218
Years from randomisation
Patients at risk (events)
Plat
410
(91)
Plat & Pac
392
(69)
267
286
(85)
(81)
126
147
(43)
(36)
55
75
(18)
(24)
20
29
ICON 4: Time Since Completion of Last Chemotherapy
Hazard ratio (99% CI)
OS:
< 12 months
> 12 months
0
pi = 0.21
0.5
1
1.5
2
PFS:
< 12 months
> 12 months
0
pi = 0.87
0.5
Paclitaxel-platinum better
1
1.5
2
Conventional platinum better
ICON4: Previous Exposure to Taxanes
Hazard ratio (99% CI)
OS:
no
pi = 0.49
yes
0
0.5
1
1.5
2
PFS:
no
pi = 0.93
yes
0
0.5
Paclitaxel-platinum better
1
1.5
2
Conventional platinum better
GEMZAR-Carboplatin vs Carboplatin
in PS Ovarian Cancer Patients
Stratify according to
• Platinum-free interval
( 6-12 or > 12 mos)
• Type of 1st-line
platinum therapy
(Platinum-Paclitaxel
or other platinum Tx)
• bidimensionally
measurable disease
(yes or no)
GEMZAR 1000 d 1+8
R
A
N
D
O
M
I
Z
E
Carboplatin AUC 4 d 1
Carboplatin AUC 5 d 1
Treatment was every 21
days for 6 cycles in both
arms
Progression-free Survival by Therapy
1.0
0.9
Hazard ratio = 0.72 (95% CI 0.58 - 0.90)
Log-rank p-value = 0.0031
Progression-Free Probability
0.8
0.7
0.6
0.5
Median = 5.8m (5.2 - 7.1m)
0.4
Median = 8.6m (7.9 - 9.7m)
Cb 178 pts / 162 evts
GCb 178 pts / 163 evts
0.3
0.2
0.1
0.0
0
Pts at risk
178
178
6
12
18
24
30
36
42
months
82
125
29
47
10
17
5
5
4
1
2
0
1
0
Cb
GCb
Progression-free Survival
Platinum-free Interval 6-12 months
1.0
Hazard ratio = 0.69 (95% CI 0.49 – 0.97)
Log-rank p-value = 0.0311
0.9
Progression-Free Probability
0.8
Median = 5.2m (4.1 - 6.9m)
Median = 7.9m (6.3 - 8.7m)
0.7
0.6
Cb 71 pts / 65 evts
GCb 71 pts / 69 evts
0.5
0.4
0.3
0.2
0.1
0.0
0
Pts at risk
71
71
6
12
18
24
27
44
6
17
2
5
0
0
months
Cb
GCb
Progression-free Survival
Platinum-free Interval >12 months
1.0
Hazard ratio = 0.72 (95% CI 0.54 – 0.96)
Log-rank p-value = 0.0254
0.9
Progression-Free Probability
0.8
Median = 6.7m (5.6 - 8.2m)
Median = 9.7m (8.4 - 10.9m)
0.7
0.6
Cb 107 pts / 97
GCb 106 pts / 93
0.5
evts
evts
0.4
0.3
0.2
0.1
0.0
0
Pts at risk
107
106
6
12
18
24
30
36
42
55
80
23
30
8
12
5
5
4
1
2
0
1
0
months
Cb
GCb
Progression-free Survival
Previous Platinum + Paclitaxel
1.0
Hazard ratio = 0.63 (95% CI 0.48 – 0.82)
Log-rank p-value = 0.0006
0.9
Progression-Free Probability
0.8
0.7
Median = 5.9m (4.8 - 7.2m)
Median = 9.7m (8.5 - 10.9m)
0.6
Cb 120 pts / 112 evts
GCb 122 pts / 113 evts
0.5
0.4
0.3
0.2
0.1
0.0
0
Pts at risk
120
122
6
12
18
24
30
36
months
58
91
17
37
5
11
2
4
2
1
0
0
Cb
GCb
OVAR 2.5 and ICON 4 Toxicity Results
100
90
Percent of Patients
80
70
GCb from OVAR 2.5
60
Pac+Plt from ICON 4
50
40
30
20
10
0
Alopecia (> grade 2)
Neuropathy (> grade 2) Hematologic toxicities
requiring treatment
modification
Infection (requiring
treatment modification)
Conclusions: Second line
Platin sensitive ovarian cancer
 Combination platin-based chemotherapy (TC or GC)
improves PFS (and OS).
 Gemc/Carbo has the advantage of not increasing
the neurotoxicity and alopecia. (ICON4 has a much
lower incidence of paclitaxel in first-line than in our usual
practice)
 In patients relapsing between 6 – 12 months,
Gemc/Carbo results in improved PFS and is
suggested as the preferred regimen.
 In patients with a treatment-free interval of > 12
months combination chemotherapy (TC or GC) is
recommended.
Platinum-PLD combination
Calypso Trial
CAeLYx in Platinum Sensitive Ovarian Cancer
GCIG Trial GINECO/AGO/NCIC/A-AGO/ NSGO/ANZOG/MITO/EORTC
Carboplatin AUC5/ Paclitaxel 175 mg/m2 (q 3 weeks)
versus
Carboplatin AUC5/ PLD 30 mg/m2 (q 4 weeks)
Platinum sensitive (> 6 months PFI)
820 patients
(Accrual 3/2007: 660/820->950)
 Primary aim:
Non inferiority Trial - Progression Free Survival [ HR > 0.77; 80% power]
 Secondary aim:
Overall survival, Toxicity. QoL
Recurrent
Platin-Resistant
Ovarian Cancer
Platinum-Refractory Ovarian Cancer
Single-Agent Activity
Cumulative response rate
(mean; 95% confidence)
35
30
25
20
15
10
5
0
Recurrent Epithelial Ovarian Carcinoma:
A Randomized Phase III study of Peglyated
Liposomal Doxorubicin versus Topotecan
Enrollment
• Recurrent epithelial
ovarian cancer
• 474 patients
• 104 US and international
sites
Endpoints
• Primary
– Time to progression
• Secondary
– Overall survival
– Response rate
– Toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
Liposomal doxorubicin
50 mg/m2 q 28 d
Topotecan 1.5 mg/m2/day for
5 consecutive days, q 21 d
Gordon AN, et al. J Clin Oncol. 2001
ECCO 2003:
5-yr follow up
Liposomal doxorubicin > Topotecan
ALL CASES
35%
24%
Taxol/
Taxol/Carbo Weekly in Recurrent Ovarian
Carcinoma (Rotterdam regimen)
Induction therapy
Taxol
90 mg /m2
Carboplatin AUC 4
day 1, 8, 15 and day 29, 35, 42
week
0 1 2
4
5
6
3-weekly TC
9
12
15
3 - weekly TC
week 18
21 24
Response evaluation
1-weekly TC
Response evaluation
Evaluation
Taxol 540 mg/m²/9 weeks =
60 mg/m²week
Carbo 24AUC/9 weeks =
2,7 AUC/week
Response evaluation
Maintenance therapy
2
Followed by 6 cycles 3- weekly Taxol 175 mg/m and Carboplatin
AUC 6
Weekly Taxol/Carboplatin
Response according to last PFI
PFI
 6m 6-12m  12m
N
46
19
33
Response after 8 weeks
CR
PR
SD
PD
4%
46%
28%
15%
5%
63%
26%
5%
12%
48%
33%
6%
Response after 6 cycles weekly TC
100%
80%
CR
PR
SD
PD
60%
40%
20%
RR
50%
69%
61%
0%
<6m
6 -12 m
> 12 m
Overall response
Overall response
CR
PR
SD
PD
17%
39%
22%
15%
37%
42%
16%
5%
24%
56%
15%
6%
RR
57%
79%
79%
100%
80%
CR
PR
SD
PD
60%
40%
20%
0%
< 6m
6 -12m
> 12m
Taxol/ Carbodose dense Recurrent Ovarian
Carcinoma (Leuven regimen, n =34)
Taxol
90 mg /m2
Carboplatin AUC 4
day 1, 8 q 3 weeks for 6 cycles
week
0 1
3
4
6
7
“dose dense” TC
week 9 10
12 13
15 16
Response evaluation
Evaluation
“dose dense” TC
Response evaluation
Taxol 1080 mg/m²/18
weeks = 60 mg/m²/week
Carbo 48AUC/18 weeks = 2,7 AUC/week
TC Dose dense (Leuven)
(Cadron et al, Gynecol Oncol in press)
Median = 4th line
100%
1
1
6
1
80%
60%
40%
2
3
3
7
2
20%
2
2
0%
RR
< 6 months
6-12 months
> 12 months
9/17 (53%)
5/6
5/7
10/13 (77%)
PD
SD
PR
CR
Some ongoing Phase II-III trials
at the
University Hospitals Leuven
Chemotherapy
EORTC PROVE Study
(Platin Resistant OVarian Epithelial cancer)
Stage one
Phase II study
Randomization
99 patients
 6 Six cycles 3-weekly
Caelyx 40 mg/m²
 6 Six cycles 3-weekly
Caelyx 30 mg/m²
Carboplatin AUC 5
Six weekly Taxol Carboplatin +
 6 Three 3-weekly Taxol
Carboplatin
Stage two
Phase III study
Randomization 350 patients
Arm A highest response
3-weekly Caelyx
or Caelyx/Carboplatin?
Primary Endpoint:
Secondary Endpoints:
Arm B highest response
Weekly Taxol/Carboplatin +
3-weekly Taxol/Carboplatin?
Progression free survival,
Response rate and response duration,
Overall Survival, Toxicity profile
Quality of Life
ALIMTA®
Platinum Resistant Ovarian Cancer
Studies
• Recurrent ovarian, fallopian tube, or
primary peritoneal cancer
• One prior regimen
• TFI < 6 months
• Measurable disease
• GOG Protocol 126 series
(Phase II, 900 mg/m2 q21d)
• Lilly JMHF
(Randomized Phase II 500 mg vs 900 mg/m2 q21d)
GSH Resistance: TLK286
• A novel glutathione analog
prodrug activated by
glutathione S-transferase
P1-1
• Rationally-designed to
exploit the overexpression
of the enzyme GST P1-1
present in ovarian cancer
• Cleavage releases two
reactive fragments that
activate the stress response
apoptotic pathway
• Antitumor activity in cell
culture and xenograft
models
NH2
H
N
HO2C
O
O
S
Cl
N
H
O
GST P1-1
Cleavage
O
N
Cl
Cl
HCl
O
O
N P
CO2H
Cl
Telik/TLK286 (TelcytaTM)
ASSIST-1
ASSIST-3
Recurrent Ovarian Cancer
3rd Line
Recurrent Ovarian Cancer
2nd Line
Refractory & Resistant
vs.
Caelyx
TLK286 +
Carboplatin
TLK286
Topotecan
N = 440
Ongoing
Caelyx
TLK286 (TelcytaTM) Randomized
Phase III
ASSIST-5
Recurrent Ovarian Cancer
2nd Line
Refractory & Resistant
TLK286 +
Caelyx
Caelyx
Ongoing
An Open-label Multicenter Randomized Phase 3 Study
Comparing CAELYX® and YONDELIS™ with
CAELYX alone in Relapsed Ovarian Cancer
•
Advanced Recurrent
Epithelial Ovarian Cancer
– One prior regimen
– Evaluable and measurable
disease
– Platinum sensitive and
resistant
R
A
N
D
O
M
I
Z
E
Primary endpoint: OS
Other endpoints: PFS, RR, Safety
Accrual 7/3/2007: 450/650
Caelyx® 30 mg/m2 plus
Yondelis® 1.1mg/m2
Every 3 weeks
Caelyx® 50 mg/m2 q 4 wks
Translational Research
•Pharmacokinetics
•Pharmacogenomics
•Pharmacoeconomics
•Quality of Life
•Circulating tumor cells
TARGETED THERAPY IN
OVARIAN CANCER
Targets of Potential Interest
In Ovarian Cancer
Receptors / signalling
ErbB family
Ras, raf, MAPK
P13K, Akt
PKC
pTEN
SURFACE ANTIGENS
MUC16/CA125
MUC1
Folate receptor
Growth factors
TGF alpha
INACTIVATION / LOSS
p53
PTEN
SPARC
NOEY2
OVCA1
DOC2
BRCA1/2
ACTIVATION
OVEREXPRESSION
Receptor kinases
(EGFr, HER2, FMS, VEGFr)
LPA
PI3K, AKT, p7056
Telomerase
C-myc
Angiogenesis
VEGF
bFGF
Apoptosis related
XIAP
BCL-2
TRAIL
Cell Cycle
RB
P53
Cyclins
ERB family
MoAb
EGFR/HER1 (ErbB1)*
HER2 (ErbB2)o
HER3 (ErbB3)
HER4 (ErbB4)
TKI
Ovarian Cancer
ERB targeted therapy
Reference
n
Response
rate
Stable
disease
Erlotinib
(Tarceva)
Gordon 2005
34
6%
44%
Gefitininb
(Iressa)
Schilder 2005
27
3%
15%
CI-1033
Campos 2005
105
0%
50%
Pertuzumab
(2C4)
Gordon 2006
117
4%
7%
Trastuzumab
(Herceptin)
Bookman 2003
41
7%
39%
TKIs
MoAbs
Ovarian Cancer
ERB targeted therapy
Reference
n
Response
rate
Stable
disease
Erlotinnib
(Tarceva)
Gordon 2005
34
6%
44%
Gefitininb
(Iressa)
Schilder 2005
27
3%
15%
CI-1033
Campos 2005
105
0%
50%
Pertuzumab
(2C4)
Gordon 2006
117
4%
7%
Trastuzumab
(Herceptin)
Bookman
2003
41
7%
39%
TKIs
MoAbs
Tarceva Maintenance Trial
EORTC-GINECO-AAGOANZOG-(MANGO)-(MRC)
• High risk stage I &
stage II-IV
Platinum-based
regimen
q 21 j / 6 - 9 cycles
SD
PR
CR
R
A
N
D
O
M
I
S
A
T
I
O
N
Tissue and blood samples
Erlonitib
(TarcevaTM)
150 mg/d
2 years
Observation
Accrual 1/5/2006: 431/800
ERBB2 Trastuzumab (GOG 160)
IHC
2+ 61 ( 7.3%)
3+ 34 ( 4.1%)
7.3%
Bookman et al. JCO 21:283-290, 2003
Randomized Pertuzumab (HER2)
Phase II in Platin-sensitive ovarian cancer
Arm A
• Relapse 2nd line
•Platin-free > 6 months
Accrual closed 11/2006: n = 147
R
A
N
D
O
M
I
S
A
T
I
O
N
6 courses of
Paclitaxel/Carbo or
Gemci/Carbo
Arm B
As Arm A plus
concomittant
Pertuzumab 3 wkly
iv, followed by 11
courses
maintenance
Pertuzumab
VEGF and Gynecologic Cancers
 Present in most gynecologic cancers
 Higher levels associated with:
Ovarian
Higher stage
Presence of
ascites
Distant
metastasis
Decreased
survival
Uterine
Higher grade
Greater
depth of
myometrial
invasion
LVSI
Nodal
metastasis
Shorter DFS
Cervical
Higher
stage
LVSI
Paramet
rial
spread
Worse
DFS and
OS
Targeting Approaches for the VEGF
Pathway
Soluble VEGF receptors
(VEGF-Trap)
VEGF
VEGF
Anti-VEGF
antibody
(Bevacizumab)
AntiVEGFR
antibodies
Ribozymes
VEGFR
SiRNA
Small
molecule
inhibitors
Progression-Free Survival.
GOG0170D: Bevacizumab Phase II
1.0
GOG0170-D
AVASTIN (n = 62)
PFS @ 6 m = 0.42
0.8
0.6
GOG0126 Series (n = 220)
Platinum-Resistant Disease
PFS @ 6 m = 0.16 ( SE 0.025)
0.4
0.2
0.0
0
6
12
18
Months on Study
Burger et al., Proc Ann Meet ASCO 24:A5009
Ovarian cancer
Multiple molecular drivers
Ovarian cancer
Multiple molecular drivers
‘Dirty’ drugs are good drugs
Enzastaurin – A Serine/Threonine Kinase Inhibitor
Growth factor
e.g. VEGF
Cell membrane
P
Receptor e.g. FLT1/KDR
(endothelial cells)
P
P
PI3K
PTEN
(tumor cells)
PLC
ENZASTAURIN
PDK1
P
PKC
X
P
Cytoplasm
AKT
X
X
X
P
GSK3
P
P70S6K
X
P = phosphate
X
X
Cell Proliferation
Cell Motility
Angiogenesis
Nucleus
Adapted from Graff J, et al.
Cancer Res. 2005, 65:16
Many new drugs,
Exciting results expected.