2012 ALGORITHM FOR
MANAGEMENT OF ADVANCED
OVARIAN CANCER
Bradley J. Monk, MD, FACS, FACOG
Professor and Director
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Creighton University School of Medicine at
St. Joseph’s Hospital and Medical Center,
a Member of Catholic Healthcare West
Phoenix, Arizona USA
bradley.monk@chw.edu
Newly Diagnosed Advanced Ovarian Cancer
Ovarian Carcinoma: Incidence and Mortality
• Incidence in US women
– 21,880 cases in 2010
– Eighth most common cancer
– Second most common gynecologic cancer
– 1.5% lifetime risk of getting ovarian cancer
• Mortality in US women
– 14,850 deaths in 2010
– Fifth most common cause of cancer death
– Most common cause of death due to gynecologic
cancer
– 1.0% lifetime risk of dying of ovarian cancer
ACS. Available at: http://www.cancer.org/
Cancer in the United Sates of America
ACS. Available at: http://www.cancer.org/
First-line Therapy Global Standard Treatment
Surgery with maximum
cytoreduction effort
IV Platinum + Taxane Chemotherapy
(Carboplatin + Paclitaxel) x 6
2004 Consensus Statements on the Management of Ovarian Cancer:
Final Document of the 3rd International GCIG Ovarian Cancer Consensus Conference (GCIG OCCC 2004).
Annals Of Oncology 16 (Supplement 8) Viii7–viii12, 2005
Basis for Current Standard:
Systemic Therapy
• Studies showing paclitaxel/cisplatin superior to
cyclophosphamide/cisplatin
– GOG Protocol 111[1]
– EORTC-NCIC OV 10[2]
• Studies showing paclitaxel/carboplatin at least
equivalent to paclitaxel/cisplatin in efficacy
– AGO Trial[3]
– GOG Protocol 158[4]
1. McGuire WP, et al. N Eng J Med .1996;334:1-6.
2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92:699-708.
3. DuBois A, et al. J Natl Cancer Inst. 2003;95:1320-1329.
4. Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200.
First-line Therapy: Acceptable but Uncommon
1.
2.
3.
4.
5.
6.
Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal Chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after
complete remission
First-line Therapy: Acceptable but Uncommon
1.
2.
3.
4.
5.
6.
Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal Chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after
complete remission
IGCS Meeting October 25th 2009 Bangkok
N Engl J Med. 2010 Sep 2;363(10):943-53
RANDOMISED TRIAL COMPARING
PRIMARY DEBULKING SURGERY (PDS) WITH
NEOADJUVANT CHEMOTHERAPY (NACT)
FOLLOWED BY INTERVAL DEBULKING (IDS) IN
STAGE IIIC-IV OVARIAN, FALLOPIAN TUBE
AND PERITONEAL CANCER.
RANDOMISED EORTC-GCG/NCIC-CTG TRIAL ON
NACT + IDS VERSUS PDS
Ovarian, tubal or peritonal cancer
FIGO stage IIIc-IV (n = 718)
Randomization
Primary Debulking
Surgery
3 x Platinum based CT
Interval debulking
(not obligatory)
> 3 x Platinum based CT
Neoadjuvant
chemotherapy
3 x Platinum based CT
Interval debulking if no PD
> 3 x Platinum based CT
Primary Endpoint: Overall survival
Secondary endpoints: Progression Free Survival, Quality of Life, Complications
NACT + IDS versus PDS: ITT
Overall survival
100
90
80
Median survial
70
PDS: 29 months
60
IDS: 30 months
50
40
HR for IDS:0.98 (0.85, 1.14)
30
20
10
0
(years)
0
O N
259 361
251 357
2
4
Number of patients at risk :
183
68
191
56
6
16
11
8
2
1
10
Treatment
Upfront debulking surger
Neoadjuvant chemothera
First-line Therapy: Acceptable but Uncommon
1.
2.
3.
4.
5.
6.
Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal Chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after
complete remission
Role of IP Chemotherapy for Optimally Debulked
Advanced-Stage Ovarian Cancer
GOG
1041
Improved outcome in
CP-treated patients when
cisplatin administered IP
(relative risk, 0.76)
GOG
1142
Improved outcome in
TP-treated patients when
cisplatin administered IP
(relative risk, 0.78)
GOG
1723
Improved outcome in
TP-treated patients when
paclitaxel and cisplatin
administered IP
(relative risk, 0.73)
CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin.
1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955.
2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007.
3. Armstrong DK et al. N Engl J Med. 2006;354:34-43.
Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/
41495.cfm. Accessed March 9, 2006.
GOG172: Ovarian (optimal III)
•
•
•
•
Epithelial Ovarian Cancer
Optimal Stage III
No prior therapy
Elective Second-Look
2
Cisplatin
75
mg/m
I
Paclitaxel 135 mg/m2 (24 h)
II
Open:
Closed:
Accrual:
Cisplatin 100 mg/m2 IP d1
Paclitaxel 135 mg/m2 (24 h) IV d1
Paclitaxel 60 mg/m2 IP d8
23-Mar-98
29-Jan-01
416 pts (evaluable)
Armstrong, et al. NEJM 354:34-43, 2006
GOG Protocol 172
Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03
By Treatment Group
1.0
0.9
IP median overall survival = 65.6 months
Proportion Surviving
0.8
0.7
0.6
0.5
IV median overall survival = 49.7 months
0.4
0.3
0.2
Rx Group
Rx Group
IV
IV
IP
IP
0.1
0.0
0
12
Lost to
Follow-up
5
11
Alive
93
117
24
Alive
Dead Total
210
78 117
93 88
205
Dead
Total
127
101
210
205
36
Months on Study
IV = Intravenous; IP = Intraperitoneal.
Adapted with permission from Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
48
60
GOG Protocol 172 Toxicity
IV, %
(N = 210)
IP, %
(N = 201)
G3/4
Leukopenia*
64
76
G3/4
Platelet
4
12
G3/4
GI*
24
46
G3/4
Renal*
2
7
G3/4
Neurologic Event*
9
19
G3/4
Fatigue*
4
18
G3/4
Infection*
6
16
G3/4
Metabolic*
7
27
G3/4
Pain*
1
11
*P ≤ 0.05
No difference in QOL at 12 months
IV = Intravenous; IP = Intraperitoneal; GI = Gastrointestinal; QOL = Quality of life.
Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
GOG 252:
Stage II/III Disease: Small Volume Residual
•
•
•
Epithelial Ovarian Cancer
Optimal Stage III
No prior therapy
Carboplatin AUC=6 (IV)
I
Paclitaxel 80 mg/m2 (d1, 8, 15 3h)
Bevacizumab (C2+ C22) x 21 days
II
• Phase III
• PFS primary endpoint
Open: 27 Jul 2009
Closed: 30 Nov 2011
Accrual: 1100
Study Chair: J Walker
III
Carboplatin AUC=6 (IP)
Paclitaxel 80 mg/m2 (d1, 8, 15 3h)
Bevacizumab (C2+ C22) x 21 days
Cisplatin 75 mg/m2 (IP d2)
Paclitaxel 135 mg/m2 (d1, 3h)
Paclitaxel 60 mg/m2 (d8, IP)
Bevacizumab (C2+ C22) x 21 days
ClinicalTrials.gov Identifier: NCT00951496
First-line Therapy: Acceptable but Uncommon
1.
2.
3.
4.
5.
6.
Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal Chemotherapy
Weekly dosing
Docetaxel instead of paclitaxel
Maintenance or consolidation chemotherapy after
complete remission
JGOG: Dose-Dense Weekly Paclitaxel
•
•
•
•
•
•
•
•
Epithelial Ovarian or Peritoneal
Stage II - IV
No prior therapy
Stratfied: residual disease,
stage, and histology
Primary endpoint: PFS
Secondary endpoint: OS
I
II
Paclitaxel 180 mg/m2
Carbolatin AUC = 6
x6-9
Carbolatin AUC = 6
x6-9
2
Paclitaxel 80 mg/m /w x3
Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer
patients completed all protocol therapy
Improved PFS with dose-dense weekly paclitaxel
Accrual: 637 pts (intent-to-treat)
Isonishi S, et al. J Clin Oncol. 2008; 26:A5506.
JGOG: Dose-Dense Weekly Paclitaxel
Katsumata N et al Lancet. 2009 Oct 17;374(9698):1331-8.
GOG 262:
Stage III/IV Disease: Large Volume Residual
R
A
N
D
O
M
I
Z
E
Paclitaxel 80 mg/m2 IV every week +
Carboplatin AUC 6 IV every 3 weeks x 6 cycles
with optional Bevacizumab 15 mg/kg IV starting
with cycle 2 until disease progression
Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6
IV every 3 weeks x 6 cycles with optional
Bevacizumab 15 mg/kg IV starting with cycle 2
until disease progression
N = 625
Primary Endpoint = Progression free survival
Activated: Sep 27 2010
Study Chair: J Chan
ClinicalTrials.gov Identifier: NCT01167712
First-line Therapy: Acceptable but Uncommon
1.
2.
3.
4.
5.
6.
Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal Chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after
complete remission
23
Phase III Trial of Bevacizumab in the Primary
Treatment of Advanced Epithelial Ovarian,
Primary Peritoneal, or Fallopian Tube Cancer:
A Gynecologic Oncology Group (GOG) Study
R.A. Burger,1 M.F. Brady,2 M.A. Bookman,3
J.L. Walker,4 H.D. Homesley,5 J. Fowler,6
B.J. Monk,7 B.E. Greer,8 M. Boente,9 S.X. Liang10
1Fox
Chase Cancer Center, Philadelphia, PA; 2Gynecologic Oncology Group
Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY;
3University of Arizona Cancer Center, Tucson, AZ; 4University of Oklahoma
Health Sciences Center, Oklahoma City, OK; 5Brody School of Medicine,
Greenville, NC; 6James Cancer Hospital at the Ohio State University, Hilliard,
OH; 7University of California, Irvine Medical Center, Orange, CA; 8Seattle Cancer
Care Alliance, Seattle, WA; 9Minnesota Oncology and Hematology, Minneapolis,
MN; 10State University of New York at Stony Brook, Stony Brook, NY, USA
J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1)
N Engl J Med. 2011 Dec 29;365(26):2473-83.
GOG-0218: Schema
Arm
Carboplatin (C) AUC 6
Front-line:
Epithelial OV, PP
or FT cancer
• Stage III optimal
(macroscopic)
• Stage III
suboptimal
• Stage IV
n=1800 (planned)
Paclitaxel (P) 175 mg/m2
R
A
N
D
O
M
I
Z
E
I
Placebo
Carboplatin (C) AUC 6
1:1:1
Paclitaxel (P) 175 mg/m2
BEV 15 mg/kg
II
Placebo
Carboplatin (C) AUC 6
Stratification variables:
• GOG performance status
(PS)
• Stage/debulking status
Paclitaxel (P) 175 mg/m2
III
BEV 15 mg/kg
Cytotoxic
(6 cycles)
Maintenance
(16 cycles)
15 months
GOG-0218: Investigator-Assessed PFS
Proportion surviving progression free
1.0
0.9
Patients with event, n (%)
0.8
Median PFS, months
0.7
Arm I
CP
(n=625)
Arm II
CP + BEV
(n=625)
Arm III
CP + BEV  BEV
(n=623)
423
(67.7)
418
(66.9)
360
(57.8)
10.3
11.2
14.1
0.908
(0.759–1.040)
0.717
(0.625–0.824)
0.080*
<0.0001*
Stratified analysis HR
(95% CI)
0.6
One-sided p-value (log rank)
0.5
0.4
0.3
0.2
CP (Arm I)
+ BEV (Arm II)
0.1
+ BEV → BEV maintenance (Arm III)
0
0
12
24
Months since randomization
36
*p-value boundary = 0.0116
GOG-0218: Subgroup Analyses of PFS
CP + BEV  BEV (Arm III) vs CP (Arm I)
Hazard ratio
Stage 3 optimal (n=434)
0.618
Stage 3 suboptimal (n=496)
0.763
Stage 4 (n=318)
0.698
PS 0 (n=616)
0.710
PS 1/2 (n=632)
0.690
Age <60 years (n=629)
0.680
Age 60–69 years (n=409)
0.763
Age 70 years (n=210)
0.678
Experimental arm
(CP + BEV  BEV;
Arm III) better
0.33
0.5 0.67
Control arm
(CP; Arm I) better
1.0
1.5
Treatment hazard ratio
2.0
3.0
27
ICON7: a phase III Gynaecologic Cancer
InterGroup (GCIG) trial of adding bevacizumab
to standard chemotherapy in women with newly
diagnosed epithelial ovarian, primary peritoneal
or fallopian tube cancer
Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan
Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey,
Philip Beale, Andreas Cervantes, Amit Oza
on behalf of GCIG ICON7 collaborators
(MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG,
GEICO, NCIC-CTG)
ESMO
2010N Engl J Med. 2011 Dec 29;365(26):2484-96.
ICON7: Study Design
Carboplatin AUC 6*
Front-line EOC,
PP or FT cancer
Paclitaxel 175 mg/m2
• Stage I-IIA (Gr 3
or CC)
• Stage IIB/C
• Stage III
• Stage IV
Carboplatin AUC 6*
n=1528
Primary endpoints:
PFS
Secondary
endpoints: OS, RR,
safety, QOL,
cost-effectiveness,
translational
No IRC present
Paclitaxel 175 mg/m2
Stratification variables:
• Stage/surgery
• Time since surgery
• GCIG group
**
Bevacizumab
7.5 mg/kg
AVASTIN
12 months
*Might vary based on GCIG group
**Omit cycle 1 bevacizumab if <4 weeks from surgery
Perren, et al. ESMO 2010
ICON 7 PFS Benefit: Academic Analysis
CP
CPB7.5+
392 (51)
367 (48)
17.3
19.0
Proportion alive without progression
1.00
Events, n (%)
Median, months
0.75
Log-rank test
p=0.0041
HR (95% CI)
0.81 (0.70–0.94)
0.50
0.25
CP
CPB7.5+
17.3
19.0
0
0
3
6
9
12
15
18
21
24
27
30
216
263
143
144
91
50
25
73
36
19
Perren, et al. ESMO 2010
Time (months)
Number at risk
CP
764
CPB7.5+
764
723
748
693
715
556
647
464
585
307
399
ICON 7 Subgroups
Origin of cancer
Age
No. of events/no. of patients
Research
Control
HR
<60
202/449
210/450
0.84
60–69
134/242
142/237
0.76
31/73
40/77
0.82
0
154/334
145/358
1.01
1
175/366
210/354
0.66
2
27/45
31/43
0.78
274/525
278/529
0.85
Mucinous
12/19
10/15
0.77
Endometroid
26/60
25/57
0.81
Clear cell
22/67
22/60
0.90
I
6/54
9/65
0.73
II
14/83
19/80
0.72
III
277/523
290/522
0.79
IV
70/104
74/97
0.69
Residual
disease
Optimal (≤1 cm)
226/559
233/552
0.87
Suboptimal (>1cm)
131/192
145/195
0.68
Grade
Grade 1
10/41
16/56
0.76
Grade 2
86/175
77/142
0.77
Grade 3
267/538
294/556
0.81
≥70
ECOG PS
Histology
FIGO
Serous
Age: Trend p=0.69, interaction p=0.83; ECOG: Trend p=0.027, interaction p=0.022
Histology: Interaction test p=0.085; FIGO: Trend p=0.71, interaction p=0.91
Residual disease: Trend p=0.10; Grade: Trend p=0.76, interaction p=0.95
Hazard ratio (fixed)
0
0.5
CPB7.5+ better
1
1.5
CP better
Perren, et al. ESMO 2010
2
First-line Therapy: Acceptable but Uncommon
1.
2.
3.
4.
5.
6.
Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal Chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after
complete remission
GOG 178—Investigating Paclitaxel as
Consolidation
R
A
277 stage III/IV
N
patients in complete D
clinical remission
O
M
I
Z
E
Paclitaxel 175 mg/m2
every 28 days × 3 months
Paclitaxel 175 mg/m2
every 28 days × 12 months
CR = Complete response.
Markman M, et al. J Clin Oncol. 2003;21:2460-2465.
GOG 178
Progression-free survival
100
Percentage
80
P = .0023
60
40
20
0
Paclitaxel 12 courses
Paclitaxel 3 courses
0
12
At risk Failed
110
20
112
34
24
36
Months after registration
Markman M, et al. J Clin Oncol. 2003;21:2460-2465.
Median,
months
28
21
48
GOG-0212
Phase III Maintenance Therapy Trial
Macromolecular complex
of paclitaxel poliglumex
Patients with stage III/IV
epithelial ovarian or primary
peritoneal cancer, GOG PS ≤
2, and complete response
after surgery plus taxane and
carboplatin
(Planned N = 1400-1550)
Primary endpoint: survival
Secondary endpoints: PFS, toxicity, QoL
www.clinicaltrials.gov/ct2/show/NCT00108745.
Paclitaxel
Every 28 days for up to 12 courses
Paclitaxel poliglumex
Every 28 days for up to 12 courses
No treatment
Recurrent Disease
CHEMOTHERPAY
When Does Advanced Ovarian Cancer Recur?
Population
Optimal Stage 3
Suboptimal 3 & 4
All Stage 3 & 4
Study
Treatment
PFS
GOG 114
IV Carb & Pac, IP Cis
28 mos
GOG 172
IV Pac, IP Cis & Pac
24 mos
GOG 158
IV Pac & Carb
21 mos
GOG 114
IV Pac & Cis
22 mos
GOG 158
IV Pac & Cis
19 mos
GOG 172
IV Pac & Cis
18 mos
GOG 111
IV Pac & Cis
18 mos
GOG 162
IV Pac Cis
12 mos
GOG 152
IV Pac Cis
11 mos
GOG 182
IV Pac/Carbo x 8
16 mos
Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; GOG = Gynecologic Oncology
Group; IP = intraperitoneal; Pac = paclitaxel.
Treatment Considerations and Goals:
Recurrent Ovarian Cancer
• Treatment considerations in the management of
recurrent ovarian cancer
–
–
–
–
Disease-free interval
Existing toxicities remaining due to the 1st-line therapy
Volume of disease at the time of relapse
Serologic relapse (CA-125)
• Primary goals of therapy for the treatment of recurrent
ovarian cancer
–
–
–
–
–
Progression-free survival (PFS)
Increased survival
Prevention of symptoms
Palliation of symptoms
Quality of life (QoL)
Ovarian Cancer
Treatment Considerations
Recurrent Disease
First-Line Treatment
Cure
Goal
Palliation
High
Toxicity
Acceptance
Low
Less Important
Convenience
More Important
The Traditional Treatment Paradigm
Recurrence After First-line Chemotherapy
Platinum
Refractory/Resistant
Platinum
Sensitive
< 6 Months
> 6 Months
Non-Platinum
Single Agent
Chemotherapy
Doublet
FDA-Approved Drugs in Ovarian
Cancer
OCEANS
Carboplatin AUC 4
Platinumsensitive,
recurrent
OC, PP, FTC
No prior
bevacizumab
n=480
Gemcitabine 1000 mg/m2
d1/8
Placebo to progression
Carboplatin AUC 4
Gemcitabine 1000 mg/m2
d1/8
Bevacizumab 15 mg/kg to progression
Primary endpoint:
PFS
Secondary
endpoints:
ORR, OS, DR, safety
Exploratory
endpoints:
IRC, CA 125
response, ascites
IRC present
Stratification variables:
• Time to recurrence
• Cytoreductive surgery
ClinicalTrials.gov Identifier: NCT00434642
OCEANS: Primary analysis of PFS
Proportion progression free
1.0
0.8
CG + PL
(n=242)
CG + BV
(n=242)
Events, n (%)
187 (77)
151 (62)
Median PFS,
months (95% CI)
8.4
(8.3–9.7)
12.4
(11.4–12.7)
Stratified analysis
HR (95% CI)
Log-rank p-value
0.6
0.484
(0.388–0.605)
<0.0001
0.4
0.2
0
0
No. at risk
CG + PL
CG + BV
6
12
18
24
30
11
33
3
11
0
0
Months
242
242
177
203
45
92
ASCO 2011
OCEANS: Objective Response
%
Difference: 21.1%
p<0.0001
100
78.5
80
60
57.4
40
PR = 48
PR = 61
Duration of response
Median, months
HR (95% CI)
20
0
CG + PL
(n=139)
CG + BV
(n=190)
7.4
10.4
0.534
(0.408–0.698)
p<0.0001a
CR = 9
CG + PL
(n=242)
CR = 17
aCompared
for descriptive purposes only
CG + BV
(n=242)
ASCO 2011
OCEANS: Interim OS
1.0
Proportion alive
0.8
0.6
Events, n (%)
0.4
Median OS,
months (95% CI)
0.2
Stratified analysis
HR (95% CI)
Log-rank p-value
CG + PL
(n=242)
CG + BV
(n=242)
78 (32)
63 (26)
29.9
(26.4–NE)
35.5
(30.0–NE)
0.751
(0.537–1.052)
0.094a
0
No. at risk:
CG + PL
CG + BV
0
6
12
18
Months
24
30
36
42
242
242
235
238
195
200
131
146
77
82
26
42
8
8
0
0
NE = not estimable
ap-value does not cross pre-specified boundary of 0.001
ASCO 2011
Summary and Looking Towards the Future
Unanswered Questions Regarding Bevacizumab in Ovarian
Cancer
1.
2.
3.
4.
5.
6.
7.
Best clinical setting (frontline vs recurrence)
Single agent or combination
Dose
Duration
Continuation beyond progression
Cost effectiveness
Impact on patient reported outcomes (PRO or QOL)
• Other agents that effect angiogenesis and the tumor
vasculature active and in late stage development
NCCN “ Preferred” Agents in
“Platinum Resistant” Ovarian Cancer
Level IIA
•
•
•
•
•
•
•
Docetaxel
Etoposide, oral
Gemcitabine
PLD
Weekly paclitaxel
Topotecan
Bevacizumab
National Comprehensive Cancer Network (NCCN)
www.nccn.org
Summary and Conclusions
• Advanced ovarian cancer is very lethal despite
many active medicines
• IV carboplatin and paclitaxel standard adjuvant
front-line therapy
• Little survival benefit in recurrent setting
• No approved targeted agent
• No agent approved since 2006
2012:Phase III Registration Studies
in Ovarian Cancer*
Front-line added to chemotherapy then as Maintenance
1.
2.
BIBF 1120 (OVAR 12)
AMG 386 (with Carboplatin or Paclitaxel)
Maintenance alone
1.
2.
Polyglutamate paclitaxel (GOG 212)
Pazopanib (OVAR 16)
Platinum-resistant recurrent ovarian cancer
1.
2.
3.
4.
Karenitecin
Bevacizumab (with chemotherapy - AURELIA)
AMG 386 (with PLD or Paclitaxel)
EC-145 (with PLD)
Platinum-sensitive recurrent ovarian cancer
1.
2.
3.
4.
5.
Bevacizumab (with chemotherapy - OCEANS, GOG 213)
Trabectedin (with PLD)
Cediranib (with chemotherapy - ICON7)
Farletuzumab (with Carboplatin or Paclitaxel)
Water soluble formulation of Paclitaxel
*Phase II studies of PARP inhibitors, NKTR-102 and
XL-184 may lead to FDA approval
PLD = Pegylated Liposomal Doxorubicin
Farletuzumab (MORAb-003): Phase II
Platinum Resistant Patients
•
•
•
•
•
Histologically or cytologically
confirmed non-mucinous
epithelial ovarian cancer
including primary peritoneal or
fallopian tube malignancies
Measurable disease by CT or
MRI scan
Relapse within < 6 months after
first-line platinum/taxane
chemotherapy
Up to 4 prior lines of therapy
Neurologic function: neuropathy
(sensory and motor) ≤CTCAE
Grade 1
R
A
N
D
O
M
I
Z
E
Weekly paclitaxel (80mg/m2) x 12
then 3 out of 4 weeks
with placebo (N=183)
Weekly paclitaxel (80mg/m2) x 12
then 3 out of 4 weeks
with placebo MORAb-003 2.5 mg/kg
(N=367)
Co-Primary Endpoints = Progression-free survival and Overall survival
N = 550
ClinicalTrials.gov Identifier: NCT00738699 (FAR122)
Farletuzumab (MORAb-003): Phase II
Platinum Resistant Patients
• November 28, 2011
– Study stopped by IDMC for futility
– 40% of OS events = 161 deaths
– HR boundaries PFS > 0.9 and OS > 1.00
– Corresponding conditional power < 1% and
one sided P value was > 0.1985 for PFS and
> 0.5000 for OS
– No new safety issues identified
Folate Linked Imaging Agent and Drugs
Imaging
EC20 imaging agent
Agent
Cleavable
Bond
Folate
EC145 therapeutic
Spacer
Desacetylvinblastine
PRECEDENT – A Randomized Phase II Trial of PLD ±
EC145 in Platinum-Resistant Ovarian Cancer (EC-FV-04)
2:1 Randomization
Recurrent EOC
1st or 2nd Relapse
< 6 mo platinum based
therapy
R
A
N
D
N = 149
O
M
I
Z
E
PLD 50 mg/m2
1° Endpoint
PFS
HR 0.68 at 95 events
2° Endpoint
ORR and OS
Correlate EC 20 scan and response
PLD 50 mg/m2 q 28 days
EC145 2.5 mg/m2 q MWF every other wk
Optional
EC20 Scan
n = 94
Naumann RW, et al. ASCO 2011. Abstract 5045.
PLD= Pegylated liposomal doxorubicin
PRECEDENT Trial
Final PFS Results
Probability of Progression-Free Survival
Progression-Free Survival
EC145 + PLD
Median PFS
Hazard Ratio (2-sided P value)
EC145/PLD
PLD
n = 100
n = 49
21.7 weeks
11.7 weeks
0.626 (P = 0.031)
+ Censored
PLD Alone
Weeks From Randomization Date
PLD= Pegylated liposomal doxorubicin
Naumann RW, et al. ASCO 2011. Abstract 5045.
PRECEDENT Trial
Preliminary Survival Results
Median Follow-up
Note: OS data are expected
to mature late 2011. Current
median follow-up: 25.6 wks
Censoring rate: > 60%
EC145 + PLD
PLD Alone
Overall Survival
Hazard Ratio (2-sided P value)
6-month survival rate
EC145+PLD
PLD Alone
n = 100
n = 49
0.879 (P = 0.680)
80.8%
71.8%
PLD= Pegylated liposomal doxorubicin
Naumann RW, et al. ASCO 2011. Abstract 5045.
Disappointing Mature Overall Survival (OS)
Press Release - Dec 13, 2011
• The median OS in the EC145 study arm = 14.1 months
• The median OS in the PLD control = 16.9 months
• HR = 1.099 intent-to-treat
http://www.endocyte.com/wp-content/uploads/2011/04/2011.12.13_EU-Supplemental-Analysis.pdf
Study for Women With Platinum
Resistant Ovarian Cancer Evaluating
EC145 in Combination With Doxil®
(PROCEED)
•
•
•
Primary or secondary
platinum-resistant
ovarian cancer.
Measurable disease
(RECIST v1.1-defined)
Prior platinum-based
chemotherapy for
management of
primary regimens
R
A
N
D
O
M
I
Z
E
Estimated Enrollment: 500
Study Start Date: September 2010
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: August 2012
Primary Endpoint: PFS
Secondary Endpoints: OS, toxicity
• EC145 IV days 1,3,5 and
15,17,19 of a 4-week cycle
• PLD 50 mg/m2 (IBW) every
4 weeks.
• Placebo IV days 1,3,5 and
15,17,19 of a 4-week cycle
• PLD 50 mg/m2 (IBW) every
4 weeks.
PLD= Pegylated liposomal doxorubicin
ClinicalTrials.gov Identifier: NCT01170650
ESMO 2010
Phase II study of the oral PARP inhibitor olaparib (AZD2281) versus
liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or
BRCA2 mutations
Stan Kaye,1 Bella Kaufman,2 Jan Lubinski,3
Ursula Matulonis,4 Charlie Gourley,5 Beth Karlan,6
Dianna Taylor,7 Mark Wickens,7 James Carmichael7
1. Royal Marsden Hospital, Sutton, Surrey, UK
2. Chaim Sheba Medical Center, Tel Hashomer, Israel
3. Pomeranian Medical University, Szczecin, Poland
4. Dana-Farber Cancer Institute, Boston, MA, USA
5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK
6. Cedars-Sinai Medical Center, Los Angeles, CA, USA
7. AstraZeneca, Alderley Park, Macclesfield, UK
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710.
Clinicaltrials.gov number, NCT00628251
Study Design
Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib
(200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD)
Olaparib
200 mg bid in
28-day cycles
BRCA1/2 germline
carriers with Ovarian Ca
Progressive or recurrent
disease < 12 months
after previous platinumbased chemotherapy
Randomized
1:1:1
Olaparib
400 mg bid in
28-day cycles
mg/m2
PLD 50
IV
every 4 weeks
Stats: HR 0.55 (median PFS of 4 to 7.3 mos)
N planned: 90 (30/arm)
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710.
PD or withdrawal
from treatment for
other reason
As above or max
lifetime cumulative
dose reached
Patients in PLD group were allowed to cross over
to
olaparib 400 mg bid on confirmed PD
J Clin Oncol. 2011 Dec 27. [Epub ahead of print]
Proportion of Patients Progression Free
Progression-Free Survival
1.0
Median PFS (80% CI)
0.9
Olaparib 200 mg:
Olaparib 400 mg:
6.5 (5.6-8.0) months
8.8 (6.3-9.2) months
0.8
PLD 50 mg/m2:
7.1 (5.5-7.8) months
0.7
Olaparib 200 mg
Olaparib 400 mg
0.6
PLD
0.5
Stats: HR 0.55 (median PFS of 4 to 7.3 mos)
N planned: 90 (30/arm)
0.4
0.3
HR* vs PLD (80% CI)
Olaparib 200 mg: 0.91 (0.60-1.39); P = 0.78
0.2
Olaparib 400 mg: 0.86 (0.56-1.30); P = 0.63
0.1
Olaparib 200 mg + 400 mg: 0.88 (0.62-1.28); P = 0.66
0
0
2
4
6
8
Time From Randomization (months)
10
12
Number of patients at risk:
Olaparib 200 mg
Olaparib 400 mg
PLD
32
32
33
24
28
25
21
21
18
13
17
15
8
12
8
3
1
3
*HR < 1 favors olaparib.
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710.
J Clin Oncol. 2011 Dec 27. [Epub ahead of print]
0
0
0
Phase II randomized placebo-controlled
study of olaparib (AZD2281) in patients
with platinum-sensitive relapsed
serous ovarian cancer
Jonathan A. Ledermann
J Clin Oncol 29: 2011 (suppl; abstr 5003)
Maintenance Olaparib:
Study design
Patients
•Platinum-sensitive high-grade
serous ovarian cancer
•≥2 previous platinum
regimens
•Maintained PR or CR
following last platinum regimen
Olaparib
400mg bid,
orally
(n=136)
Randomized 1:1
Placebo
(n=129)
Primary endpoint
PFS by RECIST
Secondary
endpoints
TTP by CA-125
(GCIG criteria) or
RECIST, OS,
safety
82 sites in 16 countries
Ledermann
J Clin
Oncol
2011;29
(suppl; abstr
5003)
Lederman
J et aletJal.
Clin
Oncol
29:
2011 (suppl;
abstr
5003
Progression-free survival
Proportion of patients
progression free
Olaparib
Placebo
1.0
No. of events: Total patients (%) 60:136 (44.1) 93:129 (72.1)
0.9
Median PFS (months)
4.8
8.4
0.8
Hazard ratio 0.35 (95% CI, 0.25–0.49)
P<0.00001
0.7
0.6
0.5
0.4
0.3
0.2
Randomized treatment
Placebo
Olaparib 400 mg bid
0.1
0
0
3
9
12
15
18
Time from randomization (months)
At risk (n)
Olaparib 136
Placebo 129
6
104
51
23
6
0
0
72
23
7
1
0
0
Lederman J et al J Clin Oncol 29: 2011 (suppl; abstr 5003)
Olaparib:
Another PARP Inhibitor Abandoned in
Ovarian Cancer
Press Release - Dec 20, 2011
• The previously reported progression free survival benefit
is unlikely to translate into an overall survival benefit, the
definitive measure of patient benefit in ovarian cancer
• Attempts to identify a suitable tablet dose for use in
Phase III studies have not been successful.
http://www.astrazeneca.com/Media/Press-releases/Article/20111220-az-updates-olaparib-TC5214-development
Thank You
Bradley.monk@chw.edu