Clinical Conundrums: Choosing
the Best Management Approaches
in Patients With Ovarian Cancer
Thomas J. Herzog, MD
Director, Division of Gynecologic
Oncology
Columbia University College of
Physicians and Surgeons
New York, New York
This program is supported by an educational grant from
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Controversies in the Treatment
of Newly Diagnosed Ovarian
Cancer
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Ovarian Cancer: Initial Chemotherapy
 Standard frontline chemotherapy is paclitaxel 175 mg/m2
plus carboplatin AUC 6-7, every 21 days for 6 cycles
 Result of several studies over last decade
– GOG 111[1] and OV 10[2]: paclitaxel/cisplatin vs
cyclophosphamide/cisplatin
– GOG 158[3] and AGO OVAR-3[4]: carboplatin instead of
cisplatin
1. McGuire WP, et al. N Engl J Med. 1996;334:1-6. 2. Piccart MJ, et al. J Natl Cancer Inst.
2000;92:699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21:3194-3200. 4. du Bois AD, et al.
J Natl Cancer Inst. 2003;95:1320-1329.
What About Alternative
Taxane Therapy?
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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SCOTROC: Clinical Response*
Outcome, %
Paclitaxel/Carboplatin
(n = 296)
Docetaxel/Carboplatin
(n = 300)
CR
28
28
PR
31
30
ORR
59
59
NC
27
29
PD
10
9
Missing/not evaluable
4
4
*Similar results for patients with CA-125 elevation only.
Vasey P, et.al. J Natl Cancer Inst. 2004;96:1682-1691.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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SCOTROC: Toxicity
Adverse Event, %
Paclitaxel/
Carboplatin
Docetaxel/
Carboplatin
P Value
 Neutropenia
84
94
< .001
 Thrombocytopenia
10
9
.595
 Anemia
8
11
.112
Platelets
11
10
.27
Neuropathy (grades 2-4)
30
11
< .001
Hematologic toxicity (grades 3-4 )
Vasey P, et.al. J Natl Cancer Inst. 2004;96:1682-1691.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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JGOG: Dose-Dense Wkly Paclitaxel in
Stage II-IV
I
Carboplatin AUC 6
Paclitaxel 180 mg/m2 wk x 3
x 6-9
II
Carboplatin AUC 6
Paclitaxel 80 mg/m2 wk x 3
x 6-9
R
Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer
patients completed all protocol therapy
Accrual: 637 patients (631 intent to treat)
Katsumata N, et al. Lancet. 2009;374:1331-1338.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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JGOG: Dose-Dense Wkly Paclitaxel
Treatment Arm
n
Median PFS
(mos)
Carboplatin AUC 6
Paclitaxel 180 mg/m2 3 x wkly
319
17.2
Carboplatin AUC 6
Paclitaxel 80 mg/m2/wk x 3
312
28.0
P Value
.015 (HR: 0.714
(95% CI: 0.5810.879)
 OS at 3 yrs: wkly (72.1%) > 3 wkly (65.1%); HR: 0.75
(95% CI: 0.57-0.98; P = .03)
Katsumata N, et al. Lancet. 2009;374:1331-1338.
Will Adding a Third Drug Help?
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG0182: Pac/Carbo vs Triplet or
Sequential Doublet Combinations (Ph III)
 Paclitaxel/carboplatin x 8 (control)
 Paclitaxel/carboplatin/gemcitabine x 8
 Paclitaxel/carboplatin/PLD (4) x 8
 Topotecan/carboplatin x 4  paclitaxel/carboplatin x 4
 Gemcitabine/carboplatin x 4  paclitaxel/carboplatin x 4
Closed to accrual September 1, 2004
Bookman MA, et al. J Clin Oncol. 2009;27:1419-1425.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Proportion of Patients
Achieving PFS
GOG0182-ICON5: PFS
Events
Treatment Cancer Prog Total
864
178
686
CP
864
177
687
CPG
862
199
663
CPD
861
174
687
CT → CP
861
173
688
CG → CP
1.00
0.75
Adjusted HR
HR
(95% CI)
1.008 Reference Arm
1.006 (0.924-1.143)
0.984 (0.884-1.095)
1.066 (0.958-1.186)
1.037 (0.932-1.253)
0.50
0.25
0
0
12
24
36
48
Mos Since Randomization
60
72
Patients at risk, n
CP
864
565
284
174
27
80
CPG
864
579
275
153
27
68
CPD
862
574
277
162
32
63
CT → CP
861
547
259
154
27
67
CG → CP
861
563
255
153
23
78
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Bookman MA, et al. J Clin
Oncol. 2009;27:1419-1425.
P
.610
.796
.239
.503
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG0182-ICON5: Overall Survival
Treatment
CP
CPG
CPD
CT → CP
CG → CP
Proportion of Patients
Achieving OS
1.00
0.75
Events
Alive Dead Total
864
391
473
864
399
465
862
424
438
861
394
477
861
361
500
Adjusted HR
HR
(95% CI)
1.000 Reference arm
1.006 (0.895-1.144)
0.962 (0.836-1.085)
1.061 (0.925-1.194)
1.114
(0.982-1.264)
0.50
0.25
0
0
12
24
36
48
Mos Since Randomization
60
72
Patients at Risk, n
CP
864
780
625
426
72
203
CPG
864
780
622
424
70
214
CPD
862
762
592
425
80
209
CT → CP
861
778
593
423
73
200
CG → CP
861
773
589
395
66
203
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Bookman MA, et al. J Clin
Oncol. 2009;27:1419-1425.
P
.923
.462
.447
.093
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Other Recent 3-Drug Frontline Trials
Group(s)
Standard Arm
Experimental Arm (s)
N
Benefit
AGO/GINECO[1]
Paclitaxel/carboplatin (TC)
TC epirubicin
1282
NS
NSGO/EORTC
NCIC CTG[2]
Paclitaxel/carboplatin (TC)
TC epirubicin
888
NS
Bolis[3]
Paclitaxel/carboplatin (TC)
TC topotecan
326
NS
AGO/GINECO[4]
Paclitaxel/carboplatin (TC)
TC → topotecan
consolidation
1308
NS
AGO/GINECO
NSGO[5]
Paclitaxel/carboplatin (TC)
TC gemcitabine
1742
NS
NCIC CTG
EORTC/GEICO[6]
Paclitaxel/carboplatin (TC)
Cis topotecan → TC
819
NS
1. Du Bois A, et al. J Clin Oncol. 2006;24:1127-1135. 2. Kristensen G, et al. ASCO 2002. Abstract 805.
3. Scarfone G, et al. ASCO 2006. Abstract 5003. 4. Pfisterer J, et al. J Natl Cancer Inst. 2006;98:1036-1045.
5. Herrstedt J, et al. ASCO 2009. Abstract LBA5510. 6. Hoskins PJ, et al. ASCO 2008. Abstract LBA5505.
What About IP Therapy?
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Role of IP Chemotherapy: Optimally
Debulked Ovarian Cancer
GOG 104[1]
Improved outcome in CTX cisplatin-treated patients when
cisplatin given IP
(relative risk: 0.76)
GOG 114[2]
Improved outcome in patients when cisplatin administered IP
(relative risk: 0.78)
GOG 172[3]
Improved outcome in patients when paclitaxel and cisplatin
administered IP
(relative risk: 0.73)
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.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG 172: Survival
Outcome
IV
IP
RR
P Value
Median PFS, mos
18.3
23.8
0.80
.05
 Visible
15.4
18.3
0.81
 Micro
35.2
37.6
0.80
Median OS, mos
49.7
65.6
0.75
 Visible
39.1
52.6
0.77
 Micro
78.2
NA
0.69
.03
Copyright © 2006 Massachusetts Medical Society. All rights reserved. Armstrong DK, et al. N Engl J Med.
2006;354:34-43.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG 172: Survival
Outcome
IV
IP
RR
P Value
Median PFS, mos
18.3
23.8
0.80
.05
 Visible
15.4
18.3
0.81
 Micro
35.2
37.6
0.80
Median OS, mos
49.7
65.6
0.75
 Visible
39.1
52.6
0.77
 Micro
78.2
NA
0.69
.03
Copyright © 2006 Massachusetts Medical Society. All rights reserved. Armstrong DK, et al. N Engl J Med.
2006;354:34-43.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG 172: OS
1.0
Proportion Surviving
0.9
0.8
IP therapy
0.7
0.6
0.5
0.4
IV therapy
0.3
0.2
0.1
P = .03
0
0
6
12
18
24
30
36
42
48
54
60
Mos of Study
Copyright © 2006 Massachusetts Medical Society. All rights reserved. Armstrong DK, et al. N Engl J Med.
2006;354:34-43.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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IP Compared With IV Chemotherapy
Phase III Trials
25
PFS: % increase
OS: % increase
20
15
10
5
0
Alberts
GOG 104[1]
Markman
GOG 114[2]
Armstrong
GOG 172[3]
1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:10011007. 3. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
Will Adding a Targeted
Therapy Help?
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG 218
OvCa
III/IV
Subopt
PI: Burger RA
ClinicalTrials.gov. NCT00262847.
Paclitaxel 175 mg/m2/3 hrs
Carboplatin AUC 6
q21d x 6
Placebo Day 1 x 5
begin cycle 2
Placebo
q 21d
x 15 mos
Paclitaxel 175 mg/m2/3 hrs
Carboplatin AUC 6
q21d x 6
Bevacizumab* Day 1 x 5
begin cycle 2
Placebo
q 21d
x 15 mos
Paclitaxel 175 mg/m2/3 hrs
Carboplatin AUC 6
q21d x 6
Bevacizumab* Day 1 x 5
begin cycle 2
Bevacizumab*
q 21d
x 15 mos
*Bevacizumab 15 mg/kg IV
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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ICON 7 (Frontline European Trial)
Stages I-IV ovarian and peritoneal
cancer
R
A
N
– Stratified according to stage,
D
optimal status region or country O
M
I
Z
E
Accrual goal: 1444 patients
Primary endpoint: PFS
Other endpoints: OS (10 mos), RR, Toxicity
Carboplatin AUC 6 + Paclitaxel
175 mg/m2/3 hrs q21d x 6
Carboplatin AUC 6 + Paclitaxel
175 mg/m2/3 hrs q21d x 6 +
Bevacizumab at 7.5 mg/kg
followed by Bevacizumab 7.5 mg/kg
q21d x 12 mos
Translational Research
 Tissue and serum markers of angiogenesis
 Genomics
 DCE-MRI
 Quality of life
 Health economics
ClinicalTrials.gov. NCT00483782.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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First-line Maintenance (EORTC) With
Translational Substudy
Stage Ic to IV epithelial
ovarian cancer, having
achieved CR/PR/SD on
platinum-based chemo
(6-9 courses)
R
A
N
D
O
M
I
Z
E
N = 830
Endpoints: PFS and OS
Recruitment completed, study ongoing
ClinicalTrials.gov. NCT00263822.
Observation
Erlotinib 150 mg/day for
up to 2 yrs or until PD
Prognostic Factors in
Ovarian Cancer
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Age and Ovarian Cancer Outcome
Age, Yrs
Median PFS,
Mos
P Value
Median OS,
Mos
P Value
< 40
21.8
.03
60.1
< .001
40-50
17.8
47.9
50-59
17.5
47.7
60-69
16.8
44.5
≥ 70
15.8
36.6
Winter WE III, et al. J Clin Oncol. 2007;25:3621-3627.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Other Prognostic Factors: Debulking
Status
Disease Residual
Median PFS,
Mos
P Value
Median OS,
Mos
P Value
Microscopic
33.0
< .001
71.9
< .001
0.1-1 cm
16.8
42.4
> 1 cm
14.1
35.0
Winter WE III, et al. J Clin Oncol. 2007;25:3621-3627.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Other Prognostic Factors: Histology
Histology
Median PFS,
Mos
P Value
Median OS,
Mos
P Value
Serous
16.9
.006
45.1
< .001
Endometrioid
24.8
56.0
Clear cell
11.4
24.0
Mucinous
10.5
14.8
Winter WE III, et al. J Clin Oncol. 2007;25:3621-3627.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Elderly Patients: Prognostic Analysis
 Analysis of 2 consecutive trials from the Groupe d’Investigateurs Nationaux pour
l’Etude des Cancers Ovariens
Patient Characteristic
HR
95% CI
P Value
Age (continuous)
1.07
1.01-1.13
.013
Stage (IV vs III)
3.05
1.58-5.89
.001
Performance score (2-3 vs 0-1)
1.84
0.97-3.51
.064
Symptoms of depression
5.20
2.46-10.99
< .001
Paclitaxel-based chemotherapy
(CP vs CC combination)
2.14
1.10-4.15
.025
This table reports the prognostic factors of poorer survival identified in the
proportional hazards model (Cox Regression Model)
Trédan O, et al. Ann Oncol. 2007;18:256-262.
Does Having a BRCA Mutation
Affect Ovarian Cancer Prognosis?
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Ovarian Cancer Relapse: Effect of BRCA
Mutations
 Retrospective cohort study that
included 933 consecutive
ovarian cancers at a single
institution
 Mean age of diagnosis
significantly younger for BRCA1
vs BRCA 2 (54 vs 62 yrs, P =
.04)
 Patients restricted to women of
Jewish origin (N = 189)
 Median time to recurrence
higher in hereditary group vs
nonhereditary group (14 vs 7
mos, P < .001)
– 88 cases with evidence of
germline foundation
mutation in BRCA 1 or
BRCA2
– Remaining 101 cases
included in comparison
group
Boyd J, et al. JAMA. 2000;283:2260-2265.
 Improved survival in hereditary
group vs nonhereditary group
(P = .004)
 BRCA mutation status indep.
prognostic variable in stage III
disease (P = .03)
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Ovarian Cancer Survival: Effect of BRCA
Mutations
 71 Jewish women with epithelial
ovarian cancer tested for 3
BRCA founder mutations; 32
patients analyzed for in vitro
chemoresistance
 34 pts (48%) had germline
BRCA mutations
 Disease developed at a
younger age in pts with BRCA
mutation vs those without (50 vs
59 yrs, P = .001)
 Higher response rates to
primary therapy in pts with
BRCA mutations vs those
without (P = .001)
 In vitro chemoresistance
predicted tumor response to
platinum therapy in pts with
BRCA mutation (P = .001)
 Improved OS in pts with BRCA
mutation at advanced stage vs
those without (91 vs 54 mos, P
= .046)
 Longer DFI with BRCA mutation
(49 vs 19 mos, P .016)
Cass I, et al. Cancer. 2003;97:2187-2195.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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BRCA1 and BRCA2 Mutated Ovarian
Carcinomas
 BRCA1 and BRCA2 are critical proteins in DNA repair via
homologous recombination
 BRCA-associated cancers develop after a deletion or
mutation of the wild-type allele
 Normal nonmalignant cells retain the wild-type allele and
intact BRCA function
 Cells defective in BRCA1 or BRCA2 are more sensitive to
ionizing radiation and platinum compounds
 BRCA-deficient cells are dependent on an alternate,
PARP-dependent DNA repair pathway
Ongoing and Recently Completed
Clinical Trials in Ovarian Cancer
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG Phase I Trials: IP Carboplatin-Based
Regimens
Ovarian, peritoneal
or FT cancer
Stages II-III
Optimal not required
GOG 9917[1]
IV Paclitaxel 135 mg/m2/3 hrs on Day 1
IP Carboplatin (dose esc) on Day 1
q3wks x 6
Ovarian, peritoneal
or FT cancer
stages III-III
Optimal not required
Ovarian CS allowed
GOG 9916[2]
IV Paclitaxel 135 mg/m2/3 hrs on Day 1 or
IV Docetaxel 100 mg/m2/1 hr on Day 1
Followed by
IP Carboplatin (dose esc) on Day 1
IP Paclitaxel 60 mg/m2 on Day 8
q3wks x 6-8
Expanded cohorts with bevacizumab ongoing for both trials
1. ClinicalTrials.gov. NCT00079430. 2. ClinicalTrials.gov. NCT00085358.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Dana Farber/Inter-SPORE Treatment
Schema
IV
C Carboplatin AUC 6
IP
T Paclitaxel 60 mg/m2
Cycle 1
Cycle 2
Cycle 3
Bevacizumab 15 mg/kg
Cycle 4
Cycle 5
Cycle 6
P
O
R
T
Debulk
and
port
PK
Courtesy of C. Krasner
S
L
O
PK
PK
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG Ovarian Strategy: 252, 262
IV Paclitaxel 135 mg/m2 on Day 1
IP Cisplatin 75 mg/m2 on Day 2
IP Paclitaxel 60 mg/m2 on Day 8
IV Bevacizumab 15 mg/kg
252
Optimal
(≤ 1 cm residual)
262 (under
development)
Suboptimal
(> 1 cm residual)
ClinicalTrials.gov. NCT00951496.
Bevacizumab q 3 wk
Maintenance x 22
IV Paclitaxel 80 mg/m2 wkly
IP Carboplatin AUC 6
IV Bevacizumab 15 mg/kg
IV Paclitaxel 80 mg/m2 wkly
IV Carboplatin AUC 6 q3wks
IV Bevacizumab 15 mg/kg q3wks
IV Paclitaxel 175 mg/m2
IV Carboplatin AUC 6
IV Bevacizumab 15 mg/kg
Control/
Experimental
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Confirmation Trial
Every 3 Wks
Carboplatin AUC 5
Paclitaxel 175 mg/m2
MITO7
500 patients
Wkly
Carboplatin AUC 2
Paclitaxel 60 mg/m2
ClinicalTrials.gov. NCT00660842.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG 9923
Phase A (cycle repeated q21d for a total of 6 cycles)
Regimen 1 (Phase A)
Paclitaxel 175 mg/m2 on Day 1
Carboplatin AUC 6 on Day 1
Bevacizumab 15 mg/kg on Day 1*
Eligible Patients
ABT-888 BID on Days 1-21†
Newly diagnosed epithelial
ovarian, fallopian tube, or
Regimen 2(Phase A)
primary peritoneal cancer FIGO
Paclitaxel 80 mg/m2 on Days 1, 8, 15
stage II-IV defined surgically
Carboplatin AUC 6 on Day 1
Phase B
Bevacizumab will be continued
as maintenance for cycles 7-22
q21d
Bevacizumab 15 mg/kg on Day 1*
ABT-888 BID on Days 1-21†
*Bevacizumab started in cycle 2.
†ABT-888 will be dose escalated according to the schedule below to determine the MTD; a feasibility phase will follow.
During the dose-escalation phase, patients will be enrolled in cohorts of 3 patients each alternating between regimens 1
and 2. During the feasibility phase, 11 additional patients will be enrolled in regimen 1, followed by 11 in regimen 2, with an
additional 16 patients following per regimen, if necessary according to the statistical design.
ABT-888 Dose Escalation Schedule
Dose Level
Level -1
Level 1
Level 2
Level 3
Level 4
Level 5
Level 6
ClinicalTrials.gov. NCT00989651.
ABT-888 Dose, mg (oral, BID)
20 mg
30 mg
50 mg
80 mg
100 mg
150 mg
200 mg
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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OV.21: Optimally Debulked Patients After
Neoadjuvant Chemotherapy
Stratification and Randomization
Phase II Portion
Arm 1
IV Paclitaxel 135 mg/m2
on Day 1 + IV Carboplatin
AUC 5 (measured GFR) or
AUC 6 (calculated GFR) on
Day 1; IV Paclitaxel 60 mg/m2
on Day 8; cycles given q21d
x 3 cycles
Arm 2
IV Paclitaxel 135 mg/m2
on Day 1 + IP Cisplatin
75 mg/m2 on Day 1; IP
Paclitaxel 60 mg/m2 on Day 8;
cycles given q21d x 3 cycles
Assess Phase II Outcomes
(Sample Size = 150)
Proceed to Phase III Portion
ClinicalTrials.gov. NCT00993655.
Arm 3
IV Paclitaxel 135 mg/m2
on Day 1 + IP Carboplatin
AUC 5 (measured GFR) or
AUC 6 (calculated GFR) on
Day 1; IP Paclitaxel 60 mg/m2
on Day 8; cycles given q21d
x 3 cycles
Relevance of CA-125 Levels:
Placing Novel Data Into Clinical
Context
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Background: Recurrent Ovarian Cancer
 Nearly 70% of advanced stage cancers relapse
 Treatment of recurrent disease is complex with a myriad
options
 Elevation of CA-125 levels may be first indication of
recurrent disease
 Marker reliability may be extraneously influenced by
biologics
 Emerging data to inform clinicians on the role of
observation vs treatment
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Current Questions in Recurrent Disease
 How do you define recurrence?
– Physical exam
– Imaging
– Chemical
 When do you treat?
– Symptoms
– Imaged lesions
– Chemical
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Ovarian Carcinoma: CA-125
 Serum glycoprotein (OC-125)
 Discovered during a search to boost an immunotherapy
(Corynebacterium parvum)[1]
 Blood test introduced in 1981
– Present in 82% ovarian cancers; 1% in controls[2]
 CA-125 cloned in 2001[3]
– Mapped to chromosome 19 (p13.3)
– Gene: MUC16
– Very large molecule
1. Bast RC, et al. J Clin Invest. 1981;68:1331-1337. 2. Bast RC, et al. N Engl J Med. 1983;309:883-887.
3. Yin BW, et al. J Biol Chem. 2001;276:27371-27375.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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CA-125: Uses
Screening
Surveillance
CA-125
Prognostication
Detection
Choosing the Best Management Approaches in Patients With Ovarian Cancer
clinicaloptions.com/oncology
CA-125 Level Variation in Ovarian Cancer
Characteristic
Variation (N = 25)
Analytical imprecision, %
12.1
Intraindividual biological variation, %
24.0
Interindividual biological variation, %
43.1
Index of individuality
0.62
Tuxen MK, et al. Scand J Clin Lab Invest. 2000;60:713-721.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Recurrent Ovarian Cancer: Diagnosis
25
CA-125
Doubling
Patients (n)
20
Median: 1.5 mos
CA-125 “lead time”: 3 mos
20
16
15
10
7
5
1
0
2
3 3
3
1
1
7
4 4
2
-12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1
3
1
2 3 4 5 6
1
7 8
1
9 10 11 12
Mos From Clinical Progression
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Rustin GJ, et
al. J Clin Oncol. 2001;19:4054-4057.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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EORTC 55955: Schema
Previous ovarian, PP,
tubal cancer
Previous platinum chemo
Normal CA-125 following
first treatment
 Accrual goal: 1400
 Objectives: OS, TFS, QoL
R
A
N
D
O
M
I
Z
E
Conventional Surveillance
(“Early”)
Blinded CA-125 q3mos
Monitored CA-125 (“Delayed”)
If elevated, repeat in 4 wks
Confirmed elevation prompts
Chemotherapy
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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When to Treat?
Proportion Alive Not
Started Second-Line
Chemotherapy
Time From Randomization to Second-Line Chemotherapy
1.00
Median, Mos
Early
0.8
Delayed
5.6
HR: 0.29 (95% CI: 0.24-0.35; P < .00001)
0.75
0.50
0.25
0
0
3
6
9
12
15
18
21
24
10
42
9
33
Mos Since Randomization
Patients at Risk, n
Early
265
23
Delayed
264 177
16
116
14
91
11
69
11
56
10
49
Rustin G, et al. ASCO 2009. Abstract 1. Reprinted with permission from the author.
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Proportion Surviving
Overall Survival
Early
Delayed
Abs diff at 2 yrs: -0.1%
(95% CI diff: -6.8, 6.3%)
1.00
0.75
0.50
0.25
HR: 1.00 (95% CI: 0.82-1.22; P = .98)
0
0
6
12
18
24
30
36
42
48
54
60
38
38
31
31
22
19
Mos Since Randomization
Patients at Risk, n
Early
265 247 211 165 131 94
Delayed
264 236 203 167 129 103
72
69
51
53
Rustin G, et al. ASCO 2009. Abstract 1. Reprinted with permission from the author.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Platinum Sensitivity
0 Mos
6 Mos
12 Mos
Primary
Treatment
Refractory
Resistant
End of
Frontline
Therapy
Sensitive
Our patient
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Pros & Cons of Treating CA-125 Increase
Pros
Cons
 Stay ahead of disease
 Potential Rx of false positives
 Improve survival?
 No improvement in OS
 Prevent symptoms
 Exhaust treatment options
 Maximize QoL
 Toxicity
 “Active approach” to care
 Impaired QoL
 Intuitive to do something
 Cost
 Minimize patient anxiety
 No ideal agent available
 Avoids patient “relocating”
 May be homeopathic only
 Shortens visit time
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Modifying Influences on Clinical Practice
Advocacy Groups
New Agents
CA-125 and Rustin Data
3rd Party Payers
Applicability of UK to US
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Management of Ascites
Intervention
Paracentesis
 First-line treatment for ascites in ovarian cancer patients 1]
 Most patients need regular paracentesis[2]
Pleurx catheter
 Enables patients to manage drainage from pleural effusion at
home and reduces risk for septic complications[3]
IP chemotherapy
 Associated with many complications and toxicities[4]
Bevacizumab
 IP administration shown be safe and effective when
administered to palliate symptoms in patients with refractory
malignant ascites[5]
Catumaxomab
 Trifunctional anti-EpCAM x anti-CD3 antibody
 Associated with significant reduction in ascites flow rate in
ovarian cancer patients[6] and with longer puncture-free survival
and time to next paracentesis[7]
1. Sehouli J. Symptomorientierte Therapien: Aszites. In: Multimodales Management des Ovarialkarzinoms. Sehouli J and
Lichtenegger W (eds.). Bremen: UNI-MED, pp. 129-134, 2006. 2. Adam R, Adam Y. J Am Coll Sur. 2004;198: 999-1011.
3. Iyengar T, Herzog TJ. Am J Hosp Pallit Care. 2002;19:35-38. 4. Woopen H, Sehouli J. Anticancer Res. 2009;29:3353-3360.
5. El-Shami, et al. ASCO 2007. Abstract 9043. 6. Burges A, et al. Clin Cancer Res. 2007;13:3899-3905. 7. Heiss MM, et al. Int J
Cancer. 2010 Apr 27 [Epub ahead of print].
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Conclusions: CA-125 in Ovarian Cancer
 Nearly 70% of advanced stage cancers relapse
 Many patients will have relevant marker—usually first sign
of recurrence with 3 mos of lead time
 Marker reliability influenced by biologics
 Traditional monitoring paradigms have been challenged by
recent phase III data
 Reconciling contemporary data with needs of providers
and patients during era of economic restraint remains
problematic
 Is UK data completely applicable to all non-UK
populations?
Best Management Approaches for
Patients With Platinum-Sensitive
Recurrent Disease
Choosing the Best Management Approaches in Patients With Ovarian Cancer
clinicaloptions.com/oncology
100
90
80
70
60
50
40
30
20
10
1000
900
800
700
600
500
400
300
200
100
0
0
0-3 Prog
0-3 Non-PD
3-12 Mos
12-18 Mos
18+ Mos
PFS, days
90
176
174
275
339
OS, days
217
375
375
657
957
9
24
35
52
62
Response, %
Pujade-Lauraine E, et al. ASCO 2002. Abstract 829.
Percentage
Days
Recurrent Ovarian Cancer: Effect of
Platinum-Free Interval and Survival
Who Are the Best Candidates?
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Secondary Cytoreduction: Patients With
Short PFIs Do Not Benefit?
– Optimal (no visible
tumor): 82%
– All cisplatin based
– PFI: 6 mos
 Time to second surgery:
16.8 mos (range: 6-109)
Cumulative Survival
 Patients (N = 106)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
> 36 mos
13-36 mos
6-12 mos
0
12
24
36
48
60
72
84
Survival Time (Mos)
PFI = Platinum-free interval
Eisenkop SM, et al. Cancer. 2000;88:144-153.
96
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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AGO DESKTOP OVAR II: Design

ECOG performance score: 0

No residuals after primary surgery (or, if unknown, initially FIGO I/II)

Absence of ascites > 500 mL
Surgery is planned?
No (basic collective 1)
Yes
Predictive score positive (all items) ?
Yes
Laparotomy
No
Only descriptive analysis of further therapy
Platinum-based combination chemotherapy
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AGO DESKTOP OVAR II: Surgical Results
Frequency of complete resection by applying the AGO score
100
90
80
70
60
DESKTOP
50
Hypothesis
40
75
76
Score Positive:
All Patients
Score Positive:
First Relapse
30
68
20
10
0
Score Positive:
Second Relapse
Complete resection in 76% of the study collective =
AGO score could predict complete resection in at least 2 out of 3 patients
Harter P, et al. Ann Surg Oncol. 2006;13:1702-1710.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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AGO-OVAR DESKTOP III (Protocol AGOOVAR OP.4)
A randomized trial evaluating cytoreductive surgery
in patients with platinum-sensitive recurrent ovarian cancer
Stratified by
platinum-free interval
6-12 vs > 12 mos,
first-line platinumbased chx: yes vs no
R
A
N
D
O
M
I
Z
E
Cytoreductive
surgery
Platinum-based
chemotherapy*
recommended
No surgery
*Recommended platinum-based chemotherapy regimens:
 Carboplatin/paclitaxel
 Carboplatin/gemcitabine
 Carboplatin/pegliposomal doxorubicin
 Or other platinum combinations in prospective trials
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG 213
Recurrent ovarian and peritoneal primary cancer
TFI > 6 mos
Surgical candidate?
Yes
No
Randomize
Randomize
Surgery
No surgery
To chemotherapy
randomization
Carboplatin
Paclitaxel
Carboplatin
Paclitaxel
Bevacizumab
Maintenance
bevacizumab
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Recurrent Ovarian Cancer: Definition of
Disease Sensitivity
P
R
E
V
I
O
U
S
T
R
E
A
T
M
E
N
T
Time to Recurrence (Mos)
0
3
6
12
18
24
Refractory
Resistant
Sensitive
Very sensitive
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FDA-Approved Drugs in Ovarian Cancer
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Potential Advantages to Nonplatinum
Agents in Intermediately Sensitive Disease
Decreased toxicity
Prolonged platinum-free interval
Alternative mechanism of action
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Positive Trials in Recurrent Ovarian
Cancer
 Paclitaxel vs topotecan[1,2]
 Topotecan vs pegylated liposomal doxorubicin (PLD)[3,4]
 Platinum vs platinum + paclitaxel[5]
 Carboplatin vs carboplatin + gemcitabine[6]
 Carboplatin + PLD vs carboplatin + paclitaxel[7]
 PLD vs PLD + trabectedin[8]
1. ten Bokkel Huinink WW, et al. J Clin Oncol. 1997;15:2183-2193. 2. ten Bokkel Huinink WW, et al.
Ann Oncol. 2004;15:100-103. 3. Gordon AN, et al J Clin Oncol. 2001;19:3312-3322. 4. Gordon AN, et al.
Gynecol Oncol. 2004;95:1-8. 5. Parmar MK, et al. Lancet. 2003;361:2099-2106. 6. Pfisterer J, et al. J Clin
Oncol. 2006;24:4699-4707. 7. Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. 8. Monk BJ, et al.
ESMO 2008. Abstract LBA4
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Platinum
Platinum +
Paclitaxel
Platinum
sensitive, %
100
100
Response
rate, %
54
Median
PFS, mos
9
12
.0004
Median OS,
mos
24
29
.02
66
P Value
.06
Parmar MK, et al. Lancet. 2003;361:2099-2106.
Proportion Surviving
 N = 802 (776 evaluable)
Proportion Surviving
Progression Free
Platinum vs Platinum + Paclitaxel
1.0
PFS
Paclitaxel plus platinum
Conventional treatment
HR: 0.76 (0.66-0.89;
P = .004)
0.8
0.6
0.4
0.2
0
0
1
2
3
4
Yrs From Randomization
Survival
Paclitaxel plus platinum
Conventional treatment
HR: 0.82 (0.69-0.97;
P = .023)
0
1
2
3
4
Yrs From Randomization
1.0
0.8
0.6
0.4
0.2
0
5
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ICON 4: “A Mixed Bag”
Site
Accrual
Met?
Previous
TFI,Criteria
Mos Previous
Entry
Taxane?
Chemo
Meas.
Disease
Relapse
Criteria
MRCCTU
Yes
Not req.
>6
> 1*
Not req.
CA-125
IRFMN
Yes
Not req.
> 12
1
Required
Meas.
AGO
No
Required
>6
1
Not req.
Meas.
*4% > 2.
TFI (median): not stated
TFI > 12 mos for 75% (both arms)
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Phase III Trial of Carboplatin/Gemcitabine:
Study Design
Platinum-free interval
(6-12 or > 12 mos)
Type of first-line platinum therapy
(platinum/paclitaxel or other
platinum therapy)
Bidimensionally measurable
disease (yes or no)
RANDOMIZED
Stratified by:
Gemcitabine 1000 mg/m² Days 1, 8
Carboplatin AUC 4 Day 1
q3w for 6 cycles*
Carboplatin AUC 5 Day 1
q3w for 6 cycles*
*Patients were treated for 6 cycles in the
absence of progressive disease or
unacceptable toxicity.
At investigator discretion, benefiting patients
could receive a maximum of 10 cycles.
Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
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Phase III Registration Trial Carbo/Gem:
Prespecified Subgroup Analysis for PFS
Median PFS
Gemcitabine/Carboplatin
, Mos
Carboplatin, Mos
Progression-free interval
(6-12 mos)
7.9
5.2
Progression-free interval
(> 12 mos)
9.7
6.7
Previous platinum and
paclitaxel
9.7
5.9
Previous platinum
(no paclitaxel)
7.6
5.7
American Society of Clinical Oncology. ASCO Virtual Meeting 2003; Abstract and presentation 5005,
slides 13-16.
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OVA-301: Study Design
R
A
N
D
O
M
I
Z
A
T
I
O
N
PLD 50 mg/m2
90-min infusion q4w
PLD 30 mg/m² 90-min infusion
followed by
Trabectedin* 1.1 mg/m² 3-hr
infusion q3w
*Premedication with dexamethasone is required.
Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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OVA-301: PFS Primary Endpoint by
Independent Radiologist—Measurable*
100
PFS events: 389
HR: 0.79 (0.65-0.96; P = .0190)
# censored: 256
90
80
70
60
Trabectedin + PLD 7.3 mos
PLD 5.8 mos
50
40
30
20
10
0
0
Patients at Risk, n
PLD
Trabectedin/PLD
2
4
6
8
317 208 139 93 54
328 225 176 121 86
10 12 14 16
PFS (Mos)
18
20
22
24
26
28
35
63
4
10
0
7
0
6
0
4
0
0
0
0
22
33
14
22
6
13
*27 subjects nonmeasurable (9 trab + PLD [2 not treated], 18 PLD [1 not treated])
Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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OVA-301: PFS (PFI > 6 Mos) by Independent
Radiologist (All Measurable* Subjects)
100
PFS events: 226
HR: 0.73 (0.56-0.95; P = .0170)
# censored: 191
90
80
70
60
Trabectedin + PLD 9.2 mos
PLD 7.5 mos
50
40
30
20
10
0
0
Patients at Risk, n
PLD
Trabectedin/PLD
2
4
6
8
202 138 102 71 45
215 164 133 102 72
10 12 14 16
PFS (Mos)
18
20
22
24
26
28
30
56
3
10
0
7
0
6
0
4
0
0
0
0
17
30
11
20
*9 not treated and 18 nonmeasurable.
Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].
5
13
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Favorable Opinion for Trabectedin by
EMEA
 September 24, 2009: The EMEA Committee for Medicinal
Products for Human Use (CHMP) adopted a positive
opinion to recommend the variation to the terms of the
marketing authorization for the medicinal product
trabectedin. The CHMP adopted a new indication as
follows:
– “[Trabectedin] in combination with pegylated liposomal
doxorubicin (PLD) is indicated for the treatment of patients
with relapsed platinum-sensitive ovarian cancer”
EMEA. Available at: http://www.emea.europa.eu/pdfs/human/opinion/Yondelis_60855009en.pdf.
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OVA-301: Results Among Partially
Sensitive Subpopulation
Measure
Trabectedin + PLD
PLD
P Value
Response rate,* %
33
15
.0041
Median PFS,* mos
7.4
5.5
.00152 (HR, 0.65)
Median OS, mos
20.7
17.2
.0090 (HR, 0.59)
Time from randomization
to subsequent platinumbased therapy, mos
15.3
11.6
.0093 (HR, 0.60)
*By independent radiologist review
Poveda A, et al. ASCO 2010. Abstract 5012.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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PLD + Carbo in Ovarian Cancer Pts Who
Recur Within 6-12 Mos: Phase II Study

PLD 30 mg/m2 followed by carboplatin AUC 5 mg/mL/min every 4 wks

N = 54

75% received at least 6 cycles

RECIST RR: 46% (4% CR and 42% PR)
– Additional 33% experiencing disease stabilization > 6 mos

CA-125 RR: 66% (28% CR and 38% PR)
– Additional 18% experiencing disease stabilization > 6 mos

Median TTP: 10.0 mos (range: 1.5-25.0)

Median OS: 19.1 mos (range: 2.2-38.9)

Most frequent adverse effects were neutropenia, thrombocytopenia, and
constipation
Power P, et al. Gynecol Oncol. 2009;114:410-414.
CALYPSO Trial
Carboplatin + PLD vs
Carboplatin + Paclitaxel in
Relapsed, Partially PlatinumSensitive Ovarian Cancer
Paul Vasey
on behalf of all GCIC collaborators
ECCO ESMO 2009
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CALYPSO Study Schema
International, Intergroup, Open-label, Randomized Phase III Study
Ovarian cancer in
relapse > 6 mos
after first- or secondline platinum + taxane
chemotherapy
Stratification
 Center
R
A
N
D
O
M
I
Z
E
Experimental arm: CD
PLD 30 mg/m2 IV Day 1
Carboplatin AUC 5 Day 1
q28 days x 6 courses*
Control arm: CP
Paclitaxel 175 mg/m2 IV Day 1
Carboplatin AUC 5 Day 1
q21 days x 6 courses*
 Measureable disease
(yes vs no)
 Therapy-free interval
(6-12 mos vs > 12 mos)
*Or progression in patients with SD or PR.
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Accrual
 AGO-OVAR (Germany), GINECO (France, Switzerland, Turkey,
Saudi Arabia), NSGO (Denmark, Finland, Norway, Sweden),
NCIC-CTC (Canada), ANZGOG (Australia, New Zealand), AGO
(Austria), EORTC (Netherlands, Belgium, Spain), MITO (Italy),
MANGO (Italy)
Treatment
Therapy-Free Interval
Total
CD, n (%)
CP, n (%)
6-12 mos
161 (35)
183 (36)
344 (35)
> 12 mos
305 (65)
326 (64)
631 (65)
Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Progression-Free Survival (ITT):
Primary Endpoint
CD
CP
Median PFS, mos
11.3
9.4
HR (95% CI)
0.82 (0.72-0.94)
Proportion not Progressing
1.0
0.8
Log-rank P value
(superiority)
0.6
.005
P value (noninferiority)
0.4
< .001
CD
CP
0.2
0
0
Patients at Risk, n
CD
467
CP
509
6
397
405
12
18
Mos From Randomization
188
152
60
45
24
30
20
10
4
2
Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. Reprinted with permission from the author.
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PFS 6-12 Month Segment
Median PFS, mo
HR (95% CI)
CD
CP
9.4
8.8
0.73 (0.58, 0.90)
Log-rank P-value
(superiority)
0.004
P-value (non-inferiority)
<0.001
Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. Reprinted with permission from the author.
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Cediranib (AZD 2171)*
 Cediranib is a tyrosine kinase inhibitor of vascular
endothelial growth factor receptor (VEGFR)-1, VEGFR-2,
VEGFR-3, and c-kit
 Blocking VEGFR-2 inhibits VEGF signaling, angiogenesis,
and tumor growth
 Highly potent
 Orally bioavailable
 Toxicity: hypertension, fatigue, diarrhea, nausea
*AZD 2171 is an investigational agent.
Wedge SR, et al. Cancer Res. 2005;65:4389-4400.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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Cediranib (AZD 2171)*

Phase II study in recurrent EOC or
peritoneal or fallopian tube cancer

N = 46

RR: 8 (17%; 95% CI: 7.6% to
30.8%)
– All PRs, no CRs

Grade 4 toxicities
– CNS hemorrhage (n = 1)
– Hypertriglyceridemia/hypercholeste
rolemia/elevated lipase (n = 1)
– Dehydration/elevated creatinine
(n = 1)

Grade 3 toxicities (> 20% of pts)

Median PFS: 5.2 mos
– Hypertension (46%)

Median OS not reached
– Fatigue (24%)
– Diarrhea (13%)

Grade 2 hypothyroidism occurred in
43% of patients

No bowel perforations or fistulas
occurred
*AZD 2171 is an investigational agent.
Matulonis UA , et al. J Clin Oncol.
2009;27:5601-5606.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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ICON 6 (Second-Line European Trial)
Randomized 2:3:3
Platinum-based chemotherapy
(± taxane) q21 days x 6 cycles
+ Placebo
Patients with platinumsensitive ovarian cancer
Relapsed > 6 mos following
first-line platinum-based
treatment
Platinum-based chemotherapy
(± taxane) q21 days x 6 cycles
+ oral Cediranib daily during
chemo, then 18 mos of Placebo
Measurable disease
(N = 33)*
Platinum-based chemotherapy
(± taxane) q21 days x 6 cycles
+ oral Cediranib during chemo
and until progression or 18 mos
*Planned: phase II (N = 300), phase III (N = 2000).
ClinicalTrials.gov. NCT0000544973.
Choosing the Best Management Approaches in Patients With Ovarian Cancer
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GOG 213
Recurrent Ovarian and Peritoneal Primary Cancer
TFI > 6 mos
Surgical Candidate?
Yes
No
Randomize
Randomize
Surgery
No Surgery
To Chemotherapy
Randomization
Carboplatin
Paclitaxel
Carboplatin
Paclitaxel
Bevacizumab
Maintenance
Bevacizumab
ClinicalTrials.gov. NCT00565851.
Management of Patients in Challenging
Clinical Situations: Platinum Resistance
and Other Clinical Scenarios
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Case #3: Treatment History
Progression
Diagnosis
Symptoms
Primary
Chemo x 6
Recurrent
Chemo x 6
Staging
Now What?
5
mos
?
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Treatment Considerations
 Recognize her situation is not
curable but treatable
 Survey carefully for pre-existing
toxicities
 Assess her likelihood for response
 Develop your approach:
– Standard: NCCN guidelines
– Experimental: Clinical study
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Practice Guidelines (2010)
 Pts with PD, SD, or persistent disease receiving primary
chemotherapy should receive
– Supportive care
– Recurrence therapy
– Referral to a clinical trial
 Pts achieving CR and relapse within 6 mos following chemotherapy
OR pts with stage II-IV disease with PR should receive
– Observation
– Recurrence therapy (such as with non-platinum-based single agent
therapy)
– Referral to a clinical trial
NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v.2.2010.
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Practice Guidelines (2010): Recurrence
Therapies — Preferred Regimens
 Cytotoxic regimens
Platinum-resistant disease
Single-agent (non-platinum based)
 PLD
 Docetaxel
 Gemcitabine
 Etoposide (oral)
 Pemetrexed
 Topotecan
 Paclitaxel (wkly)
 Targeted therapy: Bevacizumab
NCCN. Clinical Practice Guidelines in Oncology. Ovarian Cancer v.2.2010.
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Summary of Phase III Single-Agent Trials:
Recurrent Ovarian Cancer
Drug A
Drug B
N
TTP (wks)
P
OS (wks)
P
Comment
Topotecan
Paclitaxel
226
23 vs 14
NS
61 vs 43
NS
50% Cross-over
Paclitaxel
(bolus)
Paclitaxel
(weekly)
208
38 vs 26
NS
34 vs 59
NS
Less toxicity w/
weekly
Oxaliplatin
Paclitaxel
86
12 vs 14
NS
42 vs 37
NS
74% platinum
resistant
PLD
Topotecan
481
16 vs 17
NS
60 vs 57
NS
54% platinum
resistant; OS
benefit in platinumsensitive subgroup
PLD
Paclitaxel
214
22 vs 22
NS
46 vs 56
NS
All pts taxanenaive
Topotecan
Treosulfan
357
22 vs 12
.001
56 vs 48
.02
2nd – 3rd line
therapy
PLD
Gemcitabine
195
16 vs 13
NS
59 vs 55
NS
PLD
Gemcitabine
153
16 vs 20
NS
55 vs 50
NS
56% platinum
resistant
PLD or
Topotecan
Canfosfamide
461
19 vs 9
< .01
59 vs 37
(PLD: 62 vs Topo: 47)
< .0001
ASSIST-1 trial
All 3rd line
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Chemoresistant Queue GOG126: Taxanes
Drug
Study
N
RR, %
PFS (mos)
OS (mos)
Docetaxel
126-L
58
22
2.1
12.7
Paclitaxel wkly
126-N
48
21
3.6
NS
nab-paclitaxel
126-R
51
23
4.5
17.4
Paclitaxel
poliglumex
186-C
49
16
2.8
15.4
Controversial: Taxane-free interval – effect not observed in GOG 126-L
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Pemetrexed
O
O
N
H
 Anti-folate
OH
O
O
OH
HN
H2N
N
N
H
N-[4-[2-(2-amino-3,4-dihydro-4-oxo7H-pyrrolo[2,3-d]pyrimidin-5yl)ethyl]benzoyl]-L-glutamic acid
– Approved in malignant
mesothelioma and
advanced or metastatic
NSCLC
– Enters via reduced folate
carrier and a selective
high capacity transporter
– Active against DHFR, TS,
GARFT
 Phase II study
– GOG 126-Q
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Pemetrexed in Ovarian Cancer
GOG 126-Q
Characteristic
Tox Heme (Gr 3/4)
48
ANC: 42%
Plat-R, measurable
RBC: 15%
1
Platelets: 13%
900 mg/m2 IV (21 d)
Constitutional: 15%
(%)
Non-Heme (Gr 3/4)
1(2%)+9(19%): 21%
GI/Nausea: 15%
17 (35%)
Neuro: 10%
2.8 mos/11.4 mos
Alopecia (Gr 2): 10%
N
Patients
No. of chemo lines
Regimen
Response
CR+PR
SD
PFS/OS
Miller DS, et al. ASCO 2009. Abstract e16507.
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Chemotherapy vs Hormones
N = 241 platinum/taxane-resistant
PFS
1.00
0.75
0.50
87 d vs 62 d
P = .024
Tamoxifen
0.25
Chemotherapy
(PLD vs Pac-Wkly)
0.75
Chemotherapy
(PLD vs Pac-Wkly)
0.50
OS
1.00
328 d vs 278 d
P = .56
0.25
Tamoxifen
0.00
0.00
0
10
20
months
30
40
Kristensen GB, et al. IGCS 2008. Abstract 2008_1175.
0
10
20
30
months
40
50
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PLD + Trabectedin vs PLD:
Phase III Registration Trial
 Recurrent ovarian cancer R
A
– One prior regimen
N
– Evaluable and measurable D
O
disease
M
I
– Platinum sensitive and
Z
resistant
E
 Accrual goal: 650 patients
PLD 30 mg/m2 + q3 weeks
Trabectedin 1.1 mg/m2
PLD 50 mg/m2 q 4 wks
 Translational research
 Primary endpoint: OS
– Pharmacokinetics
 Other endpoints: PFS, RR,
safety
– Pharmacoeconomics
– Pharmacogenomics
– Quality of life
– Circulating tumor cells
Monk BJ, et al. J Clin Oncol . June 1, 2010 [Epub ahead of print].
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OVA-301: PFS (TFI < 6 mos)
1.00
90
PFS events: 163
HR: 0.95 (0.70-1.30)
P =.7540
# censored: 65
Percent of Subjects
80
70
60
50
40
Trabectedin+PLD
4.0 mos
30
PLD
3.7 mos
20
10
0
0
2
4
6
37
43
22
19
RR: 12% vs 13% (rad review)
No. Subjects at Risk
PLD
Trabectedin/PLD
115 70
113 61
8 10 12 14 16 18 20 22
Progression-free survival (months)
9
14
5
7
Monk BJ, et al. J Clin Oncol. June 1, 2010 [Epub ahead of print].
5
13
3
2
1
0
1
0
0
0
0
0
24
26
28
0
0
0
0
0
0
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GOG 170 Series: Track Record
PFS ≥ 6 (%)
Bevacizumab
Sorafenib Temsirolimus
Imatinib
Gefitinib
Mifepristone
Enzastaurin
Lapatinib
Vorinostat
Response Rate (%)
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Phase II Studies of Bevacizumab in
Recurrent Ovarian Cancer
Measure, %
Cannistra et al[1]
(N = 44)
Garcia et al[2]
(N = 70)
Burger et al[3]
(N = 62)
100%
34%
Previous regimens
1
2
52%
3
48%
66%
Response rate
 CR
0%
0%
3%
 PR
16%
24%
18%
Gastrointestinal perforations
11%
6%
0%
Arterial thrombosis
7%
4%
0%
Bevacizumab-related deaths
7%
4%
0%
1. Cannistra SA, et al. J Clin Oncol. 2007;25:5180-5186.
2. Garcia AA, et al. J Clin Oncol. 2008;26:76-82.
3. Burger RA, et al. J Clin Oncol. 2007;25:5165-5171.
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Platinum-Sensitivity and Bevacizumab
Parameter
Wald P
HR
(95% CI)
GOG PS
> 0 vs 0
0.25
1.49 (0.76-2.9)
Plat-S
Y vs N
0.47
0.80 (0.44-1.46)
Age
0.91
1.0 (0.98-1.02)
Prior chemo
2 vs 1
0.12
0.62 (0.33-1.14)
(Garcia, et al.)
Estimated Probability of
Progression-Free Survival
GOG-170D (Burger et al.)
Platinum-sensitive (n=42)
Platinum-resistant (n=28)
All patients (n=70)
Log-rank P=.004
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
6
12
18
24
30
Time Since Start of Bevacizumab +
Cyclophosphamide Treatment (months)
Burger RA, et al. J Clin Oncol. 2007;25:5165-5171. Reprinted with permission. © 2008 American Society of Clinical
Oncology. All rights reserved. Garcia AA, et al. J Clin Oncol. 2008;26:76-82. Reprinted with permission. © 2008 American
Society of Clinical Oncology. All rights reserved.
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Toxicity from Target and Off Target
Constituents
 Hypertension
– CNS
 VTE
– Arterial and venous
 Proteinuria
 Hemorrhage
 Cardiac:
 GI toxicity
– CHF
– Perforation
– Conduction abnormalities
– Fistula
 Endocrine
– Thyroid
 Dermatologic
– Rash
– Wound disruption
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Extraluminal Air
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Treatment-Emergent Toxicity: Perforation
(~5% incidence in recurrent population)
 Morbid situation
– Mortality > 50%
– Challenging counseling due to several factors such as
disease status, patient’s intentions, clinical condition at
presentation
 Management approach (discontinue agent) and:
– Non-interventional: comfort care
– Conservative care: observation, nutritional support,
octreotide, drains, antibiotics
– Surgical: intestinal resection/bypass, stomata…
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Poly (ADP-Ribose) Polymerase (PARP)
If PARP is inhibited, SSB
repair prevented, leading
to increased double strand
DNA breaks
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Clinical Activity: Phase I
Fong PC, et al. ASCO 2008. Abstract 5510.
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Phase II Trial Olaparib in BRCA-Deficient
Recurrent Ovarian Cancer: Efficacy

Patients with confirmed BRCA 1/2 mutation, recurrent (stage IIIB/IIIC/IV)
ovarian cancer after failure of ≥ 1 platinum-based chemotherapy
Olaparib 400 mg BID
(n = 33)
Olaparib 100 mg BID
(n = 24)
Response by RECIST
11 (33%)
3 (13%)
Platinum-sensitive
1/7 (14%)
2/8 (25%)
10/26 (38%)
1/16 (6%)
20 (61%)
4 (17%)
290 days (126-513)
269 days (169-288)
5.8 months
1.9 months
(n = 33)
(n = 24)
Nausea
2 (6%)
3 (13%)
Vomiting
2 (6%)
2 (8%)
Discontinuation due to AEs
4 (12%)
1 (4%)
Dose interruption due to AEs
12 (36%)
4 (17%)
Platinum-resistant
Response by RECIST and/or GCIC
Median DOR (range)
Median PFS
Grade 3/4 adverse events
Audeh MW, et al. ASCO 2009. Abstract 5500.
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PARPi Trials: Ongoing/Planned
 17 ovarian trials listed on
Clinicaltrials.gov Web site
 Single agent and in
combination with chemo
 PARP agents
 Populations
– AG014699
– Known BRCA germline
– Olaparib
– High grade serous
– BSI-201
– MK4827
– ABT-888
– 20-30% HR dysfunction
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Investigational Agents
Biologics
Chemotherapy and Others
 AMG-386 (Tie2)
 Epothilones
 Pazopanib
– Ixabepilone
 BIBF-1120
 BMP-1350 (karenitecan)
 IMC-1121B
 NKTR-102
 Fosbretabulin
 EC-145
 IMC-3G3
 Farletuzumab
 IGF-1R inhibitors
 Rapalogs
 PARPi
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NKTR-102: Peg-Irinotecan
Platinumresistant
ovarian cancer
patients
(N = 70)
145 mg/m2 q14d
145 mg/m2 q21d
Stage I
N = 20/
regimen
Stage 2
N = 15/
regimen
Primary
Endpoint:
Objective
response
rate (GCIG)
Prior to entering the study:
77% of patients in first stage progressed within 3 months of the last platinum dose
44% of patients in the first stage progressed within 3 weeks of the last platinum dose
Preliminary results from first 39 patients in study*
Response Measure, %
Confirmed Response
q14d
q21d
GCIG response rate (RECIST and CA-125)
32 (6/19)
35 (7/20)
RECIST response rate
21 (4/19)
22 (4/18)
*Full results for 71 patients to be presented at ASCO Annual Meeting, Sunday, June 6, 2010, 11:15 am
(Vergote I, et al, Abstract 5013).
Data on file. Nektar Therapeutics.
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Utilizing the Folate Receptor: EC145
 Folate-Vinca conjugate
 Relevant for imaging
targeting and therapy
Reddy JA, et al. Cancer Res. 2007;67:4434-4442.
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EC145: Novel Folate Receptor Targeted
Therapeutic
 Randomized Phase II, Platinum-resistant ovarian
 Prior therapy: no more than 2 priors
 Regimen:
– PLD 50 mg/m2 IBW q 28 days
– PLD 50 mg/m2 IBW q 28 days + EC145 2.5 mg weeks 1 and 3 (cycle: 28
days)
 Toxicity similar in both arms: total AEs, SAEs, TETs
Arm
PFS
HR
P
PLD
11.7 wks
-
-
PLD+EC145
24.0 wks
0.497
0.014
Naumann W, et al. ASCO 2010. Abstract LBA5012b.
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Developmental Strategies
 Chemotherapy with biologics
 Chemotherapy combinations
 Biological combinations
 Patient profiling – biomarker driven design
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Recommendations: Therapy
 My bias would be to first consider a clinical trial such as
126 series or biologic 170-series
 Off-protocol: a taxane vs PLD vs topotecan
– Decision based on antecedent toxicity, patient schedule
preference, insurance
 In the absence of CR or toxicity, treat to progression
– Wait for definitive evidence of progression
– CA-125 trends may be discordant to efficacy determination
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