1. Please take a moment to complete the short
Welcome!
Please take a moment to complete the short
pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities.

3. Faculty Disclosures
The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:
Presenter, MD: Research: Pharma Company; Consultant: Pharma Company
TO BE FILLED IN BY PRESENTING PHYSICIAN(S)
Off-label discussion disclosure:  
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

4. Steering Committee Disclosures
The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:
Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis
Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech

5. Non-faculty Disclosures
Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:
Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose

6. Educational Objectives
At the conclusion of this activity, participants should be able to demonstrate the ability to:
Review the recently updated clinical practice guidelines for advanced ovarian cancer
Compare the available treatment regimens and platinum- sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data
Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly

7. Basis for Basic 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]
AGO, Arbeitsgemeinschaft Gynaekologische Onkologie ; EORTC, European Organisation for Research and Treatment of Cancer; GOG, Gynecologic Oncology Group; NCIC, National Cancer Institute of Canada.
Systemic therapy is given based on 4 large studies conducted between 1993 and The first 2 studies compared cyclophosphamide/cisplatin with paclitaxel/cisplatin and showed that paclitaxel/cisplatin was superior. The second 2 studies compared paclitaxel/cisplatin with paclitaxel/carboplatin and showed equivalency or, in 1 case, borderline superiority for paclitaxel/carboplatin.
1. McGuire WP et al. N Eng J Med .1996;334:1-6.
2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:
3. DuBois A et al. J Natl Cancer Inst. 2003;95:
4. Ozols RF et al. J Clin Oncol. 2003;21:

8. First-line Therapy: Acceptable Approaches
Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission

9. First-line Therapy: Acceptable Approaches
Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission

10. 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
Neoadjuvant chemotherapy
3 x Platinum based CT
3 x Platinum based CT
Interval debulking
(not obligatory)
Interval debulking if no PD
≥ 3 x Platinum based CT
≥ 3 x Platinum based CT
Primary Endpoint: Overall survival
Secondary endpoints: Progression Free Survival, Quality of Life, Complications
IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:

11. NACT + IDS versus PDS: ITT
Median survial
PDS: 29 months
IDS: 30 months
HR for IDS:0.98 (0.85, 1.14)
IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:

12. First-line Therapy: Acceptable Approaches
Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission

13. 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: Markman M, et al. J Clin Oncol. 2001;19: Armstrong DK et al. N Engl J Med. 2006;354: Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: cfm. Accessed March 9, 2006.

14. IP median overall survival = 65.6 months
GOG Protocol 172
IV median overall survival = 49.7 months
IP median overall survival = 65.6 months
Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03
Rx Group Lost to Alive Dead Total Follow-up IV IP
IV = Intravenous; IP = Intraperitoneal
Armstrong DK,et al. N Engl J Med. 2006;354:34-43.

15. IP Compared to IV Chemotherapy Phase III Trials
Red bar indicates the increase in overall survival from the intraperitoneal arm of GOG 172 compared with to patients treated with paclitaxel and carboplatin (PC) from GOG protocol 158. Armstrong DK and Brady MF. Intraperitoneal therapy for ovarian cancer: A treatment ready for prime time. J Clin Oncol Oct 1;24(28):
GOG 104
GOG 114
GOG 172
OS GOG 172 IP
c/w OS GOG 158 PC
Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):

16. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy
127.6
60.4
41.1
Months
When stratified by individual study, patients receiving IP chemotherapy on GOG 172 with no residual had the best out come measures with PFS of 60 months and OS of 128 months.
Landrum L et.al. GOG Symposium, July 2012.

17. GOG 252 Stage II/III Disease: Small Volume Residual
Epithelial Ovarian Cancer
Optimal Stage III
No prior therapy
Phase III
PFS primary endpoint
Carboplatin AUC=6 (IV)
Paclitaxel 80 mg/m2 (d1, 8, 15 3h)
Bevacizumab (C2+ C22) x 21 days I
Carboplatin AUC=6 (IP)
Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days II
Cisplatin 75 mg/m2 (IP d2)
Paclitaxel 135 mg/m2 (d1, 3h)
Paclitaxel 60 mg/m2 (d8, IP)
Bevacizumab (C2+ C22) x 21 days
III
Open: 27 Jul 2009
Closed: 30 Nov 2011
Accrual: 1100
Study Chair: J Walker
ClinicalTrials.gov Identifier: NCT 17

18. First-line Therapy: Acceptable Approaches
Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission

19. 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
Paclitaxel 180 mg/m2
Carbolatin AUC = 6 I
x6-9
Carbolatin AUC = 6
Paclitaxel 80 mg/m2/w x3 II
x6-9
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. 19

20. JGOG: Dose-dense Weekly Paclitaxel
Katsumata N et al Lancet. 2009;374:

21. GOG 262 Stage III/IV Disease: Large Volume ResidualN 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
Study Chair: J Chan
ClinicalTrials.gov Identifier: NCT

22. First-line Therapy: Acceptable Approaches
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. GOG-0218: Schema I II III Arm Carboplatin (C) AUC 6
2008
GOG-0218: Schema
Arm
Carboplatin (C) AUC 6 I
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
Placebo
Carboplatin (C) AUC 6
1:1:1
RANDOM I
Z E II
Paclitaxel (P) 175 mg/m2
BEV 15 mg/kg
Placebo
Carboplatin (C) AUC 6
Stratification variables:
GOG performance status (PS)
Stage/debulking status
III
Paclitaxel (P) 175 mg/m2
BEV 15 mg/kg
Cytotoxic (6 cycles)
Maintenance
(16 cycles)
15 months
Burger RA et al. N Engl J Med. 2011;365: 23 23

24. GOG-0218: Investigator-assessed PFS
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Arm I
CP (n=625)
Arm II
CP + BEV (n=625)
Patients with event, n (%)
423 (67.7)
418
(66.9)
Median PFS, months
10.3
11.2
Stratified analysis HR (95% CI)
0.908
(0.759–1.040)
One-sided P-value (log rank)
0.080*
Arm III
CP + BEV  BEV (n=623)
360
(57.8)
14.1
0.717
(0.625–0.824)
<0.0001*
Proportion surviving progression free
CP (Arm I)
+ BEV (Arm II)
+ BEV → BEV maintenance (Arm III)
Months since randomization
*P-value boundary =
Burger RA et al. N Engl J Med. 2011;365: 24

25. GOG-0218 CA-125 to Determine Progression
Protocol-defined PFS analysis
CA-125-censored PFS analysis
Median PFS
CP (Arm I)
10.3 months
12.0 months
CP + BEV  BEV (Arm III)
14.1 months
18.0 months
Absolute diff. median PFS
3.8 months
6.0 months
Hazard ratio
0.717
0.645
Censored for CA125, % 20 29
Burger RA et al. N Engl J Med. 2011;365:

26. GOG-0218 Interim Survival Analysis
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Proportion Alive
Arm I CP
(n=625)
Arm II
CP + BEV
Arm III
CP + BEV  BEV
(n=623)
Patients with events,
n (%)
156
(25.0)
150
(24.0)
138
(22.2)
Median, months
39.3
38.7
39.7
HRa
(95% CI)
1.036
(0.827–1.297)
0.915
(0.727–1.152)
One-sided P value
0.361
0.252
Months since randomization
625/625/623
442/432/437
173/162/171
46/39/40
No. at risk
aStratified analysis
Burger RA et al. N Engl J Med. 2011;365:

27. ICON7: Study Design Primary endpoints: PFS
Carboplatin AUC 6*
Front-line EOC, PP or FT cancer
Stage I-IIA (Gr 3 or CC)
Stage IIB/C
Stage III
Stage IV
n=1528
Primary endpoints:
PFS
Secondary endpoints: OS, RR, safety, QOL,
cost-effectiveness,
translational
No IRC present
Arm A
Paclitaxel 175 mg/m2
Arm B
Carboplatin AUC 6*
Paclitaxel 175 mg/m2
Stratification variables:
Stage/surgery
Time since surgery
GCIG group
AVASTIN **
Bevacizumab 7.5 mg/kg
12 months
*Might vary based on GCIG group
**Omit cycle 1 bevacizumab if <4 weeks from surgery
Perren T et al. N Engl J Med. 2011;365:
Perren et al. ESMO 2010.

28. ICON 7 Summary of Updated Results
Parameter
Protocol-defined Analysis
Bulk Disease Analysis
PFS
HR = 0.87, P = 0.039 CP
17.4 months
CP + BEVBEV
19.8 months OS
HR = 0.84, P = 0.099
HR = 0.64, P = 0.002
28.8 months
36.6 months
Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006).
Perren T et al. N Engl J Med. 2011;365:

29. First-line Therapy: Acceptable Approaches
Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission

30. GOG 178—Investigating Paclitaxel as Consolidation
Paclitaxel 175 mg/m2
every 28 days × 3 months
277 stage III/IV patients in complete
clinical remission
RANDOM I
Z E
Paclitaxel 175 mg/m2
every 28 days × 12 months
CR = Complete response.
Markman M et al. J Clin Oncol. 2003;21:

31. GOG 178 Progression-free survival Percentage Months after registration
100 80
Percentage
P = 60 40
Median,
months 20
At risk
Failed
Paclitaxel 12 courses
110 20 28
Paclitaxel 3 courses
112 34 21 12 24 36 48
Months after registration
Markman M et al. J Clin Oncol. 2003;21:

32. 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 = )
Paclitaxel
Every 28 days for up to 12 courses
Paclitaxel poliglumex
Every 28 days for up to 12 courses
No treatment
GOG PS, Gynecologic Oncology Group performance score; PFS, progression-free survival; QoL, quality of life
Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL 32

33. Summary: Initial Treatment of Advanced Ovarian Cancer
Surgery
Attempt at maximal surgical cytoreduction
Neoadjuvant chemo before surgery is an option for poor surgical candidates
Chemotherapy
6-8 cycles taxane-platinum combination is standard
IP admin benefits patients with low volume (optimal) disease but has increased toxicity
NED patients treated with IP have a median survival of over 9 years
Weekly (dose-dense) paclitaxel improves outcome in one study
Confirmatory North American trials recently completed
Bevacizumab during and after chemotherapy improves PFS but not OS

34. Case Discussions

35. Case 1: A Newly Diagnosed Patient With Ovarian Cancer
58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0.
What would you recommend for this patient?
Neoadjuvant chemotherapy
Primary radical debulking surgery

36. What Would You Recommend for This Patient?
Neoadjuvant chemotherapy
Primary radical debulking surgery

37. Primary Cytoreduction
Meta-analysis: 53 studies (1989–1998)
81 cohorts (Stage III/IV)
n = 6885 patients
Results
Expert centers have high optimal rates
Optimal vs not: 11 mos (50% increase)
Each 10%  in cytoreduction = 5.5%  in survival
Platinum intensity = NS
Bristow. J Clin Oncol. 2002;20:1248.

38. The Impact of Residual Tumor: What Is Optimal Debulking?
% Progression-Free Survival
HR (95% CI) mm – 10 mm vs. 0 mm: (2.26; 2.81) >10 mm vs 1 mm – 10 mm: (1.24; 1.50)
log-rank: P<0.0001
0 mm
1 mm – 10 mm
>10 mm
Generated from 3 prospective Phase III trials (OVAR 3,5, & 7)
n = 3126 pts
% Overall Survival
HR (95% CI) 1 mm – 10 mm vs. 0 mm: (2.37; 3.07) >10 mm vs 1 mm – 10 mm: (1.21; 1.49)
log-rank: P<0.0001
0 mm
1 mm – 10 mm
>10 mm
DuBois. Cancer. 2009;115:1234.

39. Case 1 What would you recommend for this patient at this point?
She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well…
The pathology shows a high-grade serous carcinoma.
The surgeon noted small volume residual (5-9mm) disease throughout the abdomen.
What would you recommend for this patient at this point?
IP chemotherapy
IV chemotherapy
Adding bevacizumab to either IV or IP

40. Case 1 Question 2
What would you recommend for this patient at this point?
IP chemotherapy
IV chemotherapy
Adding bevacizumab to either IV or IP
All the above answers are reasonable treatment choices.
When would you start the bevacizumab?
Cycle 1, 2 or 3?
After the chemotherapy (maintenance)?

41. Case 2: Platinum Sensitive Ovarian Cancer
52-year-old woman with high-grade serous carcinoma of the fallopian tube
Optimally debulked in 2010
Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011
CA125
at presentation 5800
nadir post therapy 7
In 2012 : Increasing Ca125 (1200)
Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy
Symptomatic: abdominal bloating, early satiety, and mild shortness of breath
Disease free interval: months
Genetic testing: BRCA1/2 negative

42. Case 2 Question 1 What treatment would you recommend for this patient?
Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin
PLD, carboplatin and bevacizumab
Gemcitabine and carboplatin
Gemcitabine, carboplatin and bevacizumab
Paclitaxel and carboplatin
Weekly paclitaxel and carboplatin
Paclitaxel, carboplatin and PARP inhibitor
PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin
PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial
Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005)
Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial)
Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less
Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease
PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. Howeve this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012)

43. Case 2, Question 1
What treatment would you recommend for this patient?
Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin)
PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial)
Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005)
Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial)
Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less)
Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease
Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012)

44. She Asks You Whether There Is Any Role for Surgery for Her
Which of the following are true regarding secondary debulking?
It is not considered for patients like her who relapse months after completing initial chemotherapy
The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery
Survival is improved for secondary debulking even if all disease can’t be removed at surgery
Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery
1 and 3
2 and 4
All of the above
Correct answer, #6, 2 and 4. secondary debulking can be considered in patients who relapse more than 6months after completing initial chemotherapy. Carcinomatosis and significant estra-peritoneal disease are contraindications to secondary debulking. Survival is improved only if all visible disease can be completely resected.

45. Secondary Debulking Candidate Selection
Onda et al. J Cancer. 2005;92:1026.

46. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64.

47. Accrual 864 pts PFS primary endpoint
GCIG CALYPSO Trial
Accrual 864 pts PFS primary endpoint
PLD 30 mg/m2
Carboplatin AUC = 5
q 28 days x 6
Ovarian Cancer
Platinum Sens.
Stratify:
≤ 0.5 cm
> cm
RANDOM I
Z E
Paclitaxel 175 mg/m2
Carboplatin AUC = 5
q 21 days x 6
Trial is ongoing:
For more details:
Drugs:
carboplatin (Paraplatin®)
paclitaxel (Onxol®, Taxol®)
pegylated liposomal doxorubicin (Doxil®)
GCIG = Gynecologic Cancer Intergroup
PFS = progression-free survival
PLD = pegylated liposomal doxorubicin
Pujade-Lauraine E et al. J Clin Oncol. 2010;28: 47

48. GCIG CALYPSO Trial
Progression-free survival (PFS). HR, hazard ratio; PLD, pegylated liposomal doxorubicin.
Pujade-Lauraine E et al. J Clin Oncol. 2010;28:

49. Selected Non-hematologic Toxicities During Treatment
Alopecia
CD (n=466)
CP (n=501)
Alopecia grade 2* 7%
84%
*P< 0.001
Pujade-Lauraine E et al. J Clin Oncol. 2010;28:

50. Targeted Agents in Ovarian Cancer
Signaling/Angiogenesis
Bevacizumab/Aflibercept
RTKI’s:
Pazopanib
Cabozantinib
Sorafenib, etc
Cediranib
Nintedanib
Trebananib, MEDI-3617
PI3K/Akt/mTOR
MEKi
Folate:
Vintafolide (EC-145)
Farletuzumab
NKTR-102
Taxanes/epothilones
Immunotherapy – vaccines and inducers
EP-100
PARPi
ErbB3

51. OCEANS: Study schema Platinum-sensitive recurrent OCa CG + PL C AUC 4
Measurable disease
ECOG 0/1
No prior chemo for recurrent OC
No prior BV
(n=484)
G 1000 mg/m2, d1 & 8
PL q3w until progression
C AUC 4
G 1000 mg/m2, d1 & 8
CG + BV
Stratification variables:
Platinum-free interval (6–12 vs >12 months)
Cytoreductive surgery for recurrent disease (yes vs no)
BV 15 mg/kg q3w until progression
Carbo/gem from AGO trial (identical dose and schedule), allowed up to 10 cycles in responding pts.
Bev continued until progression in contrast to GOG-0218 and ICON7.
All pts had measurable disease as defined by RECIST (older criteria).
Stratification by cytoreductive surgery was probably not necessary as all pts had measurable disease – driven by thoughts that treatment paradigm was changing in US
CG for 6 (up to 10) cycles
BV = bevacizumab; PL = placebo
aEpithelial ovarian, primary peritoneal, or fallopian tube cancer
Aghajanian C et al. J Clin Oncol. 2012;30:

52. OCEANS: Primary Analysis of PFS
CG + PL
(n=242)
CG + BV
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
0.484
(0.388–0.605)
<0.0001
1.0
0.8
0.6
0.4
0.2
Proportion progression free 6 12 18 24 30
Months
No. at risk
242
177 45 11 3
CG + PL
242
203 92 33 11
CG + BV
Aghajanian C et al. J Clin Oncol. 2012;30: 52

53. OCEANS: Third Interim OS Analysisa
GC + PL
(n=242)
GC + BV
Events, n (%)
142 (58.7)
144 (59.5)
Median OS, months (95% CI)
33.7
(29.3‒38.7)
33.4
(30.3‒35.8)
HR (95% CI) Log-rank P value
0.960 (0.760–1.214)
P=0.7360
1.0
0.8
0.6
0.4
0.2
Proportion surviving
Months
Number at risk:
GC + PL
GC + BV
aData cutoff date: March 30, Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients)
Aghajanian et al. ESMO 2012.

54. Farletuzumab - MORAb-003-002 Phase II: Design
Epithelial Ovarian Cancer
First platinum-sensitive relapse
First remission of 6-18 months
Evaluable disease by CA125
Asymptomatic relapse
Symptomatic relapse
Single-agent farletuzumab
Until progression
Original Carbo/Taxane regimen
Plus farletuzumab x 6
Single-agent ORR
Combination ORR
Compare lengths of first and second remissions
Farletuzumab maintenance Rx
For responders
White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001.

55. MorAb-003-002: Study Conclusions
Overall response rate 70%
Response rate similar in early (6-12 month) and late (12+ months) recurrent patients
High rates of CA-125 normalization (89%)
1/5 patients had a PFI2 ≥ PFI1
Phase III studies
Platinum-sensitive: fully enrolled
Platinum-resistant (weekly paclitaxel): met futility endpoint
White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001.

56. Completion of 4–6 x 21-day cycles of chemotherapy
Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer
Patients with:
Platinum-sensitive advanced ovarian cancer
A serous histology or serous component
Measurable disease
≤3 previous platinum-containing regimens
Progression free for ≥6 months following completion of last platinum-containing regimen
Olaparib 200 mg bid* (d1–10 every 21 days)
+ paclitaxel 175 mg/m2 (iv, d1)
+ carboplatin AUC4 (iv, d1)
Maintenance phase
Olaparib 400 mg bid continuously
n=81
n=66
Randomization (1:1)
All patients followed for objective radiologic progression and survival
Completion of 4–6 x 21-day cycles of chemotherapy
Maintenance phase
No further study treatment
Paclitaxel 175 mg/m2 (iv, d1)
+ carboplatin AUC6 (iv d1)
n=81
n=55
Multinational study; 43 sites in 12 countries
* Capsule formulation
Arm A
Arm B
Oza A. ASCO 2012; Abstract 5001.

57. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS
1.0
0.9
O/P/C
P/C
Events: Total patients (%)
47:81 (58.0)
55:81 (67.9)
Median (months)
12.2
9.6
Hazard ratio = % CI (0.34, 0.77) P=0.0012
0.8
0.7
0.6
Proportion of patients progression free
0.5
0.4
0.3
0.2
Olaparib + P + C (AUC4)
0.1
P + C (AUC6) 2 4 6 8 10 12 14 16 18 20
Number of patients at risk
Time from randomization (months)
O/P/C 81 80 76 71 55 37 34 20 3
P/C 81 68 65 57 40 18 15 8 2 1
Oza A. ASCO 2012; Abstract 5001.

58. GOG 9927: Phase I Combination
Platinum sensitive recurrent EOC
Chemotherapy based on CALYPSO
Primary endpoint: 1st or 2nd cycle DLT
Secondary endpoints: RR, PFS, Toxicity
TR: PARPi in PBMCs, BRCA status
PLD 30 mg/m2
Carboplatin AUC 5
Arm I
Veliparib PO daily continuously
Cycles: 28 days
Planned administration: 6 cycles
Arm II
Veliparib PO daily D1-7
Dose Level
ABT-888 Dose
(mg, oral, BID)
Level -1
20 mg
Level 1
30 mg
Level 2
50 mg
Level 3
80 mg
Level 4
100 mg
Level 5
150 mg
Level 6
200 mg
Level 7
250 mg
Level 8
300 mg
Level 9
350 mg
Level 10
400 mg

59. Summary for Platinum-sensitive Recurrent Ovarian Cancer
Consider Secondary Debulking
Platinum retreatment is standard
Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival
Options:
Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?)
Gemcitabine Carboplatin +/- Bevacizumab
PLD Carboplatin 59

60. Case 3: Platinum Resistant Ovarian Cancer
60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery
Diagnosis of ovarian cancer made by paracentesis
Deemed unresectable by a gynecologic oncologist
Treated with neoadjuvant paclitaxel and carboplatin x 3 without response
Then treated with topotecan (daily x 5 regimen) x 3 without response
Required paracentesis weekly for palliation
CA-125=6916
What treatment would you recommend?

61. Case 3 Question 1 What treatment would you recommend for this patient?
Pegylated liposomal doxorubicin (PLD, doxil, lipodox)
Weekly paclitaxel
Gemcitabine
Bevacizumab
Weekly paclitaxel and bevacizumab
Gemcitabine, carboplatin and bevacizumab
Answer 1: PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population
Answer 2:Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen
Answer 3: although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%
Answer 4: Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population
Answer 5: based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable
Answer 6: platinum-based therapy is not indicated in this patient with platinum-refractory disease.
Naumann RW, Coleman RL. Management strategies for recurrent platinum-resistant ovarian cancer. Drugs Jul 30;71(11):

62. Case 3 Question 1 What treatment would you recommend for this patient?
Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population)
Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen)
Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%)
Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population)
Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable)
Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.)
Answer 1: PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population
Answer 2:Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen
Answer 3: although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%
Answer 4: Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population
Answer 5: based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable
Answer 6: platinum-based therapy is not indicated in this patient with platinum-refractory disease.
Naumann RW, Coleman RL. Management strategies for recurrent platinum-resistant ovarian cancer. Drugs Jul 30;71(11):

63. Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her
1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case.
Correct answer is 5, all of the above are true statements about bevacizumab in this case.

64. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011.

65. Active Agents in Ovarian Cancer
FDA approved
Altretamine
Carboplatin
Cisplatin
Gemcitabine/
Paclitaxel (Taxol)
Pegylated liposomal doxorubicin (Doxil)
Topotecan
Not FDA approved, compendium listed
Chlorambucil
Cyclophosphamide
Docetaxel
Doxorubicin
Epirubicin
Etoposide
5-FU/LV
Gemcitabine
Ifosfamide
Irinotecan
Melphalan
Methotrexate
Thiotepa
Vinorelbine
Bevacizumab
Pemetrexed*
Nab-Paclitaxel*
Not FDA approved, not compendium listed
Aromatase inhibitors
Tamoxifen
Drugs:
5-FU/LV, or 5-fluorouracil/leucovorin (Adrucil®/Wellcovorin®)
altretamine (Hexalen®)
bevacizumab injection (Avastin®)
carboplatin (Paraplatin®)
chlorambucil (Leukeran®)
cisplatin (Platinol®-AQ)
cyclophosphamide (Cytoxan®, Neosar®)
docetaxel (Taxotere®)
doxorubicin (Adriamycin®, Doxil® Rubex®)
epirubicin injection (Ellence®)
etoposide oral and injection (Etopophos®, Toposar®, VePesid®)
gemcitabine hydrochloride (Gemzar®)
ifosfamide (Ifex®)
ironotecan (Camptosar®)
melphalan (Alkeran®)
methotrexate (Rheumatrex®, Trexall®)
paclitaxel (Onxol®, Taxol®)
pemetrexed (Alimta®)
tamoxifen (Nolvadex®)
thiotepa (Thioplex®)
topotecan hydrochloride (Hycamtin®)
vinorelbine tartrate (Navelbine®) 65

66. Platinum-resistant Ovarian Cancer Cytotoxic Therapy
STUDY*
AGENT N
RESPONSE RATE
126-J
Docetaxel 58
22%
126-N
Weekly Paclitaxel 48
21%
126-M
Ixabepilone 50
14%
126-Q
Pemetrexed
126-R
nab-Paxlitaxel 47
23%
*1 prior line
Thresholds: 10%, 25%
NXTR-102 topoisomerase I polymer conjugate (provides continuous concentration of active drug with reduced peak concentrations)
Randomized phase II, NKTR-102*
145 mg/m2 q14 d 33
21%
145 mg/m2 q21 d 31
23%
*Median of 3 prior lines
Vergote IB et al. J Clin Oncol 2010;28:15s(suppl; abstr 5013).

67. Bevacizumab in Relapsed Ovarian Cancer
GOG 170-D*
(N = 62)
NCI 5789**
(N = 70)
Phase II Study***
(N = 44)
Study Treatment
Single agent BV 15 mg/kg q 3 wk
BV 10 mg/kg q 2 wks + low dose oral cyclophos.
Single agent
BV 15 mg/kg
q 3 wk
Prior Regimens
1 – 21/62 (34%)
2 - 41/62 (62%)
Median = 2
Range 1-3
2 - 23/44 (52%)
3 - 21/44 (48%)
Platinum Resistant
42%
40%
100%
Efficacy
ORR
6-mo PFS
21%
39%
24%
56%
16%
27%
GIP or fistula
4 (6%)
5 (11%)
*Burger RA et al. J Clin Oncol 2007; 25: 5165–5171.
**Garcia AA et al. J Clin Oncol 2008; 26: 76–82.
***Cannistra SA et al. J Clin Oncol 2007; 25: 5180–5186.

68. Ovarian Cancer: Targeted Therapy
STUDY
AGENT
Target n
RESPONSE RATE
Sanofi-Aventis
Aflibercept
(VEGF-TRAP)1
VEGF
2 mg/kg
215
3.8%
4 mg/kg
7.3%
NCIC-CTEP
Sunitinib2
VEGF/PDGF 30
3.3%
DFCI-CTEP
Cediranib3
VEGF/c-kit 46
17%
Exelixis
Cabozantinib4
VEGFR2/c-met 70
24%
GlaxoSmith
Kline
Pazopanib5
VEGFR/PDGFR/c-kit 36
18%
Boehringer Ingleheim
Nintedanib6
VEGFR/PDGFR/FGFR 43
16.3% at 36 weeks
vs. placebo 40
5% at 36 weeks
uPAR = urokinase plasminogen activator receptor
1Tew et al. J Clin Oncol 2007;25:(suppl; abstr 5508). 2Biagi et al. Ann Oncol. 2011;22: Matulonis UA et al. J Clin Oncol. 2009;27: Buckanovich et al. J Clin Oncol. 2011;29(suppl; abstr 5008).
5Friedlander et.al. Gyn Oncol. 2010,. 6Ledermann et al. J Clin Oncol. 2011;29:3798.

69. Recurrent Ovarian Cancer Randomized Phase II Studies
Weekly Paclitaxel
AMG mg/kg IV weekly
n=53
Ovarian, primary peritoneal, or fallopian tube cancer
n=161
1-3 prior lines
Weekly Paclitaxel
AMG mg/kg IV weekly
n=53
RANDOM I
Z E
Weekly Paclitaxel
Placebo
n=55
AMG-386
10 mg/kg IV
weekly PD
AMG-386 blocks interactions between Ang1 and Ang2 and their receptor Tie2. AMG-386 peptide-Fc fusion protein (peptibody).
Paclitaxel 80 mg/m2 IV weekly, 3 weeks on/1 week off
10 mg/kg
3 mg/kg
Placebo
*Median PFS, months
7.2
5.7
4.6
*HR (Arm A+B vs placebo) = 0.76 (80% CI, 0.59, 0.98), p=0.17, Trend test, p=0.037
ORR (CR+PR)
37%
19%
27%
Karlan BY et al. J Clin Oncol. 2010;28:15s(suppl; abstr 5000).

70. Recurrent Ovarian Cancer Randomized Phase II Studies
STUDY*
AGENTS
186-G
Bevacizumab-Everolimus vs
Bevacizumab-Placebo
Completed accrual
186-I
Bevacizumab-Fosbretabulin vs
Bevacizumab
Accrual in progress
186-J
Weekly Paclitaxel-Pazopanib vs
Weekly Paclitaxel-Placebo
*1-3 prior lines
Primary endpoint: PFS

71. Olaparib: An Orally Active PARP Inhibitor in Ovarian Cancer
Phase I and BRCA mutation expansion studies in ovarian cancer patients1
Olaparib multicenter Phase II BRCA mutation ovarian cancer study2
Olaparib multicenter Phase II BRCA+/– study (ovarian cancer patients)3
Olaparib patients
n=50
n=33
n=64
Olaparib dose
200 mg bid
400 mg bid
RECIST response (CR + PR)
28%
33%
BRCA+ 41%
BRCA– 24%
Disease control rate*
34%
69%
BRCA+ 76%
BRCA– 62%
Median duration of response
7.0 months
9.5 months
Not reported
*Complete response (CR) + partial response (PR) + stable disease (SD)
Provides clinical evidence of activity in ovarian cancer patients with and without BRCA1/2 mutations
1. Fong PC et al. J Clin Oncol 2010;28:2512– Audeh MW et al. Lancet 2010;376:245– Gelmon KA et al. Lancet Oncol 2011;12:852–861.

72. AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC)
Non-Platinum Chemotherapy
Treat to progression
Recurrent EOC
platinum resistant
≤ 2 prior therapies
no clinical or radiologic evidence of bowel involvement
RANDOM I
Z E
Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg
Treat to progression
N = 361
Chemotherapy Options
Paclitaxel 80 mg/m2 d 1,8,15, 22 q28
Topotecan 4 mg/m2 d 1, 8 ,15 q28 or
Topotecan 1.25 mg/m2 d 1-5 q21
PLD 40 mg/m2 d 1 q28
Stratified
chemotherapy
PFI (< 3 vs 3-6 mo)
prior anti-angiogenesis
Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.

73. AURELIA Progression-free Survival
1.0
0.8
0.6
0.4
0.2
0.0 6 12 T
ime (months)
Estimated Probability 18 30 24
182 93 37 8 1 20
179
140 88 4 49
BEV + CT C
Number at risk
Events, n (%)
Median PFS, months
(95% CI)
166 (91%)
3.4
( )
135 (75%)
(n = 182)
BEV + C
(n = 179)
6.7
( )
HR (unadjusted)
Log-rnak P
-value
(2-sided, unadjusted)
0.48
( )
< 0.001
Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.

74. aTwo-sided chi-square test with Schouten correction
Response Rates For Chemotherapy Alone Weekly Paclitaxel, Pegylated Liposomal Doxorubicin or Topotecan) or With Bevacizumab (BEV + CT)
P<0.001a
P=0.001a
P<0.001a
Patients (%)
Tables , ,
aTwo-sided chi-square test with Schouten correction
Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.

75. Questions about AURELIA
Given known single agent response to bevacizumab, how would a bevacizumab alone arm compare?
Is it better to use chemo with bevacizumab rather than sequentially?
This should be answered by the overall survival data due in 2013, since patients on the chemo alone arm could subsequently get bevacizumab
Should we limit this therapy to patients at low risk of GI perforation?
Will these same benefits be seen in patients who had bevacizumab with initial chemotherapy?

76. Phase II Trial of Olaparib vs PLD in BRCA-associated Recurrent Ovarian Cancer
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
n=32
PD or withdrawal from treatment for other reason
Patients:
BRCA1/2 germline mutation
Recurrent Ovarian Cancer
Olaparib
400 mg bid
n=32
Randomized
1:1:1
Patients with recurrence >12 months after completion of most recent platinum-based chemotherapy could be considered for inclusion if there was medical contraindication to further platinum therapy and was discussed and agreed by study sponsor
As above or max lifetime cumulative dose reached
PLD 50 mg/m2 IV
n=33
One cycle=28 days
Patients in PLD group were allowed to cross-over to
olaparib 400 mg bid on confirmed PD
Kaye SB et al. J Clin Oncol. 2012;30: 76

77. RECIST and CA-125 Responses
Patients, n (%)
Olaparib
200 mg bid (n=32)
400 mg bid (n=32)
PLD
(n=33)
Confirmed RECIST response
8 (25)
10 (31)
6 (18)
CA-125 response by GCIG*
11 (34)
18 (56)
11 (33)
Confirmed RECIST response and/or CA-125 response†
12 (38)
19 (59)
13 (39)
*GCIG criteria is confirmed ≥50% reduction in CA-125 levels that had to be maintained for ≥28 days;
†CA-125 response in the absence of RECIST progression
Kaye SB et al. J Clin Oncol. 2012;30: 77

78. Platinum resistant ovarian cancer patients
PRECEDENT: Randomized phase II PLD +/- Vintafolide (EC145) in platinum-resistant ovarian cancer patients
PLD= 50 mg/m2 (IBW) q 28 d
PLD only
n= 149 patients
n= 94 patients
Platinum resistant ovarian cancer patients
2:1 Randomization
Optional
etarfolatide
(EC20) Scan
Patients were enrolled at a total of 56 clinical centers in the United States (47), Canada (5) and Poland (4)
Vintafolide + PLD
Vintafolide = 2.5mg TIW wks 1, 3
PLD=50 mg/m2 (IBW) q 28 d
Primary Endpoint: PFS (investigator-assessed)
Secondary Endpoint: OS, RR, response duration
Exploratory Endpoint: Scan result and outcome
PI: Naumann, RW
Naumann et al. J Clin Oncol. 2011(suppl; abstr 5045).

79. Primary Endpoint PFS Results
EC145+PLD
n=100
PLD
n=49
Median time to event
5.0 months
2.7 months
HR (2-sided p-value)
0.63 (P-value=0.031)
PLD Alone
Vintafolide + PLD
Naumann et al. J Clin Oncol. 2011(suppl; abstr 5045).

80. Summary for Platinum-resistant Recurrent Ovarian Cancer
No benefit for combination chemotherapy
Sequential single-agent chemotherapy is standard
Multiple targeted agents with some demonstrated activity
Multiple trials of chemotherapy plus a targeted agent showing increased ORR or PFS (but none to date with OS advantage)
Chemotherapy plus bevacizumab (Aurelia)
Weekly paclitaxel plus trebananib (AMG-386)
PLD plus vintafolide 80

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