Judith K. Wolf, MD Professor

1
Treatment of Ovarian Cancer21st Century and
Beyond
Judith K. Wolf Professor Gynecologic Oncology

• Judith K. Wolf, MDProfessor Department of
  Gynecologic Oncology University of Texas M.D.
  Anderson Cancer Center Houston, TX

2
Ovarian Cancer 2010

• 1/71 lifetime risk1
• 5-year survival rates (by year of diagnosis)2
• 1990-1992 42.5
• 1993-1995 43.5
• 1996-2003 45
• Mortality relatively unchanged but statistically
  significant improvement in 5-year survival rates

1. SEER (Surveillance, Epidemiology, and End
Results) Program Web site. http//seer.cancer.
gov/statfacts/html/ovary.html. Accessed April 22,
2007. 2. http//seer.cancer.gov/csr/1975_2004/resu
lts_merged/sect_21_ovary.pdf. Accessed April 22,
2007.
3
Ovarian Cancer Staging

• Stage I - Limited to ovaries
• A. Unilateral ovary
• B. Bilateral ovaries
• C. Positive cytology
• Stage II - Limited to pelvis
• A. Extends to uterus or tubes
• B. other pelvic organs
• C. Positive cytology
• Stage III Spread to upper abdomen or regional
  lymph nodes
• A. Microscopic spread
• B. Macroscopic lt 2 cm
• C. Macroscopic gt 2 cm
• Stage IV - Spread outside peritoneum, pleura or
  parenchymal

liver metastases
4
Ovarian Cancer FIGO Staging System

• Stage Description Incidence Survival
• I Confined to ovaries 20 73
• II Confined to pelvis 5 45
• III Confined to abdomen/ 58
  21 lymph nodes
• IV Distant metastases 17 lt5

Jelic S, et al. Program and abstracts of the 27th
Congress of the European Society for Medical
Oncology 2002 Nice, France. Mocharnuk R.
Medscape Web site. http//www.medscape.com/viewart
icle/444134. Accessed May 2, 2007.
FIGO International Federation of Gynecology and
Obstetrics
5
Ovarian Cancer Surgical Debulking and Staging
Exploration
Biopsies (Staging)
TAH/ BSO

• Goals (Debulking)
• Assessment of extent of disease
• Optimal tumor reduction

Washings/ Ascites (Staging)
TAH total abdominal hysterectomy BSO
bilateral salphingo-oophorectomy
6
First-line Therapy Standard Treatment Options
Surgery with maximum cytoreduction effort lt1cm
residual disease
Platinum Taxane Chemotherapy(Carboplatin
Paclitaxel)
7
Chemotherapy

• Standard front-line chemotherapy in the US today
  is carboplatin, AUC 6 to 7.5, paclitaxel 175
  mg/m2 every 21 days for 6 cycles
• Result of several studies over last decade
• GOG 1111 and OV 102 - paclitaxel/cisplatin vs
  cyclophosphamide/cisplatin
• GOG 1583 and AGO OVAR-34 - carboplatin instead of
  cisplatin

1. McGuire WP, et al. N Engl J Med.
1996334(1)1-6.2. Piccart MJ, et al. J Natl
Cancer Inst. 200092(9)699-708. 3. Ozols RF, et
al. J Clin Oncol. 200321(17)3194-3200.4. du
Bois AD, et al. J Natl Cancer Inst.
200395(17)1320-1329.
GOG Gynecologic Oncology GroupAGO
ArbeitsgemeinschaftGynaekologische Onkologie
8
The Role of Paclitaxel in First-line Therapy for
Ovarian Carcinoma
Study Pts Regimen Median PFS (mo) Median OS (mo)
GOG 1321 377 III suboptimal-IV Cisplatin/Paclitaxel (24 h) x 6 14.1 26.3
GOG 1321 377 III suboptimal-IV Cisplatin 100 mg/m2 x 6 16.4 30.2
GOG 1321 377 III suboptimal-IV Paclitaxel 200 mg/m2 (24 h) 10.8 25.9
ICON32 2074 I-IV Carboplatin/ Paclitaxel (3 h) 17.3 36.1
ICON32 2074 I-IV Carboplatin or CAP 16.1 35.4
CAP cyclophosphamide, doxorubicin,
cisplatinGOG Gynecologic Oncology GroupICON
International Collaborative Ovarian Neoplasm
Group OS overall survivalPFS
progression-free survival
CR/PR rates on paclitaxel monotherapy (42) vs
cisplatin regimens (67), P lt.001
1. Muggia FM, et al. J Clin Oncol.
200018(1)106-115. 2. International
Collaborative Ovarian Neoplasm Group. Lancet.
2002360(9332)505-515.
9
The Schedule of Paclitaxel in First-line Therapy
for Ovarian Carcinoma
Study Pts Regimen Median PFS (mo) Median OS (mo)
GOG 1581 792 III optimal Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h) 19.4 48.8
GOG 1581 792 III optimal Carboplatin AUC 7.5Paclitaxel 175 mg/m2 (3 h) 20.7 56.7
GOG 1581 792 III optimal RR progression 0.88 (95 CI) and RR death 0.86 (95 CI) HR 0.86 (99 CI)
AGO2 798 IIB-IV Cisplatin 75 mg/m2Paclitaxel 185 mg/m2 (24 h) 19.1 44.1
AGO2 798 IIB-IV Carboplatin AUC 6Paclitaxel 185 mg/m2 (3 h) 17.2 43.3
AGO2 798 IIB-IV HR 1.050 (95 CI) HR 1.045 (95 CI)
More toxicity with the cisplatin regimens More toxicity with the cisplatin regimens More toxicity with the cisplatin regimens More toxicity with the cisplatin regimens More toxicity with the cisplatin regimens
AGO Arbeitsgemeinschaft Gynaekologische
OnkologieCI confidence intervalGOG
Gynecologic Oncology GroupHR hazard ratio OS
overall survivalPFS progression-free
survivalRR relative risk
1. Bookman MA, et al. Int J Gynecol Cancer.
200313(s2)149155. 2. du Bois AD, et al. J
Natl Cancer Inst. 200395(17)1320-1329.
10
SCOTROC Trial
R A N D O M I Z E
Carboplatin AUC 5, docetaxel 75 mg/m2 (1
h)Q3W x 6 Carboplatin AUC 5, paclitaxel 175
mg/m2 (3 h)Q3W x 6

• Ovarian cancer stage Ic-IV
• Primary peritoneal cancer
• N 1077

SCOTROC Scottish Randomized Trial in Ovarian
CancerQ3W once every 3 weeks
Vasey PA, et al. J Natl Cancer Inst.
200496(22)1682-1691.
11
SCOTROC Results

• Parameter DC PC
• Response (standard) 59 60
• Response (CA-125) 76 77
• Progression-free survival 15 mos 14.8 mos
• Overall survival at 24 months 64 69

DC docetaxel-carboplatinPC
paclitaxel-carboplatinSCOTROC Scottish
Randomized Trial in Ovarian Cancer
Vasey PA, et al. J Natl Cancer Inst.
200496(22)1682-1691.
12
SCOTROC Conclusion

• PC vs DC PC the Standard
• Overall toxicity clearly favors paclitaxel
  regimen for all except neurotoxicity and
  arthralgia/myalgia
• Differences in neurotoxicity related to taxane in
  each regimen should be reversible
• Myelotoxicity worse with docetaxel and prevents
  use of what may be optimal dose of carboplatin
• Paclitaxel/carboplatin remains the standard of
  care in order to maximize efficacy, minimize
  life-threatening toxicity

DC docetaxel-carboplatinPC
paclitaxel-carboplatin
Vasey PA, et al. J Natl Cancer Inst.
200496(22)1682-1691.
13
GOG 182-ICON5 International Study for Stage
III/IV
Regimen I (control) Paclitaxel 175 mg/m2 IV (3
h) d 1 Carboplatin AUC 6 IV d 1
Regimen II (triplet A) Paclitaxel 135 mg/m2 IV
(3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine
800 mg/m2/d IV d 1, 8
Regimens I, II, and III 8 cycles, 21-d cycle
interval Regimens IV and V 4 cycles, 21-d cycle
interval

• Randomization
• All patients
• Equal proportions on each regimen
• Primary end points PFS, OS, RR

Regimen III (triplet B) Paclitaxel 135 mg/m2 IV
(3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30
mg/m2 IV d 1 Every other cycle
Regimen IV (sequential module A) Carboplatin AUC
5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3
Regimen IV (sequential module B) Paclitaxel 175
mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1
Regimen V (sequential module A) Carboplatin AUC
6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8
Regimen V (sequential module B) Paclitaxel 175
mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1
GOG Gynecologic Oncology Group ICON
International Collaborative Ovarian Neoplasm
Group OS overall survival PFS
progression-free survival RR response rate
Bookman MA. J Clin Oncol. 200624(18S)Abstract
5002.
14
GOG0182-ICON5 Progression-Free Survival
Median PFS and HR (95 CI) 16.1 1.000 16.4
0.990 (0.884-1.107) 16.4 0.998
(0.891-1.117) 15.3 1.094
(0.979-1.224) 15.4 1.052 (0.940-1.176)
C carboplatinD pegylated liposomal
doxorubicinG gemcitabineP paclitaxel PFS
progression-free survivalT topotecan
Bookman MA. J Clin Oncol. 200624(18S)Abstract
5002.
15
GOG0182-ICON5 Overall Survival
Median OS and HR (95 CI) 40.0 1.000 40.4
0.978 (0.838-1.141) 42.8 0.972
(0.832-1.136) 39.1 1.068
(0.918-1.244) 40.2 1.035 (0.888-1.206)
C carboplatinD pegylated lipososomal
doxorubicinG gemcitabineP paclitaxel 0S
overall survivalT topotecan
Bookman MA. J Clin Oncol. 200624(18S)Abstract
5002.
16
Current GOG Frontline Trial
GOG 218
gt Microscopic residual EOC, PPC cancer
Paclitaxel Carboplatin Placebo
Paclitaxel Carboplatin Bevacizumab
Paclitaxel Carboplatin Bevacizumab
Bevacizumab 16 cycles
Placebo 16 cycles
Placebo 16 cycles
EOC epithelial ovarian cancerFT fallopian
tubeGOG Gynecologic Oncology GroupPFS
progression-free survivalPPC primary
peritoneal cancerQOL quality of life
N 2,000 patients Survival, PFS primary
endpoints Biologic QOL endpoints
17
EORTC-55971
Upfront Debulking Surgery vs Neoadjuvant
ChemotherapyStage IIIc or IV Epithelial Ovarian
Carcinoma
Cytoreductive Surgery
3 Courses Platinum-Based Chemotherapy
3 Courses Platinum-Based Chemotherapy
IDS With Response or Stable Disease
IDS Allowed
Repeat ChemotherapySLS allowed
Repeat ChemotherapySLS allowed
EORTC European Organisation for Research and
Treatment of CancerIDS Interval Debulking
SurgerySLS Second-Look Surgery
The EORTC Groups Web site. Gynaecological Cancer
Group Active Study Protocols. http//groups.eortc.
be/gcg/studyprotocols.htm55971. Accessed June
12, 2007.
18
GC vs TC Induction Regimens Followed by T
Consolidation Study Design
Histologic diagnosis and prior resection of
stage IC-IV epithelial ovarian, primary
peritoneal, or fallopian tube carcinoma
Induction GC Gemcitabine 1000 mg/m2 Days 1, 8
Carboplatin AUC 5 Day 1 x 6 cycles every 21 days
Induction TC Paclitaxel 175 mg/m2 Day 1
Carboplatin AUC 6 Day 1 x 6 cycles q 21 days
Clinical CR
Anything other than CR (PR, SD, PD)
Anything other than CR (PR, SD, PD)
ElectiveT Consolidation Therapy Paclitaxel 135
mg/m2 every 28 days for 12 cycles
Single-agent crossover Paclitaxel 175 mg/m2 Day 1
Single-agent crossover Gemcitabine 1000 mg/m2
Days 1, 8
Gordon A, et al. ASCO 2008. Abstract 5536.
19
GC vs TC Induction Regimens Followed by T
Consolidation Response Rates
Best response, n () Induction GC (n 66) Induction TC (n 58) P Value
CR 30 (45.5) 26 (44.8)
PR 13 (19.7) 12 (20.7)
SD 5 (7.6) 8 (13.8)
PD 6 (9.1) 4 (6.9)
Data not available 12 (18.2) 8 (13.8)
ORR (CR PR) 43 (65.2) 38 (65.5) ? .999
DCR (CR PR SD) 48 (72.7) 46 (79.3) .410
CR required a normalized CA-125.
Gordon A, et al. ASCO 2008. Abstract 5536.
20
GC vs TC Induction Regimens Followed by T
Consolidation Pt-Based Toxicity
Toxicity, n () Induction GC (n 219) Induction TC (n 220) P Value
Hematologic
G3/4 thrombocytopenia 88 (40.2) 55 (25.1) 30 (13.6) 10 (4.5) ? .0001
G3/4 anemia 52 (23.7) 20 (9.1) ? .0001
Nonhematologic
? G2 neuropathy 24 (11.0) 43 (19.5) .0165
G2 alopecia 79 (36.1) 110 (50.0) .0038
Platelet transfusion 7 (3.2) 0 (0) .0073
Gordon A, et al. ASCO 2008. Abstract 5536.
21
Conventional vs Dose-Dense TC (NOVEL) Study
Design
Ovarian epithelial, primary peritoneal, or
fallopian tube cancer with FIGO stage II-IV
Stratified by residual disease 1 cm vs gt 1
cm FIGO stage II vs III vs IVhistology clear
cell/mucinous vs serous/others
Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1
Carboplatin AUC 6.0 Day 1 every 21 days for
6-9 cycles
Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2
Days 1, 8, 15 Carboplatin AUC 6.0 Day 1 every
21 days for 6-9 cycles
Isonishi S, et al. ASCO 2008. Abstract 5506.
22
Conventional vs Dose-Dense TC (NOVEL) Clinical
Responses
Measurable Patients, Patients,
Measurable c-TC (n 135) dd-TC (n 147)
Objective response 53 56
CR 16 20
PR 38 36
NC 31 29
PD 7 3
NE 9 12
P .72
Isonishi S, et al. ASCO 2008. Abstract 5506.
Evaluated by WHO criteria
23
Conventional vs Dose-Dense TC (NOVEL) PFS
Isonishi S, et al. ASCO 2008. Abstract 5506.
1.0
0.9
dd-TC
0.8
c-TC
0.7
0.6
Proportion Surviving Progression Free
0.5
0.4
0.3
0.2
0.1
0.0
0
12
30
54
6
18
42
24
48
36
Mos From Randomization
Treatment n Event Median PFS, mos P Value HR 95 CI
c-TC 319 200 17.2
dd-TC 312 160 28.0 .0015 0.714 0.581-0.879
24
Ovarian Carcinoma Clinical Course
Secondary Cytoreduction
Interval Cytoreduction
Second-Look
Diagnosis
Progression
Death
Chemo 2
Symptoms
Chemotherapy 1
Chemo 3
Consolidation/ Maintenance
Cure
Supportive Care
Staging Primary cytoreduction
25
Goals of TreatmentRelapsed Ovarian Cancer

• Prolong Survival
• Delay Time to Progression
• Control Disease-Related Symptoms
• Minimize Treatment-Related Symptoms
• Maintain or Improve Quality of Life

26
Issues Impacting Therapy for Recurrent Ovarian
Cancer

• Treatment-free interval
• Impact of consolidation/maintenance therapy
• Number of prior regimens
• Response to prior therapy
• Toxicity from prior therapy
• Prior use of growth factors
• Transfusion requirements
• Neuropathy
• Volume and site(s) of disease
• Ascites/GI symptoms
• Performance status

27
Surveillance Options for Ovarian Cancer Patients
in Remission

• Second-look laparotomy
• Physical examination
• Include pelvic examination
• CA-125
• Imaging
• CT scan
• MRI?
• PET scan?

CT computed tomography MRI magnetic resonance
imaging PET positron emission tomography
28
Ovarian CancerHow is Relapse Defined?

• Continuous rise in CA-125
• CA-125 above 100
• Radiographic recurrence
• Symptomatic recurrence
• Physical examination findings
• Combination of above

29
When Does Ovarian Cancer Recur?
Population Study Treatment PFS
Optimal St III GOG 114 IV Carb Pac, IP Cis 28 mos
GOG 172 IV Pac, IP Cis Pac 24 mos
GOG 158 IV Pac Carb 21 mos
GOG 114 IV Pac Cis 22 mos
GOG 158 IV Pac Cis 19 mos
GOG 172 IV Pac Cis 18 mos
Suboptimal III IV GOG 111 IV Pac Cis 18 mos
GOG 162 IV Pac Cis 12 mos
GOG 152 IV Pac Cis 11 mos
Stage IC-IV SCOTROC Doc Carbo 15 mos
Stage IC-IV SCOTROC Pac Carbo 15 mos
All Stage III IV GOG 182 IV Pac/Carbo x 8 16 mos
Carb carboplatin Cis cisplatin Doc
docetaxel pac paclitaxelGOG Gynecologic
Oncology Group IP intraperitoneal Pac
paclitaxel
30
Active Agents in Ovarian Cancer
FDA approved FDA approved FDA approved
Altretamine Carboplatin Cisplatin
Gemcitabine/ Carboplatin Paclitaxel Pegylated liposomal doxorubicin
Topotecan
Not FDA approved, compendium listed Not FDA approved, compendium listed Not FDA approved, compendium listed
Chlorambucil Cyclophosphamide Docetaxel
Doxorubicin Epirubicin Etoposide
5-FU/LV Gemcitabine Ifosfamide
Irinotecan Melphalan Methotrexate
Thiotepa Vinorelbine
Not FDA approved, not compendium listed Not FDA approved, not compendium listed Not FDA approved, not compendium listed
Aromatase inhibitors Bevacizumab Pemetrexed
Tamoxifen
31
Effect of Platinum-Free Intervalon Response Rate
Non-Platinum Therapy

15
20
30
30

Response to Second-line Platinum Therapy Response to Second-line Platinum Therapy Response to Second-line Platinum Therapy
Platinum-Free Interval (mos) Markman Gore Blackledge
0-6 17 10
7-12 27 17 29
13-18 33 27 63
19-24 33 27 94
gt24 59 57
Markman M, et al. J Clin Oncol.
19919(3)389-393. Gore ME, et al. Gynecol
Oncol. 199036207-211. Blackledge G, et al. Br J
Cancer. 198959650-653.
32
Ovarian Cancer at First RelapseDefinition of
Sensitivity
P R I M A R Y T R E A T M E N T
0 3 6 12 18 24
Months
Refractory
Resistant
Sensitive
Very Sensitive
Defined as measurable recurrence, not biochemical
(CA-125) recurrence
33
ICON 4 Schema
R A N D O M I Z E
Conventional platinum-based chemotherapy

• Relapsed ovarian or primary
• Peritoneal requiring chemotherapy
• Previous platinum-based chemotherapy

Paclitaxel plus platinum chemotherapy

• Prior chemotherapy
• Carboplatin (31)
• Paclitaxel/platinum (40)
• Other (30)
• TFI gt 12 months for 75

ICON International Collaborative Ovarian
Neoplasm Group TFI treatment-free interval
Parmar MK, et al. Lancet. 20033612099-2106.
34
ICON 4 Response
(Difference of 12 95 CI -0.1 to 24 p0.06)
CR complete response ICON International
CollaborativeOvarian Neoplasm Group Pac
paclitaxel Plat platinum PR partial
response
Parmar MK, et al. Lancet. 20033612099-2106.
35
Ovarian Carcinoma ICON 4 Progression-Free
Survival
1.0

Hazard ratio 0.76 (95 CI 0.66 - 0.89 p lt
0.001)
0.9
0.8
0.7
Absolute difference at 1 year 10 (40 to
50 95 CI 4 to 15)
Proportion alive and progression-free
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
Years from randomization
Patients at risk
Pac-Plat
392 179 52
25 17
Plat
410 157 45
17 7
ICON International Collaborative Ovarian
Neoplasm Group Pac paclitaxel Plat platinum
Parmar MK, et al. Lancet. 20033612099-2106.
36
ICON 4 Overall Survival
Hazard ratio 0.82 (95 CI 0.69 - 0.97 p
0.023)
1.0
0.9

Absolute difference 2 years 7 (50 to 57
95 CI 1 to 12)
0.8
0.7
Proportion alive
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
Years from randomization
Patients at risk
Pac-Plat
392 306 167
96 43
Plat
410 295 150
68 33
ICON International Collaborative Ovarian
Neoplasm Group Pac paclitaxel Plat platinum
Parmar MK, et al. Lancet. 20033612099-2106.
37
Gem/Carbo vs Carbo Design

• Recurrent ovarian cancer
• 6 months after platinum
• Strata
• PFI (6 - 12, gt12 months)
• 1st-line therapy (platinum paclitaxel)
• Measurable vs evaluable
• Primary endpoint PFS

Gemcitabine 1,000 mg/m2 days 1 8
Plus Carboplatin AUC 4 day 1
RANDOMIZE
every 21 days 6
Carboplatin AUC 5 day 1
every 21 days 6
Carbo carboplatin Gem gemcitabine PFI
progression-free interval PFS progression-free
survival
Pfisterer J, et al. J Clin Oncol. 2006
244699-4707.
38
AGO OVAR 2.5 Primary Endpoint Progression-Free
Survival
Log-rank p-value 0.0038 Unadjusted HR 0.72
(0.57 to 0.90) Adjusted HR 0.71 (0.57 to 0.89)
GCb median 8.6 mo Censoring 12.4
GCb Arm (N178)
Cb Arm (N178)
Cb median 5.8 moCensoring 12.9
Adjusted for PFI, Tumor size
AGO Arbeitsgemeinschaft Gynaekologische
Onkologie GCb gemcitabine Cb carboplatin
Pfisterer J, et al. J Clin Oncol.
2006244699-4707.
39
AGO OVAR 2.5 Efficacy Results Overall Survival
1.0
0.9
Median 18.0 mo Censoring 18.5
GCb Arm (N178)
0.8
Cb Arm (N178)
0.7
Proportion Surviving
0.6
Log-rank p-value 0.7349 Unadjusted HR 0.96
(0.75 to 1.23) Adjusted HR 0.92 (0.72 to 1.16)
0.5
0.4
Median 17.3 mo Censoring 22.5
0.3
0.2
0.1
0.0
0
6
12
18
60
54
48
42
36
30
24
Months
AGO Arbeitsgemeinschaft Gynaekologische
Onkologie GCb gemcitabine Cb carboplatin
Adjusted for PFI, Tumor size and performance
status
Pfisterer J, et al. J Clin Oncol.
2006244699-4707.
40
GCIG CALYPSO Trial
Accrual Completed (Target accrual 864 pts)PFS
1 endpoint
PLD 30 mg/m2 Carboplatin AUC 5 q 28 days x 6
R A N D O M I Z E
Ovarian Cancer Platinum Sens. Stratify lt 0.5
cm gt 0.5-2 cm
Paclitaxel 175 mg/m2 Carboplatin AUC 5 q 21
days x 6
GCIG Gynecologic Cancer Intergroup PFS
progression-free survival PLD pegylated
liposomal doxorubicin
41
Farletuzumab (MORAb-003) in Platinum-Sensitive
EOC Study Rationale

• FRA is overexpressed in most EOC largely absent
  from normal tissue
• Binding of MORAb-003 to FRA blocks
  phosphorylation by Lyn kinase mediates
  FRA-expressing tumor cell killing suppresses
  tumor growth in xenograft models
• Phase I study of single agent MORAb-003
  demonstrated no significant adverse effects and
  suggested efficacy in platinum-resistant EOC

42
MORAb-003 in Platinum-Sensitive EOC Phase II
Study Design

• Patients with platinum-sensitive EOC in first
  relapseafter first remission of 6-18 months
  durationwith evaluable disease by
  CA125(Enrolled N 58eligible n 54)

Asymptomatic relapse
Symptomatic relapse
Original Carbo/Taxane regimen Farletuzumab for
6 cycles (n 26)
Single-agent Farletuzumab until progression(n
28)
Single-agent ORR
Combination ORR
Farletuzumab maintenance Rx for responders
Compare lengths of first and second remissions
Armstrong DK, et al. ASCO 2008. Abstract 5500.
43
MORAb-003-002 Phase II Treatment Arms

• All arms
• MORAb-003 100 mg/m2 weekly
• Run-in phase with 6 subjects at 37.5 and 6 at
  62.5 mg/m2
• Combination therapy arm every 21 days x 6 cycles
• Carboplatin AUC 5-6
• Taxane
• Paclitaxel 175 mg/m2 over 3 hours or
• Docetaxel 75 mg/m2

Armstrong DK, et al. ASCO 2008. Abstract 5500.
44
Comparison of First vs Second Remission Length n
6
Subject 1st Remission, Mos 2nd Remission, Mos Status
1 8.3 19.5 Still in remission
2 10.8 19.1 Still in remission
3 10.1 15.8 Still in remission
4 9.5 9.6 Still in remission
5 8.2 8.2 Relapsing
6 6.5 7.8 Still in remission
Data as of May 5, 2008.
Armstrong DK, et al. ASCO 2008. Abstract 5500.
45
MORAb-003-002 Clinical Responses by RECIST
(Combination Therapy)

• Best response
• CR 7.4
• PR 62.9
• SD 25.9
• PD 3.7
• Based on all scans submitted as of December 3,
  2007 ( 30)
• By independent central reader
• MORAb-003 well tolerated no increase observed in
  toxicity profile in combination arm

ORR 70.3
Patient benefit 96.3
Armstrong DK, et al. ASCO 2008. Abstract 5500.
46
Secondary Cytoreduction

• Controversial
• Inconsistent definitions
• Benefit appears confined to patients likely to
  respond to additional chemo
• gt12 month PFI
• Isolated site of recurrence
• Disease completely resectable

PFI progression-free interval
47
Ovarian Cancer Secondary Cytoreduction
Post-Surgery Survival
Author Janicke Segna Zang Gadducci Eisenkop Munk
arah Scarabelli Tay Total/Range
Year 1992 1993 2000 2000 2000 2001 2001 2002
N 30 100 60 30 114 25 148 46 553
Survival Median mos 16 16.6 13 21 16.8 26 13-
26
TTP mos lt12 lt12 lt12 lt17.5 lt12 lt24 lt12 lt12
Survival Median mos 8 8.8 8 15 25 42 12 6 6-42
Survival Median mos (P) 29 (0.002) 22.9
(0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57
(NS) 32 (0.001) 39 (0.001) 12-56
TTP mos gt12 gt12 gt12 gt17.5 gt36 gt24 12-24 gt24
TTP time to progression
48
GOG 213- PI Robert Coleman
Recurrent ovarian or peritoneal cancer TFI gt6 mos
Surgery
Randomize to Chemotherapy
YES
No surgery
Surgical Candidate?
NO
Carboplatin Paclitaxel
Carboplatin Paclitaxel Bevacizumab
Bevacizumab Maintenance
GOG Gynecologic Oncology GroupTFI
treatment-free interval
49
Effect of Platinum-Free Intervalon Response Rate
Non-Platinum Therapy

15
20
30
30

Response to Second-line Platinum Therapy Response to Second-line Platinum Therapy Response to Second-line Platinum Therapy
Platinum-Free Interval (mos) Markman Gore Blackledge
0-6 17 10
7-12 27 17 29
13-18 33 27 63
19-24 33 27 94
gt24 59 57
Markman M, et al. J Clin Oncol.
19919(3)389-393. Gore ME, et al. Gynecol
Oncol. 199036207-211. Blackledge G, et al. Br J
Cancer. 198959650-653.
50
Recent Phase II GOG Studies in Platinum-Resistant
Ovarian Cancer

• Study Agents Response/comm
• 126-B CDDP Cyclosporine-A 3/23 (13) Inactive
• 126-C Hexamethylmelamine 3/30 (10) Inactive
• 126-D Pyrazoloacridine 2/24 (8.4) Inactive
• 126-E PSC833 paclitaxel 1/16 (6) Inactive
• 126-G CI-958 1/25 (4) Inactive
• 126-H Topotecan (24 h) 1/25 (4) Inactive
• 126-I 9-amino-camptothecin 8/58 (14) Moderate
• 126-J Docetaxel 13/58 (22) Active
  (post-paclitaxel)

CDDP c/s-diamminedichloroplatinum
(cisplatin) GOG gynecologic oncology group
Bookman MA. Semin Oncol 200229(suppl 1)20-31.
51
Recent Phase II GOG Studies in Platinum-Resistant
Ovarian Cancer

• Study Agents Response/comm
• 126-K Oxaliplatin 1/25 (4) Inactive
• 126-L Gemcitabine/CDDP 9/57 (16) Moderate
• 126-M Ixabepilone 7/50 (14) Moderate
• 126-N Paclitaxel weekly 10/48 (21) Active
• (post-paclitaxel)
• 126-O Triapine-CDDP Not Feasible
• 126-P Paclitaxel Celecoxib Closed Early
• 126-Q Pemetrexed 10/48 (21) Active
• 126-R Abraxane Accrual in Progress

CDDP c/s-diamminedichloroplatinum
(cisplatin) GOG gynecologic oncology group
Bookman MA. Semin Oncol 200229(suppl 1)20-31.
52
Pemetrexed in Platinum-Resistant EOC Phase II
GOG Study Schema
Patients with persistent or recurrent
platinum-resistant EOC or primary peritoneal
cancer who have failed on higher priority
treatment protocols
Pemetrexed 900 mg/m2 IV every 21 days for 1
cycle patients who have received previous
radiotherapy will initiate pemetrexed at level I
reduction dose until disease progression or
adverse effect prohibits further therapy
Day -7Folic acid, Vitamin B12 Day -6Folic acid Day -5Stop NSAID, folic acid Days -4,-3Folic acid Day -2Stop NSAID, folic acid Day -1Dexamethasone, folic acid Day 1Chemotherapy, dexamethasone, folic acid Day 2Dexamethasone,folic acid
Miller DS, et al. ASCO 2008. Abstract 5524.
53
Phase II GOG Study Evaluation of Pemetrexed
Clinical Responses
Category No. of Cases Pts,
Response
CR 1 2.1
PR 9 18.8
SD 17 35.4
Increasing disease 18 37.5
Not evaluable 3 6.3
Total 48 100
Miller DS, et al. ASCO 2008. Abstract 5524.
1 patient remains on therapy.
54
Cochrane Review of Tamoxifen for Relapsed Ovarian
Cancer

• 13 studies (11non-randomized series, 1
  non-randomized phase II and 1 randomized trial)
• 59 of 568 women (10.4) treated with tamoxifen
  achieved an objective response (RR)
• RR varied from 0 to 56
• Stable disease, for variable periods of 4 weeks
  or more, in 109 of 356 (30.6) from 8 studies
• Not enough data to assess duration of RR,
  survival, or the effect of tamoxifen on quality
  of life
• No reliable data from randomized controlled trials

RR response rate
Williams CJ. Cochrane Database Syst Rev.
2000(2)CD001034.
55
GOG Experience

• GOG 160 Trastuzumab
• GOG 170
• Human Interleukin-12 (170B) Lapatinib (170G)
• Gefitinib (170C) Vorinostat (170H)
• Bevacizumab (170D) Temsirolimus (170I)
• Imatinib (170E) Enzastaurin (170J)
• Bay 43-9006 (170F) Mifepristone (170K)

Insufficiently Active Too Early Active
Ongoing GOG Phase II Effort
GOG Gynecologic Oncology Group
56
Antiangiogenic Agents in Testing for Treatment
of Ovarian Cancer
Agent Targets Ligand binding Bevacizumab VEGF
-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and
-2 Receptor binding Volociximab ?5?1
integrin IMC-1121B VEGFR-2 Receptor tyrosine
kinase inhibition Valatanib VEGFR-1, -2, -3,
PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2,
-3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3,
PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3,
Flt-3, c-kit, PDGFR- ? Non-receptor kinase
inhibition Temsirolimus, everolimus mTOR Enzastau
rin PKC- ? Dasatinib Src kinase
EGFR epidermal growth factor receptor Mab
monoclonal antibody mTOR mammalian target of
rapamycin PDGF-R platelet derived growth
factor receptor PKC-b protein kinase C-beta
VEGF vascular endothelial growth factor
57
Rationale for Targeting VEGF in Treatment of
Epithelial Ovarian Cancer

• Human tumors
• VEGF over-expressed in epithelial ovarian
  cancers, associated with
• Ascites formation
• Malignant progression
• Poor prognosis
• Preclinical models of solid tumors
• Anti-VEGF therapy
• Slowing of tumor progression
• Resolution of malignant effusions
• Synergy with cytotoxic agents

Han ES, et al. Expert Rev Anticancer Ther.
20077(10)1339-1345.Burger RA. J Clin Oncol.
200725(20)2902-2908.
VEGF vascular endothelial growth factor
58
Agents Targeting the VEGF Pathway
VEGF
Soluble VEGFRs (VEGF-TRAP)
VEGFR-2
VEGFR-1
Endothelial Cell
Small-Molecule Inhibitors
VEGF vascular endothelial growth factor VEGFR
VEGF receptor
Podar K, et al. Blood. 2005105(4)1383-1395.
59
Bevacizumab - Toxicity

• Proteinuria (usually G1 G2)
• Muco-cutaneous hemorrhage
• Common G1 epistaxis
• Rare (possibly life-threatening) G2-G4 tumor site
  hemorrhage (primarily lung cancer trials)
• Arterial thromboembolism
• Uncommon (3 - 5)
• Risk factors age gt 65, prior arterial TE
• Risk of venous thromboembolism not increased
• GI perforation wound healing
• Perforation uncommon (2 - 4 in solid tumor
  population)
• Wound dehiscence rate 1

G1, G2 immunoglobulins GI gastrointestinal TE
thromboembolism
Han ES, et al. Expert Rev Anticancer Ther.
20077(10)1339-1345.Burger RA. J Clin Oncol.
200725(20)2902-2908.
60
Phase II Studies of Bevacizumabin Ovarian
Cancer
Cannistra 2007 Burger 2007 Garcia 2008
Number of Pts 44 62 70
Prior Regimens 2 52 3 48 1 34 2 66 Median 2 Range 1-3
Response Rate 16 (PRs) 18 (PRs) 3 (CRs) 24 (PRs)
GI Perforations 11 0 6
Arterial Thromboembolism 7 0 4
Deaths 7 0 4
Cannistra SA, et al. J Clin Oncol.
200725(33)5180-5186.Burger RA, et al. J Clin
Oncol. 200725(33)5165-5171.Garcia AA, et al. J
Clin Oncol. 200826(1)76-82.
CR complete response GI gastrointestinal PR
partial response
61
GI Perforations with Bevacizumabin Ovarian Cancer
Study GI (Gastrointestinal) Perforations
Burger (GOG 170D) 0/62 (0)
Garcia (ASCO 2005) 2/29 (6.9)
Cannistra (ASCO 2006) 5/44 (11.4)
Wright (ASCO 2006) 4/62 (6.5)
Friberg (ASCO 2006) 2/13 (15.4)
Monk (Gyn Oncol 2006) 1/32 (3.1)
Wright (Cancer 2006) 2/23 (8.7)
Bidus (Gyn Oncol 2006) 0/3 (0)
Penson (ASCO 2006) 0/30
Total 16/298 (5.4)
GI gastrointestinal
Han E, et al. Gynecol Oncol. 2007105(1)3-6.
62
NCI Registered Phase II Trials Anti-VEGF
Cytotoxic
Protocol Drug Class PI Status
MDA-2006-0329 AVE-0005 - Docetaxel Receptor Coleman Active
NCT00129727 Bev (CT) MAb Penson Active
TEACO Bev Ox/Docetaxel MAb Herzog Active
MCC-105366c Bev Docetaxel MAb Wenham Active
ALSSOPR0501 Bev Paclitaxel Protein-Bound MAb Schwartzberg Active
NCT00343044 Bev Topotecan MAb McGonigle Active
NCT00267696 Bev Carbo/Gem MAb Copeland Active
AVF3953 Bev IV Paclitaxel/IP ? Bev MAb McMeekin Active
NCT00418093 Bev Ox/Gem MAb Horowitz Active
Bev bevacizumab Carbo carboplatin Gem
gemcitabine IP intraperitoneal Mab
monoclonal antibody Ox Oxaliplatin VEGF
vascular endothelial growth factor
Front Line Carboplatin and Paclitaxel
63
NCI Registered Phase II TrialsVEGF EGFR
Inhibitors
Protocol Drug Class PI Status
NCI Bev Erlotinib MAb Friberg Active
NCT00130520 Bev Erlotinib MAb Alberts Active
NCT00520013 Bev /- Erlotinib Consolidation MAb Campos Active
Bev bevacizumab EGFR epidermal growth factor
receptor Mab monoclonal antibody VEGF
vascular endothelial growth factor
64
NCI Registered Phase II TrialsOther
Anti-Angiogenic Agents
Protocol Drug Target(s) PI Status
GOG 170-J Enzastaurin (TKI) PKC -b Usha Suspended
NCT00391118 CT /- Enzastaurin ? Enzastaurin PKC -b (Not Listed) Active
GOG 170-E Imatinib (TKI) PDGF-R Schilder Completed
NCT00039585 Imatinib (TKI) PDGF-R Kohn Completed
NCT00516841 Volociximab (MAb) ?5?1 Integrin Multiple Active
NCT00479817 AMG 386 (Peptibody) Angiopoietins (Not Listed) Active
CT chemotherapy GOG gynecologic oncology
group EGFR epidermal growth factor receptor
Mab monoclonal antibody PDGF-R platelet
derived growth factor receptor PKC-b protein
kinase C-beta TKI tyrosine kinase inhibitor
65
Bev Topotecan in Platinum Refractory Ovarian
Cancer Study Design

• Single arm, 2-site phase II trial

PD as defined by RECIST criteria
Platinum-refractory OC recurrence lt 6 mos of
platinum therapy received max of 2 previous
chemotherapy regimens (N 40)
Bevacizumab 10 mg/kg Days 1, 15 Topotecan 4
mg/m2 Days 1, 8, 15 for 28-day cycles
Excessive toxicity according to prespecified
criteria
Treatment continued until 1 of the following
events
Toxicity requiring topotecan delay gt 2 weeks or
bevacizumab delay gt 2 months
Topotecan-related toxicities requiring gt 2 dose
reductions
McGonigle KF, et al. ASCO 2008. Abstract 5551.
66
OS Patients With Platinum-Resistant Ovarian
Cancer (N 30)
Bev Topotecan
1.0
.75
.50
Patients Surviving ()
.25
0.0
0
2
4
6
8
10
12
14
16
18
20
Time (Mos)
McGonigle KF, et al. ASCO 2008. Abstract 5551.
67
PFS in Patients Receiving Bev Topotecan by No.
of Prior Regimens
Patients with 1 previous therapy (n 16)
1.0
Patients with 2 previous therapies (n 14)
P .040 by log rank test
.75
.50
Patients Without PD ()
.25
0.0
0
4
10
20
2
6
14
16
8
18
12
Time (Mos)
McGonigle KF, et al. ASCO 2008. Abstract 5551.
68
Best Response of Bev Topotecan by No. of Prior
Regimens
No. of Previous Regimens Best Response (N 24) Best Response (N 24) Best Response (N 24)
No. of Previous Regimens PR or SD PD Total
1 previous chemotherapy 5 9 14
2 previous chemotherapies 8 2 10
Total 13 11 24
McGonigle KF, et al. ASCO 2008. Abstract 5551.
69
OS in Patients Receiving Bev Topotecan by No.
of Prior Regimens
1.0
.75
.50
Patients Surviving ()
Patients with 1 previous therapy (n 16)
.25
Patients with 2 previous therapies (n 14)
P .043 by log-rank test
0.0
0
4
10
20
2
6
14
16
8
18
12
Time (Mos)
McGonigle KF, et al. ASCO 2008. Abstract 5551.
70
Ovarian Cancer at First RelapseDefinition of
Sensitivity
P R I M A R Y T R E A T M E N T
0 3 6 12 18 24
Months
Refractory
Resistant
Sensitive
Very Sensitive
Defined as measurable recurrence, not biochemical
(CA-125) recurrence
71
Platinum-Resistant Recurrence

• Drugs active in platinum-resistant disease
• Single agent regimens
• Treatment to progression, unacceptable toxicity,
  or clinical complete remission with each regimen
• Sequential use of agents with goal of palliation

72
Thank you!