Judith K. Wolf, MD Professor Department of Gynecologic Oncology University of Texas M.D. Anderson Cancer Center Houston, TX Treatment of Ovarian Cancer

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

Treatment of Ovarian Cancer21st Century and Beyond

Judith K. WolfProfessorGynecologic Oncology

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/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007.

Ovarian Cancer StagingStage 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 < 2 cm

C. Macroscopic > 2 cm

Stage IV - Spread outside peritoneum, pleura or parenchymal

liver metastases

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% <5%

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/viewarticle/444134. Accessed May 2, 2007.

FIGO = International Federation of Gynecology and Obstetrics

Ovarian Cancer Surgical Debulking and Staging

Exploration

Washings/Ascites

(Staging)

TAH/BSO

Biopsies(Staging)

Goals (Debulking)•Assessment of extent of disease

•Optimal tumor reduction

TAH = total abdominal hysterectomy

BSO = bilateral salphingo-oophorectomy

First-line Therapy – Standard Treatment Options

Platinum + Taxane Chemotherapy(Carboplatin + Paclitaxel)

Surgery with maximum cytoreduction effort <1cm

residual disease

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. 1996;334(1):1-6.2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200.4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329.

GOG = Gynecologic Oncology GroupAGO = ArbeitsgemeinschaftGynaekologische Onkologie

The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma

Study # Pts RegimenMedian PFS

(mo)Median OS

(mo)

GOG 1321

377III suboptimal-IV

Cisplatin/Paclitaxel (24 h) x 6

14.1 26.3

Cisplatin 100 mg/m2 x 6 16.4 30.2Paclitaxel 200 mg/m2 (24 h)* 10.8 25.9

ICON32

2074I-IV

Carboplatin/Paclitaxel (3 h)

17.3 36.1

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

1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515.

*CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001

The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma

Study # Pts Regimen Median PFS (mo) Median OS (mo)

GOG 1581

792III optimal

Cisplatin 75 mg/m2

Paclitaxel 135 mg/m2 (24 h)19.4 48.8

Carboplatin AUC 7.5Paclitaxel 175 mg/m2 (3 h) *

20.7 56.7

* RR progression 0.88 (95% CI) and RR death 0.86 (95% CI)

HR =0.86(99% CI)

AGO2 798IIB-IV

Cisplatin 75 mg/m2

Paclitaxel 185 mg/m2 (24 h)19.1 44.1

Carboplatin AUC 6Paclitaxel 185 mg/m2 (3 h)

17.2 43.3

HR = 1.050 (95% CI)

HR =1.045 (95% CI)

More toxicity with the cisplatin regimens

1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329.

AGO = Arbeitsgemeinschaft Gynaekologische OnkologieCI = confidence intervalGOG = Gynecologic Oncology GroupHR = hazard ratio; OS = overall survivalPFS = progression-free survivalRR = relative risk

• Ovarian cancer stage Ic-IV

• Primary peritoneal cancer

• N = 1077

Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h)Q3W x 6

Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h)Q3W x 6

RANDOMIZE

SCOTROC: Trial

Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691.

SCOTROC = Scottish Randomized Trial in Ovarian CancerQ3W = once every 3 weeks

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

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

Regimen I (control)Paclitaxel 175 mg/m2 IV (3 h) d 1Carboplatin AUC 6 IV d 1

Regimen II (triplet A)Paclitaxel 135 mg/m2 IV (3 h) d 1Carboplatin AUC 5 IV d 1Gemcitabine 800 mg/m2/d IV d 1, 8

Regimen III (triplet B)Paclitaxel 135 mg/m2 IV (3 h) d 1Carboplatin AUC 5 IV d 1Doxil 30 mg/m2 IV d 1 Every other cycle

Regimen IV (sequential module A)Carboplatin AUC 5 IV d 3Topotecan 1.25 mg/m2/d IV d 1-3

Regimen V (sequential module A)Carboplatin AUC 6 IV d 8Gemcitabine 1000 mg/m2/d IV d 1, 8

Regimen IV (sequential module B)Paclitaxel 175 mg/m2 IV (3 h) d 1Carboplatin AUC 6 IV d 1

Regimen V (sequential module B)Paclitaxel 175 mg/m2 IV (3 h) d 1Carboplatin AUC 6 IV d 1

Randomization• All patients• Equal proportions on

each regimen• Primary end points:

PFS, OS, RR

GOG 182-ICON5 International Study for Stage III/IV

Regimens I, II, and III: 8 cycles, 21-d cycle intervalRegimens IV and V: 4 cycles, 21-d cycle interval

Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.

GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate

GOG0182-ICON5: Progression-Free Survival

Median PFS and HR (95% CI)

16.1 1.00016.4 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

GOG0182-ICON5: Overall Survival

Median OS and HR (95% CI)

40.0 1.00040.4 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

Current GOG Frontline Trial

> Microscopic residual > Microscopic residual EOC, PPC cancerEOC, PPC cancer

PaclitaxelPaclitaxelCarboplatinCarboplatin

PlaceboPlacebo


BevacizumabBevacizumab


BevacizumabBevacizumab

Bevacizumab ×16 cycles

GOG 218GOG 218

N = 2,000 patientsSurvival, PFS primary endpoints

Biologic & QOL endpoints

Placebo×16 cycles

Placebo ×16 cycles

EOC = epithelial ovarian cancerFT = fallopian tubeGOG = Gynecologic Oncology GroupPFS = progression-free survivalPPC = primary peritoneal cancerQOL = quality of life

IDS AllowedIDS With

Response or Stable Disease

Repeat ChemotherapySLS allowed

Repeat ChemotherapySLS allowed

EORTC-55971

The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007.

EORTC = European Organisation for Research and Treatment of CancerIDS = Interval Debulking SurgerySLS = Second-Look Surgery

Cytoreductive Surgery+

3 Courses Platinum-Based Chemotherapy

Upfront Debulking Surgery vs Neoadjuvant Chemotherapy

Stage IIIc or IV Epithelial Ovarian Carcinoma

3 Courses Platinum-Based Chemotherapy

GC vs TC Induction Regimens Followed by T Consolidation: Study Design

Gordon A, et al. ASCO 2008. Abstract 5536.

Anything other than CR(PR, SD, PD)

Anything other than CR(PR, SD, PD)

Clinical CR

Single-agent crossoverPaclitaxel 175 mg/m2 Day 1

Single-agent crossoverGemcitabine 1000 mg/m2 Days 1,

8

ElectiveT Consolidation Therapy

Paclitaxel 135 mg/m2 every 28 days for 12 cycles

Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal,

or fallopian tube carcinoma

Induction GCGemcitabine 1000 mg/m2 Days 1,

8 + Carboplatin AUC 5 Day 1

x 6 cycles every 21 days

Induction TCPaclitaxel 175 mg/m2 Day 1+ Carboplatin AUC 6 Day 1

x 6 cycles q 21 days

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.

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

Conventional vs Dose-Dense TC (NOVEL): Study Design

Ovarian epithelial, primary peritoneal, or fallopian tube cancer with

FIGO stage II-IV

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 1every 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 1every 21 days for 6-9 cycles

Stratified by residual disease ≤ 1 cm vs > 1 cm;

FIGO stage II vs III vs IV;histology: clear cell/mucinous vs serous/others

Isonishi S, et al. ASCO 2008. Abstract 5506.

P = .72

Evaluated by WHO criteria

Conventional vs Dose-Dense TC (NOVEL): Clinical Responses

MeasurablePatients, %

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


Treatment n Event Median PFS,

mosP Value HR 95 %CI

c-TC 319 200 17.2

dd-TC 312 160 28.0 .0015 0.714 0.581-0.879

Conventional vs Dose-Dense TC (NOVEL): PFS

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dd-TCc-TC

Ovarian Carcinoma: Clinical Course

SymptomsSymptoms

Diagnosis

Chemotherapy #1Chemotherapy #1

StagingPrimary cytoreduction

Interval Cytoreduction

Progression

Chemo #2Chemo #2 Chemo #3+Chemo #3+

SupportiveCare

Death

Consolidation/Maintenance

Consolidation/Maintenance

Cure

SecondaryCytoreductionSecond-Look

Goals of Treatment:Relapsed Ovarian Cancer

• Prolong Survival

• Delay Time to Progression

• Control Disease-Related Symptoms

• Minimize Treatment-Related Symptoms

• Maintain or Improve Quality of Life

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

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 tomographyMRI = magnetic resonance imaging PET = positron emission tomography

Ovarian Cancer:How is Relapse Defined?

• Continuous rise in CA-125

• CA-125 above 100

• Radiographic recurrence

• Symptomatic recurrence

• Physical examination findings

• Combination of above

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



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

When Does Ovarian Cancer Recur?

Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel;GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel

Active Agents in Ovarian CancerFDA approved

Altretamine Carboplatin Cisplatin

Gemcitabine/

Carboplatin

Paclitaxel Pegylated liposomal doxorubicin

Topotecan

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

Aromatase inhibitors Bevacizumab Pemetrexed

Tamoxifen

Effect of Platinum-Free Intervalon Response Rate% Response to Second-line

Platinum Therapy

Platinum-Free Interval (mos) Markman Gore Blackledge

0-617%

10%

7-12 27% 29%

13-1833% 27%

63%

19-24 94%

>24 59% 57%

Non-Platinum Therapy

15%

20%

30%

30%

Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211.Blackledge G, et al. Br J Cancer. 1989;59:650-653.


Refractory

PRI

MARY

TREATMENT

Resistant

Sensitive

0 3 6 12 18 24Months

“Very Sensitive”

Ovarian Cancer at First RelapseDefinition of Sensitivity

Defined as measurable recurrence, not biochemical (CA-125) recurrence

ICON 4 Schema

• Relapsed ovarian or primary

• Peritoneal requiring chemotherapy

• Previous platinum-based chemotherapy

Conventional platinum-based chemotherapy

Paclitaxel plusplatinum chemotherapy

RANDOMIZEPrior chemotherapy

• Carboplatin (31%)• Paclitaxel/platinum (40%)• Other (30%)

TFI > 12 months for 75%

Parmar MK, et al. Lancet. 2003;361:2099-2106.ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval

ICON 4 Response

Plat (n = 128)

Pac-Plat (n = 119)

CR or PR 54% 66%

(Difference of 12%; 95% CI -0.1% to 24%; p=0.06)

CR = complete response; ICON = International CollaborativeOvarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response;

CR = complete response; ICON = International CollaborativeOvarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106.

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0 1 2 3 4

Patients at risk Pac-Plat 392 179 52 25 17Plat 410 157 45 17 7

Years from randomization

Pac-PlatPlat

Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001)

Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%)

Ovarian Carcinoma: ICON 4 Progression-Free Survival

Parmar MK, et al. Lancet. 2003;361:2099-2106.ICON = International Collaborative Ovarian Neoplasm Group;Pac = paclitaxel; Plat = platinum

Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023)

Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%)

Patients at riskPac-Plat 392 306 167 96 43Plat 410 295 150 68 33

0.0

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ICON 4: Overall Survival

Parmar MK, et al. Lancet. 2003;361:2099-2106.ICON = International Collaborative Ovarian Neoplasm Group;Pac = paclitaxel; Plat = platinum

RANDOMIZE

Gemcitabine 1,000 mg/m2

days 1 + 8 Plus

Carboplatin AUC 4 day 1

every 21 days × 6

• Recurrent ovarian cancer

• 6+ months after platinum

• Strata

– PFI (6 - 12, >12 months)

– 1st-line therapy (platinum ± paclitaxel)

– Measurable vs evaluable

• Primary endpoint = PFS

Gem/Carbo vs Carbo: Design

Carboplatin AUC 5 day 1

every 21 days × 6

Carbo = carboplatinGem = gemcitabinePFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707.

AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival

0 3 6 9 12 15 18 21 24 27 30 33 36 39

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GCb: median = 8.6 mo Censoring: 12.4%

Cb: median = 5.8 moCensoring: 12.9%

Cb Arm (N=178)

GCb Arm (N=178)

Log-rank p-value = 0.0038

Unadjusted HR = 0.72 (0.57 to 0.90)

Adjusted HR* = 0.71 (0.57 to 0.89)

* Adjusted for PFI, Tumor size

Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin

AGO OVAR 2.5 Efficacy Results:

Overall Survival

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Median = 18.0 mo Censoring: 18.5%

Median = 17.3 mo Censoring: 22.5%

Cb Arm (N=178)

GCb Arm (N=178)

* Adjusted for PFI, Tumor size and performance status

Log-rank p-value = 0.7349

Unadjusted HR = 0.96 (0.75 to 1.23)

Adjusted* HR = 0.92 (0.72 to 1.16)

Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.

AGO = ArbeitsgemeinschaftGynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin

GCIG CALYPSO Trial

Ovarian CancerPlatinum Sens.Stratify:< 0.5 cm> 0.5-2 cm

RANDOMIZE

PLD30 mg/m2

Carboplatin AUC = 5q 28 days x 6

Paclitaxel 175 mg/m2

Carboplatin AUC = 5q 21 days x 6

GCIG = Gynecologic Cancer IntergroupPFS = progression-free survivalPLD = pegylated liposomal doxorubicin

Accrual Completed (Target accrual 864 pts)

PFS 1° endpoint

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

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

Patients with platinum-sensitive EOC in first relapseafter first remission of 6-18 months duration

with evaluable disease by CA125(Enrolled N = 58;eligible n = 54)

Asymptomatic relapse

Single-agent Farletuzumab until progression

(n = 28)

Original Carbo/Taxane regimen+ Farletuzumab for 6 cycles

(n = 26)

Symptomatic relapse

Compare lengths of first and second remissions

Farletuzumab maintenance Rx for responders

Single-agent ORR Combination ORR

Armstrong DK, et al. ASCO 2008. Abstract 5500.

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

MORAb-003-002 Phase II: Treatment Arms


Comparison of First vs Second Remission Length: n = 6

Data as of May 5, 2008.

Subject 1st Remission, Mos

2nd Remission, Mos

Status

1 8.3 19.5+ Still in remission




5 8.2 8.2 Relapsing



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%


Secondary Cytoreduction

• Controversial

• Inconsistent definitions

• Benefit appears confined to patients likely to respond to additional chemo:

• >12 month PFI• Isolated site of

recurrence• Disease completely

resectable

KidneyKidney

Resected LiverResected LiverDiaphragmDiaphragm

KidneyKidney

Vena CavaVena Cava

Tumor MassTumor Mass

Renal VeinRenal Vein

PFI = progression-free interval

TTP

mos>12>12>12

>17.5>36>24

12-24>24

Ovarian Cancer Secondary Cytoreduction:

Post-Surgery SurvivalAuthor

JanickeSegnaZangGadducciEisenkopMunkarahScarabelliTay

Total/Range

Year

19921993200020002000200120012002

N

301006030

11425

14846

553

SurvivalMedian

mos16

16.61321

16.8

26

13-26

TTP

mos<12<12<12

<17.5<12<24<12<12

SurvivalMedian

mos8

8.88

152542126

6-42

SurvivalMedian 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 = time to progressionTTP = time to progression

GOG 213- PI Robert Coleman

Surgical

Candidate?

Recurrent ovarian or peritoneal cancer

TFI >6 mos

YES

NO

Surgery

No surgery

Carboplatin + Paclitaxel Carboplatin + Paclitaxel

+ Bevacizumab

+ Bevacizumab Maintenance

Randomize to Chemotherapy

GOG = Gynecologic Oncology GroupTFI = treatment-free interval

Effect of Platinum-Free Intervalon Response Rate% Response to Second-line

Platinum Therapy

Platinum-Free Interval (mos) Markman Gore Blackledge

0-617%

10%

7-12 27% 29%

13-1833% 27%

63%

19-24 94%

>24 59% 57%

Non-Platinum Therapy

15%

20%

30%

30%



Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer

Study Agents Response/comm126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive126-C Hexamethylmelamine 3/30 (10%) Inactive126-D Pyrazoloacridine 2/24 (8.4%) Inactive126-E PSC833 + paclitaxel 1/16 (6%) Inactive126-G CI-958 1/25 (4%) Inactive126-H Topotecan (24 h) 1/25 (4%) Inactive126-I 9-amino-camptothecin 8/58 (14%)

Moderate126-J Docetaxel 13/58 (22%) Active

(post-paclitaxel)

Bookman MA. Semin Oncol 2002;29(suppl 1):20-31.CDDP = c/s-diamminedichloroplatinum (cisplatin)GOG = gynecologic oncology groupCDDP = c/s-diamminedichloroplatinum (cisplatin)GOG = gynecologic oncology group

Recent Phase II GOG Studies in Platinum-Resistant Ovarian CancerStudy Agents Response/comm126-K Oxaliplatin 1/25 (4%) Inactive126-L Gemcitabine/CDDP 9/57 (16%) Moderate126-M Ixabepilone 7/50 (14%)

Moderate126-N Paclitaxel weekly 10/48 (21%) Active

(post-paclitaxel)126-O Triapine-CDDP Not Feasible126-P Paclitaxel & Celecoxib Closed Early126-Q Pemetrexed 10/48 (21%) Active126-R Abraxane Accrual in Progress

Bookman MA. Semin Oncol 2002;29(suppl 1):20-31.CDDP = c/s-diamminedichloroplatinum (cisplatin)GOG = gynecologic oncology groupCDDP = c/s-diamminedichloroplatinum (cisplatin)GOG = gynecologic oncology group

Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema

Miller DS, et al. ASCO 2008. Abstract 5524.

Day -7

Folic acid,

Vitamin B12

Day -6

Folic acid

Day -5

Stop NSAID, folic acid

Days -4,-3Folic acid

Day -2

Stop NSAID,

folic acid

Day -1

Dexamethasone, folic acid

Day 1

Chemotherapy, dexamethasone

, folic acid

Day 2

Dexamethasone,

folic acid

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

Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses

Miller DS, et al. ASCO 2008. Abstract 5524.

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

*1 patient remains on therapy.

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

Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rateRR = response rate

GOG Experience• GOG 160: Trastuzumab

• GOG 170Human Interleukin-12 (170B) Lapatinib (170G)

Gefitinib (170C) Vorinostat (170H)

Bevacizumab (170D) Temsirolimus (170I)

Imatinib (170E) Enzastaurin (170J)

Bay 43-9006 (170F) Mifepristone (170K)

Ongoing GOG Phase II Effort

Insufficiently ActiveToo EarlyActive

GOG = Gynecologic Oncology Group

Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer

Agent TargetsLigand binding:

Bevacizumab VEGF-AVEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2

Receptor binding:Volociximab 51 integrinIMC-1121B VEGFR-2

Receptor tyrosine kinase inhibition:Valatanib VEGFR-1, -2, -3, PDGFR, and c-kitSunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kitSorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-

Non-receptor kinase inhibition:Temsirolimus, everolimus mTOREnzastaurin 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

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

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. 2007;7(10):1339-1345.Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor VEGF = vascular endothelial growth factor

Agents Targeting the VEGF Pathway

VEGFR-2VEGFR-1

PPPPPP

PPPPPPPP

PP

Endothelial Cell Small-Molecule Inhibitors

Anti-VEGFR Antibodies

VEGFAnti-VEGF Antibodies(bevacizumab)

Soluble VEGFRs

(VEGF-TRAP)

Podar K, et al. Blood. 2005;105(4):1383-1395.VEGF = vascular endothelial growth factorVEGFR = VEGF receptor VEGF = vascular endothelial growth factorVEGFR = VEGF receptor

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 > 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%

Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345.Burger RA. J Clin Oncol. 2007;25(20):2902-2908.

G1, G2 = immunoglobulinsGI = gastrointestinalTE = thromboembolism

G1, G2 = immunoglobulinsGI = gastrointestinalTE = thromboembolism

Phase II Studies of Bevacizumabin Ovarian Cancer

Cannistra 2007

Burger2007

Garcia2008

Number of Pts 44 62 70

Prior Regimens2= 52%3= 48%

1= 34%2 = 66%

Median = 2Range 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. 2007;25(33):5180-5186.Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171.Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82.

Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186.Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171.Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82.

CR = complete responseGI = gastrointestinalPR = partial response

CR = complete responseGI = gastrointestinalPR = partial response

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%)

Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinalGI = gastrointestinal

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

* Front Line**Carboplatin and Paclitaxel

Bev = bevacizumab; Carbo = carboplatinGem = gemcitabine; IP = intraperitonealMab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor

Bev = bevacizumab; Carbo = carboplatinGem = gemcitabine; IP = intraperitonealMab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor

NCI Registered Phase II Trials:VEGF + EGFR Inhibitors

Protocol Drug Class PI Status

NCIBev +Erlotinib MAb

Friberg Active

NCT00130520 Alberts Active

NCT00520013 Bev +/- Erlotinib Consolidation

MAb Campos Active

Bev = bevacizumabEGFR = epidermal growth factor receptor Mab = monoclonal antibodyVEGF = vascular endothelial growth factor

Bev = bevacizumabEGFR = epidermal growth factor receptor Mab = monoclonal antibodyVEGF = vascular endothelial growth factor

Protocol Drug Target(s) PI StatusGOG 170-J Enzastaurin

(TKI)PKC -b Usha Suspended

NCT00391118 CT +/- [Enzastaurin Enzastaurin]

(Not Listed) Active

GOG 170-EImatinib (TKI) PDGF-R

SchilderCompleted

NCT00039585 Kohn

NCT00516841 Volociximab (MAb)

51 IntegrinMultiple Active

NCT00479817 AMG 386 (Peptibody)

Angiopoietins(Not Listed) Active

NCI Registered Phase II Trials:Other Anti-Angiogenic Agents

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

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

Bev + Topotecan in Platinum Refractory Ovarian Cancer: Study

Design

McGonigle KF, et al. ASCO 2008. Abstract 5551.

Platinum-refractory OC; recurrence

< 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

PD as defined by RECIST criteria

Excessive toxicity according to

prespecified criteria

Toxicity requiring topotecan delay

> 2 weeks or bevacizumab delay

> 2 months

Topotecan-related toxicities requiring > 2 dose reductions

Treatment continued until

1 of the following events

Single arm, 2-site phase II trial

OS: Patients With Platinum-Resistant Ovarian Cancer (N = 30)


0.0

.25

.50

.75

1.0

Pat

ien

ts S

urv

ivin

g (

%)

Time (Mos)

0 2 4 6 8 10 12 14 16 18 20

Bev + Topotecan

PFS in Patients Receiving Bev + Topotecan by No. of Prior Regimens


0.0

.25

.50

.75

1.0

0 4 10 20Time (Mos)

Pat

ien

ts W

ith

ou

t P

D (

%)

2 6 14 18168 12

Patients with 1 previous therapy (n = 16)

Patients with 2 previous therapies (n = 14)

P = .040 by log rank test

Best Response of Bev + Topotecan by No. of Prior Regimens


No. of Previous Regimens

Best Response (N =24)

PR or SD PD Total

1 previous chemotherapy

5 9 14

2 previous chemotherapies

8 2 10

Total 13 11 24

OS in Patients Receiving Bev + Topotecan by No. of Prior Regimens


0.0

.25

.50

.75

1.0

0 4 10 20Time (Mos)

Pat

ien

ts S

urv

ivin

g (

%)

2 6 14 18168 12

Patients with 1 previous therapy (n = 16)

Patients with 2 previous therapies (n = 14)

P = .043 by log-rank test

Refractory

PRI

MARY

TREATMENT

Resistant

Sensitive

0 3 6 12 18 24Months

“Very Sensitive”

Ovarian Cancer at First RelapseDefinition of Sensitivity

Defined as measurable recurrence, not biochemical (CA-125) 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

Platinum-Resistant Recurrence

Documents

Judith K. Wolf, MD Professor Department of Gynecologic Oncology University of Texas M.D. Anderson Cancer Center Houston, TX Treatment of Ovarian Cancer