Highlights in the Management of Ovarian Cancer

Roma 5 ottobre 2007

“Novel therapeutic approaches" Sandro Pignata

National Cancer Institute

Naples Italy

Results in Advanced Ovarian Cancer

• Overall response rate 75-80%• Clinical complete response 50-75%• Recurrence rate 6-12 mts 40-50%• Recurrence rate >12 mts 20-30%• Disease-free interval 18-24 mo• Median survival 28-56 mo• % Five-year survival 15-30%

TARGETED THERAPY IN OVARIAN CANCER

• Antiangiogenetic Agents• Signal Transduction Inhibitors• Monoclonal Antibodies• Vaccines

New Directions in Drug Development

• Chemotherapy: Epothilone, Pemetrexed (Alimta), TLK 286, …• Antibodies: Anti-Epcam, ACA125, …• EGFR: Gefitinib, Erlotinib, Cetuximab,..• Antiangiogenesis and VEGF: Bevacizimab, DXMAA,

VEGF trap, PlGFab, pazopamib ..• c-erb-family(Trastuzumab, pertuzumab, TAK-165, CP724,714,

2C4, IMC-225, EMD72000), Lapatinib (GW572016), • FTI (Lonafarnib, SCH6636, R115777, BMS214662), • Raf-1 (Bay 43-90006), MEK (CI-1040), Erbitux, …• M-tor inhibitors• Multiple targets: Enzastaurin, ...

AND MANY OTHERS

Anti-Angiogenesis: Ovarian Cancer

Vascular endothelial growth factor (VEGF) Tumor angiogenesis (blood vessel formation) Vascular permeability Over-expression in ovarian cancer

Poor prognosis Malignant Ascites

The Angiogenic Switch and Antiangiogenic Therapy

Somatic mutation

Smallavascular

tumor

Tumor secretion of proangiogenic

factors stimulates angiogenesis

Rapid tumor growth and metastasis

Angiogenic inhibitors may reverse this process

VEGF Expression in Tumors

• Gastrointestinal tumors

– Esophageal carcinomas

– Gastric carcinomas

– Small bowel carcinomas

– Colorectal carcinomas

– Hepatocellular carcinomas

• Breast carcinomas

• Lung carcinomas

• Genitourinary carcinomas

• Prostate carcinomas

• Thyroid carcinomas

• Intracranial tumors

– Glioblastoma multiforme

– Meningioma

– Capillary hemangioblastoma

• Female reproductive tumors

– Ovarian carcinomas

– Uterine cervix carcinomas

• Germ cell tumors

• Angiosarcoma

• Hematologic

*Via mRNA in situ hybridization.

Class Examples TargetsStage of Development Company

Agents targeting the VEGF ligand

Antibodies

Bevacizumab(Avastin™)

VEGF Approved Genentech

HuMV833 VEGF Phase I completed MERCK

2C3 VEGF* Preclinical Peregrine

Soluble receptors

VEGF-TRAP VEGF and PlGF Phase II Sanophi-Aventis

Agents targeting the VEGF receptorsSmall- molecule inhibitors

SU11248 VEGFR-2, PDGFR, c-Kit Phase III Pfizer

PTK787 VEGFR-1/2, PDGFR, c-Kit

Phase III Novartis

ZD6474 VEGFR-2, EGFR/FGFR-1

Phase II AstraZeneca

Antibodies IMC-1121b VEGFR-2 Preclinical ImClone

Ribozymes Angiozyme VEGFR-1 Phase II RPI

*Inhibits interaction with VEGFR-2 only.

Selected Agents Targeting the VEGF Pathway

Targeting VEGF Pathway

Company: Genentech Inc (Roche, EU)

Actions: VEGF antagonist Angiogenesis Inhibitor

Technologies: Recombinant Humanized Mab

Intravenous Formulation

Schedule: 5 mg/kg q 14 days

15 mg/Kg q 21 days

Study N Treatment RR %

PFS at 6 month

(%)

Prior RX GIP

GOG 170-D

63 BV 15 mg/kg IV 3 wk

18 42 42% platinum sensitive,up to 2 priors

0

NCT

5789

29 BV 10 mg/kg IV 2 wk +

CTX 50 mg

daily

28 57 42% platinum sensitive,up to 2 priors

2(3%)

Cannistra et al

44 BV 15 mg/kg IV 3 wk

16 27.4 Platinum resistant,up to 3 priors

5(11%)

Phase II Trial of Bevacizumab in Persistent or Recurrent Ovarian or Primary Peritoneal

Cancer: GOG 170 D

Bevacizumab 15 mg/kg q3wk

• Epithelial Ovarian Cancer• ≤ 2 Prior Therapies• RECIST Measurable• PS 0,1• Two-stage accrual design• Primary endpoint PFS @6 m

Open: Apr-02Closed: Aug-04Accrual: 62 pts Burger et al., Proc Ann Meet ASCO 24:A5009

• Overall response rate 12/62 (19.4%), including 3 CR• 42% of pts alive and free of progression at 6 m• Median number of cycles = 7, range = 1 to 29

BEVACIZUMAB IN PATIENTS WITH ADVANCED PLATINUM RESISTANT OVARIAN CANCER

Toxicity: SAE 18/44 pts (41%) GI perforations 5 (11%) Bowel Obstruction 5 (11%) A-TE Events 4 (9%) Delayed Wound Healing 2 (5%) Pulmonary and Encephalopaty Hypertension 2 (5%) (Cannistra, ASCO 2006)

53 PATIENTS PLANNED44 ENROLLED (early stopped)

Bevacizumab 15 mg/Kg q 21N of previous CT lines: 2 (20 pts); 3 (24 pts)

Efficacy: ORR: 7/44 (16%) Median duration of Response: 12 wks

• Hypertension is a consistent safety signal

• The most serious adverse events are gastrointestinal perforation, would healing issues, and arterial thrombotic events

• Serious bleeding, nephrotic syndrome, hypertensive crisis, and RPLS have been described as well

Summary of Bevacizumab Safety ProfileSummary of Bevacizumab Safety Profile

•• Epithelial Ovarian or Primary Peritoneal Cancer•• Suboptimal Cytoreduction•• Collaborative design (GOG, NCI, Genentech )

GOG218: Ovarian (stage III-IV)

x 6

Paclitaxel 175 mg/mq (3 h)Carboplatin AUC=6.0Bevacizumab 15 mg/kg q21d*

II

x 6IPaclitaxel 175 mg/m

2(3 h)

Carboplatin AUC=6.0Placebo q21d*

Placebo(14 m total)

Placebo(14 m total)

Bevacizumab(14 m total)x 6

Paclitaxel 175 mg/m2(3 h)Carboplatin AUC=6.0Bevacizumab 15 mg/kg q21d*

III

Open: Sep-05------

Target Accrual: 2000 pts (3 Y) Accrual 11/2006: 190

BEVACIZUMAB

Bevacizumab (AvastinTM) trial ICON 7

RANDOMISATION

RANDOMISATION

Carboplatin AUC 6

Paclitaxel 175 mg/m²

q 21 x 6 cycles

q 21 x 6 cycles

Carboplatin AUC 6

Paclitaxel 175 mg/m²

Bevacizumab 7.5 mg/m²

Observation

Bevacizumab 7.5 mg/m²

q 21 x 12 cycles

RANDOMISATION

RANDOMISATION

Gemcitabine 1000 mg/mq

days 1 and 8

Carboplatin AUC 4 day 1

Bevacizumab 15 mg/kg day 1

q 21 days x 6 *

BV

(to 51 wks)

Platinum Sensitive Ovarian CancerOCEAN STUDY-RANDOMIZED PHASE II

Memorial Sloan Kettering US

Gemcitabine 1000 mg/mq

days 1 and 8

Carboplatin AUC 4 day 1

Placebo IV day 1

q 21 days x 6

Placebo

(to 51 wks)

BV

to PD

*Up to 10 cycles allowed

VEGF- Trap Fusion Protein

• Fusion Protein-key domains from:– Human VEGF Receptor 1+2– Human IgG1 Fc

• All Human amino acid sequences• High affinity:binds VEGF more

tightly that native receptors or monoclonal antibodies

• Blocks all VEGF-A isoforms and Placental Growth Factor (PlGF)

• Smaller than monoclonal antibodies (MW 115,000)

• Long elimination half-life in humans (2 weeks)

• Treatment arms: – AVE 0005 4.0 mg/kg iv q 1– AVE 0005 2.0 mg/kg iv q 14

Phase II Trial VEGF Trap Ovarian Cancer Study design

Recurrent Ovarian Cancer3-4 lines treatmentPlatinum-resistant

Resistant: Topotecan and/or LiposomalDoxorubicin

VEGF Trap2 mg/kg IVq 2 weeks

VEGF Trap4 mg/kg IVq 2 weeks

Randomized (1:1)Double-BlindedN=200

Radiological Response:•PR = 10% (Stage 1,n=84)•PR = 8%(Stage 2,n=162)

Prolonged disease control•SD=41% at 14 wks•CA-125 responses (13%) and ascites resolution(29%)

VEGF Trap demostrates an acceptable safety profile•Low incidence of GI perforation (1%)

First pt May 2006Patients randomized 162Ongoing treatment 35 ptsEstimate accrual 200 pts

TEW WP. ASCO 2007. Abs 5508

RANDOMISATION

RANDOMISATION

Placebo

Every 2 wks

AVE0005(VEGF Trap)

Every 2 wks

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study of the Effect of Intravenous AVE0005 (VEGF Trap) Administered Every 2 Weeks in

Advanced Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites

Primary Outcome Measures:  • Time to repeat paracentesis

Secondary Outcome Measures:  • Ascites Impact Measure (patient questionnaire) • 60-Day frequency of paracentesis • Safety • Tolerability • Tumor assessments • Quality of life

Total Enrollment:  54 Study start: June 2006

from The National Cancer Institute’s PDQ® database

Tumors require new blood vessels ( angiogenesis ) toTumors require new blood vessels ( angiogenesis ) tostimulate their growthstimulate their growth

VEGF is a growth factor that promotes angiogenesis via itsVEGF is a growth factor that promotes angiogenesis via itsreceptor, VEGFR. The VEGFR is a protein kinasereceptor, VEGFR. The VEGFR is a protein kinase

Pazopanib blocks the kinase of the VEGFR, and PDGFR thus Pazopanib blocks the kinase of the VEGFR, and PDGFR thus inhibiting angiogenesis and tumor growthinhibiting angiogenesis and tumor growth

Pazopanib – A Multi-Targeted Inhibitor

Once-daily, oral therapy to inhibitOnce-daily, oral therapy to inhibitangiogenesis & block tumor growthangiogenesis & block tumor growth

Pazopanib (GW786034) in women with advanced epithelial ovarian, fallopian tube and peritoneal

cancers: Initial results of a phase II study.

• Pts with epithelial ovarian, fallopian tube or primary peritoneal carcinoma;

• ECOG PS 0-1

• complete CA-125 response to initial platinum-based CT

• 1-2 prior regimens

• Two stage design

• Primary endpoint CA-125 response

Pazopanib 800 mg QD until PD

• CA125 response rate 7/15 (47%), SD 4/15 (27%), PD 4/15 (27%) • Median time to response 29 days• Most common G ¾ AEs diarrhea and ALT elevations

Ongoing the stage II of enrollementM Friedlander. ASCO 2007. Abs 5561

Anti-EGF receptor: Ovarian Cancer

Epidermal growth factor (EGF) Cell proliferation Apoptosis Angiogenesis

The HER Family of Receptor

HER2/Neu Activation in Ovarian Cancer

• Majority of ovarian cancer cell lines and tumors express HER receptor

• Co-expression of HER1 and HER2 occurs in ovarian tumors more frequently than in normal ovarian epithelium

• EGF and heregulin stimulate ovariarian cancer cell proliferation

• HER2 gene amplification occurs in 5-8% ovarian tumors

Ovarian Carcinoma EGFR targeted therapy

Autors n Response rate

Stable disease

TKIsErlotinib (Tarceva)

Gordon 2005 34 6% 44%

Gefitininb (Iressa)

Schilder 2005 27 3% 15%

CI-1033 Campos 2005 105 0% 50%

MoAbsPertuzumab (2C4)

Gordon 2006 117 4% 7%

Trastuzumab (Herceptin)

Bookman 2003 41 7% 39%

Autors n Response rate

Stable disease

TKIsErlotinib (Tarceva)

Gordon 2005 34 6% 44%

Gefitininb (Iressa)

Schilder 2005 27 3% 15%

CI-1033 Campos 2005 105 0% 50%

MoAbsPertuzumab (2C4)

Gordon 2006 117 4% 7%

Trastuzumab (Herceptin)

Bookman 2003

41 7% 39%

Ovarian Carcinoma EGFR targeted therapy

Ovarian Carcinoma EGFR targeted therapy

Autori n Response rate

Stable disease

TKIsErlotinnib (Tarceva)

Gordon 2005 34 6% 44%

Gefitininb (Iressa)

Schilder 2005 27 3% 15%

CI-1033 Campos 2005 105 0% 50%

MoAbsPertuzumab (2C4)

Gordon 2006 117 4% 7%

Trastuzumab (Herceptin)

Bookman 2003

41 7% 39%

HER2 expression

% patients

11.4% 5%

0

10

20

30

40

50

60

70

80

0 1 2 3

11.4% 5%

HER2 expression

% patients

Tarceva Maintenance Trial

EORTC-GINECO-AAGO-MRC-ANZOG-MANGO

RANDOMISAtIOn

Platinum-based regimen

q 21j / 6 - 9 cycles

Observation

Erlonitib (TarcevaTM)

150 mg/d

2 yearsSD

PR

CR

High risk stage I and stage II-IV

Accrual : 550/800

Phase II of Bevacizumab & Erlotinib for Ovarian, Peritoneal, and Fallopian CA

1 cycle= 3 weeks

Week 1 Week 2 Week 3

Bevacizumab 15 mg/kg

Erlotinib 150 mg po daily

Authors conclusion: • The combinations is active in this population and the trial hasmet the estabilished efficacy criteria for continuing into second stage of accrual

• Response rate 16%

• Rash, diarrhea and myalgia was the most commonly toxicities

• There appeared to be an increased rate of bowel perforation

G. Fridberg. ASCO 2006. Abs 5018

Dual inhibition of ErbB1(EGFR/HER1) and ErbB2(HER2/neu)

Gordon. JCO 2006

Randomized Pertuzumab (HER2) Phase II in Platin-sensitive ovarian cancer

RANDOMISATION

As Arm A plus concomittant

Pertuzumab 3 wkly iv, followed by 11

courses maintenance Pertuzumab

6 courses of Paclitaxel/Carbo or

Gem/Carbo

• Relapse 2nd line

•Platin-free>6 months

Accrual closed 11/2006: n = 147

Arm A

Arm B

Multi-target: Ovarian Cancer

Tkinase Apoptosis Angiogenesis

A Phase II Study of Sunitinib (SU11248; NSC 736511; IND 74019) in Patients With Recurrent Epithelial

Ovarian,Fallopian Tube or Primary Peritoneal Carcinoma

• Histologically Ovarian epithelial cancer,Fallopian tube cancer,Primary peritoneal cancer

• Advanced and/or metastatic disease

• 1 but no more than 2 prior chemotherapy regimens

• Measurable disease

• Primary endpoint objective

response

oral sunitinib once daily on days 1-28

every 42 days for up to 6 courses

Total Enrollment:  25 Study start: January 2007

from The National Cancer Institute’s PDQ® database

A randomized Phase II Study of Paclitaxel/Carboplatin With or Without Sorafenib in the First-Line Treatment of Patients With Stage

II/IV Epithelial Ovarian cancer

RANDOMISATION

RANDOMISATION

Carboplatin AUC 6

Paclitaxel 175 mg/m²

q 21 x 6 cycles

q 21 x 6 cycles

Carboplatin AUC 6

Paclitaxel 175 mg/m²

Sorafenib 400mg PO bid

Observation

Sorafenib to PD

Or 12 months

SCRI

Study start: Oct 2006Expected completion: Oct 2009

Total enrollment: 60 pts from The National Cancer Institute’s PDQ® database

A Phase II Study Of Sorafenib and Bevacizumab in Epithelial Ovarian, Fallopian and Peritoneal Cancer

Open: Jan-05Accrual goal: 78 pts Ongoing

Sorafenib 400 mg po biddays 1-5Bevacizumab 15mg/kg IV days 1and 15

Every 28 days

• Histologically confirmed refractory or recurrent ovarian epithelial, fallopian tube, or primary peritoneal cavity •Disease progression within 6 months of up-front platinum-containing therapy • Disease amenable to percutaneous or skin biopsy

• Not previously treated with bevacizumab

• Measurable disease, defined as tumor ≥ 1 cm

• Primary endpoint clinical response rate (complete or partial)

from The National Cancer Institute’s PDQ® database

Company: Marshal Edwards Inc

Actions: Anticancer, chemosensitizer

Inhibitor of antiapoptotic proteins XIAP

and FLIP

Topoisomerase inhibitor

Technologies: Intravenous and oral formulation

Topic: Restores sensitivity to Taxane drugs and

Platinum agents

PHENOXODIOL(syntethic analog of isoflavones Genistein)

Phase II multicenter multinational trial on Phenoxodiol in 40 recurrent advanced ovarian and

primary peritoneal cancer refractory to Taxane-based and/or Platinum based chemotherapy

Overall Disease Control: 77% (11% CR+22% PR+44% SD)

Marshal Edwards Press Release 2005

Patients were enrolled 7 months after completing the last course of treatment and would received Phenoxodiol on 2 consecutive days followed by a single weekly administration of Paclitaxel or Cisplatin over a 6-week treatment cycle.

Phase III b: if marketing approval primary end point: OS

ONGOING…

OVArian TUmor REsponse

(OVATURE) trial

Phenoxodiol would be introduced into their chemiotherapy schedules only when they showed disease progression

Phase II b: comparison the oral and iv forms of Phenoxodiol (100 patients)

Phase III a: patients enrolled at the preferred dosage form primary end point: RR and TTP

Resistance modulation: Ovarian Cancer

Glutathione

GSH Resistance: TLK286 • A novel glutathione analog

prodrug activated by glutathione S-transferase P1-1

• Rationally-designed to exploit the overexpression of the enzyme GST P1-1 present in ovarian cance

• Toxicity: mild hematologic toxicity

• Schedule: – 1000 mg/mq q21 – 960 mg/mq weekly x3 q 28

• Hightest Dev Status: Phase III (HNC, ovary, NSCLC)

GST P1-1Cleavage

P

O

N

N

ClCl

Cl

Cl

O

HN

S

NH

CO2H

O

OHO2C

NH2

O

O

HCl

Telik/TLK286 (TelcytaTM)ASSIST ((AsAssessment of sessment of SSurvival urvival IIn n SSolid olid TTumor)umor)

ASSIST-1

TLK286

Recurrent Ovarian Cancer3rd Line

Caelyx

Topotecan

vs.

ASSIST-3

TLK286 +Carboplatin

Recurrent Ovarian Cancer2nd Line

Refractory & Resistant

Caelyx

No PATIENTS: 461 ptsRR (TLK286) 4.3% vs 10.3%

PFS: 2.3 m vs 4.4 mOS: 8.5 m vs 13,6 m

No PATIENTS: 247 ptsPFS: 3.5 both arms OS: not reached

I. Vergote ASCO 2007 P. Rose. ASCO 2007

Telik/TLK286 (TelcytaTM)ASSIST ((AsAssessment of sessment of SSurvival urvival IIn n SSolid olid TTumor)umor)

ASSIST-5

TLK286 +Caelyx

Recurrent Ovarian Cancer2nd Line

Refractory & Resistant

Caelyx

START DATE: MAY 2006No PATIENTS: 244 pts

PRIMARY END POINT: PFS and OS SECONDARY END POINT: RR ONGOING…….

Vaccines: Ovarian Cancer

Anti Ca 125 antibodies

PFS SFLTPFS ITT

MONOCLONAL Ab THERAPY Oregovomab (B43.13) vs Placebo

Berek, JCO 2004

- residual disease <2cm - CA 125 <65 pre-3rd cycle - CA 125 N pre-study n = 34/33

TTR (med) Oregovomab = 24.4mos Placebo

= 10.8mos p = 0.0596

Abagovomab

• Murine monoclonal antibody able to induce an active response against the CA125 TAA

• Immunization generates antibodies against this antigen (Ab1)

• Ab1 can generate anti-idiotypic antibodies against Ab1, termed Ab2

• Immunization by anti-idiotypic antibodies is expected to induce a specific humoral immune response (AB3 and AB1‘) against cells expressing original TAA

• Abagovomab proved to be effective in generating a specific immune response against CA125-positive cells in previous trials

ABAGOVOMAB: Mechanism of Action

TAA CA 125

Ab 1’

Tumor

cell

Abagovomab

(Ab2)

HAMAHAMA

Ab3Ab3

THERAPEUTIC VACCINETHERAPEUTIC VACCINE

Immunological Consolidation with

MAB ACA125

Chemotherapy

Wagner U et al: Clin Canc Res 2001; 7:1154-62

Maintenance Therapy with Abagovomab (MAB-ACA125)

MIMOSA (AGO-OVAR 10) Design

First-line platinum/taxanechemotherapy

RANDOMIZATION

NED/CR

Strata:

• res. Tumor ≤ 1cm; > 1cm

• FIGO stage (III; IV)

• Serum CA125 after first 3 cycles of chemotherapy(≤ 35 U/ml, > 35 U/ml)

Abagovomab 2mg/ml s.c.

Placebo suspension s.c.

Double blind observation period

2:1 ratio

Induction phase: first 4 injections every 2 weeks

Maintenance phase: injections every 4 weeks, starting from week 10

Accrual 253/800 Oct 2007

Cluster of Ecteinascidia turbinata, a “sea squirt” or tunicate

from the Caribbean Sea

Yondelis: Tetrahydroisoquinoline

alkaloid, MW=762.

Yondelis™, trabectedin, ET-743

1996: PharmaMar starts clinical development of ET-7432001: Joint development of ET-743 by Johnson & Johnson Pharm R&D andPharmaMar

PHASE II TRIAL ON TRABECTEDINA IN RECURRENT OVARIAN CANCER

294 pts

Platinum resistant 108 8 2.1

Platinum sensitive 186 34 5.8

No RR (%) PFS (Median)

McMeekin DS, ASCO, 2007

An Open-label Multicenter Randomized Phase 3 Study Comparing CAELYX® and YONDELIS™ with CAELYX alone in Relapsed Ovarian Cancer

• Advanced Recurrent Epithelial Ovarian Cancer

– One prior regimen– Evaluable and measurable

disease– Platinum sensitive and resistant

Primary endpoint: OSOther endpoints: PFS, RR, Safety

Translational Research•Pharmacokinetics•Pharmacogenomics•Pharmacoeconomics•Quality of Life•Circulating tumor cells

RANDOMIZE

Caelyx® 50 mg/m2 q 4 wks

Caelyx® 30 mg/m2 plusYondelis® 1.1mg/m2Every 3 weeks

Accrual 7/11/2006: 374/650

Many new drugs.Exciting results expected.

Thank you !!!!!