highlights in the management of ovarian cancer roma 5 ottobre 2007 “novel therapeutic...
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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 !!!!!