nick reed glasgow uk n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
The emerging role of targeted therapy in treatment of epithelial ovarian cancer PowerPoint Presentation
Download Presentation
The emerging role of targeted therapy in treatment of epithelial ovarian cancer

Loading in 2 Seconds...

play fullscreen
1 / 49

The emerging role of targeted therapy in treatment of epithelial ovarian cancer - PowerPoint PPT Presentation


  • 238 Views
  • Uploaded on

Nick Reed Glasgow, UK. The emerging role of targeted therapy in treatment of epithelial ovarian cancer. Changing Paradigms of Ovarian cancer. New management approaches required Traditional Surgical management Adjuvant chemotherapy Scheduling of treatments Chronic disease process

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'The emerging role of targeted therapy in treatment of epithelial ovarian cancer' - gladys


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
changing paradigms of ovarian cancer
Changing Paradigms of Ovarian cancer
  • New management approaches required
  • Traditional
    • Surgical management
    • Adjuvant chemotherapy
    • Scheduling of treatments
    • Chronic disease process
    • Tailoring treatments
new challenges becoming a chronic disease
New ChallengesBecoming a chronic disease?
  • Changing pattern
  • More chronic disease process
  • Many patients reaching 4th 5th or 6th line
  • Issues of costs and reimbursement
  • Issues of patient expectation
  • Need for new drugs and technologies
focus on first line therapy
Focus on First-line Therapy
  • If carboplatin + paclitaxel is current ‘standard of care’, where do we go from here?
    • Is there a better taxane?
    • Are 3 drugs better than 2?
    • Is Neo-Adjuvant chemotherapy better?
    • Should we treat for longer than 6 cycles?
      • If so, what with? And for how long?
    • Is intraperitoneal delivery a better treatment?
    • Can we utilise biological therapies?
small molecules kis vs antibodies
Small molecules KIs vs Antibodies
  • TKIs Small molecules
  • TKI antibodies (mabs)
  • EGFR antibodies
  • VEGFR,AAG and VDAs
  • PDGFR,FGFR, IGFR
  • Folate receptor antagonists
  • HDAC
  • PARP
  • SRC
  • To name but a few
targeting tumour metabolism
Targeting Tumour Metabolism

Tennant, Duran and Gottlieb, Nature cancer reviews 2010

pathway identification by microarray analysis
Pathway Identification by microarray analysis

Landen, Birrer and Sood JCO 2008

so where do we begin
So where do we begin?

How do identify candidate targets?

studies in ovarian cancers to date completed not reported
Studies in Ovarian cancers to date, completed not reported
  • EORTC 55041 Tarceva (Erlotinib) 1st line
  • ICON 6 Cediranib Rel PtS
  • ICON 7 Bevacizumab 1st line
  • GOG 218 Bevacizumab 1st line
  • BI BIBF1120 BIBF 1120 Maintain
ongoing major trials
Ongoing major trials
  • AGO OVAR 16 BIBF 1120 1st line
  • AGO GCIG Pazopanib 1st line
  • Imclone 3G3 PDGFR Rel
  • Morphotek Farletuzumab Rel
  • Phase 2s in SRCs, PARPs, Sorafenib, mTOR
  • 173 trials listed in NCI Index of studies
effects of her1 egfr activation

Extracellular

Intracellular

Transactivation

P

P

Src PLCg GAP Grb2 Shc Nck Vav Grb7 Crk

PKC

Ras

Abl

JNK

PI3KAkt

MAPK

Proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis

Effects of HER1/EGFR Activation
anti her monoclonal antibodies

Erbitux

Herceptin

Cell membrane

Erlotinib

Tyrosine-kinase domain

HER1/EGFR

HER2

Anti-HER monoclonal antibodies

Whilst EGFR commonly demonstrated in OvCa, little clinical activity

  • Inhibit cell-cycle progression; potentiate apoptosis
  • Decrease production of angiogenic factors
  • Recruit natural killer cells to tumours
  • Enhance receptor internalisation

Agus D, et al. Cancer Cell 2002;2:127–37Baselga J. Cancer Cell 2002;2:93–95

eortc 55041 1 st major trial
EORTC 55041 1st major trial
  • Tarceva Trial Design

A randomised, multicentre, phase III study of Tarceva versus observation in patients with no evidence of disease progression after first line, platinum-based chemotherapy for high-risk Stage I and Stages II-IV ovarían epithelial, primary peritoneal, or fallopian tube cancer

  • Primary Objective
    • Progression-free survival.
  • Secondary Objectives
    • Overall survival.
    • Toxicity profile.
    • Quality of life.
    • Rash (surrogate marker of efficacy).
slide20

Study design EORTC 55041

First line, platinum-based chemotherapy

CR, PR, or SD

Screening

STUDY ENTRY

Randomization

TarcevaTM until progression

(up to 2 years)

Observation until progression

1st results expected 2011

agents targeting the vegf pathway
Agents Targeting theVEGF Pathway

Antibodies inhibiting VEGF receptors

Soluble VEGF receptors

(VEGF-TRAP)

Antibodies inhibiting VEGF(e.g. bevacizumab)

 Permeability

VEGF

Cation channel

VEGF receptor-2

Small-molecules inhibiting VEGF receptors (TKIs)(e.g cediranib)

– P

P–

– P

– P

P–

P–

– P

P–

P–

P–

– P

– P

Migration, permeability, DNA synthesis, survival

Ribozymes

(Angiozyme)

Angiogenesis

Lymphangiogenesis

icon7 design 1 st line
ICON7 Design: 1st Line
  • Stratification factors: stage, residual disease status, country

Carboplatin/ paclitaxel

observation

1520

stage IIB-IV patients

+ poor risk stage 1

Carboplatin/ paclitaxel + bevacizumab

bevacizumab

Treatment:

Carboplatin AUC = 6

Paclitaxel 175 mg/m2

Bevacizumab 7.5 mg/kg

(All treatments q 3 weeks)

6 cycles

(4.5 months)

12 cycles

(7.5 months)

1st report expected ESMO or IGCS 2010

gog 218 1 st line
GOG 218 : 1st line

Carboplatin AUC6

Primary endpoint: OS

Secondary endpoint: PFS

Arm A

Paclitaxel 175 mg/m2

Placebo

Carboplatin AUC6

Sub-optimally debulked Stage III/ IV OC

N=2000

Arm B

Paclitaxel 175 mg/m2

Bevacizumab (15 mg/kg)

Placebo

Placebo

Carboplatin AUC6

Arm C

Paclitaxel 175 mg/m2

1:1:1 Randomization

Bevacizumab (15 mg/kg)

Stratification variables: PS (0-1 vs 2), stage (III vs IV)

15 months*

Cycles (q3wk)*

* Taxane consolidation therapy prohibited

gog 218 asco 2010 1st results
GOG 218: ASCO 2010 1st results
  • Early release of data
  • Provisional report of PFS improved in maintenance arm of GOG 218
  • Note higher dose than ICON 7
  • 15 mg/kg cf 7.5 mg/kg
  • What is likely impact in US practice this year?
  • Unlikely to change UK practice
other studies in 1 st line
Other studies in 1st line
  • AGO BIBF1120
  • AGO/GCIG Pazopanib AGO-Ovar 16
bibf 1120 mechanism of action
BIBF 1120 – mechanism of action
  • BIBF 1120 is a potent tripleangiokinase inhibitor that simultaneously acts on three receptors involved in the formation of blood vessels1:
    • vascular endothelial growth factor receptor (VEGFR)
    • platelet-derived growth factor receptor (PDGFR)
    • fibroblast growth factor receptor (FGFR)
  • These growth factors and receptors play an important role in angiogenesis; their inhibition plays a critical role in the prevention of tumour growth and spread2,3
  • PGDGF and VEGF are over-expressed and associated with poor prognosis and poor outcome in NSCLC3,4

1. Hilberg F et al. Eur J Cancer 2004;2:50. 2. Hilberg F et al. Manuscript in preparation. 3. Bremnes RM et al. Lung Cancer 2006;51:143-158. 4. Shikada Y et al. Cancer Res 2005; 65:7241–7248.

relapsed disease focus on current uk european studies
Relapsed disease - Focus on Current UK/European studies
  • ICON 6 - Cediranib
  • Morphotek - Farletuzumab (Folate receptor)
  • Imclone 3G3 - PDGFR
  • PARPs
  • mTOR, HDACs, SRC (AZ), p1k3/akt
  • IGFR
icon 6 design schema

Arm B

Chemotherapy

Plus

cediranib

during Chemotherapy

Arm C

Chemotherapy

plus

cediranib

during Chemotherapy

Arm A

Reference arm

6 cycles of chemotherapy

plus

Placebo

No Progressive disease

Placebo

Maximum 18 months

from randomisation

No Progressive disease

Placebo

Maximum 18 months from randomisation

No Progressive disease

Maintenance

cediranib after chemotherapy

Maximum 18 months from randomisation

ICON 6 Design schema

2:3:3 RANDOMISATION

icon 6 design
ICON 6 design
  • 1st phase completed
  • Now starting 2nd phase with international collaboration
folate the role in the cell
Folate- The role in the cell

Transfers 1-carbon chemical units from donor to acceptor molecules

Critical to synthesis of nucleotide precursors of DNA

Kinetic or proliferative state of cell influences rate of internalization of folate

Folate entry proceeds via one of two distinct pathways, RFC and FR

slide34

Folate Receptor

  • 1960s: Folate Binding Protein in milk (FBP)
  • 1970s: FBP in CML cells, kidney, cord serum & folate deficient serum (carcinoma, cirrhosis uraemia & pregnancy)
  • 1979s: FBP described as a membrane protein
  • Mid 1980s: membrane localization “endocytosis” defined
  • Late 1980s: 4 laboratories cloned FR from placenta and malignant cell lines GPI anchor recognized
  • 1990s: Gene at 11q13, MoAb (Mov18&19) & LK26 molecular studies, transfection, targeting drugs & development of transgenic animals
morab 003 pre clinical data
MORAb-003: Pre-Clinical Data

USAN name: farletuzumab

Humanized MAB to Folate Receptor Alpha

Blocks phosphorylation by Lyn kinase

Active in ADCC assays

Active in xenograft model

Favorable toxicity profile in primate studies

37

morab 003 farletuzumab randomized phase ii trial
MORAb-003 (Farletuzumab)Randomized Phase II Trial

Accrual Ongoing (Target accrual 126 pts)2:1 Randomization

PFS Primary Endpoint

Weekly Paclitaxel

Plus Farletuzumab

2.5mg/kg IV weekly

R

A

N

D

O

M

I

Z

E

Recurrent

Platinum-

resistant

Ovarian cancer

Weekly Paclitaxel

Plus Placebo

morab 003 farletuzumab randomized phase iii trial
MORAb-003 (Farletuzumab)Randomized Phase III Trial

Accrual Ongoing (Target accrual 900 pts)1:1:1 Randomization

PFS Primary Endpoint

Carbo/Taxane

Plus Farletuzumab

1.25 mg/kg IV weekly

R

A

N

D

O

M

I

Z

E

Recurrent

Platinum-

sensitive

Ovarian cancer

Carbo/Taxane

Plus Farletuzumab

2.5 mg/kg IV weekly

Carbo/Taxane

Plus Placebo

parp azd 2281
PARP- AZD 2281

Yap et al ASCO 2008

early data on parp
Early data on PARP

Yap et al ASCO 2008

challenges with tats 1
Challenges with TATs 1
  • Does presence of target even matter?
    • Discordance of Herceptin in breast/ovary tumours
    • Poor correlation with degree of overexpression of EGFR and response to Iressa
  • How does one select which biological to incorporate into primary therapy?
    • Is ‘response’ in phase II necessary?
    • Combinations of biologicals?
  • Which correlative studies are best?
    • QoL?
    • Pharmacoeconomic?
challenges with tats 2
Challenges with TATs 2
  • New side effects
  • Need for extra vigilance
  • Need to avoid dilution effect too quickly
  • Different end points and response criteria
  • RECIST less useful
  • PET CT. Novel radionuclides
  • DCE MRI
dce mri of a patient treated with 2 x 250 mg of bibf 1120 in a phase i trial
DCE-MRI of a patient treated with 2 x 250 mg of BIBF 1120 in a phase I trial
  • New ways of predicting and assessing response

Before treatment

After 4 weeks

After 8 weeks

the way forward
The way forward
  • Continued support of clinical trials
  • We are only at the beginning
  • Many of our targeted agents are “dirty”
  • It has taken 40 years to achieve our level of expertise with current agents
  • Infancy