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Targeted Therapy in Metastatic Prostate and Renal Cell Cancers. Nancy A. Dawson, M.D. University of Maryland Greenebaum Cancer Center. Vascular Endothelial Growth Factor (VEGF) Targeted Therapy.

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targeted therapy in metastatic prostate and renal cell cancers

Targeted Therapy in Metastatic Prostate and Renal Cell Cancers

Nancy A. Dawson, M.D.

University of Maryland

Greenebaum Cancer Center

slide2

Vascular Endothelial Growth Factor (VEGF) Targeted Therapy

VEGF expression is regulated by a number of factors including cytokines, growth factors, hormones, hypoxia and tumor suppressor genes.

Pertinent to renal cell carcinoma, VEGF expression results from inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene observed in the majority of RCC, thus identifying VEGF as a critical component of RCC tumor angiogenesis and a particularly relevant therapeutic target in RCC.

biology of rcc
Biology of RCC
  • VHL syndrome is characterized by a germline mutation of chromosome 3p and development of RCC
  • Non-inherited clear cell RCC is characterized by VHL gene tumor suppressor gene inactivation
  • VHL gene inactivation leads constitutive expression of an oxygen-regulated transcription factor (HIFa) and induction of hypoxia-inducible genes including VEGF
  • VEGF overexpression promotes tumor angiogenesis
clear cell rcc is characterized by vhl gene inactivation
Clear cell RCC is characterized by VHL gene inactivation

VHL gene inactivation in clear cell renal carcinoma: selected series

* No significant VHL gene mutation (1%; 2/136) or methlyation (2%; 3/135) observed in non-clear cell RCC

Rini BI et al. J Clin Onc In press

vegf overexpression promotes tumor angiogenesis and rcc progression
VEGF overexpression promotes tumor angiogenesis and RCC progression
  • Cytoplasmic VEGF expression in primary clear cell RCC (n=62) correlated with stage, grade and microvessel count and demonstrated independent prognostic significance for overall survival (p=0.01) in a retrospective series.(Paradis et al. Virchows Arch 436, 2000)
  • Elevated serum VEGF levels have been demonstrated in RCC patients versus controls and generally correlate with stage and grade. Assoc. w/ survival in univariate analysis.(Jacobsen J et al. JUrol 163, 2000)
therapeutic inhibition of vegf in rcc
Therapeutic inhibition of VEGF in RCC
  • Miscellaneous anti-VEGF agents
    • Thalidomide
    • AE-941 (Neovastat)
  • Binding antibodies to the VEGF protein
    • Bevacizumab (Avastin)
    • VEGF-trap
  • VEGFR inhibitors
    • SU11248
    • PTK787
    • BAY 43-9006
thalidomide thalomid
Thalidomide (Thalomid®)
  • Thalidomide has an anti-angiogenic mechanism
    • Reduction of both bFGF- and VEGF-induced corneal neovascularization in animal models.
    • Reduction of bFGF and VEGF expression with resulting inhibitory effects on endothelial cell proliferation.
  • Other potential anti-tumor effects: reduction in TNF-alpha production, induction of G1 cell cycle arrest/apoptosis and modulation of stimulated NK cells and T lymphocytes
phase iii trial of ifna thalidomide
Phase III trial of IFNA +/- thalidomide

Untreated, metastatic RCC (n=342)

Response rate 7.6% 3.1%

TTP (months) 2.8 2.8

OS (months) 13.1 10.8

IFNA 1 MU BID

+

Thalidomide (200-1,000 mg/day)

IFNA 1 MU BID

*all p values = n.s.

I + T with worse QOL, fatigue, clots (12 vs. 4 pts.)

Gordon MS et al. ASCO 2004 (#4516)

ae 941 neovastat
AE-941 (Neovastat®)
  • Compound prepared by homogenization and purification of shark cartilage.
  • Inhibits several VEGF-dependent processes through competitive binding with VEGFR-2.
  • A phase I study of AE-941 was conducted in 144 patients with refractory solid tumors, and a subset of 22 metastatic RCC was reported. (Batist, Ann Oncol 2002)
    • Two objective responses were observed (overall response rate 9%).
ae 941 neovastat12
AE-941 (Neovastat®)

Cytokine-refractory, metastatic RCC (n=302)

Response rate % <5%*

TTP (months) 2*

OS (months) 12.3*

AE-941 240mL/day

placebo

*p = n.s for all values vs. placebo

Escudier B et al. ASCO 2004 (#4547)

therapeutic inhibition of vegf in rcc antibody mediated blockade of vegf protein
Therapeutic inhibition of VEGF in RCC: antibody-mediated blockade of VEGF protein
  • Anti-VEGF antibody (bevacizumab, Avastin®)
    • Recombinant human monoclonal antibody against VEGF created by transferring the VEGF-binding regions of the murine antibody to a humanized IgG1 framework (93% human, 7% murine).
    • Binds and neutralizes all biologically active isoforms of VEGF.
bevacizumab in rcc
Bevacizumab in RCC

PLACEBO Q 2 WEEKS

(n=40)

RANDOMIZE

PD

Treatment-refractory, metastatic RCC

BEVACIZUMAB (3 MG/KG) Q 2 WEEKS

(n=37)

BEVACIZUMAB (10 MG/KG) Q 2 WEEKS

(n=39)

Yang JC et al. NEJM 349(5), 2003

bevacizumab in rcc15
Bevacizumab in RCC

Placebo Low-dose High-dose Bevacizumab Bevacizumab

Response rate 0% 0% 10%

TTP (months) 2.5 3.0* 4.8**

OS (months) 13.0 15.1 15.5

*p=0.041 vs. placebo; **p < 0.001 vs.placebo

Yang JC et al. NEJM 349(5), 2003

slide16
CALGB 90206: A Randomized Phase III Trial of Interferon Alpha-2b or Interferon Alpha-2b Plus Bevacizumab in Advanced Renal Carcinoma

RANDOMIZE

IFNA 9 MU TIW

STRATIFY

UNTREATED, METASTATIC CLEAR CELL RCC

IFNA 9 MU TIW +

Bevacizumab 10 mg/kg IV q d1 and d15

  • Patients will be stratified for nephrectomy status and Motzer risk group (0, 1-2 or 3+ risk factors).
therapeutic inhibition of vegf in rcc receptor blockade su11248
Therapeutic inhibition of VEGF in RCC: receptor blockade (SU11248)
  • Oxindole TK inhibitor
  • Orally bioavailable small molecule
  • Selective multitargetinhibition of:
    • PDGF-R
    • VEGF-R
    • Kit
    • Flt-3
  • Plasma half-life  40 hours

CH3

O

H3C

CH3

N

N

H

CH3

F

N

H

O

N

H

Mendel et al. Clin Cancer Res 9, 2003

su11248 in cytokine refractory rcc
SU11248 in cytokine-refractory RCC
  • Single-arm, multi-institutional phase II of SU11248 in metastatic, cytokine-refractory RCC patients
    • 50mg p.o. QD: 4 weeks on / 2 weeks off
  • Results (n=63):
  • Of 21 patients who achieved a PR, 14 remain progression-free (range 5.1+ - 12.0+ months).

Motzer R, Rini B, Michaelson D et al. Proc ASCO 2004

slide19

SU11248 Phase II: Clinical Results

Baseline

After 4 weeks of SU11248

After 8 weeks of SU11248

bay 43 9006
BAY 43-9006
  • BAY 43-9006 is a Raf kinase inhibitor
  • Raf-MEK-ERK pathway involved in tumor growth
  • VEGF and PDGFR inhibitor(Wilhelm AACR 2003)
bay 43 9006 trial schema

Continue

BAY 43-9006

Continue

BAY 43-9006

12 weeks

% SD

24 weeks

Placebo*

12 weeks

Off study

*Placebo pts with PD may cross over to BAY 43-9006

BAY 43-9006: Trial Schema

> 25%

Tumorshrinkage

BAY 43-9006

12 week

run-in

-25% to +25%Tumor

stabilization

> 25%Tumor

growth

bay 43 9006 in rcc
BAY 43-9006 in RCC
  • 203 total RCC pts -> 106 reached 12-week re-eval. point -> 89 evaluable
  • Results (n=89):
  • Median TTP in pts. continuing drug = 48 weeks; 23 weeks in randomized pts.

Ratain M et al. Proc ASCO 2004

conclusions
Conclusions
  • VHL gene inactivation is a frequent event in clear cell RCC leading to VEGF overexpression
  • Therapeutic inhibition of VEGF via antibody or receptor blockade results in anti-tumor activity in metastatic RCC
the future of anti vegf therapy in rcc
The future of anti-VEGF therapy in RCC
  • Definitive phase III trials of anti-VEGF therapy
    • In combination with initial cytokine therapy (CALGB: IFN vs. IFN/Avastin)
    • First-line therapy vs. cytokines (SU11248 vs. IFN)
    • Second-line therapy vs. placebo (BAY 43-9006) or single-agent (SU11248)
    • Adjuvant BAY 43-9006 vs.placebo adjuvant trial planned (ECOG)
  • Combination therapy
    • Bevacizumab + OSI-779 (EGFR inhibitor) rPII completed
    • CALGB planning rPII of PTK787 vs. RAD-001 (mTOR inhibitor) vs. PTK/RAD
    • Many others . . . . .
egfr targeted therapy rationale
EGFR-Targeted Therapy Rationale
  • EGFR is constitutively expressed in normal kidney.
  • EGFR by IHC is over-expressed in 75-90% of kidney neoplasms.
  • Over-expression of EGFR appears to play a role in tumor initiation and progression in RCC.
  • Mab C225, an anti-EGFR monoclonal antibody, can delay tumor growth in human RCC tumor xenografts.
trial design
Trial Design
  • ZD1839 500 mg po qd.
  • Dose modification to 250 mg qd based on toxicity. No reescalation or further reduction permitted.
  • Response based on RECIST.
  • Primary EP = RR (CR+PR+SD).
  • Secondary EP = TTP, OS, Toxicity, EGFR status correlation.
  • Two-stage optimal design. Study closed if < 11/21 responses.
prostate cancer treatment paradigms
Prostate CancerTreatment Paradigms

Relapsed

and

newly diagnosed M+

Hormone

refractory

Clinically

localized

Docetaxel-based

regimens

Local treatment

Endocrine

Improves survival

emerging options in castrate metastatic prostate cancer cmpc
Emerging Options in Castrate Metastatic Prostate Cancer (CMPC)
  • Newer cytotoxic combinations
    • Calcitriol + docetaxel, satraplatin, ixabepilone
  • Antiangiogenesis inhibitors
  • Gene therapy/tumor vaccines/oncolytic viruses
    • Provenge (PSMA stimulated dendritic cells), GVAX (GM-CSF secreting tumor cells), CG787
  • Monoclonal antibodies
    • PSMA targeted radiopharmaceutical or toxin (DM-1)
  • Endothelin-receptor antagonists (atrasentan)
biomolecular markers in cmpc
Biomolecular Markers in CMPC

Multivariate model of plasma VEGF levels predicting survival time among 197 patients

George DJ, et al. Clin Cancer Res. 2001 Jul;7(7):1932-6.

docetaxel plus thalidomide in cmpc
Docetaxel Plus Thalidomide in CMPC

NCI Randomized Phase 2 Trial

Taxotere

Docetaxel/Thalidomide

(n=50)

R

A

N

D

O

M

I

Z

E

AIPC

(n=75)

Endpoint: PSA Decline

Docetaxel

(n=25)

Dose:

Docetaxel = 30 mg/m2 q wk x 3 of 4

Thalidomide = 200 mg/day

Dahut WL, et. al. 2002 ASCO Annual Meeting Proceedings. Abstract 730.

docetaxel plus thalidomide results
Docetaxel Plus Thalidomide: Results

Dahut WL, et. al. 2002 ASCO Annual Meeting Proceedings. Abstract 730.

cancer and leukemia group b phase 2 studies
Cancer and Leukemia Group B:Phase 2 Studies

Picus J, et al. Proc Am Soc Clin Oncol. 2003 ASCO Annual Meeting Proceedings. Abstract 1578.

avastin bevacizumab
Avastin™ (bevacizumab)
  • Recombinant humanized monoclonal IgG1 antibody1
  • Recognizes all isoforms of VEGF2
  • Estimated half-life is approximately 20 days (range, 11-50 days)1
  • Approved for the use in metastatic Colon Cancer

1. Avastin™ (Avastin) PI. February 2004.

2. Presta et al. Cancer Res. 1997;57:4593.

slide35

Randomized Phase 3 Trial for Castrate Metastatic Disease

Eligibility

Metastatic PC

T <50 ng/ml

No prior chemo

Adequate hem, renal,

and liver function

Stratification

Halabi

nomogram

Docetaxel q 3 wks +

Prednisone + Placebo

Docetaxel q 3 wks +

bevacizumab +

prednisone

RANDOMIZE

N = 1020 patients

CALGB, ECOG, NCIC

atrasentan a selective endothelin a receptor antagonist
Atrasentan: A Selective Endothelin-A Receptor Antagonist

Orally bioavailable

Once daily dosing

1800 x more selective for ETAthan ETB

Opgenorth TJ, et al. J Pharmacol Exp Ther. 1996 Feb;276(2):473-81.

Carducci MA, et al.J Clin Oncol. 2002 Apr 15;20(8):2171-80.

Nelson JB, Carducci MA. BJU Int. 2000 Apr;85 Suppl 2:45-8.

Nelson, Prostate J 1999;1:126.

hazard ratios confirm consistency of results

Meta-analysis

Intent-to-treat

M00-211

M96-594

M96-594

M00-211

Intent-to-treat

Intent-to-treat

Per-protocol

Per-protocol

Hazard Ratios Confirm Consistency of Results

Cox proportional hazards modeling—time to disease progression

Favors Placebo

Favors Atrasentan 10 mg

1.189

P=.014

1.130

P=.131

1.260

P=.008

1.239

P=.142

1.484

P=.010

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

Data on file.

atrasentan adverse events
Atrasentan Adverse Events*

Common adverse events reported by >5% of subjects

(% incidence)

M00-211

M96-594

Adverse event

Placebo

(n=397)

Atrasentan

(n=404)

Placebo

(n=104)

Atrasentan

2.5 mg

(n=95)

Atrasentan

10 mg

(n=89)

Peripheral edema

12

40

17

34

34

Rhinitis

14

36

15

25

28

Headache

14

21

10

16

20

Infection

8

13

10

15

11

Dyspnea

4

9

4

6

17

Rash

4

7

8

5

12

Dry mouth

2

6

3

3

4

*Premature discontinuation due to AE=8.9% vs 5.5% for atrasentan and placebo, respectively, in M00-211.

meta analysis time to disease progression

0

56

112

168

224

280

336

392

448

504

Meta-analysis Time-to-disease Progression

1.0

Intent-to-treat

N=1097

0.9

Log rank

P=.013

0.8

HR=1.19

Atrasentan

n=592

0.7

0.6

0.5

Probability of No Disease Progression

0.4

0.3

0.2

Placebo

n=505

0.1

0.0

Days Since Randomization

Data on file.

atrasentan
Atrasentan
  • Delays disease progression in men with metastatic CMPC
    • Meta-analysis of data from 1097 men in 2 large, randomized, controlled studies
  • Reduces incidence of and delays time to onset of bone pain
  • Provides quality of life benefit
    • Maintains good health state for longer
  • Has a favorable safety profile
psma protein structure
PSMA Protein Structure

transmembrane

region

Javelin peptides:

hsp antigen presentation

dendritic cell loading

PSM1 and PSM2

Cross species

DNA Immunization:

T cell and antibody

response

Internal Domain Antibodies:

includes CYT-356 epitope

Binds “dead” cells

External Domain Antibodies:

J591, MSKCC (Ab)

Bind viable cells, Internalized

the antibody j591 mln2704
The Antibody: J591 (MLN2704)
  • Extracellular domain of PSMA
  • Equivocal to weak reactivity
    • Subcortical white matter brain
    • Epididymis
  • Internalizes following binding
  • Excellent correlation with bone and/or CT
saha selected for development as a broad anti cancer agent
SAHA selected for development as a broad anti-cancer agent
  • Small molecule, MW < 300
  • 45 nM inhibitor of HDAC activity
  • Induces histone acetylation and alters gene expression (p21, TBP-2 and others)
  • Blocks proliferation of cultured cells
  • Inhibits tumor growth in animal models

SuberoylAnilide Hydroxamic Acid

slide49

6 hrs

12 hrs

SAHA

(mg/kg)

0

25

50

0

25

50

 Ac-H3

Coomassie

stain

 Ac-H4

Coomassie

stain

SAHA inhibits tumor growth in CWR22 human prostate xenografts in mice and increases histone acetylation in tumors

  • No evidence of toxicity by:
  • weight gain, hematological
  • parameters or extensive
  • necropsy at doses of
  • 25 or 50 mg/kg SAHA

Start

Treatment

Butler et al.

slide50

Emerging Therapies in CMPC

PSMA Ab

Vaccine B\T cells

Dendritic

Ansamycins (17-AAG)

TK Inhibitors (ZD1839,OSI774)

Mono Abs (C225, Herceptin, 2c4)

Atrasentan

Src

PD173855/PD179483)

Grb2/Shc

PI3K

LY294002

PTEN

Sos

AKT

Bad

Antisense (G3139)

BCL-2

FTI

(BMS 214662)

Ras

mTOR

Rapamycin, CCI-779

G2

Raf

Ansamycins

Tubulin

(Epothilone B)

S

M

  • Flavopiridol

Cyclin D/

CDK4

Satraplatin

PD98059

MEK

G1

SERM3

ER

MAPK

NF-kB

Proteasome inhibitors (PS341)

Casodex

AR

Altered Gene

Expression

HDAC inhibitors (SAHA)

Vit D, Retinoids