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Ovarian Cancer
PI3K/AKT/m-TOR pathway
and
SRC Inhibitors
Orlando – 29th May 2009
Nicoletta Colombo
Università Milano Bicocca
Istituto Europeo di Oncologia
Milano
© Colombo IEO 2009
PI3K-AKT-m-TOR pathway
© Colombo IEO 2009
© Colombo IEO 2009
SF 1126
XL147
GDC-0941
XL765
BZ235
BGT226
XL765
BZ235
BGT 226
GSK690693
Perifosine
PX316
API-2/TCN
AT13148
A-443654
Temsirolimus
Everolinus
Deferolimus
Deforolimus
© Colombo IEO 2009
PI3K inhibitors
Safety of XL147 in combination with paclitaxel and
carboplatin in adults with Solid Tumors
(NSC lung, endometrial , ovarian cancer)
•
•
•
•
•
Phase I
Sponsored by Exelixis
NCT00756847
Currently recruiting participants
MD Anderson Cancer center and University of
WI Paul P Carbone Comprehensive Cancer
Center, Madison , Wisconsin
© Colombo IEO 2009
SF 1126
XL147
GDC-0941
XL765
BZ235
BGT226
XL765
BZ235
BGT 226
GSK690693
Perifosine
PX316
API-2/TCN
AT13148
A-443654
Temsirolimus
Everolinus
Deferolimus
Deforolimus
© Colombo IEO 2009
AKT inhibitors
Perifosine and Docetaxel in patients
with relapsed epithelial ovarian cancer
•
•
•
•
Phase 1
Currently recruiting participants
NCT00431054
Sponsored by MD Anderson Cancer
Center and Keryx Biopharmaceuticals
© Colombo IEO 2009
Growth Factors
IGF-1, EGF, TGFα, VEGF,
etc
Growth Factors and the mTOR
Pathway
 mTOR
PI3-K
–
–
PTEN
Oxygen, energy,
and nutrients
Ras/Raf
Akt/PKB
Abl
ER
TSC2 TSC1
Intracellular protein
Central controller of
cell growth and
proliferation
 mTOR signaling is often
deregulated in cancer
Ras/Raf
pathway
kinases
mTOR
 Downstream inhibition of
mTOR has potential for
–
S6K1
Antiproliferative effects on
tumor cells
4E-BP1
S6
Protein Production
–
elF-4E
–
Cell Growth
and Proliferation
Angiogenesis
Angiogenesis inhibition
Enhancement of the effects
of chemotherapy
© Colombo IEO 2009
Potential mTOR-dependent cancers
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M TOR inhibitors
Rapamycin is not a good candidate for parenteral
administration because of its poor water solubility
and stability. Other compounds have been
developped with improved pharmaceutical
properties:
•CCI 779 (temsirolimus)
•RAD 001 (everolimus)
•AP 23573 (deforolimus)
© Colombo IEO 2009
mTOR Inhibition in Ovarian Cancer Therapy: Current Trials
NCT Identifier
Agent(s)
Study Design
NCT00429793
Temsirolimus
Ph II, nonrandomized; pts
with persistent or recurrent
EOC or PPC
(GOG)
NCT00408655
(NCIC)
NCT00523432
(Univ Chicago)
NCT00703170
Washington
University
NCT00703625
Temsirolimus +
Ph I, open label; in pts with
carboplatin/paclitaxel
advanced endometrial
cancer, ovarian cancer
Temsirolimus +
topotecan
Ph I, open label,
nonrandomized; in pts with
gynecologic malignancies
Temsirolimus+
doxil
Resistant solid
malignancies
Temsirolimus+
docetaxel
Resistant solid
malignancies
© Colombo IEO 2009
Temsirolimus + Topotecan: Ph I in Gynecologic
Malignancies
• Pts with advanced/
recurrent gynecologic
malignancies (Ov: 5 pts;
EM: 2 pts; uterine: 2 pts;
Cx: 1 pt)
– < 3 prior chemo regimens
– Pts with/without whole-pelvis RT
dose-escalated separately
• Topotecan 1 mg/m2 d 1, 8,
15; temsirolimus 25 mg d
1, 8, 15, 22, 28 of a 29-d
cycle
• Combination not tolerable
in pts with prior pelvic RT
– 4/6 pts had DLT effects at
starting dose (RT: 1; no RT: 3)
– DLTs also seen in 2/4 pts on
topotecan 1 mg/m2 +
temsirolimus 15 mg wkly
• 1 pt had prior RT
• Best clinical response: SD
in 6/7 evaluable pts
Temkin SM, et al. SGO 2009. Abstract.
© Colombo IEO 2009
mTOR inhibitors: Combination Therapy
mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies
Agent
Rationale
EGFR
inhibitors
Defects in the mTOR pathway may counter the effects of EGFR
inhibitors. Combined treatment beneficial in preclinical studies1
Cytotoxic
chemotherapy
Cytotoxic drugs (platinum derivatives, taxanes,
anthracyclines, gemcitabine) improved antitumor effects in
preclinical models in combo with mTOR inhibitors2-4
Antiangiogenic
agents
mTOR inhibition affects angiogenesis through mechanisms that
enhance those of anti-VEGF/anti-VEGFR inhibitors5
Antiestrogens
Defects in the mTOR pathway may render estrogen-dependent
tumor cells resistant to antiestrogens and aromatase
inhibitors. Combinations effective preclinically6-8
Radiation
In preclinical studies, mTOR inhibition enhances cell killing
induced by radiation (interfering repair of damage to DNA9)
© Colombo IEO 2009
Dose-finding study of CaelyxTM
and RAD001(everolimus) in patients with advanced solid tumors
Step 1
Dose finding
with dose escalation
Step 2
Expansion phase
@ the RD
 Define MTD & RD
 3 centers (IOSI, INT, IEO)
 2 centers (IOSI, INT),
 Groups of 12 homogeneous
pts with selected tumors
 Standard 3+3 cohort design
 PK
 Tumors of interest prostate,
ovary, breast, corpus uteri
© Colombo IEO 2009
Bevacizumab with or without Everolimus in treating
patients with recurrent or persistent ovarian epithelial
cancer, fallopian tube cancer, or primary peritoneal cancer
• NCT00886691
• Sponsored: Gynecologic Oncology Group
(NCI)
• Randomized Phase II
• Not yet open for recruitment
© Colombo IEO 2009
The Biology of Src
• Src is deregulated in
many human cancers
Integrins
Extracellular
matrix
GF
GF receptor
P Src
P
Focal
adhesion
complex
Growth factor
induced
mitogenesis
Promotes
G1/S
Cadherins
Migration
Invasion
Osteoclast
function

Promotes invasion
and migration through
disruption of focal
adhesion complexes
and E-cadherin

Promotes proliferation
and survival through
receptor crosstalk
and signal
transduction
modulation
Actin cytoskeleton
Promotes survival
© Colombo IEO 2009
Src, a kinase at the crossroad of growth factor- and
adhesion-mediated signaling
Extracellular matrix:
Growth factors:
Fibronectin
Collagen
Vitronectin
Fibrin
…..
EGF
PDGF
VEGF
…..
Ras-Raf-MAPK
P190-RhoGAP
Cell migration
Ras-Raf.MAPK
PI 3K-Akt-mTOR
STAT3-cMyc
Proliferation - Survival
Modified after G. W. McLean et al., Nat Cancer Rev (2005) 5: 505
© Colombo IEO 2009
Src Inhibition in Ovarian Cancer Therapy
• Activated in most ovarian cancers
• Overexpressed in most late-stage ovarian
cancer tumors and in ovarian cancer cell
lines[1,2]
• Promotes tumor survival and chemotherapy
resistance in the ID8 murine ovarian cancer cell
line[3]
• Src inhibition shown to enhance paclitaxelmediated cytotoxicity in ovarian cancer cell
lines[3,4]
1. Budde RJ, et al Biochem Biophys Res. 1994;14:171-175. 2. Wiener JR, et al.
Gynecol Oncol. 2003;88:73-79. 3. Pengetnze Y, et al. Biochem Biophys Res
Commun. 2003;309:337-383. 4. Chen T, et al. Mol Cancer Ther. 2005;4:217-224.
© Colombo IEO 2009
AZD0530 – A Potent, Selective Inhibitor
of Src Family Kinases
O
O
O
O
N
Cl
N
N
N
O
N
AZD0530: anilinoquinazoline
• Reversible, competitive binding at active
conformation of ATP pocket
• Favorable PK and bioavailability
– Suitable for once-daily
oral dosing
– t½ in healthy volunteer studies ~40
hours
Isolated protein kinase IC50, nM
cSrc
2.7
cYes
4
Lck
<4
Lyn
5
c-Fyn
10
v-abl
30
c-kit
200
Csk
843
PDGFR β
>5,000
PDGFR α
>10,000
Anti-migratory IC50
MDA-MB-231 (Breast)
Tamoxifen-resistant MCF-7 (Breast)
A549 (NSCLC)
nM
<50
100
140
Green TP et al. Proc Am Assoc Cancer
Res 2005;46:2537
© Colombo IEO 2009
AZD0530 Src Kinase Inhibition
in Ovarian Cancer
AZD0530 prolongs median survival through enhanced cytotoxicity of paclitaxel in in vivo
models of resistant ovarian cancer
Effects of AZD0530 alone and in combination with paclitaxel in
mice bearing ID8TaxR i.p xenografts
Chen: NCI/EORTC/AACR 2007
© Colombo IEO 2009
Phase I study of AZD0530 Drug-related adverse
events and hematologic safety profile
•
•
•
Few (3/30) dose interruptions after
21 days of continuous dosing
11/81 patients discontinued therapy
for toxicity related events
7/81 patients discontinued therapy
for drug-related adverse events
Hematologic adverse events
Patients with reduced count, n (%)
Hemoglobin
Platelets
Neutrophils
•
All grades
70 (86)
18 (22)
15 (19)
CTC grade 3–4
10 (12)
0
3 (4)
Neutropenic nadir recovered without
need for treatment interruption or
supportive care in the majority of patients
Patients, n (%)
Adverse event
(n=81)
Nausea
18 (22)
Asthenia/fatigue
17 (21)
Anorexia
15 (19)
Vomiting
14 (17)
Diarrhea
10 (12)
Pyrexia
6 (7)
Myalgia
5 (6)
Cough
4 (5)
Constipation
3 (4)
Abdominal pain
2 (2)
Peripheral edema
2 (2)
Dysguesia
2 (2)
Headache
2 (2)
Pruritis
2 (2)
Dyspnea
2 (2)
Onychoclasis
2 (2)
© Colombo IEO 2009
Phase I study of AZD0530
Efficacy – time on AZD0530 treatment
Treatment duration (days)
0
20
40
60
80
100
120
140
160
180
200
220
13 patients (16%) were treated
for 12 weeks or more
Individual patients
12 weeks
Tumor type
Colorectal
Pancreas
Breast
Other
0
Tumor type
Pancreas
GIST
Pancreas
Sarcoma
Colorectal
Colorectal
Melanoma
Colorecal
Melanoma
Sarcoma
Breast
Colorectal
Colorectal
Days on
treatment
217
175
155
150
115
105
100
91
91
90
86
85
84
20
© Colombo IEO 2009
Phase I study of AZD0530
Summary
• A daily dose of 175mg AZD0530 monotherapy has been
defined as the MTD
• Chronic therapy with 175mg AZD0530 daily is well
tolerated and provides an exposure greater than that
required to inhibit the target in preclinical assays
• Major toxicities: anemia, nausea, asthenia, anorexia,
vomiting, diarrhea.
• 13 patients (16%) were treated for 12 weeks or more
(pancreas, sarcoma, colorectal, melanoma)
© Colombo IEO 2009
A Phase I Study To Assess the Safety and Tolerability
ofAZD0530 in Combination With Carboplatin and/or Paclitaxel
• Dose exploration is ongoing in each treatment arm
• AZD0530 has been declared tolerable at the following doses
and combinations:
– AZD0530 175 mg once daily in combination with carboplatin
AUC 5 + paclitaxel 175 mg/m2 administered every 3 weeks
– AZD0530 125 mg once daily in combination with carboplatin
AUC 5 administered every 3 weeks
– AZD0530 250 mg once daily in combination with paclitaxel
175 mg/m2 administerd every 3 weeks
– AZD0530 175 mg once daily in combination with paclitaxel
80 mg/m2 administered weekly
© Colombo IEO 2009
OVERT1
Phase II Randomised, Double-blind, Placebo-controlled, Multi-centre Study
Patients with:
 Histologically proven
epithelial ovarian
cancer
 1 or 2 prior platinumcontaining Tx lines
 Radiological evidence
of disease progression
/ recurrence at least 6
months following
treatment cessation of
prior platinumcontaining therapy
•
•
•
End points
AZD0530*
(175mg OD)
+ CP
Randomisation
(1:1 ratio)
Placebo*
+ CP
 ORR
 PFS
 Survival
 Safety
 PK of AZD0530
/ metabolite
 Tumour
biomarkers
analysis
 QoL,
symptoms
* Up to 6 (or 8) q3 weekly chemo cycles + concurrent daily AZD0530 / placebo taken until
radiological progression / withdrawal from study medication;
CP, Carboplatin (AUC6), Paclitaxel 175 mg/m2 on day 1 every 3 weeks;
Stratified for number of prior platinum-containing treatment lines (1 or 2) and treatmentfree interval (6 to 12 months or > 12 months);
© Colombo
IEO 2009of life
ORR, objective response rate; QoL,
quality
Considered Ovarian
Development Programme
• A Phase III study of AZD0530 plus carboplatinpaclitaxel versus placebo plus carboplatinpaclitaxel in women with newly diagnosed,
previously untreated, advanced ovarian cancer
• A phase III study of AZD0530 plus carboplatinpaclitaxel versus placebo plus carboplatinpaclitaxel in women with advanced ovarian
cancer sensitive to platinum-based therapy
© Colombo IEO 2009
Summary
• AZD0530 is a highly potent and selective, orally
available, once-daily Src inhibitor
• Acceptable side effect profile both as
monotherapy and in combination with
chemotherapy
• AZD0530 is being evaluated clinically
in a range of tumour types
• OVERT1 study is the first randomised evaluation
of the clinical benefit of Src inhibition
© Colombo IEO 2009