1. No category

First-in-man study of E-3810, a novel VEGFR and FGFR inhibitor, in patients with advanced solid tumors
J. C. Soria1, F. G. De Braud2, R. Cereda3, R. Bahleda1, A. Delmonte2, E. Angevin1, A. Varga1, C. Noberasco2, E. Dall’O’5,
N. Lassau1, C. Dromain1, M. Bellomi2, F. Farace1, F. Bertolini2, M. Zucchetti4, S. Marsoni5, M. G. Camboni3
Abs
TPS149
1SITEP,
Institut Gustave Roussy, Villejuif, France; 2European Institute of Oncology, Milan, Italy; 3EOS S.p.A., Milan, Italy; 4Mario Negri Institute, Milan, Italy; 5SENDO, Milan, Italy
OBJECTIVES
BACKGROUND
 VEGF and FGF and their cognate receptors are key players in promoting tumor angiogenesis.
FGF may play a role in the mechanisms of resistance to VEGF inhibitors. Deregulated FGF/FGFR
signaling may directly drive cancer cell proliferation/survival in some tumors; FGFR1 amplification
has been described in patients with breast, bladder, ovary cancer, rhabdomyosarcoma, 8p11 EMS
and more recently in squamous cell lung cancer.
Co-selective inhibition of VEGF and FGF receptors could thus block tumor angiogenesis, circumvent
FGF-mediated resistance and target proliferation in FGF-driven tumors
 E-3810, is a novel dual inhibitor of the tyrosine kinase
activity of VEGFR1, 2 and 3 and FGFR1 with activity
at low nM concentrations (1)
E-3810
Kinase
VEGFR family
VEGFR-1
VEGFR-2
VEGFR-3
FGFR family
FGFR-1
FGFR-2
FGFR-3
FGFR-4
PDGFR family
c-kit
PDGFRα
PDGFRβ
CSF-1R
D1
D3
D7
17
83
238
>1000
TRIAL DESIGN
First-in-man, open-label, uncontrolled study
496
175
525
5
Dose-escalation
E-3810
10 mg/kg
E-3810 inhibition of FGF-dependent cell
proliferation
MCF-7
MCF-7
75
% of Ctr
% of Ctr
% of Ctr
50
50 ng/ml bFGF
E-3810 antitumor activity in xenografts
with different FGFR1 and FGF2 expression
75
50
50
25
25
25
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
Cell Line
125
0
-0.25 0.00
E-3810 IC50 (mM)
10% FBS
0.25
MDA-MB-134
19 ± 2
5±1
MCF-7
30 ± 2
15 ± 2
LNCAP
17 ± 4
3±1
OVCAR-3
17 ± 3
22 ± 2
75
1.0
1.5
2.0
1.00
1.00
log uM
1.25
1.25
1.50
1.50
1.75
1.75
0
-1.0
-0.5
0.0
0.5
1.0
1.5
Xenograft
% inhibition at the
end of treatment
Maximum effect
FGFR-1
expression
FGF-2
expression
LXFL-1121
87
regression
High
Low\Medium
LXFE-409
85
regression
High
Low\Medium
LXFA-400
72
stabilization
High
Low\Medium
RXF-631
87
regression
Medium
High
2.00
2.00
75
25
0.5
0.75
100
25
log uM
0.75
0.50
125
50
0.0
0.50
0.25
log uMOVCAR-3
50
-0.5
0.00
50 ng/ml bFGF
% of Ctr
% of Ctr
100
0
-0.25
2.00
log uM
LNCAP
0
-1.0
(= dose level immediately below the MTD)
Patients :
 tumors bearing FGFR1 amplification
(e.g. breast, NSSCLC) assessed by
FISH or CGH
 relapsing after response or SD (6 mo+)
to antiangiogenic treatment (e.g. renal,
liver, CRC)
100
75
0
-0.25
Patients:
 any advanced/metastatic solid tumor,
relapsed or refractory to standard
therapy
Cohort expansion at RD
DLTs
10 % FBS
100
100
Dose escalation up to MTD
 Standard 3+3 design
 Starting daily dose 5 mg (1/12 of the
MTD in monkey)
 Dose doubled until the first G2 toxicity
or G2 uncontrolled hypertension;
smaller increments thereafter
125
Expansion basket phase
(= dose level with DLTs in ≥ 2/6 pts)
D 14
Vehicle
125
SAFETY ASSESSMENTS
 Serial CBC and biochemistry (including thyroid function)
 Cardiac monitoring (five ECGs and two 24-hour Holter on C1, then monthly)
 Routine BP monitoring including self-assessment between visits
 Hypertension management with standard algorithm by independent cardiologist
PHARMACOKINETICS
 Serial blood sampling on D1, D7 and D28 and predose sampling on D4, D14 and D21
 Plasma levels of E-3810 assessed by a validated LC-MS/MS method (6)
CORRELATIVE STUDIES
ORAL E-3810 – once daily on a continuous schedule over 4-week cycles
 If clinical benefit, treatment can continue beyond cycle 1 until progression
7
25
10
 FGFR inhibition results in enhanced E-3810 cytotoxic activity in cell lines with FGF-driven growth (4);
likewise antitumor activity appeared somewhat higher in tumor xenografts expressing high FGFR-1
and/or FGF ligand (5), suggesting that a better clinical response might be achieved in patients with
deregulated FGF/FGFR signaling pathway
MDA-MB-134
TREATMENT
IC50(nM)
Assays were done with ATP conc. at the respective Km
D -1
125




To establish the safety profile, Dose-Limiting Toxicities (DLT) and Maximum Tolerated
Dose (MTD)
To select the Recommended Dose (RD)
To characterize the pharmacokinetic (PK) profile after single and repeated administration
To evaluate the effect on tumor perfusion and circulating biomarkers of angiogenesis
To preliminarily evaluate the antitumor activity
In vitro kinase inhibition profile of E-3810
 In several tumor xenograft models, E-3810 showed strong anti-tumor properties at well-tolerated
oral doses coupled with a substantial antiangiogenic activity as indicated by different markers and
imaging techniques (1, 2, 3)
DCE-MRI imaging in rats
Treatment with E-3810 for
14 days reduced tumor size,
Ktrans and contrast agent
uptake (iAUC, shown in
Figure) in tumor

SAFETY and PK
RXF-486
87
regression
Low
High
MAXF-401
64
stabilization
Low
Low
LXFA-983
34
stabilization
Low
Low
2.0
log uM
 E-3810 has good oral bioavailability, no major metabolic liabilities and a PK profile consistent with
oral daily dosing.
Occurring in the first 4-week cycle
 Febrile neutropenia G3 or ANC < 0,5 x109/L (G4) for more than 5 days
 Thrombocytopenia G3 with bleeding
 Any other G4 haematological toxicity
 Increase in AST and ALT G3 for more than 6 days
 Nausea and vomiting G3 if not controlled by antiemetic treatment
 Hypertension G3 if not controlled to G2 by 7 days antihypertensive therapy
 Any other G3/4 non hematological toxicity (alopecia excluded)
 Less than 21 doses or retreatment delayed for more than 2 consecutive weeks
Grading according to NCI-CTCAE version 4.0
Assessments over cycle 1 (baseline and predose on D7 and D28)
Additional evaluations after 12 weeks or at progression in the expansion cohort
BIOMARKERS OF ANGIOGENESIS
 Soluble VEGFR2 and VEGFR1, VEGF, bFGF and Collagen IV measured by enzyme-linked
immunosorbent assay (ELISA)
 Mature Circulating Endothelial and Progenitors Cells (CEC and CEP) measured by flow
cytometry (6 colour FACS)
IMAGING TO ASSESS ANTI-ANGIOGENESIS
 DCE-MRI of selected lesion; evaluation of tumor perfusion/permeability by transfer
constant (Ktrans) and initial Area Under the Concentration-time curve (iAUC)
 DCE-US of selected lesion; measurement of tumor blood flow (Time to peak and slope),
blood volume (AUC and peak intensity) and Mean Transit Time (MTT)
ANTITUMOR ACTIVITY
 Evaluated on imaging according to RECIST (version 1.1) every 8 weeks
 Circulating tumor cells (CTC) measured by the immunomagnetic CellSearch method
CURRENT ENROLMENT
Dose
Level
Daily
Dose
Status
Patients
Treated
Cycles
completed
DLTs
I
5 mg
Completed
3
20
NO
II
10 mg
Completed
3
6
NO
III
20 mg
Completed
4
11
NO
IV
30 mg
Ongoing
5
3
1
 Dose escalation ongoing with 15 patients enrolled at 4 dose levels
 Current daily dose 30 mg
 No DLT up to the daily dose of 20 mg - one DLT @ 30 mg
REFERENCES
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2)
3)
4)
5)
6)
Bello E. et al., Cancer Res. 2011 Feb 15;71(4):1396-405
Giavazzi R. at al., 21st AACR-EORTC-NCI, Boston, MA, USA, November 2009; Abs # A262
Bichat E. et al., 101st AACR, Washington, DC, USA, April 2010; Abs # 1367
Colella G. et al., 22nd EORTC-NCI-AACR, Berlin, Germany, November 2010; Abs # 191
Colella G. et al., 102nd AACR, Orlando, FL, USA, April 2011; Abs # 595
Sala F. et al., 59th ASMS Conference on Mass Spectrometry, Denver, USA, June 2011; Abs # 237