DC beads loaded with Irinotecan : precilinical and early clinical ...

DC beads loaded with Irinotecan :
precilinical and early clinical datas in
CRC liver metastases
T de Baere - Villejuif - France

Colorectal cancer
•World wide incidence: 400,000 patients
•60% patients will develop liver metastases
•Surgery is feasible in only a minority of
patients and most patients are treated with
systemic chemotherapy.
•Patients have a poor prognosis with
reported 1- and 3-year survival rates of
31% and 2.6%, respectively .

Colorectal cancer chemotherapy
% response rate
FOLFIRI
FOLFOX
5 FU
10 %
5FU-FA
FA
20 %
LV5FU2
25 %
55 % 55 %
Sytemic therapy
• Improvement in response rate, namely due to
Oxaliplatinum and Irinotecan

Colorectal cancer chemotherapy
% response rate
FUDR
FOLFIRI
FOLFOX
Iri.
Oxal.
5 FU
10 %
5FU-FA
FA
20 %
45 %
LV5FU2
25 %
55 % 55 %
67 %
64 %
Sytemic therapy
Intra-arterial therapy
• Improvement in response rate, namely due to
Oxaliplatinum and Irinotecan
• Intra-arterial delivery provide higher response rate
for a given drug

Rationale for intra-arterial route
Drug
% Liver
extraction
Clearance
TB (l/min)
5-FU 22-45 2-5
FUDR 69-92 5-15
IRINOTECAN 38-72 9-25
MITO-C 7-18 3-5
CDDP 8-50 0.3-0.5
DOXO 45-50 -
R art =
CL
Q A (1 - E r )
- Rart : advantage of IA vs IV
- Er :extraction ratio at 1st pass
- QA : arterial flow - CL : Body clearance of the drug

Rationale for intra-arterial route
101
R art
81
61
41
21
1 0.9
0.5
0.1
E r
R art =
CL
Q A (1 - E r )
24 18 12 6
Q A (L/h)
- Rart : advantage of IA vs IV
- Er :extraction ratio at 1st pass
- QA : arterial flow - CL : Body clearance of the drug

Rationale for intra-arterial route
101
R art
81
61
41
21
1 0.9
0.5
0.1
E r
R art =
CL
Q A (1 - E r )
24 18 12 6
Q A (L/h)
• Drug eluting embols
Complete embolization (Q A =0, R art ≈)

In vitro
Loading/elution of embolics with Irinotecan
Hepaspheres
• 100-150 μm dry/ 400-600 μm hydrated
• Poly (vinyl alcohol-co-sodium acrylate)
DC beads
• 500-700 μm hydrated
PVA (with N-acryloyl-aminoacetaldehyde dimethylacetal)
copolymerized with 2-acrylamido-2 methylpropanesulfonate
sodium salt*.
* Lewis et al J Mater Sci: Mater Med (2007) 18:1691–1699

Irinotecan loading
DC beads
- loaded within 1 hour
- 92% uptake (vs 95% Taylor & al EJPS 2007)
Hepasheres
-uptake at 1hr / 86% uptake
-Heterogenous loading

DC beads size
700
600
Mean diameter (microns)
500
400
300
200
100
0
DC beads/H2O DC beads/NaCl DC beads/50%
Visipaque
DC beads/after
catheter
DC beads in vial DC beads/Irino DC beads/Irino
apr¸ slibˇ ration
• Shrinking under irinotecan loading with return to baseline after release

Hepasphere size
700
600
Mean diameter (microns)
500
400
300
200
100
0
NaCl 0.9%
NaCl:
Visipaque 1:1
after cat
NaCl:Visipaque
1:1 cat+ comp
NaCl after Cat Irinotecan Irinotecan
coloured only
Irinotecan after
lib
• Moderate shrinkage under irinotecan loading with return to baseline
after release

Beads Elasticity
20
Elastic modulus 20% compr (kPa)
15
10
5
0
DC Beads
Irinotecan
Doxorubicin
Hepaspheres
Compression of a microsphere monolayer
to determine elastic modulus

Release measurement
Flow
Sotax CE 6 apparatus (37C) with n=6 implant cells, constant-flow
CY7 pump (NaCL 0.9%, 5 ml/min)
Spectrophotometric determination at 359 nm (irinotecan)

Irinotecan before/after release
DC beads before release
Hepaspheres before release
DC beads after release
Hepaspheres after release

Irinotecan release
DC Beads
Drug load = 92%
Drug release = 62%
t 1/2 = 1 hr
Hepasheres
Drug load = 86%
Drug release = 42%
t 1/2 = 5 min

Tumor necrosis
-Diffuse liver metastasis obtained through intra-portal vein injection of CC531-lac-Z
rat colorectal carcinoma cells
- Surgical access to GDA : occluded flow and blind delivery of embolics 7525 microns
‣Bland embolization
‣ DEBIRI 20mg/kg
‣ DEBIRI 30mg/kg
Eyol E, Clin Exp Metastasi 2008.

Tumor necrosis
-Diffuse liver metastasis obtained through intra-portal vein injection of CC531-lac-Z
rat colorectal carcinoma cells
140
120
Tumour cell number
Liver weight
100
% treatment/control
80
60
40
p=0.05
p=0.07
p=0.04
p=0.02
20
IRI-Beads animal
Bland embol animal
0
20 mg/kg 30 mg/kg Control
Irinotecan-Beads
Bland Embo
Significant reduction in tumour burden and liver weight of IRI-Beads vs
bland embolization
Eyol E, Clin Exp Metastasi 2008.

Tumor necrosis
-Diffuse liver metastasis obtained through intra-portal vein injection of CC531-lac-Z
rat colorectal carcinoma cells
In vitro 50% cell survival @ 50 μg at 48 h, 25 μg at 72 h
No group with IA or IV Irinotecan
: 48 hours
: 72 hours
Eyol E, Clin Exp Metastasi 2008.

In vivo Pharmakokinetic
VX2 liver tumor
• IV : 12 mg
• IA : 12 mg
• TACE : 6-16.5 mg (m=9.35) / 100-300 microns
– Complete stasis
PharmacoKinetic CPT11 & SN38*
• Venous sampling (10min - 24H)
• Tissue sampling (1, 6, 24H)
– Tumor
– Liver
Quantification of tumor necrosis
* SN38 is the most active metabolite of Irinotecan

Peripheral venous sampling
4500
40
4000
Serum CPT11
35
Serum SN38
3500
3000
2500
30
25
IV
IA
TACE
2000
20
1500
15
1000
IV
10
500
IA
TACE
5
0
10 20 40 60 2H 4H 6H 12H 24H
0
10 20 40 60 2H 4H 6H 12H 24H
• Reduced systemic peak levels by more than 50%
Lower systemic toxicity expected for a given dose

Peripheral sampling
4500
4000
Serum CPT11
3500
3000
2500
2000
1500
1000
500
0
IV
IA
TACE
10 20 40 60 2H 4H 6H 12H 24H
Taylor RR, Eur J Pharmaco Sciences 2007
• Reduced systemic peak levels by more than 50%
Lower systemic toxicity expected for a given dose

Tissue sampling
10000
9000
CPT11 in tumor tis
800
700
SN38 in tumor tissue
8000
7000
6000
IV
IA
TACE
600
500
IV
IA
TACE
5000
400
4000
300
3000
200
2000
1000
100
0
1H 6H 24H
0
1H 6H 24H
• High and sustained levels of drug and SN38 in the
tumor tissue: Higher exposure (AUC)
• Too short follow-up to evaluate extend of dug exposure

Tissue sampling
10000
9000
CPT11 in tumor tis
CP11 in peripheral liver
8000
7000
IV
IA
TACE
6000
5000
4000
3000
2000
1000
0
1H 6H 24H
• No differences in the level of drug in the peripheral
non-tumoral liver, excepted lower initial peak for DEB

Tumor necrosis
110%
Tumor necrosis
100
90%
70%
50%
30%
IV IA TACE
Necrosis (%)
80
60
40
20
Damaged
Necrosis
10%
-10%
1H 6H 24H
0
DEB1h DEB12h DEB24h DEB3d DEB7d DEB14d
(Hong K, et al. Clin Cancer Res 2006;12:2563–7)
• Baseline necrosis of 30%, usual in VX2 tumor
• Equivalent percent of onecrosis for IA & TACE @ 6 h
• Significantly higher necrosis for TACE @ 24 h

Tumor necrosis
1000
900
800
700
Serum ASAT
IV IA TACE
600
500
400
300
200
100
0
0H 1H 6H 24
• ≈ 10 fold increase in transaminases
• Start to decrease as early as 24 hours

Conclusion
• DC Beads can load rapidly 96% of Irinotecan
• DC Beads provide much slower and more
complete release of Irinotecan than Hepaspheres
• DC IRI-Beads produce lower systemic exposure
to Irinotecan when compare to IV or IAH
injection
• DC IRI-Beads provides higher degree of tumor
necrosis than IV or IAH injection of Irinotecan