intermediate stage hcc treatment options : deb-tace

Intermediate stage HCC treatment options: DEB-TACE

Lencioni R. Personal communication. Hong K, et al. Clin Cancer Res. 2006;12:2563-7.

www.biocompatibles.com.

FromNon-selective

treatment of the entire liver

parenchyma

ToSelective treatment

(segmentalapproaches with microcatheters)

From“Homemade”

drug-in-oil emulsions and embolic agents (“conventional”

TACE)

ToDrug-eluting bead

(calibrated embolic

microsphere)

TACE: an evolving technique toward improving the treatment of HCC

Advances in TACE delivery: DC Bead

DC Bead

Embolic microsphere developed for TACE

Actively sequesters doxorubicin hydrochloride from solution and releases it in a controlled and sustained fashion

www.biocompatibles.com

Mechanism of Loading the Drug Eluting Beads with Doxorubicin

Dex

Dex Dex

Dex

Dex

Dex

Dex

Dex Dex

Dex

Dex

Dex

Dex

SO3

SO3

SO3

SO3

SO3SO3SO3

SO3

SO3

SO3

SO3

SO3

SO3

SO3

SO3

SO3

SO3

SO3SO3

SO3

SO3

SO3

SO3

SO3

SO3

SO3

The doxorubicin is loaded and eluted by “reversible ionic exchange mechanism”

Hydrated Beads Loaded Beads

Hydration shell associated with PVA and ionic groups

Bulk (non-bound) water

Interaction of doxorubicin with SO3 groups displaces water

from the hydration shells

www.biocompatibles.com

Drug Eluting Bead Drug Distribution

Schematic showing the relative drug distribution for standard arterial chemotherapy vs conventional TACE vs PRECISION TACE with DEB

Chemotherapy TACE Drug-elutingBead

DoxorubicinArterial

Injection

1. Doxorubicin+

Iodised Oil2. Embolization

DoxorubicinDrug-eluting

Bead

DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

DEB-TACE vs. conventional TACE: Pharmacokinetics

Serum doxorubicin levels at different time points in patients receiving TACE with

DC-bead (n=13) or conventional TACE (n=5)1

DEB-TACE Conventional TACE

Baseline

Dox

orub

icin

at

seru

m (

ng/m

L)

1000

5 min

7 d20 m

in

40 min

60 min

2 h6 h

24 h48 h

800

600

400

200

0Baseline

Dox

orub

icin

at

seru

m (

ng/m

L)

1000

5 min

7 d20 m

in

40 min

60 min

2 h6 h

24 h48 h

800

600

400

200

0

DC, doxorubicin-capable (doxorubicin loaded); DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Varela M, et al. J Hepatol 2007;46:47481.

Chemoembolization of HCC with Drug-Eluting Beads DEB-TACE

Varela M et al. J Hepatol. 2007; 46(3): 474-81

RECIST EASL criteria

CR 0 (0%) 7 (25.9%)

PR 12 (44.4%) 11 (40.7%)

SD 7 (25.9%) 1 (3.7%)

P 5 (18.5%) 5 (18.5%)

NA 3 (11.1%) 3 (11.1%)

Total 27 27

CR, complete response; PR, partial response, SD, stable disease; P, progressive disease; NA, not available; OR objective response (CR+PR) of 66.6% according to EASL criteria according to an intention-to-treat perspective.

Systemic Exposure (Cmax)

1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

Varela et al [150 mg]Poon et al

Varela et al Raoul et al0

500

1000

1500

2000PRECISION TACE

Conventional TACE

CM

AX

ng

/mL

PRECISION TACE with DEB vs Conventional TACE

Systemic Exposure (AUC)

Varela et al Varela et al0

500

1000

1500

2000PRECISION TACE

Conventional TACE

AU

C (

ng

/mix

min

)

PRECISION TACE with DEB vs Conventional TACE


Trial Design

DEB=drug eluting beads (chemoembolization with DEB and doxorubicin); cTACE=conventional transarterial chemoembolization.

Randomized phase II study to assess the safety and efficacy of chemoembolization with DEB and doxorubicin (PRECISION TACE with DEB) in an international, multi-center trialPrimary endpoints: 6 month tumor RR

Measured by MRI, response criteria EASL (necrosis)Secondary endpoints: safety, response (RECIST), local tumor response (EASL), AFP, time to discharge, cardiotoxicity, QoL

Eligible Patients• HCC not suitable for curative treatments• Patients with multinodular HCC without• Vascular invasion• Extrahepatic spread• Recurrence following resection or

percutaneous ablation• Performance status ECOG 0 and 1• Patients with preserved liver function

(Child Pugh A and B)• Patients on the transplant list who may not

receive a transplant within 6 months

DEB

cTACE

n=100

n=100

RANDOMIZATION


Exclusion Criteria (Main)

Exclusion Criteria

Patients with another primary tumor

Patients previously with chemo- or radiotherapy

Advanced liver disease

Bilirubin levels >3 mg/dL

Advanced tumorial disease

Vascular invasion or extrahepatic spread

Diffuse HCC defined as >50% tumor involvement of the whole liver

Any contraindication for doxorubicin administration

Any contraindication for hepatic embolization procedures


Protocol Design and Treatment Schedule

Patient Population

Visit 1Baseline Assessment/Randomization

Visit 21st Chemoembolization Treatment

Visit 31 Month MRI

Visit 42nd Chemoembolization Treatment

Visit 53 Month MRI

Visit 63rd Chemoembolization Treatment

Visit 76 Month MRI & Study Completion


212 Patients Enrolled

ViennaAthensMainz

LilleFrankfurt

LyonZurich

GenevaParis – Villejuif (HPB)

Paris – HPSNice

Hannover

LausanneParis – Villejuif (GR)

Paris – ClichyDamstadt

0 5 10 15 20 25 301. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

Patient Demographics

* BCLC Classification according to tumor stage (Llovet et al Lancet 2003).

Characteristics DEB (n=102) cTACE (n=110)

Sex (Male/Female) 67.0 years (±9.2) 67.3 years (±8.8)

Age Mean (±sd) 88/14 97/13

Etiology (HepC/HepB/Alcohol alone/Other and Mixed 20/14/41/27 12/13/52/33

Okuda (i/II) 88/14 104/6

BCLC (A/B/C)* 26/76/0 29/81/0

No. Lesions Median (interquartile range) 2 (1-4) 2 (1-4)

Sum Longest Diameter Mean (±sd) 9.4cm (±6.15) 9.0cm (±6.00)

Liver Involvement Mean (±sd) 16.9% (±15.0) 16.5% (±14.2)


Baseline Stratification: Four Prognostic Factors

DEB (n=102) cTACE (n=110)

Characteristics n % n %

Child PughA 83 81.4 91 82.7

B 19 18.6 19 17.3

ECOG0 78 76.5 81 73.6

1 24 23.5 29 26.4

BilobarNo 54 52.9 63 57.3

Yes 48 47.1 47 42.7

Recurrent DiseaseNo 91 89.2 97 88.2

Yes 11 10.8 13 11.8


Analyzed Population

Reason DEB cTACE

Surgical Treatment 1 1

Patient or Physician Decision 3

Progression 1

Post-Consent Ineligibility 4 1

Total 9 2

T1n=93

T1n=108Analyzed Population

DEBn=102

cTACEn=108

212 PatientsRandomized

9 2


Product, Dose and Technique Guidelines

Precision TACE with DEB

2 x 2 mL vials of DEB (total 4 mL) loaded at 37.5 mg/mL for total doxorubicin dose of 150 mg

1 vial of 300-500 μm followed by 1 vial of 500-700 μm

cTACE

Doxorubicin dose of 50-75 mg/m2 to maximum of 150 mg

Physician preference for embolic

Technique for both groups

Unifocal tumors treated with selective segmental chemoembolization

Microcatheter could be used

Bilobar disease: both lobes treated within a 3-week period

Embolization to stasis in 2nd or 3rd order branches

DEB group: additional bland embolic could be used


Number of Treatments

Note: 8 DEB patients, and 5 cTACE patients received 2 sessions at T1

Percentage of Patients in the Analyzed Population Who Received 1, 2 or 3 Chemoembolization Treatments

Technical success

DEB 97% cTACE 99%

No of Treatments

100

82.8

61.3

100

81.5

56.5

0

20

40

60

80

100

1 2 3

DEB

cTACE


Doxorubicin Dose Per Treatment

Mean Dose of Doxorubicin at Embolization Procedure

DEB (mg)n=93

cTACE (mg)n=108

Treatment 1 142.1 102.9

Treatment 2 116.33 91.6

Treatment 3 96.8 68.4

160

140

120

100

80

60

40

20

0Treatment 1 Treatment 2 Treatment 3

DEB

cTACE


DEB-TACE vs. conventional TACE: Tumour response

cTACE, conventional TACE.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

OR

DEB-TACE

cTACE

CR

DCR

OR

CR

DCR

Res

pons

e (%

)

70

60

50

40

30

20

10

0DEB-TACE cTACE

59(63%)

48(52%)

25(27%)

56(52%)

47(44%)

24(22%)

PRECISION V trial

6-Month Response in Less Advanced Patients

0

20

70

50

40

60

10

30

Child Pugh B ECOG 1

Response (%)

Unilobar Not Recurrent

61

50

27

56

21

46 48

63

48

58

25

35

54

67

54

46

28 27

51

61

5245

2125

DEB cTACE

Complete ResponseObjective ResponseDisease Control


6-Month Response in More Advanced Patients

0

20

70

50

40

60

10

30

Child Pugh B ECOG 1

Res

po

nse

(%

)

P≤.05

Bilobar RecurrentDisease

DEB demonstrated statistically significantadvantage in advanced patients

Objective Response (P=.038) and Disease Control (P=.026)

63

44

25

16

21

3237

63

3229

14 17

49

59

49

40

13

27

55

73

54

31

15

DEB cTACE

Complete ResponseObjective ResponseDisease Control


DEB-TACE: Overall and progression-free survival in a Phase II trial

DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Reyes DK, et al. Cancer J 2009; 15:526532.

Time (months)

Sur

viva

l pro

babi

lity

(%)

100

40

80

60

40

20

00 10 20 30

Overall survival (median=26 mo.)

Progression-free survival (median=20 mo.)

• N=20 (total)

• Embolization repeated up to twice if <90% necrosis on MRI

DEB-TACE vs. bland embolization: Recurrence rates

Time (months)

Patients embolized at set time intervals (2 months), with a maximum of 3 embolizations

Rec

urre

nce

rate

1.0

1

0.8

0.6

0.4

0.2

0123 6 9

DEB-TACE (n=41)

Bland embolization (n=43) P < 0.0001

DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Malagari K et al. Cardiovasc Intervent Radiol 2010; 33:541-51.

Incidence of New Lesions at 6 Months

The probability of new lesions forming was the same in both study arms

DEB (n=93) cTACE (n=108)

New Lesions at 6m n % N %

New Lesions 20 21.5 20 18.5

No New Lesions 68 73.1 78 72.2

Missing 5 5.4 10 9.3


Time-to-Progression: All LesionsP

rob

abil

ity

of

No

Pro

gre

ssio

n

0

0.2

0.4

0.6

0.8

1.0

0 50 100 150 200 250 300 350

Days

CEL: Median 196 days ± 14.92

DEB: Median 217 days ± 7.84×

×

××

×

××

× ×

× ×

×××

×

×××

××


Safety-Related Events per 100 Treatments

* Related is investigator-assessed “definitely or probably related to treatment”

DEB cTACE

0

10

20

5

15

13

17

Related* Grade 3 and 4 AEsRelated* AEs

DEB cTACE0

40

80

20

60

58

79

100


Doxorubicin-Related Side Effects

Adapted from Lencioni R et al. Poster Presented at ASCO Annual Meeting; May 29-June 2, 2009; Orlando, FL.

0

10

35

40

25

20

30

5

15

DEB cTACE

Ev

ents

pe

r 1

00 P

atie

nts

P=.0001

DEB cTACEAlopecia

Skin DiscolorationMarrow SuppressionMucosis

Safety-Serious Adverse Events (SAEs)

* Related is investigator-assessed “definitely or probably related to treatment”

DEB cTACE

SAEs

0

5

20

25

15

10

Eve

nts

per

100

Tre

atm

ents

22 22

DEB cTACE

Related* SAEs

0

2

7

8

5

4

6

1

3

6

7


Gastrointestinal and Liver Serious Adverse Events (SAEs)

Liver Toxicity

Pancreatic &Gallbladder Pathology

GI Bleeding

Abscess and infection

GI Ulcer

Ascites

Hospitalization for TIPS

Intratumoral Bleeding

Other

0 2 4 6 8 10

DEBcTACE


Serious Adverse Events Advanced Disease

• Per 100 patients, events within 30 days of treatment.

ECOG 1

DEB

0

20

30

40

cTACE

10

Bilobar Disease Recurrent Disease

SA

E E

ven

t R

ates

*

Child Pugh B

19

32

26

32

24

31

27

31


Liver Toxicity: AST & ALT Levels

1: T1 Pre emb (LOCF) 2: T1 Pre discharge 3: 1 month4: T2 Pre emb 5: T2 Pre discharge 6: 3 months7: T3 Pre emb 8: T3 Pre discharge 9: 6 months

P=.001

Timepoint

cTace

DEB

AST

250

200

150

100

50

0

AS

T U

nit

s/L

1 2 3 4 5 6 7 8 9ALT

P=.001

Timepoint

200

150

100

50

0

AL

T U

nit

s/L

1 2 3 4 5 6 7 8 9


Deaths

Causes of Death DEB cTACE

Progression 1 3

Cardiac 2 1

GI Bleed 1

Infection 1 2

Liver Failure 2 2

Unknown 1

Total 8 8

DEB cTACE

Deaths Due to Disease Progression

0

1

2

3


DEB-TACE vs. conventional TACE: Tolerability

Adverse effects of systemic doxorubicin

Event DEB-TACE(n = 93)

Conventional TACE(n = 108)

Events, n Patients, n (%) Events, n Patients, n (%)

Alopecia 1 1 (1.1) 23 22 (20.4)

Marrow suppression

5 5 (5.4) 8 6 (5.6)

Mucositis 4 4 (4.3) 7 6 (5.6)

Skin discolouration

2 2 (1.2) 2 2 (1.9)

PRECISION V trial

DEB-TACE associated with improved tolerability vs conventional TACE:1

• Significant reduction in serious liver toxicity (p < 0.001)

• Significantly lower rates of doxorubicin-related side effects (p = 0.0001)

DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;33:4152.

Summary

Overall, compared to cTACE, DEB has

Greater objective response (P=.11)

Lower related SAEs and AEs

Compared to cTACE, DEB has a significant (P<.05) advantage in

Objective response in more advanced patients (P=.038)

Disease control in more advanced patients (P=.026)

Compared to cTACE, DEB has a highly significantadvantage in the (P<.01)

Reduction of doxorubicin associated side effects in all patients (P=.0001)

Reduction of liver toxicity in all patients (AST: P=.001; ALT P=.0001)


Conclusion

PRECISION TACE with DEB is safe, efficacious and reproducible

There is a significant advantage of PRECISION TACE with DEB in more advanced patients – those with more compromised liver function, poorer performance status, bilobar disease and recurrent disease – greater response, greater disease control and improved safety

Currently AASLD guidelines do not recommend chemoemboliztion for Child B and ECOG 1 patients. The PRECISION V data show that these patients can now be safely treated with PRECISION TACE with DEB

Combination of PRECISION TACE with DEB and Sorafenib is currently being investigated with the aim of further improving the

long-term outcomes of intermediate-stage HCC patients


DEB-TACE: Summary

DEB-TACE is a valuable alternative to conventional TACE, providing:

Improved pharmacokinetics with reduced systemic exposure to doxorubicin1

Reduced liver toxicity2,3

Fewer doxorubicin-related side effects2

Improved response rates in patients with negative prognostic factors, including:2

– Child-Pugh B status

– ECOG PS 1

– Bilobar disease

– Recurrent disease

DEB, drug-eluting beads; ECOG PS, Eastern Cooperative Oncology Group performance status; TACE, transarterial chemoembolization.1. Varela M, et al. J Hepatol 2007;46:474-481; 2. Lencioni R, et al. ASCO 2009, abstr 4523; 3. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

DEB-TACE vs. conventional TACE: Liver toxicity (ALT-AST levels)

DEB, drug-eluting beads; TACE, transarterial chemoembolization.1. Lencioni R, et al. ASCO 2009; abstr. 4523. Poster discussion available at: www.asco.org; 2. Lammer J, et al. Cardiovasc Intervent Radiol 2010; 33:4152.

Chemoembolization procedure1st 2nd 3rd

AS

T (

units

/L)

ALT

(un

its/L

)

DEB-TACEConventionalTACE

250

0

200

150

100

50

p=0.001

200

0

150

100

50

p<0.001

Mea

n ra

tio p

re-d

isch

arge

/pre

-TA

CE

PRECISION V trial

intermediate stage hcc treatment options : deb-tace

Documents

drugeluting beads tace

doxorubicin precision

conventional tace n

tace delivery

deb vs conventional

doxorubicin ctace

doxorubicin hydrochloride

doxorubicinthe doxorubicin