Intermediate stage HCC treatment options: TACE + sorafenib.

Intermediate stage HCC treatment options: TACE + sorafenib

1. Llovet JM, et al. Lancet. 2002;359:1734-9.2. Lo C-M, et al. Hepatology. 2002;35:1164-71.

TACE: long-term survival outcomes are unsatisfactory

3-year overall survival (OS): 26%2–29%1

Sustained objective response rate (ORR) (3–6 months): 35%1–39%2

No difference in survival of intention-to-treat (ITT) population between non-responders and control group1

100

80

60

40

20

00 12 24 36 48 60 0 6 12 18 24 30 36 42

ChemoembolizationControl

ChemoembolizationControl

100

80

60

40

20

0

p < 0.0091 p = 0.0022

Time since randomization (months)

Pro

babi

lity

of s

urvi

val (

%)

Pro

babi

lity

of s

urvi

val (

%)

Time since randomization (months)

Hypoxia in the post-TACE tumour micro-environment leads to angiogenesis

HIF-1 responds to hypoxia in tumour

VEGF is a key mediator of tumour neovascularisation (growth and permeability)

Carmeliet P, Jain RK. Nature 2000; 407: 249–57

Angiogenesis

>100μmO2

Hypoxia

HIF-1 HIF-1

Glycolysis Survival/apoptosis

VEGFAng2, NOS

PDGF-β

GeneHRE

HIF = hypoxia inducible factor; HRE = hypoxia response elementAng-2 = angiopoietin-2; NOS = nitric oxide synthasePDGF-β = platelet-derived growth factor-β

Tumour cells become more acidic and more hypoxic further they are from blood vessels

7.4

7.2

7.0

6.8

6.6

Aci

do

sis

(p

H)

14121086420

0 100 200 300 400

Distance of tumour cell from blood vessels (μm)

AcidosisOxygen

VEGF levels in the liver significantly increase after TACE: clinical data

After TACE for HCC, VEGF levels in the tumour increase

Wang B, et al. Acta Radiol 2008; 49: 523–9

Control TACE

Microvessel density (not significant)

VEGF expression:number of VEGF+ cells per 500 tumour cells (p<0.01)

58.57 ± 15.7551.69 ± 18.17

138.26 ± 65.24 243.66 ± 88.88

Microvessels visible in the pericapsular area

VEGF+ cells indicated by brown staining

p=0.018

NS

NS

Plasma VEGF levels significantly increase after TACE: clinical data

Li X, et al. W J Gastroenterol 2004; 10: 2878–82NS = not significant

0

20

40

60

80

100

120

Pla

sma

VE

GF

(n

g/L

)

pre-TACE 1 3 7

64

103

8476

Days post-TACE

(n=45) (n=30) (n=44) (n=18)

High VEGF plasma levels significantly correlate with poor outcomes after TACE

Sergio A, et al. Am J Gastroenterol 2008; 103: 914–21

Plasma VEGF concentration increased following TACE

the increase is greatest in patients who did not respond to TACE

Patients with lower plasma VEGF levels had longer survival than those with higher levels (p=0.008)

130

120

110

100

90

80

70

60

50

VE

GF

(p

g/m

L)

Pre-TACE 3 28

100

75

50

25

0S

urv

ival

pro

bab

ility

(%

)

0 10 20 30 40 50

Time since TACE (months)

RespondersTotalNon-responders

VEGF levels below medianVEGF levels above medianmedian = 43.65pg/dL

Days post-TACE

Combining TAE with an anti-angiogenic agent improves outcomes: preclinical data

Combining embolisation and an anti-angiogenic agent significantly reduced tumour volume and tumour vessel density versus embolisation alone

Jiang H et al. Int J Cancer 2007; 121: 416–24*Significant difference from HCC tumours treated with TAE alone in a rat model (p<0.01); AAV = adeno-associated virus

1,200

900

600

300

0

Tu

mo

ur

volu

me

(mm

3 )

AAV-angiostatin

TAE TAE + AAV- angiostatin

35

30

25

20

15

10

5

0V

esse

l co

un

ts p

er s

urf

ace

area

AAV-angiostatin

TAE TAE + AAV- angiostatin

*

*

Transarterial chemoembolisation leads to central necrosis with a rim of peripheral hypoxia

Dufour J-F and Jonson P. J Hepatology 2009

(A) The surviving tissue exposed to hypoxia releases growth factors such as VEGF which stimulate the growth of the residual tumor lesions. (B) When TACE is performed in combination with a systemic targeted therapy, the growth factor response is blunted preventing the growth of the residual lesions.

Rationale for adjuvant or combination use of sorafenib to prevent recurrence after TACE

Angiogenesis may play an important role in tumour progression after TACE:– Temporary increases in plasma VEGF levels observed after TACE in patients

with HCC1

– Liver VEGF levels increase after TACE2

– VEGF production correlates with both tumour response and survival after TACE3

Anti-angiogenic activity of sorafenib4 may delay tumour progression after TACE

TACE, transarterial chemoembolization; VEGF, vascular endothelial growth factor .1. Li X, et al. W J Gastroenterol 2004;10:2878–82. 2. Wang B, et al. Acta Radiologica 2008;49:523–9. 3. Sergio A, et al. Am J Gastroenterol 2008;103:914–21. 4. Wilhelm SM, et al. Mol Cancer Ther 2008; 7:3129-3140.

The rationale for combining TACE with sorafenib

Rationale for combining TACE with antiangiogenic therapy for intermediate-stage HCC

Although TACE is effective for the treatment of intermediate-stage HCC, progression is frequent

Angiogenesis may play an important role in tumor survival after TACE1

VEGF reduction correlates with both tumor response and survival after TACE2

There is a rationale for investigating the concomitant use of TACE with antiangiogenic therapy

sorafenib has antiangiogenic and antiproliferative activity3

sorafenib improved overall survival in patients with advanced HCC and is the only agent approved for the treatment of HCC and was well tolerated4,5,6

1. Li et al. W J Gastro(everolienterol 2004;10:2878-82. 2. Sergio et al. Am J Gastroenterol 2008;103:914-21. 3. Wilhelm et al. Mol Cancer Ther 2008;7:3129-40. 4. Llovet et al. New Engl J Med 2008;359:378-90. 5. Cheng et al. Lancet Oncol 2009;10:25-34. 6.Nexavar EU Summary of Product Characteristics.

Sorafenib and TACE combination: different approaches

*Repeat TACE based on efficacy of initial treatment

Sequential schedule standard

TACE, transarterial chemoembolization.1. Strebel BM, Dufour J-F. Expert Rev Anticancer Ther 2008;8:1743–9.

Interrupted schedule

Continuous schedule

TACE SorafenibTime

Sequential schedule efficacy-based*

Interrupted schedule

Systemic therapy with anti-angiogenic properties concomitantly with TACE for the treatment of HCC (1)

Agent Trial phase

Region Trial schema Primary endpoint

Efficacy data Safety data

Sorafenib15 II Asia TACE + sorafenib Safety n = 147CR: 41 patientsPR/SD: 93 patientsPD: 13 patients

Most frequent G3/4 toxicities: Skin reactionHand–foot skin reactionIncreased liver enzymes

Sorafenib16 II Asia TACE + sorafenib (n = 50)

TTP, safety

n = 50TTP 5.1 mo

Hand–foot skin reaction 40%Thrombocytopenia 28%

Sorafenib17 II Europe TACE + sorafenib (n = 72)

TTP n = 44RECIST criteria: CR 0%, PR 2%, SD 26%, PD 3%EASL criteria: CR 2%, PR 15%, SD 11%, PD 3%

45 SAEsFour Grade 5 AEs (progressive disease with liver and multi-organ failure)

Sorafenib18 II Asia TACE vs. TACE + sorafenib (n = 228)

TTUP NA NA

Sorafenib19 II Asia TACE + sorafenib (n = 63)

TTP NA NA

15. START. NCT00990860. Chao et al. ILCA 2011: abstr O-026. 16. COTSUN. NCT00919009. Park et al. J Clin Oncol 29:2011 (Suppl 4); abstr 253.

17. Socrates. NCT00618384. Erhardt et al. J Hepatol 2011;54(Suppl.):S35: abstr. 79. 18. TACTICS. NCT01217034.

19. NCT01170104.

Systemic therapy with anti-angiogenic properties concomitantly with TACE for the treatment of HCC (2)

Agent Trial phase

Region Trial schema Primary endpoint

Efficacy data Safety data

Sorafenib20 II USA DC Bead™ TACE + sorafenib (n = 50)

Safety n = 36EASL criteria: PR 54%, SD 46%RECIST criteria: SD 96%, PD 4%

Most frequent Grade 3/4 toxicities: FatigueRUQ painIncreased liver enzymes

Sorafenib21 III USA TACE or DC Bead™ TACE + placebo vs. TACE or DC Bead™ TACE + sorafenib (n = 400)

PFS NA NA

Sorafenib22 III Europe DC Bead™ TACE + placebo vs. DC Bead™ TACE + sorafenib (n = 412)

Efficacy NA NA

Sorafenib23 II Europe, Asia,

USA

DC Bead™ TACE + placebo vs. DC Bead™ TACE + sorafenib (n = 300)

TTP NA NA

20. Johns Hopkins Study. NCT00844883. Prof. J-F. Geschwind (personal communication). 21. ECOG. NCT01004978. 22. TACE-2. EudraCT: 2008-005073-36. UKCRN ID 5347. 23. SPACE. NCT00855218.

www.clinicaltrials.gov/ct2/show/NCT00478374.Dufour et al. Oncologist 2010;15:1198.

(n = 21)

Eligibility criteria

• ECOG PS 0–1

• Child–Pugh A/B (<10)

• No prior systemic treatment

• BCLC Ba

Primary endpoint

• Safety

Secondary endpoints

• VEGF levels in blood prior to and after treatment

aIn July 2008, the protocol was amended by restricting inclusion to patients with BCLC stage B disease to ensure a more homogenous patient population

Phase I trial: TACE + sorafenib (continuous) in patients with HCC

Sorafenib(dose escalation from 200 mg BID

to 400 mg BID) Initiated 1 week before first TACE,

without a pause for TACE treatment+

TACE with doxorubicin (50 mg)

Continuous administration of TACE in combination with sorafenib in patients with HCC: results

Results from May 2007 to January 2009

21 patients screened for inclusion: 14 patients received sorafenib with TACE Median age: 63.5 years 78% male 93% ECOG PS 0 93% Child–Pugh A

No dose-limiting toxicities in first three patients receiving sorafenib 200 mg BID

Subsequent patients received sorafenib 400 mg BID

27 TACE procedures performed (median of two per patient; range 1–4)

Two SAEs after first TACE: one cholecystitis, one hospitalization with thigh pain

Median duration sorafenib therapy: 246 days (range 14–547 days)

Sorafenib-related AEs Grade ≥3: hand–foot skin reaction (n = 3), weight loss (n = 2), diarrhea (n = 1), abdominal pain (n = 1), thrombocytopenia (n = 3)

VEGF levels significantly decreased after sorafenib + TACE treatment (from 93 to 67 ng/L)

Dufour et al. Oncologist 2010;15:1198.

Dufour et al. Oncologist 2010;15:1198.

Continuous administration of sorafenib in combination with TACE in patients with HCC: results

Author conclusionsContinuous administration of sorafenib 400 mg BID + TACE

was tolerableThe AE profile was similar to that of sorafenib monotherapy,

except for thrombocytopenia, which may be more frequent with this combination

There were no increases in circulating VEGF levels after TACE

Phase II trial of sorafenib + doxorubicin eluting bead-transarterial chemoembolization (DEB-TACE) for patients with HCC

Selected entry criteria:

Unresectable HCC

ECOG 0–1

Child-Pugh A–B7

50 Patients

Single arm

Continuous sorafenib for as long as is beneficial

DEB-TACE up to 4 times/year

Sorafenib held 3d pre and post DEB-TACE in the first 8 pts, then continuous schedule

EASL, European Association for the Study of the Liver; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; RECIST, Response Evaluation Criteria in Solid Tumours TACE, transarterial chemoembolization. 1. Reyes et al. AASLD 2009; abstr LB9; 2. Reyes et al. ASCO-GI 2010, abstr. 254. 3. Reyes et al. CIRSE 2010, abstr. 254. www.ClinicalTrial.gov NCT00844883.

Interim results:1, 2, 3

• 4% decrease at 3 weeks in tumor size (p=0.79)

• 49% decrease at 3 weeks in tumor enhancement (p<0.0001)

• 25% increase at 3 weeks in apparent diffusion coefficient (p=0.01)

• RECIST: partial response 1/24 (4%), stable disease 23/24 (96%)

• EASL: partial response 14/24 (58%), stable disease 10/24 (42%)

Findings: Combination did not result in greater toxicities than that reported for either therapy alone

http://www.clinicaltrial.gov/

Phase II trial of study in Asia of the combination of TACE with sorafenib in patients with hepatocellular carcinoma (START)

Repeated every 6 to 8 weeks

Sorafenib 400 mg twice daily will be initiated on Day 4 (up to Day 7) after 1st TACE (Day 1).

Sorafenib will be interrupted after the evening dose 4 days before next TACE cycle and restarted on Day 4 (up to Day 7) of the new TACE cycle.

A prospective trial investigating the combination of TACE and sorafenib in patients with unresectable HCC

www.clinicaltrials.gov/ct2/show/NCT00990860.

HCC patients

• BCLC B

• ECOG PS 0,1

• Child–Pugh score ≤ 7

• Size of largest tumor ≤ 10 cm

• TACE naive

TACE (Lipiodol and 30–60 mg

doxorubicin)+

Sorafenib(400 mg b.i.d)

Abdominal CT scan and AFP

assessed 4 weeks after

TACE to determine need

for further TACE

Primary end-point

• Child–Pugh safety (NCI–CTCAE v. 3.0)

Secondary end-point

• Efficacy

Phase II START 3rd interim analysis:baseline patient characteristics

Patient characteristics (n = 166)

Patients, n 166

Median age, years (range) 56.4 (48–64)

BCLC Staging system A/B/C, % 17.3/80.9/1.9

Child–Pugh A/B, % 91.6/7.7

HBV related, % 82

Previous treatment (n =146)

Surgical resection for primary HCC No/Yes, %

89.7/10.3

Loco-regional treatment for HCC No/Yes, %

89.0/11.0

• An interim safety analysis was performed at the end of 2010 when a total of 166 patients had received one or more doses of sorafenib

Adapted from Chao Y et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

• TACE + sorafenib was associated with good response rates:– Complete response in 41 patients – Partial response or stable disease in 93 patients– ORR was 52.4%

• Median PFS: 270 days; TTP: 280 days; OS probability of >90% after 2 years follow up

0

5

10

15

20

25

30

35

40

45

Completeresponse

Partial reponse Stable disease Progressivedisease

Pat

ient

s (%

)P

atie

nts

(%) 27.927.9

24.524.5

38.838.8

8.88.8


Phase II START 3rd interim analysis: efficacy (n = 147)

Phase II START 3rd interim analysis: safety (n = 166)

Number of patients with drug-related adverse events (%)

All Grades Grades 3/4

Skin/subcutaneous tissue disorders

62.6 10.2

Gastrointestinal disorders 23.8 3.4

General/administration site events

8.8 0.7

Abnormal lab investigations

8.8 7.5

Respiratory/thoracic/mediastinal disorders

7.5 0

Nervous system disorders

3.4 0

Vascular disorders 3.4 0

• Skin and gastrointestinal adverse events were most common drug-related adverse events


Phase II START 3rd interim analysis: top Grade 3/4 AEs (non-laboratory) (n = 166)

• Top 5 Grade 3/4 drug-related AEs (non-laboratory) were skin reaction, hand-foot skin reaction, diarrhea/vomiting, and blister


Grade 3 Grade 4 Grades 3/4

Skin reaction 4.1 0 4.1

Hand-foot skin reaction

2.7 0 2.7

Diarrhoea 1.4 0 1.4

Vomiting 1.4 0 1.4

Blister 1.4 0 1.4

Chao et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

Phase II START 3rd interim analysis: top Grade 3/4 AEs (laboratory) (n = 166)

• Top 5 Grade 3/4 drug-related AEs (laboratory) were elevated liver transferases (ALT / AST) and decreased neutrophil / platelet / white blood cell counts


Grade 3 Grade 4 Grades 3/4

Alanine aminotransferase increased

6.8 0 6.8

Aspartate aminotransferase increased

4.1 1.4 5.5

Neutrophil count decreased

4.1 0 4.1

Platelet count decreased 3.4 0 3.4

White blood cell count decreased

3.4 0 3.4

Chao Y et al. Oral presentation, ILCA Hong Kong, 2011 (abstr O-026).

Phase II START 3rd interim analysis

Author conclusions

TACE and sorafenib combination therapy was effective: 52.4% of patients had CR/PR through RECIST assessment

Clinical progression of disease in 8.8% of patients after the first cycle of TACE+ sorafenib treatment

This combination therapy achieved a median PFS of 270 days, TTP of 280 days and an OS probability of >90% after 2 years follow up

No un-expected or new safety signals from this study


Primary endpoints

• TTP

• Safety and tolerability

Secondary endpoints

• PFS

• ORR

N = 50Sorafenib 400 mg BID

+ TACE

Lipiodol + doxorubicin30–60 mg → Gelfoam

Eligibility criteria• ≥1 bi-dimensional lesion

(CT or MRI)

• Child–Pugh A or B ≤7

• ECOG PS ≤1


• Sorafenib on day 3 after first TACE• Sorafenib continuous up to 24 weeks• TACE every 4–6 weeks on demand

Phase II COTSUN Korea trial: TACE + sorafenib (continuous)

interim analysis (n = 50) Patient characteristics: Mean age: 61.5 years82% BCLC B18% BCLC C56% HBV16% HCVMedian follow-up: 5.3 months (range 1.0–13.1 months)Median number of TACE sessions: 1 (range 1–4 sessions)

Phase II COTSUN Korea trial: interim analysis (n = 50)

Results

AEs more severe than NCI–CTCAE Grade 3: Hand–foot skin reaction (40%) Thrombocytopenia (28%) ALT/AST increase (38/34%) Dose reduction of sorafenib in 50% of patients, mostly due to hand–foot

skin reaction

Median TTP was 5.1 months (range 3.8–6.3 months)

Author conclusions

Interim analysis showed that a combination of TACE and sorafenib was well tolerated and the trial could be continued

Preliminary evidence of anti-tumor activity was observed

Park J-W et al. Poster presented at ASCO GI 2011, San Francisco USA (abstr. 253).

Primary endpoint

• TTP

Secondary endpoint

• Safety

Sorafenib 400 mg BID

n = 72

Phase II SOCRATES study: TACE + sorafenib (interrupted)

Adapted from Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107). www.clinicaltrials.gov/ct2/show/NCT00618384.

Sorafenib administered for ≥14 days

TACE TACE


• Unresectable HCC

• Measurable disease (RECIST)

• ECOG PS 0–2

• Child–Pugh <B8

TACE repeated every 6 weeks*

Sorafenib withheld

3 days pre- TACE

Sorafenib withheld

3 days post- TACE

*One cycle = 6 weeks*One cycle = 6 weeks

Phase II SOCRATES study:baseline patient characteristics

Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).

Baseline Patient Characteristics

Sorafenib + TACE (n = 43)

Female/male, % (n) 14 (6) /86 (37)

Mean age, years (SD) 69 (9)

Etiology HCV/HBV/other, %

30/16/64

Child–Pugh A/B, % 81/19

Tumor size 4.5 cm (1.526)

BCLC B/C, % 84/16

AFP µg/L, mean (SD) 205 (807)

ALT U/L, mean (SD) 54 (30)

Platelets x103 µl 194 (94)

Patients were evaluated by central radiology

Patients, n (%)

CR PR SD PD Only baseline

RECISTEASL

03 (7.0)

2 (4.7)18 (41.9)

32 (74.4)11 (25.6)

2 (4.7)4 (9.3)

7 (16.2)7 (16.2)

• Patients received:– a mean of 2.6±2.2 [range 0–10] TACE applications– a mean of 8.3±7.4 [range 0–28] cycles

Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).Erhardt A et al. Poster presented at ASCO 2011, Chicago, IL, USA (abstr. 4107).

Phase II SOCRATES study:final response data (ITT: n = 43)

RECIST criteriaDiscontinuation before a radiological progression was censored

Events: 12 × progression5 × death2 × LTX3 × TACE not possible7 × only baseline•2 × TACE not possible•2 × sorafenib not tolerated•2 × death (diverticulitis, progression)•1× progression (Child B to C)

TTP: 18.9 mo (568 days)(95% CI: 515)

Phase II SOCRATES study:final TTP data (ITT: n = 43)*

Erhardt A et al. Oral presentation at EASL 2011, Berlin, Germany (abstr. 79).

*According to RECIST; data for 3 patients under investigation

OS: 20.1 months (603 d)(95% CI: 527, 741)

Phase II SOCRATES study:final overall survival data (ITT: n = 43)*


*As by April 2011: 15 out of 43 patients still alive

Phase II SOCRATES study final analysis: safety


Frequent Adverse events (>10%)

TACE + sorafenib (n = 43)

n Cycle 1 Cycle 2Cycle 3 Cycle 4

Diarrhea 25 13 8 3 1

Hand–foot skin reaction 20 8 9 3 0

Anorexia 14 9 5 0 0

Asthenia 12 10 2 0 0

Weight loss 9 6 3 0 0

ALT elevation 7 2 2 3 0

Hepatic encephalopathy 7 1 2 3 1

Thrombocytopenia 6 2 2 2 0

Ascites 6 1 4 1 0

Nausea 6 4 2 0 0

Hoarseness 6 5 1 0 0

Phase II SOCRATES study final analysis: conclusions

Combination of TACE plus Sorafenib allowed an acceptable tumor control

Combination of TACE plus Sorafenib resulted in an increased TTP and OS

Side effects were tolerable and in part related to the combination treatment compared to the monotherapeutic approaches

Present results have to be confirmed by the ongoing phase III study (SPACE Trial)


Johns Hopkins University phase II trial of doxorubicin-eluting LC Bead® TACE plus sorafenib in patients with unresectable HCC

Primary end-point: safety

Secondary end-point: tumor response (EASL, RECIST), TTP, OS

Continue until tumor progression or

toxicity

*Absolute neutrophil count > 1,500 /mm3, platelets > 50,000 /mm3, normal creatinine, total bilirubin ≤ 3, AST and ALT < 5 x upper limit of normal.

NCT00844883.Geschwind et al. J Clin Oncol 2011 [in press]

(n = 50)

Sorafenib 400 mg b.i.d. initiated

1 week before first TACE

Up to 4 treatments/6 months: TACE with doxorubicin-LC

Bead® 100 mg doxorubicin


• Unresectable HCC (beyond Milan)

• > 18 years old

• ECOG PS 0/1

• Child–Pugh A/B (< 8)

• Adequate end organ function*

+

Patient characteristics: Phase II Trial of DEB-TACE plus Sorafenib

Variable Value

Patients enrolled 35

Mean age, years (range) 64 (31–88)

Male/female 26/9

Child–Pugh status A/B 31/4

ECOG Performance Status 0/1 16/19

HBV/HCV/other etiology 2/13/20

Portal vein Thrombosis (yes/no) 11/24

BCLC B/C 12/23

Mean index tumor size, cm (SD) 7.7 ±4.2

Geschwind et al. J Clin Oncol 2011 [in press]

*ADC = apparent diffusion coefficient measured by functional diffusion weighted MR.

Tumor Response: Phase II Trial of DEB-TACE plus Sorafenib

EASLPartial response:14/26 (54%)Stable disease: 12/26 (46%)

36 patients treated to date, 35 patients completed Cycle 1 (n = 26 evaluated for efficacy)Tumor response by MR imaging

FeaturesPre-

DEB-TACEPost-

DEB-TACE

Change at 3 weeks

(%)p value

Tumor Size ± SD (cm) 7.9 ± 4.3 7.6 ± 4.5 – 4 0.79

Tumor Enhancement (%) 85 43.5 – 49 < 0.01

*ADC (x 10–3 mm2/sec) 1.2 1.54 + 25% 0.01

RECIST Stable disease: 25/26 (96%)Progressive disease: 1/26 (4%)

Geschwind et al. J Clin Oncol 2011 [in press]


68-year-old male, right lobe lesion2 cycles of DEB-TACE and sorafenibBridged to surgical resection 3 months after end of second cycle

TACE #1 TACE #2

Baseline 21 Days Post-treatment

10.3 cm, 90% enhancement

10.2 cm, 30% enhancement

Geschwind J-F et al. Presented at 2nd Asia–Pacific Primary Liver Cancer Expert Meeting, 1–3 July 2011, Osaka, Japan.

Baseline:8.1 cm, 90% enhancement

3 weeks post DEB-TACE:6.3 cm, 10% enhancement

20 months post DEB-TACE:5.7 cm, <10 % enhancement

73-year-old male, right lobe lesion 1 cycle of DEB-TACE and sorafenib Stable for 20 months



Incidence of Grade 3/4 Toxicities:Phase II Trial of DEB-TACE plus Sorafenib

All remaining toxicities were Grade 1/2 (no unexpected events)

60

50

40

30

20

10

0

All Grade 3/4 toxicities (any cause)

Pain-a

bd-RUQ

Fatigue

Incre

ased liver e

nzym

e

Lymphopenia

HFSR

Hyperbilir

ubinem

ia

Pain (o

ther)

Hypertensio

n

Incre

ased lipase

Pain in

chestDOE

PE / >coagulo

pathy

Rash /mucositi

s

Encephalopath

y

Cycle 1 (n = 27)

Cycle 2 (n = 19)

Cycle 3 (n = 12)

Pain-abd-RUQ = abdominal pain, right upper quadrantDOE = Dyspnea on exertion; PE = pulmonary embolism

Per

cen

tag

e


Phase II TACTICS randomized trial: TACE vs. TACE + sorafenib in patients with HCC

www.clinicaltrials.gov. NCT01217034.

(n = 228)


•ECOG PS 0–1

•Child–Pugh A

•No prior systemic treatment

Primary endpoint

• TTUP

Secondary endpoints

• TTP

• Overall survival

• ORR

• Tumor markers

• Safety

Sorafeniba

+TACE

TACE repeated when tumor increases

TACE

TACE repeated when tumor increases

a400 mg OD stopped 2 days before first TACE; resumption of sorafenib 3–21 days after TACEWhen tolerability is confirmed at 1 week after resumption, sorafenib is increased to 400mg BID

Status: recruiting

Phase II, randomized, double-blind, placebo-controlled study of sorafenib in intermediate-stage HCC in combination with DEB-TACE using beads loaded with doxorubicin

Study start date: March 2009

Estimated completion date: Dic 2011

DEB, drug-eluting bead; ECOG, Eastern Cooperative Oncology Group; EHS, extrahepatic spread; HCC, hepatocellular carcinoma; MVI, macrovascular invasion; OS, overall survival; TACE, transarterial chemoembolization; TTP, time to progression; TTUP, time to untreatable progression.www.ClinicalTrial.gov, NCT00855218 - EudraCT: 2008-005056-24

Endpoints

Primary TTP

Secondary OS TTUP Time to vascular

invasion Time to EHS

Eligibility criteria Unresectable HCC Multinodular HCC Child–Pugh A ECOG PS 0

Exclusion criteria EHS/MVI Contraindication to

TACE

DEB-TACE +

sorafenib 400 mg bid

DEB-TACE + placebo

SPACE: Sorafenib or Placebo in combination with TACE for intermediate stage HCC

Ra

nd

om

iza

tio

n

1:1

(n=

30

7)

http://www.clinicaltrial.gov/

Primary end-point• PFS

Secondary end-points• OS• Toxicity


Sorafenib 400 mg b.i.d.

and TACE (doxorubicin,

mitomycin C and cisplatin)

Placebo and TACE

(doxorubicin,

mitomycin C and cisplatin)

Randomization1:1

(n = 400)

Eligibility criteria• Unresectable HCC• Child–Pugh A -B7• ECOG PS 0-1

Exclusion criteria• EHS• Main portal vein

invasion• Ascites

A phase III randomized, double-blind trial of TACE with or without sorafenib in patients with unresectable HCC

– status: recruiting– contact information: ECOG Group Chair’s Office (Robert L. Comis)

ECOG: phase III study investigating the combination of sorafenib with TACE

QoL = quality of life. EudraCT: 2008-005073-36 ; ISRCTN: 93375053; UKCRN ID 5347

Eligibility criteria Unresectable HCC At least 1 unidimensional CT/MRI-measurable lesion Child–Pugh A ≤6 ECOG PS ≤1

Exclusion criteria EHS Contraindication to TACE Child–Pugh B ≥7 or C Prior embolization, systemic or radiation tx

1º endpoint PFS

2º endpoints

OS Toxicity QoL Number of TACE performed Health economics

Investigator-sponsored, randomized, placebo-controlled, double-blinded, Phase III trial evaluating sorafenib in combination with TACE in unresectable HCC

– Study start date: August 2010– Estimated completion date: 07 January 2013– Target recruitment: 412 patients (UK, Ireland, France and Italy)– Status: recruitment opened November 2010

TACE-2: Phase III study investigating the combination of sorafenib with TACE

Sorafenib 400 mg BIDcontinuous

Placebo PO BID

continuous

2-5 weeks

initiate TACE

DEB-TACE with

doxorubicin (150 mg)

1:1

Ran

do

miz

ati

on

(n =

412

)

Adjuvant Sorafenib after TACE to prevent Recurrence of Hepatocellular CarcinOma (ASTRO)

Italy, phase II, double-blind, randomised, placebo-controlled adjuvant trial after TACE-based treatments

Prior treatment• TACE ± RFA/PEI

Eligibility criteria• Child–Pugh

score 5–7 • Radiological CR

Primary endpoint• Time to recurrence

Secondary endpoints• RFS• OS• Other

Sorafenib 400 mg b.i.d.

Placebo

Randomisation 1:1(n=216)

Stratification• Unifocal vs. Multifocal

Intermediate stage HCC treatment options: TACE + sorafenib.

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