The SIRSA, SIRveNIB, SARAH and SORAMIC Clinical Trials - ITR8

The SIRSA, SIRveNIB, 

SARAH and SORAMIC 

Clinical Trials 

Pierce K.H Chow 

MBBS MBBS, MMed M.Med, FRCSE FRCSE, FAMS, FAMS PhD 

Professor, Duke-NUS Graduate School of Medicine 

Senior Consultant Surgeon, Singapore General Hospital 

Visiting Senior Consultant, National Cancer Centre 

1st Asia Pacific Symposium on Liver‐Directed Y‐90 

Microspheres Therapy 

17 

SGH – Surgery 

th Nov 2012

Aims of Treatment in HCC 

• Treatment has one of 2 possible aims: 

• Treatment for Potential Cure 

– Surgical resection (Child-Pugh A, early B) 

– Radio-frequency ablation (< 3lesions 3 lesions, < 3cm) 3 cm) 

– Transplantation (< 5 cm or < 3 lesions each < 3 cm and 

no macro-vascular invasion) 

• Treatment for Palliation 

– Loco-regional Loco regional disease 

• TACE, DC-Beads, SIRT 

– Metastatic disease 

Pierce Chow FRCSE PhD 

SGH – Surgery 2

What is the Role of 

Selective Internal Radiation Therapy 


in the treatment of 

Hepatocellular Carcinoma? 

What is the current data? 

3

Outcomes of SIRT in HCC 

Salem et al. al Gastroenterology 2010; 

138: 52–64 


Sangro B et al al. Hepatology 2011; ePub doi: 

10.1002/hep.24451

Outcomes: Survival by yBCLC Stage g 

Salem et al. Gastroenterology 2010; 138: 52–64 


Sangro B et al. Hepatology 2011; ePub doi: 10.1002/hep.24451

90 Y microspheres in Patients with HCC and PVT 

SGH – Surgery �

Is there a role for Y90 

to be combined with 

systemic y therapy py 

to improve survival in 

advanced d d HCC? 


SGH – Surgery 7

Scientific rationale 


• Ablative therapy such as Y90 is efficacious in 

causing complete or partial destruction of tumour 

• HHowever new llesions i can arise i ffrom th the li liver or 

from metastasis – systemic molecular pathway 

ttargeted t dth therapy may preventt or dl delay thi this. 

• Y90 followed by an efficacious systemic therapy 

may confer improved outcomes in advanced HCC. 

• This hypothesis was tested in the AHCC05 

(SIRSA) trial of the Asia-Pacific HCC Trials 

Group 

SGH – Surgery 8

E 

L 

I 

G 

I 

B 

L 

E 

P 

A 

T 

I 

E 

N 

T 

S 

AHCC05: Phase I/II study of sir-spheres® sir spheres® plus sorafenib 

(chemo-radiotherapy) in patients with non-resectable 

hepatocellular carcinoma 


SIRT 

PHASE I 

Patients 

commencing 

SSorafenib f ib14 14 

days after 

SIRT or 11 

days after 

SIRT 

Outcomes: OS, , downstage g to surgery/RFA g y 

PHASE II: 

SSorafenib f ib 

commencing 11 

or 14 days y after 

SIRT

Asia-Pacific HCC Trials Group 2011 

Ulaan Baator 

Seoul, 

Bundang, 

Hanoi Suwon 

Taipei 

Yangon 

Hong Kong 

Manila 

Bangkok Davao City 

Penang 

Brunei 

Kuala Lumpur Melbourne 

Singapore 

Sydney 

Jakarta 

Auckland 

Bali 

SGH – Surgery

Tumour Response 


ID SGH 024 ID SGH 025 ID SGH 001 

28 th March 2009 8 th April 2009 6 th June 2008 

11th 11 J l 2009 

th July 2009 26th August 2009 3rd July 2009 


ASCO 2010

TTumour RResponse bby RECIST1 RECIST 1.0 0 

• CComplete l regression i (CR) (CR): 4 patients i (12 (12.0%) 0%) 

• Partial Regression (PR): 8 patients (23.5%) 

• Stable Disease (SD): 15 patients (44.0%) 

• Progressive Disease (PD): 7 patients (21.0%) 

• Tumour Response Rate: 11/34 (33.5%) 

• Disease Control Rate: 27/34 (79.5%) ( ) 

– BCLC B 100% 

– BCLC C 68% 

• Mediantime-to-disease progression: 39 weeks(95% CI 27 – 73 wks) 

Response would be even higher with modified RECIST 

Pierce SGH Chow – Surgery FRCS, 

PhD 

12

Comparative Median Survival 

Asian Patients 


EEuropean US 

Patients Patients 

Study AHCC05 2010 Cheng 2009 Sangro 2011 Saleem 2010 

BCLC B 

(n=12) 

BCLC C 

(n=22) 


Y-90 + Sorafenib Sorafenib Placebo Y-90 Y-90 

20.6 mo 14.3 mo 8 mo 16.9 mo 17.2 mo 

8.2 mo 5.6 mo 4.1 mo 10.0 mo 7.3 mo 

SIRSA – 1 patient i downstaged d dto transplantation, l i 2 to RFA


For inoperable HCC 

with no metastasis 

should we treat with 

Sorafenib or SIRT?

Optimal management of HCC 

not amendable to surgical treatment 


Pierce Chow FRCS, 

PhD 

No established first first-line line 

therapy

SIRT: Survival by yBCLC Stage g 

Salem et al. Gastroenterology 2010; 138: 52–64 


Sangro B et al. Hepatology 2011; ePub doi: 10.1002/hep.24451

Asia‐Pacific Sorafenib Trial 

Overall Survival with and without Major Vacular Invasion 

and/or Extra Hepatic Disease in Child‐Pugh A patients 

Survvival 

Disstributionn 

Functioon 

1.00 

0.75 

0.50 

0.25 

With Major j Vascular Invasion/ Without Major j Vascular Invasion/ 

Extra-hepatic disease 

Extra-hepatic disease 

Nexavar (n=118) 

Median: 5.6 months 

(95% CI: 4.8, 6.7) 

Placebo (n=61) 


(95% CI: 3.4, 3 4 4.8) 4 8) 

0 

HR (S/P): 0.75 

95% CI: 0.54, 1.05 

0 4 8 12 16 20 

1.00 

0.75 

0.50 

0.25 

0 

HR (S/P): 0.45 0 45 

95% CI: 0.19, 1.06 

0 4 8 12 

Months from Randomization 

Adapted from Kang, et al. Presented at AASLD 2008 Annual Meeting. Oct 31 - Nov 4; San Francisco, CA, USA. 

Nexavar (n=32) 


(95% CI: 10.8, NR) 

Placebo (n=15) 


(95% CI: 33.3, 3 NR) 

16 20

Wh When TACE or RFA ffails il 

and a d tthe e ddisease sease pprogresses og esses but 

remains confined to the liver 


(locally advanced), 

what is the best therapy? 

Should we treat with 

Sorafenib or SIRT?

Asia-Pacific Asia Pacific Hepatocellular Carcinoma Trials Group 

5th General Meeting 


6 th February 2010


Asia-Pacific Hepatocellular Carcinoma 

Trials Group protocol 06: NCT01135056 

SGH – Surgery 20

Rational i for f comparing i SSIRT and SSorafenib f i 

therapy in locally advanced HCC 

• Both SIRT and Sorafenib demonstrated efficacy in the 

treatment of patients with locally advanced HCC, but 

with separate mechanisms of actions. 

• These 2 therapies have never been compared in a randomised 

controlled trial (RCT). We do not know what is 1st line and 

what is 2nd what is 2 line therapy in locally advanced HCC HCC. 

• A definitive RCT comparing the 2 most promising therapies in 

locally advanced HCC will impact on outcomes in a large 

number of patients and change clinical practice. 


21

Ulaan Baator 

Yangon 

Penang 

Singapore g 

Jakarta 

Bali 

Asia-Pacific HCC Trials Group: 


SIRveNIB 

Seoul, 

Bundang, 

Suwon 

Taipei 

Hong Kong 

Manila 

Davao 

City 

Brunei 

Auckland

Multi-center Clinical Trials of the AHCC 

AHCC01: NCT00003424: Randomised controlled trial of 

high-dose tamoxifen in inoperable HCC: 

1997 – 2000 


megestrol acetate in inoperable HCC: 2002 - 2007 


adjuvant radioactive therapy after curative 

surgery in HCC: 2002 - 2008 

AHCC04: NCT00247260: Phase II dose escalation trial of intratumoral 

Brachysil ® in inoperable HCC: 2005 - 2006 

AHCC05: NCT00712790: Phase I/II trial of SIR-spheres 

plus Sorafenib in patient with non-resectable HCC: 

2008 – 2010 

AHCC06: NCT01135056: Randomized Controlled Trial of SIR- 

Sphere p vs Sorafenib in locally yadvanced inoperable p 

HCC: 2010 


23

AHCC06 : SIRT versus Sorafenib in patients with 

locally advanced HCC 

Asia-Pacific, Phase III, open-label, randomised-controlled study 

Eligibility criteria 

� Locally advanced 

HCC 

�� Child Child–Pugh Pugh

SIRveNIB RCT 

Milan 


Excludes extahepatic 

metastases 

SGH – Surgery 25

Study Design 

• Investigator-initiated – supported by grants from NMRC Singapore 

and Sirtex 

• Multi-center 

• Open-label p 

• Randomized controlled 

• Target: 360 subjects 26 (+ 3) centers 


26


SIRT yttrium-90 tt i 90 phase h II & III ttrials i l 

Trial no Sponsor Size Centers Therapy 1 Therapy 2 

Primary y 

Protoco 

Outcome Start End Status l Chair 

NCT01135056 SGH 360 26 (Asia‐Pac) ( ) SirSphere p sorafenib OS Jul‐10 Jul‐15 recruitingg 

NCT01482442 

Hôpitaux 

de Paris 400 1 (France) SirSphere sorafenib OS Nov‐11 Mar‐15 recruiting 

NCT01556490 Nordion 400 2 (US) Theraspheres sorafenib OS Mar‐12 Oct‐16 recruiting 

Pierce 

Chow 

Valerie 

Vilgrain 

Riad 

Saleem 

Phase II North 

Riad 

NCT00956930 Western 124 1(US) Theraspheres TACE TTP Aug‐09 Aug 09 Aug‐18 Aug 18 recruiting Saleem 

Phase II Uni Ghent, 

L 

NCT01381211 Belgium 140 2 (Europe) Theraspheres DC‐BEADS TTP Sep‐11 Dec‐16 recruiting Defreyne 

Phase II 

SirSphere – 

Pierce 

NCT00712790 SGH 35 4 (Asia (Asia‐Pac) Pac) sorafenib ‐ TTR Jun Jun‐08 08 Jun Jun‐09 09 completed Chow 

SGH – Surgery

The SARAH Study 

To determine whether radioembolisation with SIR-Spheres ® microspheres I 

s more effective on overall survival in advanced HCC than sorafenib 

Design: g Prospective p open-label, p , multi-centre, , national (France) ( ) RCT 

Eligible Patients: 

•Unresectable HCC 

•BCLC stage C or 

•BCLC stage A/B: 

– New lesions post-radical therapy and 

unsuitable for further radical therapy or 

– No objective response after ≤2 TACE 

sessions i 

•Child-Pugh class A or B ≤7 points 

•ECOG performance status 0–1 

•Fit for sorafenib and SIRT 

Primary endpoint: Overall survival 

Sponsor: Assistance Publique – Hôpitaux de Paris 

(AP-HP) 

PI: Prof. Valérie Vilgrain 

Status: Currently enrolling 

Stratify 

• ECOG performance 

status 

• Vascular s invasion 

• Prior TACE 

• Institution 

Randomise 

1:1 

n = 400 

SIR SIR-Spheres Spheres 

sorafenib 

Secondary endpoints: Safety and toxicity 

Quality of life 

Healthcare costs 

Progression-free survival at 6 months

SIRveNIB SARAH 

• N = 360 (1:1) (Stratification: branch • N = 400 (1:1) (Stratification: ECOG, 

portal vein thrombosis, site) 

vascular invasion, ,p prior TAC, , site) ) 

• Objectives: 

• Objectives: 

– Primary: y OS (from ( 

– Primary: y Efficacy y SIRT vs 

randomization) 

Sorafenib 

– Secondary: PFS liver, PFS any – Secondary: Tolerance, safety, QoL, 

site, i tumor response rate 

ttreatment t tcostt (RECIST 1.1), QoL (EQ5D), 

liver resection rate, liver 

transplantation rate, TTP, 

• Endpoints: 

– Primary: OS (from randomization) 

toxicity, safety 

– Secondary: safety, PFS at 6 months 

• Endpoints: 

– In accordance with objectives 

(RECIST, ( , EASL), ), response p rate 

(RECIST, mRECIST, CHOI, 

EASL), QoL (EORTC QLQ-30, 

Courtesy of Stephanie and Peggy EORTC QLQ QLQ-HCC18) HCC18), treatment 

cost 

SGH – Surgery

• Inclusion criteria: 

SIRveNIB SARAH 

– Bili Bilirubin bi < 2.0 2 0 mg/dL /dL 

– Platelets: ≥ 80.000/µL 

– Leukocytes ≥ 2.500/µL 2 500/µL 

– Albumin ≥ 2.5g/dL 

• Exclusion criteria: 

– Last loco-regional treatment 

min < 4 weeks before study y 

entry 

– Complete main portal vein 

th thrombosis b i 

– Prior hepatic radiation therapy 

for HCC or other malignancy g y 


• Inclusion criteria: 

– Bilir Bilirubin bin < 50 µml/L ml/L (2,9 (2 9 mg/dL) 

– Platelets ≥ 50.000/mm3

SIRveNIB 

SARAH 

• Study schedule: 

– Max 35 days between ICF and 

treatment start 

– FU visit 1x month (FU ( 1-3), ), every y 3 

month (FU 4-x) 

– FU until death 

– Imaging: CT every 3 months 

– SIRT procedure: max 1 

– SIRT dosimetry: BSA & partition 

– Lung shunt: max 20% or max 20Gy 

to the lungs 

– Image review: centrally 

– Tumor volume calculation: centrally 


• Study schedule: 

– MMax 9 (SIRT)/ 5(S 5(Sorafenib) f ib) weeks k 

between ICF and treatment start 

– FU visit 1x month 

– FU max 35, min 12 months 

– Imaging: g g CT every y 3 months, , 

perfusion CT (M0, M1, M3, M6) 

– SIRT procedure: max 4 

– SIRT dosimetry: BSA 

– Lung shunt: max 25Gy to the lungs 

– Image review: locally/ centrally 

– Tumor volume calculation: on site

A Phase III Clinical Trial of Intra‐arterial TheraSphere® in the 

Treatment of Patients with Unresectable Hepatocellular 

Carcinoma: STOP-HCC 1 

• PI: Riad Salem 

• Randomized Phase III 

– Multicenter; ; international 

– N=400 approximately 

– Unresectable HCC 

• Kinase Inhibitor +/- TheraSphere 

• EEndpoints d i t 

• Primary 

• Overall survival (OS) 

• Secondary 

• Safety 

R 

A 

N 

D 

O 

M 

I 

Z 

E 

Treatment 

Gro Groupp 

TheraSphere 

prior to initiation 

of Standard-of- 

Care therapy: 

kinase inhibitor Endpoints 

�Primary 

oOS 

�Secondary 

oSafety 

Control Group 

Planned 

Standard-of-Care 

therapy: kinase 

inhibitor 

1 Nordion Phase III Clinical Trials: 

• conducted under Investigational Device Exemption (IDE) 

32


Hepatocellular carcinoma: ESMO–ESDO Clinical Practice 

Guidelines for diagnosis, treatment and follow-up 

Annals of Oncology 23 (Supplement 7): vii41–vii48 vii41 vii48, 2012 

SGH – Surgery 33

A complex phase III trial: 

SSorafenib f iband dMi Micro-therapy th 


Guided by Primovist Enhanced 

MRI in Patients With 

Inoperable Liver Cancer 

SORAMIC 

SGH – Surgery 34

1⁰ endpoint 

SORAMIC Trial: Schema 

SCREENING MICRO MICRO-Tx Tx SYSTEMIC Tx 

Imaging Sub-Study 

Non Non-inferiority inferiority (1 st step) or 

superiority (2 nd step) of 

Primovist Primovist-MRI MRI vs. CE CE-CT CT 

Contrastenhanced 

CT 

Primovist ® Primovist - 

enhanced MRI 


Assign to 

study arm 

Off Study 

• BCLC 0 

• BCLC D 

Local Ablation Group 

(

Future 

Downstaging before surgery 

(Neoadjuvant Therapy) 

to improve outcomes after 

resection of marginal HCC 


SGH – Surgery 36

Outcomes of 

Resection for Marginal HCC 

• Large HCC ( > 5 

cm) – 5 year OS 

– Chen 2006: 38.7% 

– Ng 2005: 39% 

• Multiple 

tumors/vascular 

invasion – 5 year OS 

– Ng g 2005: 

– Early stage – 58% 

– Late stage – 39% 


SGH – Surgery 37

MHV 

CT liver 2 nd July 09 CT abd Oct 2009 

CT abd Jan 2010 CT abd April 2010 


38


Can Neoadjuvant therapy with Y90 

improve survival after resection ? 

Histology: Residual hepatocellular carcinoma, Grade 2/4. 

- 7 cm diameter (from 13 cm) 

-approximately pp y 50% of tumor show necrosis ppost 

treatment 

SGH – Surgery 39

Future Multi-center Clinical Trial 

AHCC10: Randomized controlled trial of neoadjuvant 

therapy in for HCC beyond the 

Milan criteria 


“Surgical” Trial 

40

Thank 

You! 


SGH – Surgery 41

The SIRSA, SIRveNIB, SARAH and SORAMIC Clinical Trials - ITR8

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