future developments. trial design aasld-jnci guidelines in hcc llovet jm, et al. j natl cancer inst....

Future developments

Trial design

AASLD-JNCI guidelines in HCC

Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.

HCC trial design strategy recommended by AASLD expert panel

Combined phase 1/2 studies in cirrhotic patients will capture liver-specific toxic effects of new drugs

Randomized phase 2 trials are pivotal in HCC research because they enable reliable comparison with standard of care

Phase 3 studies remain the main source of evidence in HCC research

Phase 2/3 studies may be appropriate in very specific circumstances, where the drug proposed would require fast-track assessment


Early clinical research phase

Advanced clinical research phase

Phase 1/2 study

Randomized phase 2

Combined phase 2–3Phase 3

study


Endpoints in clinical trials recommended by AASLD expert panel

Recommended primary and secondary endpoints

Survival Time from randomization to death. Patients alive at the end of follow-up are censored•Primary endpoint in phase 3 studies assessing primary treatments•Primary/secondary endpoint in phase 2/3 studies assessing adjuvant or neoadjuvant treatments•Secondary endpoint in phase 2 studies assessing primary treatments

Time to recurrence (TTR)*

Time from randomization to recurrence. Evidence of recurrence should follow the RECIST amendments. Once evidence of HCC recurrence is confirmed, TTR will be defined as the time that recurrence was first suspected•Primary/secondary endpoint in phase 2/3 studies assessing adjuvant or neoadjuvant treatments

Time to progression* Time from randomization to radiological progression. Definition of progression is based on the RECIST amendments. Deaths during follow-up without evidence of radiological progression are censored•Primary endpoint in phase 2 studies assessing primary treatments•Secondary endpoint in phase 3 studies assessing primary treatments

Time to local recurrence*

Time from randomization to local radiological progression. Definition of progression is based on the RECIST amendments. Deaths during follow-up without evidence of radiological progression are censored•Secondary endpoint in studies assessing locoregional therapies

*Time to progression and time to local recurrence can vary considerably if evaluation interval varies among studies or between study arms of an individual study.

RECIST = Response Evaluation Criteria in Solid Tumors.


Endpoints in clinical trials recommended by AASLD expert panel

Recommended primary and secondary endpoints

Tertiary endpoints†

Cancer-specific death

Time from randomization to HCC-related death. Patients alive at the end of follow-up are censored•Competing risk analysis is recommended to assess this endpoint

Time to symptomatic progression

Time from randomization to deterioration of symptoms as assessed by a standardized questionnaire•No reliable questionnaires have been thoroughly validated in HCC research

Disease-free survival Composite endpoint. Time from randomization to either recurrence or death. Patients alive and free of recurrence at the end of follow-up are censored•Vulnerable endpoint in HCC research

Progression-free survival

Composite endpoint. Time from randomization to either radiological progression or death. Patients alive and free of progression at the end of follow-up are censored•Vulnerable endpoint in HCC research

Response rate Definition of response is based on the RECIST amendments† Tertiary endpoints include composite endpoints that are vulnerable in HCC research, such as disease-free and progression-free survival, that are difficult to measure with standard tools, such as time to symptomatic progression, or that are not time-to-event endpoints, such as response rate or disease control rate.

RECIST = Response Evaluation Criteria in Solid Tumors.

Other recommendations of AASLD expert panel on HCC trial design

Target population • selection of the target population should be based on the

Barcelona Clinic Liver Cancer staging system

• new drugs should be tested in patients with well preserved liver function (Child–Pugh A class)

Control arm in clinical trials• patients assigned to the control arm should receive standard-of-

care therapy, namely TACE for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease


Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.

Conventional and proposed trial design in HCC trials

Trial phase and component

Conventional design New proposed design

Phase 1

Study population All cancers HCC by Barcelona Clinic Liver Cancer (BCLC) Child–Pugh A

Study design Phase 1 Phase 1/2

Aim Dose definingSafety

Dose definingSafety

Endpoint Toxic effectsMaximum tolerated dose, pharmacokineticsDose defining

Toxic effectsMaximum tolerated dose and/or optimal biological dose

Phase 2

Study population Unresectable HCCChild–Pugh A and B

HCC by BCLC Child–Pugh A

Study design Single arm Randomized phase 2Single arm*

Aim Antitumor activity, safety Antitumor activity, safety

Endpoint Response rateToxicity

Time to progressionSurvival, toxicity

*Large single-arm phase 2 studies might only be considered when a contemporary historical control arm has been well characterized within other trials, and thus, inclusion criteria can be reproduced.

Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.

Trial phase and component

Conventional design New proposed design

Phase 3*

Study population Unresectable HCCChild–Pugh A and B

HCC by BCLCChild–Pugh A

Study design** Randomized controlled trial Randomized controlled trialCombined phase 2/3

Aim Clinical outcome Clinical outcome

Endpoint SurvivalResponseProgression-free survival, disease-free survival

SurvivalTime to progression (TTP)Recurrence***

*Large single-arm phase 2 studies might only be considered when a contemporary historical control arm has been well characterized within other trials, and thus, inclusion criteria can be reproduced.** Consider phase 2/3 studies for fast-track approval with strong interim analysis.*** Time to recurrence as primary endpoint in adjuvant trials.

Conventional and proposed trial design in HCC trials

Selected targeted therapies under evaluation in advanced HCC: first-line therapy

Target population

Aim Comparison Phase Status Location

Advanced HCC1 Improve sorafenib first line

Sorafenib +/– erlotinib

Phase 3 Recruiting Global

Advanced HCC2 Compare with sorafenib first line

Sorafenib vs linifanib



Sorafenib vs brivanib

Phase 3 Recruiting Regional/US


Sorafenib vs erlot + beva*


Advanced HCC5 Improve sorafenib first line

Sorafenib +/– everolimus

Phase 1/2 Active Global


Sorafenib vs sunitinib

Phase 3 Terminated Global

Advanced HCC7,8 Compare with sorafenib first line

Sorafenib vs BIBF

Phase 2 Recruiting Regional/Asia


Sorafenib vs Dovitinb

Phase 2 Recruiting Asia

Available from: http://www.clinicaltrials.gov. Last accessed March 20111. SEARCH trial: NCT00901901. 2. NCT01009593. 3. BRISK FL trial: NCT00858871.

4. NCT00881751. 5. NCT00828594. 6. NCT00699374. 7. NCT01004003. 8. NCT00987935. 9. NCT01232296

*Erlotinib + Bevacizumab

Selected targeted therapies under evaluation in advanced HCC: Second-line therapy

Target population

Aim Comparison Phase Status Location

Advanced HCC1 Second line after sorafenib

Brivanib vs placebo



Ramucirumab vs placebo


Advanced HCC3 Second line therapy ADI-PEG 20 vs placebo

Phase 3 Not yet open

US


Everolimus vs placebo


Advanced HCC5 Second line therapy ARQ 197 vs placebo

Phase 2 Recruiting Europ/US


OSI-906 vs placenbo

Phase 2 Recruiting Europ/US


TAC-101 vs placenbo

Phase 1/2 Terminated Italy

Available from: http://www.clinicaltrials.gov. Last accessed March 20111. BRISK PS trial: NCT00825955 and BRISK-APS trial: NCT01108705. 2. REACH trial: NCT01140347.

3. NCT01287585 4. EVOLVE-1 trial: NCT01035229. 5. NCT00988741. 6. NCT01101906. 7. NCT00687596.

Adapted from Finn RS. Clin Cancer Res. 2010;16:390-7.

Molecular therapies tested in HCC

Regimen Phase Sample size

Response rate (%)

Progression-free survival/time to

progression (months)

Median survival (months)

Reference

Sorafenib 3 300 2.3 5.5 (T) 10.7 (vs 7.9 placebo

Llovet et al.

Sorafenib 3 271 2.8 (T) 6.5 (vs 4.2 placebo)

Cheng et al.

Sorafenib + doxorubicin

2b 47 4 8.6 (T) 13.7 (vs 6.5 placebo)

Abou-Alfa et al.

Sunitinib 2 37 2.7 5.2 (P) 11.2 Faivre et al.

Sunitinib 2 34 2.9 3.9 (P) 9.8 Zhu et al.

Erlotinib 2 38 9 3.2 (P) 13 Philip et al.

Erlotinib 2 40 0 3.1 (P) 6.310.75

Thomas et al.

Gefitinib 2 31 3 2.8 (P) 6.5 O’Dwyer et al.

Cetuximab 2 30 0 1.4 (P) 9.6 Zhu et al.

Cetuximab 2 32 0 1.87 (T) – Gruenwald et al.

Adapted from Finn RS. Clin Cancer Res. 2010;16:390-7. Toh et al JCO 2009;27: 222s:abstr 4581; Ramanathan et al. Cancer Chem. Pharm. 2009;64:777-83

Molecular therapies tested in HCC

Regimen Phase Sample size

Response rate

(%)

Progression-free survival/time to

progression (months)

Median survival (months)

Reference

Bevacizumab 2 46 13 6.9 (P) 12.4 Siegel et al.

Bevacizumab + erlotinib

2 40 25 9 (P) 15.65 Thomas et al.

Bevacizumab + gem+oxa*

2 30 5.3 (P) 9.6 Zhu et al.

Brivanib 2

First-line

55 2.8 (T) 10 Raoul et al.

Sec-line 46 2.7 (T) 9.8 Finn et al.

Linifanib 2 44 6,8 3,7 (T) 9,7 Toh et al.

Lapatinib 2 40 5 2,3 (P) 6,2 Ramanathan etal

Lapatinib 2 26 0 1.9 (P) 12.6 Bekaii-Saab et al.*gem=gemcitabine; Oxa=oxaliplatin

Sorafenib as adjuvant Treatment in the prevention Of Recurrence of hepatocellular carcinoMa (STORM)

Phase III, randomized, double-blind, placebo-controlled study of sorafenib +/- erlotinib in advanced metastatic patients

International (Europe, Americas, Asia-Pacific)

Advanced/ metastatic Disease

Eligibility criteria Child-Pugh A PS 0 or 1

Randomization n=700

Stratification ECOG PS Geographic region MVI/EHS

Sorafenib 400 mg bid + erlotinib 150 mg daily

Sorafenib 400 mg b.i.d. + placebo

EndpointPrimary OSSecondary TTPDCRPROSafety

http://clinicaltrials.gov/; NCT00901901. DCR = disease control rate; PRO = patient-reported outcome.

Sorafenib as adjuvant Treatment in the prevention Of Recurrence of hepatocellular carcinoMa (STORM)

Phase III, randomized, double-blind, placebo-controlled study of sorafenib as adjuvant treatment of HCC after surgical resection of local ablation

International (Europe, Americas, Asia-Pacific, Japan)

Prior treatment Resection RFA PEI

Eligibility criteria Child-Pugh score 5–7 Intermediate/high risk of recurrence

Randomization n=1,100

Stratification Prior curative treatment Geographical region

Sorafenib400 mg bid

Placebo

Endpoints

RFS OS Biomarkers Other

RFA = radiofrequency ablation; PEI = percutaneous ethanol injection; RFS: recurrence-free survival.

http://clinicaltrials.gov/; NCT00692770.

Sorafenib or Placebo in combination with TACE in hepatocellular carcinoma (SPACE)

Phase II, randomized, double-blind, placebo-controlled study of TACE plus sorafenib vs TACE plus placebo

Eligibility criteria BCLC B ECOG PS 0 Child-Pugh Class A

without ascite No extrahepatic

spread No macrovascular

invasionDC-Beads-TACE

+ Placebo

EndpointsPrimary TTPSecondary OS Time to untreatable progress Time To Vascular Invasion Time To Extrahepatic Spread

TACE = transarterial chemoembolization;

TTP = time to progression; OS = overall survival.

n=300

R

A

N

D

O

M

I

Z

E

1:1

DC-Beads-TACE + Sorafenib 400 mg bid

http://clinicaltrials.gov

RTK: PDGFR FGFRVEGFR EGFR

IGFIR c-METReceptor Wnt Receptor

GrB2GEF

c-MYC c-JUN

MEK

Raf PKC

Ras PLC

-Catenin

GSK3

GBP

DSH

-Catenin

mTOR

NF-κB

PI3K

PTEN

HBx

NF-κB

BcL-XL

BAD

p53

Akt

SHC

Cell Membrane

Anzola M. J Virol Hepat. 2004; 11: 383-393; Avila MA, et al. Oncogene 2006; 25: 3866-3884; Clauss M. Semin Thromb Hemost 2000; 26: 561-569.

Signaling Pathways Provide Rationale for Combination Treatment Strategies

ERK

SurvivalTranscription/Translation

X

Erlotinib

Gefitinib

Lapatinib

Everolimus

Sorafenib

Sunitinib

X

X

X

Site of action

X

X

X

X

X

XX

Molecular targets and targeted agents in HCC

Adapted from Tanaka S, Arii S. Cancer Sci. 2009;100:1-8 Adapted from Tanaka S, Arii S. J Gastroenterol 2011; in press *published online 25 Feb 2011

Sorafenib*SunitinibVatalanibCediranibPazopanibLinifanib

AMG 386

VEGFR FGFR C-Met

VEGF

Tie2 PDGFR

Ang1/2

PDGF FGF

HGFBevacizumab

Ramucirumab

MEDI-575

ARQ 197Brivanib

RegorafenibBIBF 1120

SU6688

E70807

ForentinibXL 184

Sorafenib* is the only drug approved for HCC

EGFR

Erlotinib

Gefitinib

Cetuximab

EGF

Ras SOS Grb2

Raf

MEK

RASSF1APTEN

PI3K PDK1

AktRTK

Sorafenib*

AZD6244

ERK

AZD8055 mTOR

eIF4E 4E-BP1 p70S6K

SirolimusEverolimus

GF

Adapted from Tanaka S, Arii S. J Gastroenterol 2011; in press *published online 25 Feb 2011.

Regorafenib

Sorafenib* is the only drug approved for HCC


IKK

Agent Classification TargetSorafenib (Nexavar, BAY43-9006; Bayer) Small-molecule VEGFR2, VEGFR3, PDGFR-b, Flt-3, c-KIT tyrosine kinase, Raf

serine-threonine kinase

Regorafenib ( BAY73-4506; Bayer) Small-molecule VEGFR2, VEGFR3, PDGFR-b, Flt-3, c-KIT, Tie2 tyrosine kinase, Raf serine-threonine kinase

Sunitinib (Sutent, SU11248; Pfizer) Small-molecule VEGFR1 VEGFR2, PDGFRs, Flt-3, c-KIT tyrosine kinase

Brivanib (BMS-582664; Bristol-Myers Squibb)

Small-molecule VEGFR2, VEGFR3, FGFR tyrosine kinase

BIBF 1120 (Vargatef; Boehringer Ingelheim) Small-molecule VEGFR2, PDGFR-b, FGFR tyrosine kinase

SU6688 (TSU-68; Taiho) Small-molecule VEGFR2, PDGFR-b, FGFR tyrosine kinase

Vatalanib (PTK787/ZK222584; Novartis) Small-molecule VEGFR1, VEGFR2, VEGFR3,PDGFR-b, c-KIT tyrosine kinase

Cediranib (AZD2171; AstraZeneca) Small-molecule VEGFR1, VEGFR2, VEGFR3, PDGFRs, c-KIT tyrosine kinase

Pazopanib (Votrient, GW786034; GlaxoSmithKline)

Small-molecule VEGFR-1, VEGFR-2, VEGFR-3, PDGFRs, c-KIT tyrosine kinase

Linifanib (ABT-869; Abbott) Small-molecule VEGFR-2, PDGFR-b, CSF-1R tyrosine kinase

E7080 (Eisai) Small-molecule VEGFR3, VEGFR2, VEGFR1 tyrosine kinase

Foretinib (XL880, GSK1363089; GlaxoSmithKline)

Small-molecule VEGFR-2, c-MET tyrosine kinase

XL184 (BMS907351; Bristol-Myers Squibb) Small-molecule VEGFR-2, c-MET tyrosine kinase

ARQ 197 (Daiichi Sankyo) Small-molecule c-MET tyrosine kinase

Bevacizumab (Avastin; Roche/Genentech) Monoclonal antibody VEGF-A (neutralization)

Ramucirumab (IMC-1121B; Eli Lilly) Monoclonal antibody Monoclonal antibody VEGFR-2 (neutralization)

MEDI-575 (AstraZeneca) Monoclonal antibody PDGFR-a (neutralization)

AMG 386 (Amgen) Antibody-type peptide Angiopoietin-1, angiopoietin-2 (neutralization)

Adapted from Tanaka S, Arii S. J Gastroenterol 2011; in press *published online 25 Feb 2011.


Subway map HCC pathways

Dufour JF et al. J Hepatol. 2007; 47(6): 860-7

HCC transcriptome classification

Dufour J-F and Jonson P. J Hepatology 2009. J Hepatol. [Epub ahead of print]

BIOLOGICAL PATHWAYS TREATMENTSGROUPS

Developmental and imprinting genes,IGF2

Cell Cycle

Nucleus pore

Stress and immune

response

Amino acid metabolism E-cadherin

Molecular classification of HCCHCC genomic-based classification

Mo

lecu

lar

pat

hw

ays

Mo

lecu

lar

pat

hw

ays

IFN IFN

E2F1 p53 E2F1 p53

TGF-ßWntTGF-ßWnt

MYCAKTMYCAKT

Retained hepatocyte-like phenotype

Retained hepatocyte-like phenotype

Pu

bli

she

d

sub

clas

seP

ub

lish

ed

su

bcl

asse

EpCAM (+)EpCAM (+)

ProliferationProliferation

Cli

nic

al

ph

eno

typ

eC

lin

ica

l p

hen

oty

pe

Poor Survival Poor Survival

late TGF-ßlate TGF-ß

Good Survival Good Survival

CTNNB1CTNNB1

Large tumorLarge tumor

Moderately/poorly differentiated

Moderately/poorly differentiated

Smaller tumorSmaller tumor

Well differentiatedWell differentiated

AFT AFT

S1

S1

S2

S2

S3

S3

Hoshida Y, et al. Cancer Res. 2009;69:7385-92.Hoshida Y, et al. Cancer Res. 2009;69:7385-92.IFN = interferon; EpCAM = epithelial cell adhesion molecule.

In a meta-analysis of 603 HCC patients

• 3 HCC subtypes were observed, S1–S3

• distinguished by molecular phenotype

• correlated with tumor size, cellular differentiation, and serum α-fetoprotein levels

Outcome prediction in HCC

Villanueva A, et al. Clin Cancer Res. 2010;16:4688-94.

Model of HCC prognosis combining clinical and genomic data

In patients with early stage tumors, survival is mostly determined by genomic data coded in non-tumoral cirrhotic tissue (‘field effect’), because it determines the risk of liver dysfunction and development of a de novo HCC

As cancer progresses, genomic data from the tumor increases its prediction capacity because cancer-related death limits survival in patients with advanced disease

Very early(Stage 0)

Single nodule < 2 cm,no vascular invasion,

PST 0

Early(Stage A)

Single nodule, 3 nodules < 3 cm,no macrovascular invasion,

PST 0

Intermediate(Stage B)

Advanced(Stage C)

Macrovascular invasion,extrahepatic spread (N1, M1),

PST 1–2

Multiple nodules,no macrovascular invasion,

PST 0

Cli

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© 2010 American Association for Cancer Research`

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Translational research in HCC

future developments. trial design aasld-jnci guidelines in hcc llovet jm, et al. j natl cancer inst....

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