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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
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
Early clinical research phase
Advanced clinical research phase
Phase 1/2 study
Randomized phase 2
Combined phase 2–3Phase 3
study
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
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.
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
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;100:698-71.Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-71.
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
Phase 3 Recruiting Global
Advanced HCC3 Compare with sorafenib first line
Sorafenib vs brivanib
Phase 3 Recruiting Regional/US
Advanced HCC4 Compare with sorafenib first line
Sorafenib vs erlot + beva*
Phase 2 Recruiting Global
Advanced HCC5 Improve sorafenib first line
Sorafenib +/– everolimus
Phase 1/2 Active Global
Advanced HCC6 Compare with sorafenib first line
Sorafenib vs sunitinib
Phase 3 Terminated Global
Advanced HCC7,8 Compare with sorafenib first line
Sorafenib vs BIBF
Phase 2 Recruiting Regional/Asia
Advanced HCC9 Compare with sorafenib first line
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
Phase 3 Recruiting Global
Advanced HCC2 Second line after sorafenib
Ramucirumab vs placebo
Phase 3 Recruiting Global
Advanced HCC3 Second line therapy ADI-PEG 20 vs placebo
Phase 3 Not yet open
US
Advanced HCC4 Second line after sorafenib
Everolimus vs placebo
Phase 3 Recruiting Global
Advanced HCC5 Second line therapy ARQ 197 vs placebo
Phase 2 Recruiting Europ/US
Advanced HCC6 Second line after sorafenib
OSI-906 vs placenbo
Phase 2 Recruiting Europ/US
Advanced HCC7 Second line after sorafenib
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
Molecular targets and targeted agents in 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.
Molecular targets and targeted agents in HCC
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
nic
al s
tag
e(B
CL
C a
lgo
rith
m)
© 2010 American Association for Cancer Research`
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Liverdysfunction
Intrahepaticdissemination
Tumorbiology
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