clinicaltrials for cholangiocarcinoma – an...
TRANSCRIPT
Clinical Trials for
Cholangiocarcinoma – an
update
John BridgewaterUCL Cancer Institute, London
AMMFAnnual meeting
Stansted, 11 May 2017
Primary endpoint Patient numbersPhase 1 Dose/safety/route/
schedule12-40 Is A safe?
Phase 1b Dose/safety/route/schedule
12-40 Is A + B safe?
Phase 2 Efficacy 20-40 Does Awork?Randomisedphase 2
Efficacy 80-120 Does Aworkwell?
Phase 3 Benefit 200+ Does Aworkbetter than thegold standard?
Phase 1-3 studies
ABC-studies in context
Eckel and Schmid
Br J Cancer2007;96:896-902
2005/06: 24.5/study, 32% recruited <122012/13:16 /study, 44% recruited < 12
Cancer: Changing nature of studies
ABC-02 - schema
Eligible patients (n=400*)
Arm A
Gem 1000 mg/m2 D1,8,15 q 28d24 weeks (6 cycles)
Arm BCisplatin 25 mg/m2
+ Gem 1000 mg/m2
24 weeks (8 cycles)
Randomized 1:1(stratified by centre, primary site, PS, priortherapy and locally advanced vs. metastatic)
Primary endpoint OS
D1,8 q 21d
+ QoL
Median8.1 11.7 mo
NEJM 2010
Internationalstandardfor ABC
Why did ABC-01/2 work?
RecruitmentPhase 2 rolling into phase 3 (86/324)
InfrastructureNCRN supportHPB centralisation 0
102030405060708090
Feb-02
May-02
Aug-02
Nov-02
Feb-03
May-03
Aug-03
Nov-03
Feb-04
May-04
Aug-04
Nov-04
ActualProjected
Study description Study size Outcome DateAdvanced disease
ABC-01 Randomised phase 2 86 Published 2001-4ABC-02 Phase 3 410 Published 2004-9ABC-03 Randomised phase 2 126 Published 2011-2
ABC-04 Phase 1b 13 Published 2012-3
ABC-06 Phase 3 170 Accruing 2013-ABC-07 Phase 2 76 Accruing 2013-ABC-08ABC-09
Phase 1bPhase 2
18-2450
AccruingIn set-up
AdjuvantBILCAP Phase 3 425 Completed 2005-14ACTICCA-01 Phase 3 360 Accruing 2013-Photodynamic Therapy
Photostent-02 Phase 3 98 Submitted forpublication
2004-9
........................
.... ..... .... .....
........................
.... .....
........................
........................
........................
Maturation factors present
Normal and tumour vasculature
Tumour Blood VesselsNormal Blood Vessels
Reduced integrinexpression
Less dependent on cellsurvival factors
.... ..... Less permeable
Leaky
Preferentialexpression ofDvE3 DvE5 &D5E1 integrins
Fewer supportingcells
Growth and survivalfactors (eg, VEGF)
present
.... .....
Supporting cellspresent
VEGF: A central mediator of angiogenesis
Binding and activationof VEGF receptor
Environmental factors(Hypoxia, pH)
Growth factors(EGF, bFGF, PDGF,IGF-1, IL-1α, IL-6)
Genes involved intumorigenesis
(p53, p73, src, ras, vHL,bcr-Abl)
PP
PP
ANGIOGENESIS
ProliferationSurvival Migration
Endothelial cellactivation
VEGF
CEDIRINIB
Presented by: Juan W Valle
ABC-03 | Study schema
Cisplatin 25 mg/m2 +Gemcitabine 1000 mg/m2
Day 1 & 8, every 21 days
Cisplatin 25 mg/m2 +Gemcitabine 1000 mg/m2
Day 1 & 8, every 21 days
Cediranib 20mg od
Placebo 20mg od
Cediranib
Placebo
Diseaseprogression
CT scan T=0 CT scan Q3 Months
R 1:1
n = 136
Eligible patients• Histo-/cytologically confirmed ABC• Age ≥ 18 years | No upper limit• ECOG PS 0-1• Chemo-naïve | Advanced disease• Resolved biliary obstruction / sepsis• Life expectancy >12 weeks• Adequate haem, renal & liverfunction
• Informed consent
Translational samples
Plasma for angiogenesis ELISAsWhole blood for CTCs
Day 1 C2 - C8Day 1 C3 & C5
FFPE
Results | Objective response rate
Presented by: Juan W Valle
CediranibN (%)
PlaceboN (%) P-value*
Number of evaluable patients 59 (100) 54 (100) -
Complete Response | CR 2 (3) 0 (0) -
Partial Response | PR 24 (41) 10 (19) -
Stable Disease | SD 20 (34) 25 (46) -
Progressive Disease | PD 6 (10) 15 (28) -
Unknown 7 (12) 4 (7) -Response rate
(CR + PR) 26 (44) 10 (19) 0.0036
Disease Control rate(CR+PR+SD) 46 (78) 35 (65) -
*Pearson chi-squared test of association
Best overall response | RECIST v1.1• In patients with measurable disease at baseline
Results | Progression-free survival
Presented by: Juan W Valle
Events | N (%) Median PFS (months) 95% CI
Cediranib 59 (95) 8 6.5 - 9.3
Placebo 57 (92) 7.4 5.7 - 8.5
0
25
50
75
100
%ofpatientsaliveanddisease-free
62 52 42 23 13 5 4 4 1 0 0Cediranib62 46 38 19 10 8 4 3 2 1 0Placebo
Number at risk
0 6 12 18 24 30Time since randomisation (months)
HR = 0.97 [95% CI 0.7 - 1.4]Log rank p=0.87
PlaceboCediranib
H
BL C2 C3 C4 C5 C6 C7 C8
Time-points
End +1m
8.2
8.4
8.6
8.8
9.0
VEGFR2
Meanof
logpg
/ml
6.0
6.2
6.4
6.6
6.8
7.0G
Time-points
BL C2 C3 C4 C5 C6 C7 C8
CK18
Meanof
logU/L
End +1m
CK18 (PI3K/Akt, Wnt, ERK, MAPK signalling) VEGFR2 (endothelial proliferation)
Description of biomarker modulation following anti-angiogenic intervention
BILCAP
BILCAP
ASCO 4-6-17PRESS CONFERENCE 17-5-17
curative intent resection ofintrahepatic, hilar orextrahepatic CCAn=280
gemcitabine + cisplatin for 24 weeksgemcitabine 1000 mg/m2 (day 1, 8) qd 22cisplatin 25 mg/m2 (d 1, 8) qd 22
+ observationassessment every third month(CT/MRI and CA 19-9)R
observationassessment every third month(CT/MRI and CA 19-9)
stratification criteria• intrahepatic vs. hilary/extrahepatic CCA• lymphnode positivity vs. negativity
ACTICCA-01 design (AIO
Arnold)
N=180+ in EuropeCRUK CTAAC funding Mar 2013Slow to open in UK because of BILCAPTrial modified to include GBMay require modification if BILCAP or PRODIGE12 +ve
curative intent resection ofintrahepatic, hilar orextrahepatic CCAn=280
gemcitabine + cisplatin for 24 weeksgemcitabine 1000 mg/m2 (day 1, 8) qd 22cisplatin 25 mg/m2 (d 1, 8) qd 22
+ observationassessment every third month(CT/MRI and CA 19-9)R
observationassessment every third month(CT/MRI and CA 19-9)
stratification criteria• intrahepatic vs. hilary/extrahepatic CCA• lymphnode positivity vs. negativity
ACTICCA-01 design (AIO
Arnold)
Capecitabine?
Study description Study size Outcome DateAdvanced disease
ABC-01 Randomised phase 2 86 Published 2001-4ABC-02 Phase 3 410 Published 2004-9ABC-03 Randomised phase 2 126 Published 2011-2
ABC-04 Phase 1b 13 Published 2012-3
ABC-06 Phase 3 170 Accruing 2013-ABC-07 Phase 2 76 Accruing 2013-ABC-08ABC-09
Phase 1bPhase 2
18-2450
AccruingIn set-up
AdjuvantBILCAP Phase 3 425 Completed 2005-14ACTICCA-01 Phase 3 360 Accruing 2013-Photodynamic Therapy
Photostent-02 Phase 3 98 Submitted forpublication
2004-9
ABC-06Eligiblepatients
Arm A (81)
mFOLFOX +BSC
Arm B (81)
BSC
Randomise(stratified for PS and locallyadvanced vs. metastatic)
0S
Valle CI recruiting
n=137/162
ABC-06Eligiblepatients
Arm A (81)
mFOLFOX +BSC
Arm B (81)
BSC
Randomise(stratified for PS and locallyadvanced vs. metastatic)
0S
Valle CI recruiting
n=137/162
ABC-07
Hawkins recruiting n=5/76
ABC-06Eligiblepatients
Arm A (81)
mFOLFOX +BSC
Arm B (81)
BSC
Randomise(stratified for PS and locallyadvanced vs. metastatic)
0S
Valle CI recruiting
n=137/162
ABC-07
Hawkins recruiting n=5/76
Phase 1b Cisplatin
Acelarin
McNamara recruiting
n=9/18
ABC-08
Patients with locallyadvanced ormetastaticadenocarcinoma ofthe intra or extra-hepatic bile ducts,gallbladder cancer orampullary cancer
RANDOMIZATON
Acelarin___mg/m2
D1 + D8 of 3wkcycle
ContinueTreatmentUntilPD
Cisplatin25 mg/m2
D1 + D8 of 3wkcycle
Arm 1
Gemcitabine1000 mg/m2
D1 + D8 of 3wk cycle
Cisplatin25 mg/m2
D1 + D8 of 3wk cycle
Arm 2
+
BI.2CisGem vs Cis-Acelarin n=642NCIC Canada (Nucana, Knox)
ABC-09 (EORTC-1607-GITCG) | Markus Moehler
N=50Unresectable/metastaticBTC (IH/EH) or gallbladdercarcinoma
Pembrolizumab fixed dose 200mg q21d
Cis 25mg/m2 + Gem 1000mg/m2 d1d8 q21
Open-label first line, phase II study of CisGem pembrolizumab in advanced BTC
Primary endpoint: PFS at 6 monthsSecondary endpoints:• Response rate (RECIST v1.1)• Immune related Progression Free Survival (irPFS)• Overall Survival• Toxicity (CTCAE v4.03)• Quality of life (EORTC QoL C30 and BIL 21)
Reference for design: Valle et al, NEJM 2010
Main objective is to detect an increase in PFS at 6 months from 60% to 75%
Stratification¾ intra-hepatic vs. extra-hepatic/gallbladder¾ previous operation vs none¾ institution
Eligibility¾ ECOG 0-1; estimated life expectancy > 3 months¾ No prior chemo for locally advanced/metastatic disease, except low-dose as
radio-sensitizer¾ Prior adjuvant chemo is allowed provided neither Gem nor Cis were used and
the treatment was completed at least 6 months before trial entry.¾ Prior non-curative operation allowed if evidence of disease present¾ Adequate organ function¾ No evidence of uncontrolled infection¾ No evidence of active autoimmune disease (except well-controlled stable thyroiditis)
Pre-treatmentbiopsy
(diagnostic)Circulating T Cells
t=0
Bx, cT-cells,D6
Bx, cT-cells,D21
Bx, cT-cells,progression
CisGem D1
ABC-09 CisGem-P translational n=10
MSI/MMRSuto et al al 2002MSI 12-13%hMLH1/MSH2 <10%
CisGem-P D8 CisGem-P D8
Bridgewater-Walczak UCL CI
JSBF study | evaluating VEGF and cMET targetingSponsor| Lilly
N= 300 PatientsR
2:1
R
2:1
Ramucirumab +Gemcitabine + Cisplatin
Ramucirumab | 8mg/kg IV D1&8 3qwCisplatin | 25mg/m2 IV D1 & 8 3qwGemcitabine | 1g/m2 IV D1 & 8 3qw
Arm A1 | N=100
IV placebo +Gemcitabine + Cisplatin
Arm A2 | N=50
Merestinib +Gemcitabine + Cisplatin
Arm B1 | N=100 Arm B2 | N=50
Oral placebo +Gemcitabine + Cisplatin
IV placebo | IV D1&8 3qwCisplatin | 25mg/m2 IV D1 & 8 3qwGemcitabine | 1g/m2 IV D1 & 8 3qw
Merestinib | 80mg oral, dailyCisplatin | 25mg/m2 IV D1 & 8 3qwGemcitabine | 1g/m2 IV D1 & 8 3qw
Oral placebo | DailyCisplatin | 25mg/m2 IV D1 & 8 3qwGemcitabine | 1g/m2 IV D1 & 8 3qw
• Locally-advanced ormetastatic BTC
• First line treatment
• ECOG PS 0/1
• 1:1 randomisation
• Double-blind
Stratification factors
Primarytumour site
Gall bladderIH-CCEH-CCAmpulla of Vater
Geographicregion
Europe or North AmericaRest of the world
Metastatic status Yes/No
• CisGem treatment will be capped @ 8 cycles
• No cap of Ramucirumab/Merestinib/placebo
• Crossover is not permitted
• Appropriate best supportive care will beoffered to all
• Interim safety analysis after n=75 patientscomplete Cycle 1
S
Stratify:
• Extra-hepaticdisease• Cirrhosis• Unilobar vs. bi-lobar intendedtreatment• Albumin <35g/L
vs. ≥35g/L • ECOG Status
Randomise1:1
N = 180
Systemic chemotherapy CIS + GEM
SIR-Spheres followed by systemicchemotherapy CIS + GEM
Eligible patients withunresectable intrahepaticcholangiocarcinoma (ICC)
Eligible patients withunresectable intrahepaticcholangiocarcinoma (ICC)
SIRCCA–Study
Primary Endpoint: Survival at 18 months (18 mth survival proportion inSIRT arm (Arm B) is > chemotherapy only arm (Arm B)by at least 15 %
Co-CI’s: Bruix J & Wasan HS
Summary
• Clinical studies critical for defining best therapy• Pharma interest and activity established• Role of further conventional chemotherapy to be established• International collaboration essential
2009
ABC-02
20172013
ABC-03 BILCAP
6 first line studies2 second line
JuanValle
HarpreetWasan
John Primrose
Manuel Rodriguez-Justo
ABCTMG (CRUK UCL
trials unit)
NCRI UGI CSG
Hepatobiliary subgroup
GeL
Helen Morement
Thanks
IBTCC International Biliary Tract Cancer Collaborators