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