cholangiocarcinoma | clinical trials and...

CHOLANGIOCARCINOMA | CLINICAL TRIALS AND TARGETED THERAPIES Juan W Valle University of Manchester / The Christie Manchester, UK AMMF Annual Conference 10-May-2018

DISCLOSURES

Consulting or Advisory Role | Agios, Astra-Zeneca, Baxalta, Celgene, Delcath, Ipsen, Lilly, Merck, Midatech, Novartis, Pfizer Speakers’ Bureau | Celgene, Ipsen, Novartis, Pfizer Travel Grant | Celgene, Lilly, Novartis, NuCana Institutional Grant | Novartis

If the cancer has been completely removed by

surgery

Aim: reduce risk of cancer relapse (cure)

Adjuvant If the cancer has been

diagnosed at an advanced stage or has relapsed

Aim: stop cancer growing/spreading & improve QoL (control)

1st – line If the cancer has been

diagnosed at an advanced stage or has worsened

after 1st-line

Aim: stop cancer growing/spreading & improve QoL (control)

2nd+ – line

We all want the best treatments – benefit from those who have gone before Participation in clinical trials – improve outcomes (individuals and future patients)

WHAT DO WE MEAN? | STAGE OF DISEASE

Improving Cure Improving Living with Cancer

WHAT DO WE MEAN? | PHASES OF CLINICAL TRIALS

Phase Usual number of patients Question

1 <20 Is drug A safe?

1b <20 Are drugs A & B safe when given together?

2 (single-arm) <100 Does drug A work?

2 (randomised) <100 Does drug A work well enough to progress futher?

3 100-1000 Does drug A work better than the current best drug?

IMPROVING CURE | EARLY-STAGE DISEASE

SURGERY | CHALLENGES

Siriwardena 2014 Nat Rev Clin Oncol

ADJUVANT THERAPY| WHO DOES IT BENEFIT?

Surgery

CURE | would have been cured anyway Did not benefit from unnecessary treatment

RELAPSE | would have relapsed anyway Did not benefit from unnecessary treatment

Would have relapsed but are cured

Did benefit from treatment

Adjuvant therapy

Radiotherapy Chemotherapy Only a randomised trial will tell you this

ADJUVANT CHEMOTHERAPY | RANDOMISED TRIALS

Study [clinicaltrials.gov ID]

N Population Arms vs. Status

PRODIGE12 | France [NCT01313377]

190 Cholangio & GB Observation GemOx Completed 2017

BilCap | UK [NCT00363584]

360 Cholangio & GB Observation Capecitabine Completed 2017

BCAT| Japan [UMIN000000820]

300 Cholangio Observation Gemcitabine Completed 2018

ASCOT| Japan [UMIN000011688] JCOG1202

350 Cholangio & GB Observation S1 Recruiting

ACTICCA-1 | Germany [NCT02170090]

781 Cholangio & GB Observation CisGem Recruiting


1. Edeline et al (ASCO-GI) J Clin Oncol 2017;35:suppl 4S: abstr 225; updated at ESMO 2017 LBA29; 2. Ebata et al Br J Surg 2018; 3. Primrose et al (ASCO 2017) J Clin Oncol 35 (15) 4006

PRODIGE 121

• RFS: HR=0.88 [0.62-1.25], p=0.47 • OS: HR= 1.08 [0.70-1.66], p=0.74

BCAT2

• RFS: HR=0.93 [0.66-1.32], p=0.693 • OS: HR= 1.01 [0.70-1.45], p=0.964

BILCAP3

• RFS: HR=0.93 [0.66-1.32], p=0.693 • OS: HR= 0.81 [0.63-1.04], p=0.097 • OS: HR 0.70 [0.55-0.91], p=0.007*

* pre-planned sensitivity analysis


Study [clinicaltrials.gov ID]

N Population Arms vs. Status

PRODIGE12 | France [NCT01313377]

190 Cholangio & GB Observation GemOx No benefit

BilCap | UK [NCT00363584]

360 Cholangio & GB Observation Capecitabine Improved survival

BCAT| Japan [UMIN000000820]

300 Cholangio Observation Gemcitabine No benefit

ASCOT| Japan [UMIN000011688] JCOG1202

350 440 Cholangio & GB Observation S1 Recruiting

ACTICCA-1 | Germany [NCT02170090]

781 Cholangio & GB Observation Capecitabine CisGem Design revised

Valle et al Ann Oncol 2016;27(suppl5):v28-v37

Stronger level of recommendation

ESMO GUIDELINES

IMPROVING LIVING WITH CANCER | ADVANCED DISEASE

Best Supportive Care (no chemo)

• Median OS 2.5 - 4.5 months 1,2

Cisplatin & gemcitabine (CisGem) improves survival (over Gem alone)

• ABC-02 (n=410) OS 11.7 months 3

• BT-22 (n=84) OS 11.2 months 4

• Meta-analysis OS 11.6 months 5

1 Glimelius 1996 Ann Oncol, 2 Sharma 2010 J Clin Oncol, 3 Valle 2010 New Eng J Med, 4 Okusaka 2010 Br J Cancer, 5 Valle 2014 Ann Oncol

Gemcitabine alone5

Cisplatin + gemcitabine5 Hazard ratio = 0.65 95% CI 0.54–0.78 P < 0.001

Months

% o

f pat

ients

alive

There is an urgent need to improve outcomes

CIS-GEM | THE “FIRST STEP” ON THE LADDER

THANK YOU | PATIENTS & RESEARCHERS

Gemcitabine + nab-paclitaxel1

gemcitabine 1000mg/m2 + nab-paclitaxel 125 mg/m2 days 1, 8, 15 q28d

single-arm study 6-mo PFS: 60.5% response rate: 30.1% median PFS: 7.7 months median OS: 11.2 months

1 Sahai et al ASCO 2017 (abstr #4072)

DEVELOPMENTS IN CHEMOTHERAPY

Image from www.pancreaticcanceraction.org

1. New agents under evaluation in BTC

New Approaches


Acelarin | ABC-08 study1

1 ClinicalTrials.gov | NCT02351765; 2 Blagden et al J Clin Oncol 33, 2015 (suppl; abstr 2547)

first-in-class nucleotide analogue hENT1 independent transport no metabolism by cytidine deaminase (reduced toxic metabolites) achieves higher intracellular levels of dFdCTP than gemcitabine2

Phase IB study | acelarin and cisplatin in BTC Optimal path to approval under evaluation (phase II or phase III)

hENT1, human equilibrative nucleoside transporter-1; CDA,

cytidine deaminase; dCK, deoxycytidine kinase; dFdC,

gemcitabine; dFdU, ifluorodeoxyuridine

DEVELOPMENTS IN CHEMOTHERAPY New Approaches


Acelarin | ABC-08 study1

1 ClinicalTrials.gov | NCT02351765; 2 Blagden et al J Clin Oncol 33, 2015 (suppl; abstr 2547)

first-in-class nucleotide analogue hENT1 independent transport no metabolism by cytidine deaminase (reduced toxic metabolites) achieves higher intracellular levels of dFdCTP than gemcitabine2

Phase IB study | acelarin and cisplatin in BTC Optimal path to approval under evaluation (phase II or phase III)

DEVELOPMENTS IN CHEMOTHERAPY New Approaches

McNamara et al ASCO GI 2018


2. Triple combinations

New Approaches Combination Centre Comment

mFOLFIRINOX [NCT01643499]1 USA (Chicago)

Basket GI study; not tolerable in BTC even with genotype (UGT1A1) dosing and G-CSF

Gem/5FU/Cis [NCT01661114] USA (Ann Arbor) Single-arm phase II (n=39),

pancreas / BTC Gem/Cis/S1 [NCT02182778] Japan (Kyoto) Phase III (vs. CisGem); n=220

Gem/Cis/nab-paclitaxel2

[NCT02392637] USA (MDA and Mayo) Single-arm, phase II; n=61

1Sharma et al ASCO-GI 2017 J Clin Oncol 35, 2017 (suppl 4S; abstract 427); 2Shroff et al ASCO 2017 J Clin Oncol 35 (suppl; abstr 4018)

Schedule | gemcitabine 800mg/m2 + cisplatin 25 mg/m2 + nab-paclitaxel 100 mg/m2 ; D1,8 q21d

Promising early data - median PFS (1o endpoint): 11.8 months - response rate: 28.8% - median OS: 18.8 months


Phase III study planned (vs. CisGem)



3. New delivery mechanism

New Approaches

Chemosaturation of the liver with melphalan Investigational platform Most data in ocular melanoma Study in set-up for intrahepatic CCA1


1 ClinicalTrials.gov | NCT02415036




4. Is there a role for second-line chemotherapy?

New Approaches

Systematic review1 | 14 phase II studies; 9 retrospective studies (n=895 patients) No conclusion regarding best approach Patients are willing to participate in clinical trials PFS correlates better with OS than RR


1 Lamarca et al 2014 Ann Oncol; 2 ClinicalTrials.gov | NCT01926236




4. Is there a role for second-line chemotherapy?

New Approaches

1 Lamarca et al 2014 Ann Oncol; 2 ClinicalTrials.gov | NCT01926236


Completed recruitment | results ASCO 2019

NEW HORIZONS FOR ADVANCED BTC | TARGETED THERAPY

IMPROVING OUR UNDERSTANDING OF THE GENETIC ENVIRONMENT OF BTC

Intrahepatic cholangiocarcinoma CCA has a different profile to extrahepatic CCA or GBC 1,2

Opisthorchis viverrini (liver-fluke)*- associated CCA (TP53 mutations) is different from non-liver fluke associated CCA (BAP1, IDH1 and IDH2 mutations)3

Inflammatory subclass is different from proliferative subclass4

Table adapted from 1

1Ross (ASCO GI) J Clin Oncol 33, 2015 (suppl 3; abstr 231); 2Borger 2011 Oncologist 17(1):72; 3Chan-on 2013 Nat Genet 45(12):1474; 4Sia 2015 Nat Commun 6:6087

Up to 70% of IH-CCA patients have an actionable mutation1

1 Sia 2015 Nat Commun 6:6087

IDH-1 mutations and FGFR fusion rearrangements have emerged as potential therapeutic targets

IMPROVING OUR UNDERSTANDING OF THE GENETIC ENVIRONMENT OF BTC

ISOCITRATE DEHYDROGENASE (IDH)-1 MUTATIONS

- IDH exists as 3 isoforms 1

- IDH-1 & -2 have cancer-associated mutations which happen early in tumour development - These mutations result in novel gain-of-function enzyme activity which block normal cell

differentiation promotes tumorigenesis

1 Cairns et al Nat Rev Cancer 2011;11(2):85, 2 Figure from Valle et al Cancer Discov 2017;7(9):943-962 2-HG; 2-hydroxyglutarate, αKG; α-ketoglutarate

IDH1 mutations identified in a variety of solid tumour types

20% Intra-hepatic CC

70%

50%

Zhang et al 2016. Data Brief. 6:948

ISOCITRATE DEHYDROGENASE (IDH)-1 MUTATIONS

IDH-1 MUTATION IS DRUGGABLE Phase I study: cholangiocarcinoma (CCA), chondrosarcoma, glioma, others [NCT02073994]

CCA cohort1: n=73 [dose escalation (n=24); dose-expansion 500 mg QD (n=49)] No DLTs; drug-related AEs: fatigue, nausea, diarrhoea, vomiting Activity: median PFS 3.8 months 6-month PFS: 38.5% 12-month PFS: 20.7% RR 5% (4 PRs) OS data not mature

1 Lowery et al ASCO 2017 J Clin Oncol 35, 2017 (suppl; abstr 4015); 2 Lowery et al ASCO2017 J Clin Oncol 35 (suppl; abstr TPS4142)

AG-120 is a first-in-class, potent, oral inhibitor of the mutant IDH1 enzyme

Phase III study, second-line, placebo-controlled (ClarIDHy) [NCT02989857]

FGFR AS A POTENTIAL TARGET IN INTRAHEPATIC CHOLANGIOCARCINOMA

Fibroblast Growth Factor Receptor

Turner & Gross 2010 Nat Rev Cancer

BJG398 Phase II trial

Javle et al J Clin Oncol 2017 [Nov 28, Epub ahead of print]

BGJ398 125 mg daily Days 1-21, every 28 days

Treatment until disease progression, unacceptable toxicity, withdrawal of informed consent, or death

Key inclusion criteria • Advanced or metastatic CC • FGFR2 fusion or other genetic alterations in FGFR • Progression following prior cytotoxic therapy

Primary endpoint | RR (RECIST v1.1) Secondary endpoints | PFS, OS, best overall response (BOR), disease control rate (DCR), safety, and pharmacokinetics.

• 47 patients treated

• Majority of patients had ≥2 prior therapies

and 11% had at ≥ 4 prior regimens

• FGFR2 fusions/rearrangements were present in 38 patients

• Other FGFR genetic alterations were present in 9 patients; − FGFR2 mutations (n=3) − FGFR2 amplifications (n=4) − FGFR3 amplifications (n=2)

TARGETING FGFR IN THE CLINIC

BJG398 Phase II trial

Median duration of exposure was 188 days (6.2 months)

**All 8 patients with a partial response had an FGFR2 fusion**

Javle et al J Clin Oncol 2017 [Nov 28, Epub ahead of print]

TARGETING FGFR IN THE CLINIC

FGFR studies: o BGJ398 o TAS-120 o ARQ087 o INC-54828 o BAY1163877 o Debio1347

1 Valle et al Cancer Discovery Cancer Discov; 2017;7(9); 943–62.

TARGETS UNDER EVALUATION

BENEFITS OF “ON-TARGET” APPROACH

Verlingue et al Eur J Cancer 2017; 87,122-130

Test

MTA according to hierarchy

IDH: 10%

Drug E Drug D Drug I

RAS BRAF: 20%

mTOR ≤5%

Drug B

HER2/3 10%

Drug C

FGFR alt: 10%

Drug F

BRCA5%

Drug J

RNF43: ?

Drug G

MSI5%

Drug A

cMET amp 5% Potential

new targets /

drugs Drug H

CDKN2A 5%

SAFIR / ABC-10 STUDY

SUMMARY Outcomes following surgery may be improved with the use of adjuvant capecitabine Need more effective treatments for the majority of patients with advanced disease Novel chemotherapy agents, combinations and delivery mechanisms are under active investigation Understanding molecular subgroups is increasing potential targets…and may also be prognostic

New horizons for targeted therapy will depend on a rational approach linked to backwards and forwards translation between the lab and the clinic

IBTCC International Biliary Tract Cancer Collaborators

cholangiocarcinoma | clinical trials and...

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