Drug Development and Clinical Trial Design in Pancreatico-biliary malignancies

Jennifer Harringtona, Louise Carterb,c, Bristi Basua, Natalie Cookb,c

a. Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Department of Oncology, Box 193, Hills Road, Cambridge CB2 0QQ

b. The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BXc. Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester

M13 9PL

Corresponding author:

Dr Natalie Cook,

Senior Clinical Lecturer and Honorary Consultant in Medical Oncology

The Christie NHS Foundation Trust,

Oak Road Treatment Centre

Wilmslow Road,

Manchester, M20 4BX

T: 0161 918 7871, F: 0161 446 8342

E: Natalie.cook@christie.nhs.uk

Keywords: Pancreatic cancer; biliary tract cancer; experimental therapeutics; clinical trial design

Conflicts of interest: None

Word count for abstract: 258

Word count for body text including subheadings: 5629

1

Abstract

Pancreatico-biliary tumours arise from the pancreas, bile duct and Ampulla of Vater.

Despite their close anatomical location, they have different aetiology and biology.

However, they uniformly share a poor prognosis, with no major improvements

observed in overall survival over decades, even in the face of progress in diagnostic

imaging, surgical techniques and advances in systemic and loco-regional radiation

therapies. To date, cytotoxic treatment has been associated with modest benefits in

the advanced disease setting, and survival for patients with stage IV disease has not

exceeded a year. Therefore, there is a pressing need to identify better treatments

which may impact more significantly. . Frequently, encouraging signals of potential

efficacy for novel agents in early phase clinical trials have been followed by

disappointing failures in larger Phase III trials [1,2] , raising the valid question of how

drug development can be optimised for patients with pancreatic adenocarcinoma

and biliary tract malignancies (P-B tumours).

In this paper we summarise the current therapeutic options for these patients and

their limitations. The biological context of these cancers is reviewed, highlighting

features that may make them resistant to standard chemotherapeutics and could be

potential therapeutic targets. We discuss the role of early phase clinical trials,

defined as Phase I and non-randomised Phase 2 trials, within the clinical context and

current therapeutic landscape of P-B tumours and postulate how translational

studies and trial design may enable better realisation of emerging targets together

with a proposed model for future patient management. A detailed summary of

current Phase I clinical trials in P-B tumours is provided.

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1. Introduction

Whilst P-B cancers are relatively uncommon in the Western world, there is global

variation. In 2012, pancreatic cancer was the twelfth most common cancer in the

world, with 33, 8000 cases diagnosed, with highest incidence in North America and

Europe. There were an estimated 178100 new cases of biliary tract cancer (BTC),

with 65% of cases in less developed countries, particularly South America and

Asia[3]. Although pancreatic and BTC tumours differ in their tumour biology, they

share key driver mutations in Kras and p53 and are reviewed together here due to

similarities in presentation and treatment regimens. The majority of pancreatic

cancers are exocrine in origin, of which 85% have pancreatic ductal adenocarcinoma

(PDAC) histology. BTCs are classified depending on where they occur anatomically

and are largely divided into either intrahepatic or extrahepatic cholangiocarcinomas,

or gallbladder cancer, although cancer of the ampulla of Vater can also occur.

Increasingly there is an appreciation of the molecular differences between these

cancers depending on the site of origin[4], which is difficult to account for in clinical

trials of an already rare tumour type.

P-B tumours are frequently accompanied by significant morbidity from cachexia,

depression and inanition, resulting in poor functional performance status (PS), which

may preclude active therapeutic interventions. Many therapies require adequate

hepatic function, and dealing with reversible causes of jaundice by biliary stenting

can also introduce undesirable delays before initiation of definitive anti-cancer

therapy. Unfortunately, less than 20% of both PDAC and BTC patients present with

localised resectable tumours, and even in this group the majority progress within

three years, implying the presence of subclinical metastases at presentation. For

PDAC, the addition of adjuvant chemotherapy with gemcitabine and capecitabine is

associated with 5 year survival of 29% [5]. For BTC, the phase III randomised

BILCAP trial recently established superiority of oral capecitabine over surveillance

following resection, prolonging overall survival (OS) by a non-significant 15 months

in the intention to treat population, but by a significant 17 months in the per-protocol

population[6]. Two large phase III trials are ongoing, investigating adjuvant

3

gemcitabine plus cisplatin (ACTICCA-1 trial, NCT02170090) or oxaliplatin

(NCT01313377) versus observation/capecitabine.

For patients with “borderline” resectable PDAC, designated as such due to major

vascular impingement, upfront surgery may be attempted. However, this often

results in positive resection margins and a high likelihood of regional recurrence.

Hence management may now include neoadjuvant chemotherapy or chemo-

radiation followed by adjuvant chemotherapy. The role of radiotherapy remains

debatable with mixed results from studies comparing chemoradiation to

chemotherapy alone[7]. Recently the LAP07 study randomised patients with stable

or responding disease after induction chemotherapy with gemcitabine+/-erlotinib to

either continued chemotherapy or chemoradiation. The results showed no survival

benefit for chemoradiation compared to chemotherapy alone (median OS 15.2 vs

16.5 months), although there was a reduction in loco-regional tumour progression

(32% vs 46%, p=0 .04)[8]. Given this lack of superiority, chemotherapy only

strategies remain the most commonly used, particularly with the more effective

chemotherapy regimens now available. Similarly in BTC, there is limited evidence for

radiotherapy, selective internal radiation therapy or brachytherapy as neo-adjuvant

or adjuvant therapies[9]. The ABC-07 trial is currently assessing the addition of

stereotactic radiotherapy to cisplatin/gemcitabine chemotherapy in locally advanced

BTC (EudraCT Number: 2014-003656-31). The addition of new agents in this setting

may offer translational research opportunities due to the possibility of monitoring

treatment response using serial biomarkers during the treatment window, and

evaluating tissue from the resection specimen. However, for P-B patients diagnosed

with locally advanced or metastatic disease, the basis of treatment remains palliative

chemotherapy. This article will focus on this population.

2. Current treatment options

2.1.1 Pancreas cancer

For over two decades, single agent gemcitabine has been the mainstay of systemic

treatment for pancreatic cancer, following comparison with single agent 5-fluorouracil

(5-FU), with trials showing a small improvement in median OS 5.6 vs 4.4 months,

p=0.002, an improvement in 1 year survival rate of 18% versus 2%, and clinical

4

benefit [10]. Since then, the addition of cytotoxic therapies such as capecitabine, or

targeted agents such as the epidermal growth factor (EGFR) inhibitor erlotinib, have

resulted in small incremental benefits in survival in the late phase setting, although

changes to practice have been limited due to uncertainty over how meaningful the

survival gains were for patients in the face of increased toxicity[11]. Recent evidence

would suggest the high frequency of Kras mutations in PDAC probably affects the

efficacy of EGFR inhibitors, similar to the effect seen in colorectal cancers[12].

More recently two combination chemotherapy regimens have become widely

adopted by clinicians for treatment of advanced PDAC with good ECOG PS (PS 0 or

1), showing improved survival over gemcitabine alone. FOLFIRINOX (a combination

of oxaliplatin, irinotecan, 5-FU and leucovorin (LV)) evaluated within the ACCORD4

(PRODIGE) trial[13] resulted in improved median OS to 11.1 versus 6.8 months

(p<0.001), and improved median progression-free survival (PFS) (6.4 v 3.3 months)

and objective response rate (32% v 9%). The phase III IMPACT trial showed that the

combination of nab-paclitaxel (nabP) with gemcitabine resulted in a superior median

OS of 8.5 months vs 6.7 months for gemcitabine monotherapy (p<0.001)[14].

In general, pancreatic cancer patients who have progressed after FOLFIRINOX are

offered gemcitabine, although prospective studies to recommend this are lacking.

For patients who have progressed on gemcitabine-based therapy, the CONKO-

003[15] (oxaliplatin + 5-FU/LV vs 5-FU/LV) and PANCREOX[16] (oxaliplatin + 

5-FU/LV vs 5-FU/LV) trials provide rationale for oxaliplatin-based combinations. The

NAPOLI-1 trial[17] established superiority in a randomised trial setting of nano-

liposomal irinotecan [nal-IRI]/5-FU/LV vs 5-FU/LV after failure of gemcitabine-based

therapy (median OS 6.1 months versus 4.2 months). Unfortunately dissimilarity

between study designs precludes indirect treatment comparison of oxaliplatin- or

irinotecan-based regimens[18]. Table 1 summarises current Phase I trials in PDAC.

2.1.2 Biliary tract cancers

For BTC, gemcitabine was used as a single agent until the addition of cisplatin was

shown to improve median OS (11.7 months vs 8.1 months, p<0.001)[19] in the

practice-changing ABC-02 study[20]. There is no widely accepted second-line

standard of care, although regimens containing 5-FU and oxaliplatin are often used

5

based on retrospective studies, despite response rates of ≤10%([21–23]. When a 5-

FU/platinum combination was compared with 5-FU monotherapy, the overall

response rate was significantly higher with the combination (8 vs 1%, p=0.009), but

this did not translate into an improvement in either PFS or OS[24]. The ABC-06 trial

(NCT01926236) is currently recruiting, randomising patients previously treated with

cisplatin/gemcitabine chemotherapy to either active symptom control alone or

combined with oxaliplatin//5-FU chemotherapy. Table 2 summarises on-going Phase

I trials in BTC.

2.2 Additions to standard of care treatment

Given the established activity of the discussed combination regimens and their

adoption into first-line standard practice, questions arise regarding the appropriate

chemotherapy backbone for testing investigational agents and whether addition to

monotherapy is appropriate, especially in fit chemo-naive P-B patients. However, the

addition of new drugs to unmodified combination chemotherapy backbones could

present challenges given the toxicities seen with conventional chemotherapy

alone[13,14]. In PDAC, these include febrile neutropenia, myelosuppression and

sensory neuropathy, and in the case of FOLFIRNOX, diarrhoea. In clinical practice,

various modifications are frequently made to the FOLFIRINOX regimen, for example

omission of the 5-FU bolus, reduction of irinotecan or routine use of growth factor

support as primary prophylaxis in an attempt to improve tolerability. The gemcitabine

and nabP regimen is the more frequently utilised combination to which the addition

of new agents is investigated (see Table 1), because of ease of scheduling without

the need for continuous infusion via intravascular catheters and a perception of a

slightly more favourable toxicity profile. With the combination of cisplatin and

gemcitabine in BTC, there was a non-significant increase in Grade 3 or 4

haematological adverse events such as neutropenia over that seen with gemcitabine

alone but otherwise adverse events were similar in both groups [19].

Whilst combination cytotoxic regimens have improved survival, the associated

greater toxicity means that careful selection of appropriate patients with adequate PS

is essential. For relatively older patients, or those who are rapidly deteriorating with

poor PS and symptomatic burden, (the great majority of the advanced P-B patient

population), drug development is distinctly more complex as the ability to evaluate

6

new agents over a sufficient time period is impeded. Ethically, there may be

reservations over whether such patients should be enrolled in clinical trials when the

chances of them realising a benefit may not be outweighed by their time invested in

visits associated with intensive monitoring. Emergence of toxicities against a

background of poor functional reserve may be particularly problematic when

optimisation of quality of life should be prioritised. There is therefore an inherent

dilemma that new drugs are not being tested in the group for whom there is the most

pressing need. A natural niche for early phase trials of new drugs may be after

failure of initial systemic therapy, given the lack of consensus on the best second-

line regimen to offer P-B patients. However, this approach is constrained by the

limited numbers of patients with adequate reserve [25–27].

3. The biological context

Genomic profiling of tumours, through large scale projects such as the Cancer

Genome Atlas and the International Cancer Genome Consortium has enabled

molecular characterisation of tumours and provided valuable insights. PDAC is a

genetically complex disease with a highly diverse mutation profile. The most

commonly mutated genes in PDAC are Kras, TP53, P16 and SMAD, for which drug

development efforts have yielded very limited success. The majority of other genetic

alterations are low frequency and therapeutically “actionable” mutations are

infrequent.

In BTC recent work has identified common gene alterations beyond Kras and TP53,

reviewed in detail in [4,28,29]. These include potentially actionable mutations in the

HER and FGFR families, MAPK, PI3K/AKT/mTOR pathway and epigenetic

alterations (e.g. IDH). Interestingly, the molecular changes are dependent on the

anatomical location of the tumour with intrahepatic cholangiocarcinomas shown to

have IDH1/2 and FGFR2 alterations whereas extrahepatic cholangiocarcinomas and

gallbladder cancers are more likely to have ERBB2 or Catenin Beta 1 alterations[30].

Despite worldwide variation in their incidence, similar mutational profiles are seen.

Amongst the patients with BTC treated within the MOSCATO-01 trial where high

throughput genomics was used to match targeted agents to mutations, appropriate

targeted agents could be identified in 68%, with a disease control rate of 88% in

those receiving a matched drug, showing potential promise[31]. As Kras mutations

7

are the commonest mutations found in P-B cancers this would be a logical

therapeutic target. Unfortunately, specific biochemical properties of the Kras protein

have made this a very difficult task to undertake and to date there are no effective

Kras inhibitors available. Farnyltransferase inhibitors (FTIs), which inhibit a lipid

modification of the C terminus of the Ras protein, have not been successful in the

clinic [32]. The exact reason is unknown, although compensatory geranyltransferase

activity, preserving Ras function is a potential explanation[33].

3.1 Tumour microenvironment

The stroma consists of fibroblasts, immune cells, endothelial cells and vascular

supporting cells, collectively termed the non-cell autonomous compartment of a

tumour, or the “tumour microenvironment”. These cell types have been implicated in

promoting tumour formation, progression and metastases, and secrete multiple

different proteins. Although progress is being made in understanding the tumour

microenvironment within P-B malignancies and how it may contribute to its

behaviour, we are still at an early stage of defining the exact roles and importance of

different components in the initiation and maintenance of P-B cancers.

3.1.1. Stroma

PDAC is now generally recognised to be a hypovascular tumour associated with

dense fibrosis, due to an abundant desmoplastic stroma which lacks a functional

vasculature. Initially there was a drive to disrupt the desmoplastic reaction, as data

from a genetically engineered mouse model (GEMM) suggested that stroma could

reduce drug penetration creating a potential source of chemoresistance in

PDAC[34]. Inhibition of the Sonic hedgehog (Shh) pathway using IPI-926 reduced

tumour stroma and increased tumour vascularity, gemcitabine delivery and survival

in comparison to controls. However, stromal depletion was controversial as others

later showed that reduced stromal formation following Shh inhibition resulted in more

de-differentiated tumours and increased metastases, associated with inferior

survival[35]. The phase Ib/II trial of IPI-926 and gemcitabine in metastatic PDAC was

stopped after interim data showed that higher rates of progression and lower OS in

patients receiving the combination [36]. Although a study of a different Shh pathway

inhibitor vismodegib did not show a deleterious effect from hedgehog inhibition, no

8

improvement was seen in overall response rate, PFS or OS in patients with

metastatic PDAC, suggesting a lack of benefit from this approach in unselected

patients[37]. The timing of Shh inhibition treatment in the PDAC GEMMs was later

hypothesised to play an important role in the discrepancy in efficacy between pre-

clinical studies, with earlier treatment in less advanced disease predisposing to more

aggressive behaviour of the tumours later, possibly due to a role for Shh stroma in

restricting tumour angiogenesis[35].

An alternative approach targeting a matrix component of the stroma, hyaluronan

(HA), a glycosaminoglycan has shown some success. The enzyme hyaluronidase

digests hyaluronan and can decrease interstitial fluid pressure around the tumour,

leading to improved blood flow and drug delivery. PEGPH20 (Halozyme

Therapeutics) is a recombinant human PH20 hyaluronidase enzyme conjugated to

polyethylene glycol (PEG). In a phase II trial (HALO-109-202) patients with advanced

PDAC were randomised to first-line combination chemotherapy either with or without

PEGPH20[38]. Although the apparent benefit of PEGPH20 was a limited

improvement in PFS overall, in patients with tumours with high HA levels, adding

PEGPH20 to chemotherapy doubled PFS to 9.2 months (compared to 5.2 months).

This study suggests an intriguing benefit from stromal depletion in a targeted

population of PDAC patients.

The stroma is also being studied in BTC, particularly in intrahepatic

cholangiocarcinomas which has a dense desmoplastic stroma[39]. For example,

stroma LOXL2 overexpression is correlated with a poor prognosis[40].

3.1.2. Cancer Stem Cells

Evidence is accumulating that cancers contain cells with “stem like properties”, the

so called “tumour-initiating cells” or cancer stem cells (CSC)[41,42]. Although the

gold standard for identifying functional cancer stemness is through self-renewal and

initiation of new tumours in vivo in immunocompromised mice, molecular markers

proposed to distinguish cancer stemness in PDAC include CD133+, CD44+,

EpCAM+, CD24+ and ABCG2high[43]. These CSCs have been proposed to be

involved in chemoresistance, possibly due to their ability to endure long periods in a

nearly quiescent state, and they are capable of producing recurrences and

9

metastases. Given the relative lack of chemosensitivity of P-B malignancies with

early emergence of highly resistant disease, these CSCs are a focus of either

chemoprevention strategies, or therapeutic efforts to deplete the CSC pool in order

to enhance the activity of chemotherapy[44,45]. These approaches may include cell

surface marker-specific monoclonal antibodies to target CSCs, CSC differentiation

agonists to reduce self-renewal or inhibitors against signalling pathways implicated in

“stemness”, such as Janus kinas/signal transducers and activators of transcription

(JAK/STAT) pathway, hedgehog pathway, Wnt/b-catenin pathway, and the Notch

pathway [46–48].

3.1.3 Immune environment

Following the success of immune checkpoint blockade strategies in other tumours

such as melanoma, accumulating data has identified therapeutic targets to re-

programme the immunosuppressive microenvironment of human P-B tumours and a

wide range of ongoing clinical trials in P-B tumours involve immunotherapy (Tables 1

and 2).

3.1.3.1. PDAC

Monotherapy treatment with immune checkpoint inhibitors (ICPIs) such as anti-

CTLA4 antibodies or PD1/PDL1 antibodies in unselected pancreatic cancer have so

far yielded no convincing sign of activity [49]. PDAC development involves evasion

from immune surveillance through a number of mechanisms[50], and it has been

described as a poorly immunogenic tumour, making single agent ICPIs less

effective. In a subset of pancreatic tumours with microsatellite instability (reported at

1-2%), the increased volume of mutation-associated neo-antigens presents targets

for the immune system and potential efficacy [51].

For the majority of PDAC patients however, an alternative approach is required and

significant efforts are underway pre-clinically and clinically to boost understanding to

improve immunotherapy approaches. These include strategies to enhance tumour

antigen presentation to help T cell priming; therapies that modulate tumour

microenvironment to relieve local immunosuppression and also agents such as

PEGPH20 which breakdown the stromal desmoplastic barrier surrounding P-B

10

tumours to permit infiltrating T cells influx [52]. The use of cancer vaccines is being

evaluated in clinical trials as a T cell priming and dendritic cell activation approach.

GVAX, a whole cell vaccine comprising irradiated, allogeneic pancreatic tumour cells

genetically engineered to secrete GM-CSF is currently in phase II trials for PDAC,

and is now being trialled in combination with ICPIs.

In terms of the local immune environment, the paucity of cytotoxic CD8+ T-cells

within the tumour nest is likely to contribute to the lack of immune control of PDAC,

whilst immunosuppressive regulatory T cells are observed in PDAC models [53].

Similar approaches are being taken through targeting other cytokines alongside

checkpoint inhibition. For example, the CXCL12/CXCR4 signalling axis is implicated

in cancer metastasis, growth and survival in mouse models of PDAC [54]. Tumour-

associated macrophages (TAM) within PDAC can stimulate cancer formation and

maintenance through production of cytokines such as TNFα, leading to IL-6

production and STAT3 signalling with tumour promotion [55]. Efforts to target TAM

recruitment are under investigation, such as inhibition of the CCL2/CCR2 axis[56].

Macrophage activation, which involves the CSF-1/CSF-1R axis is being evaluated as

a therapeutic strategy, as blockade of this signalling in tumours has been shown to

deplete CD206HighTAM and re-programme remaining macrophages to support anti-

tumour immunity, and improve efficacy of both checkpoint immunotherapy and

cytotoxic agents [57,58].

3.1.3.2. BTC

Chronic inflammation is associated with development of BTC, and the tumour

microenvironment is characterised by an excess of pro-inflammatory cytokines,

particularly IL-6 (produced by Th17 cells). Both CD4+ and CD8+ T lymphocytes are

found in tumours with an associated prognostic impact [59], sparking significant

interest (reviewed in [60–62]). Molecular profiling of BTC found that the worst

prognostic group were the hyper-mutated tumours with higher expression of

checkpoint molecules such as CTLA-4 and PD-L1, the tumours which should be

most susceptible to immunotherapy [29]. Potentially sensitive subgroups of BTC

have been identified as not only hyper-mutated intrahepatic and extrahepatic

cholangiocarcinomas but also PD-L1 and HLA Class I antigen expressing

intrahepatic cholangiocarcinomas and Th17-cell rich and IL-6 secreting BTC [30]. In

11

the KEYNOTE-028 phase I study with pembrolizumab, 42% of the BTC patients

were PD-L1 positive, and of those treated the overall response rate was 17% [63].

In addition, tumour related antigens with at least moderate expression in BTC

include Wilms tumour 1 (WT1) and mucin-1 (MUC-1) and dendritic-based cell

vaccines against these have been developed [60]. An initial Phase I trial of

gemcitabine in combination with WT1 vaccine showed safety [64] but a subsequent

randomised trial of cisplatin and gemcitabine with the vaccine[ 64] was terminated.

Additional vaccine trials are ongoing (see Table 2).

3.1.4. Angiogenesis

Historic data suggested that PDAC is a vascular tumour dependent on angiogenesis,

with a pro-angiogenic signature[66]. However, the results of clinical trials targeting

angiogenesis have been largely disappointing, and highlight the difficulties in

translating encouraging pre-clinical data to the clinic. For example, although a Phase

II trial of gemcitabine plus bevacizumab showed promise [67], in a randomised

placebo controlled phase III trial, there was no significant difference in median OS

(5.8 months for gemcitabine/bevacizumab vs 5.9 months for gemcitabine/placebo) or

PFS and response rates were far lower at 13% vs 10%[68].

Interest in targeting angiogenesis signalling in BTC was stimulated by genomic

profiling of tumours showing upregulation of pro-angiogenic signalling pathways, eg

VEGF and FGFR-2, with encouraging data from pre-clinical studies (reviewed in [69].

Yet clinical studies investigating anti-angiogenic treatments, such as bevacizumab

and cediranib, either as single agent or in combination with chemotherapy [69] have

been disappointing to date [70][71]. Therefore, in both PDAC and BTC, further work

is required to identify biomarkers of response to angiogenesis inhibitors.

4. Drug Development in P-B Cancers

4.1. Pre-clinical models

To develop potentially effective new treatments, a thorough understanding of the

molecular pathogenesis of P-B cancers is essential, alongside newer approaches to

pre-clinical therapeutic testing. In general, two universal approaches have been

12

utilised in pre-clinical testing: cell-based in vitro systems and in vivo animal models.

A number of models of P-B malignancy have now been developed in genetically

engineered mice, using a variety of gene targeting and transgenic techniques[73,74].

Patient derived xenograft (PDX) models (where fresh tumours are grafted into

immunocompromised mice) are now being used as a tool in late pre-clinical drug

development[75,76], to screen novel therapeutics, evaluate markers of response and

resistance, and could be used to select drugs to treat individual patients[77].

Drawbacks include a variable transplantation failure rate, higher costs and a higher

mutation rate away from the parent tumour over time. Recent studies have also

shown that genotype-specific drug responses can be recapitulated in patient-derived

cancer organoid models, 3D cell culture based systems[78].

Organoid models also allow assessment of novel therapies in a clinically-actionable

time frame and are of great potential in P-B cancers, where the time frame is critical.

Recently, organoids were propagated from cholangiocarcinoma tumours, showing

preservation of histological architecture, metastatic potential, gene expression and

the genomic landscape of the original tumour, even following long term tissue culture

conditions[79]. The utility of such organoid systems for identifying novel targets and

screening experimental agents is anticipated to further expand potential for

personalised therapeutic strategies for P-B malignancies.

4.2 Assay development

Unfortunately it remains rare to have comprehensive information relating to tumour

pharmacokinetic (PK) and PK/Pharmacodynamic (PD) relationships from pre-clinical

work when a drug is evaluated in the clinic. Therefore it is often unknown whether

the selected therapy is actually reaching its target, let alone whether it is inhibiting

pathways or impacting tumour cell biology. Early phase clinical trial designs need to

be modified to ensure that these data are collected. P-B tumour biopsies are

notoriously difficult to obtain, particularly from the primary tumours due to location.

Even in metastatic samples, it is not always possible to obtain the amount of tumour

tissue required for informative PD assay investigations. Direct histological methods

to process endoscopic ultrasound fine needle aspiration (EUS-FNA) biopsies from

pancreatic tumours can help to diagnose malignancies. For PD assays micro-cores

13

can be generated during EUS-FNA procedures with the potential to improve the

performance of molecular techniques on these samples[80].

Heterogeneity in P-B tissue is also an issue, with multiple important cell types

playing a role in the progression of the cancer as discussed earlier. This means that

fresh biopsies, ideally from multiple sites may be needed for a true representation of

the genomics of an individual’s cancer. In addition, increasing evidence for tumour

evolution suggests that archival biopsies may no longer be representative of

disease[81]. As an alternative to tissue biopsies, circulating biomarker analysis has

proved informative. With this minimally invasive approach, circulating tumour cells

(CTCs) or circulating tumour DNA (ctDNA), which likely arise from multiple different

tumour regions, may provide the most up-to-date and detailed tumour data. We now

know it is feasible to molecularly profile single cells by next generation sequencing

(NGS) and CTCs retain their tumourgenicity confirming their relevance in

disease[82]. These circulating biomarkers also enable identification of resistance

mechanisms to novel therapies and allow serial sampling without the need for

invasive tumour biopsies[83]. It is likely that P-B trials will increasingly draw on these

to inform clinical decisions.

4.3 Experimental Clinical Trials

Although some preclinical models are thought to be more reflective of P-B cancers,

no model completely recapitulates the human situation and early phase clinical trials

will always be necessary for the development of novel therapeutics. In the future,

predictive biomarkers are likely to guide therapy in P-B cancers, as they already do

in many other cancers[84–86]. When therapies are tested using an “all comer”

approach, many novels agents investigated thus far have been found to be

ineffective late in their development. Thankfully early phase clinical trial designs are

evolving to try to improve the efficiency and effectiveness of drug development, for

example with the incorporation of predictive molecular biomarkers at an early stage,

thus potentially enabling enrichment for patients most likely to benefit. However, the

downside to this is the decreasing number of commercial trial options for patients

that do not have a predictive biomarker of interest, which unfortunately includes the

vast majority of patients with P-B malignancies. The identification of small subsets of

14

patients with specific molecular abnormalities requires a collaborative approach to

clinical trials involving multiple sites[87].

In PDAC these multi-centre collaborative efforts include the SU2C Pancreatic Dream

Team [88], together with the Pancreatic Cancer Action Network Precision Promise

trial in USA, and the Cancer Research UK PRECISION-Panc initiative[89], exploring

PDAC therapies from several angles, including targeting DNA damage repair

defects, stromal disruption and evaluating immunotherapy. Such collaborative efforts

simultaneously increase the knowledge of the molecular landscape of PDAC by

harmonising research platforms. For instance the UK-wide PRECISION-Panc

framework will enable the screening and molecular profiling of patients with PDAC,

eventually leading to enrolment in available Pancreatic canceR Individualised Multi-

arm Umbrella Study (PRIMUS) arms where patients may be recruited to the most

suitable treatment based on their molecular phenotype and/or integrated with

biomarker discovery and validation approaches. Similar collaborative approaches

are required for BTC, and international groups set up to aid clinical trials for this rarer

cancer group include the International Biliary Tract Collaborators and the

International Cholangiocarcinoma Research Network.

4.3.1 Experimental immunotherapy approaches

A rapidly evolving immunotherapy approach currently generating interest involves

adoptive cell transfer (ACT), whereby the patients’ own immune cells are harvested

and modified to treat their cancer. Chimeric Antigen Receptor (CAR)-T cell therapy is

the most developed ACT approach and this is now being tested in solid tumours

such as PDAC, colorectal cancer and breast cancer. The therapy isolates

autologous T cells from patients, and using a disarmed virus, genetically engineers

the T cells to generate surface chimeric antigen receptors, or CARs which target

antigens preferentially expressed on tumour cells. In PDAC, CAR-T therapy is being

evaluated in recently opened Phase I trials with CAR-Ts directed at the prostate

stem cell antigen (PSCA), a protein expressed in 60-80% of PDACs

(NCT02744287); and mesothelin (NCT03323944). For BTC, the field is less evolved,

but the potential for ACT was highlighted through a single cholangiocarcinoma

patient report, where whole-exomic-sequencing identified CD4+ T helper 1 tumour

infiltrating cells (TILs) recognizing a mutation in erbb2 interacting protein (ERBB2IP)

15

expressed by the cancer. After adoptive transfer of TIL containing mutation-specific

T cells, the patient achieved shrinkage of her tumour[72].

4.3.2 Optimal Biological Dose and Expansion Cohorts

The key endpoint of phase I trials is to determine the recommended phase II dose

(RP2D) based on the maximum tolerated dose (MTD) of the IMP (investigational

medicinal product) under investigation. However, in the era of molecularly targeted

agents (MTAs) and immunotherapies as opposed to chemotherapies, the MTD may

no longer be the most relevant dose. The optimal biological dose may instead be

established through identifying the dose which produces the most favourable change

in a relevant PD or PK biomarker. Given the mechanism of actions of MTAs which

may be cytostatic rather than cytotoxic, it has also been suggested that clinical

benefit rate which includes stable disease in addition to partial and complete

responses may be an appropriate method of assessing efficacy. Functional imaging

modalities, changes in tumour markers and novel biomarkers such as ctDNA may

also be able to provide earlier assessments of response[90–92], particularly

important in P-B cancers due to the poor survival rates.

Expansion cohorts in early phase clinical trials have been used to improve the

volume and quality of data by enrolling additional subjects at the RP2D, with

increasing use recently [93]. Whilst their benefits for adverse event identification and

dose determination will encourage this, as they become more disease specific, there

is concern that patients with P-B malignancies may be overlooked due to their poor

response and survival rates unless there is a specific biomarker of interest.

4.3.3 Adaptive trial design, Scheduling and Toxicity assessments

Traditional phase I designs, such 3 + 3 designs or accelerated titration, are easy to

implement but can be inefficient and time consuming [94,95]. Increasingly adaptive

or model based designs such as the continuous reassessment model or modified

toxicity probability interval designs are utilised [96,97]. A dose-effect curve is pre-

determined and then modified as the trial proceeds using toxicity (and in some cases

efficacy) data, making these designs particularly suited to combination trials [98,99].

16

Defining DLTs is also important. Both MTAs and immunotherapies are often

chronically dosed until progression occurs and as such both chronic lower grade

toxicities and the occurrence of grade 3 and 4 toxicities with later cycles is of

increasing relevance[100]. This has led to recommendations that the DLT time

period (usually the first cycle only) should remain unchanged to ensure efficiency of

trials but that the RP2D recommendation should consider all the available

information including notable toxicities occurring after cycle 1, intolerable lower grade

toxicities and those which impact dose intensity significantly[101].

Given the disappointing results from many trials of single agents in P-B

malignancies, there is increasing focus on combinations to increase response rates

and overcome mechanisms of resistance [13,14]. Given the numerous potential

combinations of chemotherapies, MTAs, immunotherapies and radiotherapy, it is

important to investigate those with a strong scientific rationale[102]. High throughput

system based approaches utilising the increasing knowledge of aberrant systems

within cancers and their microenvironments can be used to help generate these

hypotheses[103–105]. Although rule based trial designs have been proposed for

dose escalation studies of combinations of agents, it has been argued that adaptive

trial designs may be more appropriate to deal with this complexity, though as yet

uptake of these more novel complex trial designs remains low[106,107].

When carrying out phase I trials of combinations, scheduling the different IMPs may

be important. For example, pre-clinical data suggested that nabP potentiated

gemcitabine activity by reducing cytidine deaminase levels. When gemcitabine was

given 24 hours after nabP versus standard combination dosing for the first line

treatment for metastatic PDAC, a non-statistically significant improvement in

response rates and survival was seen in the novel schedule arm[108]. Overlapping

toxicities can also limit the drugs being tested from being used at effective doses

[109]. This is exemplified by trials exploring the combination of MEK and PI3K

pathway inhibitors which had a strong scientific foundation, including in P-B

malignancies, where significant overlapping toxicities of diarrhoea and rash

prevented adequate dose levels being achieved[110].

4.3.4. Phase 0, Proof of concept and Window Studies

17

The increasing popularity of window of opportunity studies, proof of concept and

Phase 0 trials can be attributed to their potential to provide further insight into novel

therapeutic mechanisms of action at an early stage of a drug’s development. Phase

0 studies in which small doses of IMP are given to patients without therapeutic intent

allow exploration of mechanism of action, PD, PK and pharmacology, and can

improve knowledge of the IMP at an early stage and thus improve the efficiency of its

development. Proof of concept studies are small studies which attempt to

demonstrate biological activity of the IMP prior to larger phase II trials, again to

streamline the drug development process. Window studies, in which a patient

delays standard of care treatment to receive a MTA for a defined period of time, for

example in the neoadjuvant setting whilst awaiting surgery, are of increasing interest

in P-B malignancies. Neoadjuvant studies may enable access to a superior volume

of cancer material and adjacent normal tissue, given the high likelihood of relapse

following surgery. Close collaborations with the P-B surgical team is essential for

these types of studies to be successful.

4.3.5 Future Approaches to Clinical Trials in P-B Malignancies

The continued poor prognosis in P-B malignancies necessitates a change in the

approach to clinical trials for this group of patients (Figure 1). Within the advanced

setting, molecular profiling of patients’ tumours to identify relevant genetic

aberrations will be of increasing importance in trial selection. Patients with relevant

genomic alterations can be treated in genetic-biomarker driven trials such as

umbrella and basket trials. However, non-genetic biomarker-driven trials, for

example focused on mechanisms influencing the immune system, tumour

metabolism and microenvironment, also need to be developed to investigate new

treatment options for patients without actionable genomic alterations. Within all

clinical trials, the importance of translational research for patients who respond and

those who develop resistance to treatments should be paramount. This will enable

the mechanisms of both response and resistance to IMPs to be interrogated, aiding

future rational trial design with these agents. In the early disease setting, patients

should be offered the opportunity to take part in neoadjuvant or adjuvant trials as the

prognoses for these groups of patients remains poor. The utility of MTA in patients

with actionable genetic alterations could be explored in the adjuvant setting whilst

18

window trials in the neoadjuvant setting could allow the mechanism of action of

MTAs to be confirmed. Given the challenges of obtaining tumour tissue patients with

P-B malignancies for translational research, liquid biopsies including cfDNA and

CTCs should be utilised as biomarkers within clinical trials. This approach to clinical

trials will require the collaboration of the entire multidisciplinary team managing these

patients to enable its success.

5.0 Summary and Conclusions

Increased understanding of the new therapeutic targets, biomarkers of activity,

along with improved knowledge of the biology of P-B cancers will hopefully have an

impact on P-B cancers in the near future. Clinically the future lies in well-designed

early phase basket or umbrella type studies, incorporating multiple biological

endpoints, to assess the novel targets under investigation. Blood based biomarkers

are likely to play a significant role in detecting mutations and monitoring response to

treatment. There remains significant unmet need in the management of P-B cancers.

Given the increasing insights into the biology of these cancers generated from

preclinical and translational studies and the continued evolution of early phase

clinical trial design to stream line drug development, there is scope for optimism for

the future.

19

Table and Figure Legends

Table 1. Ongoing Phase I clinical trials of IMPs in locally advanced or metastatic PDAC. Data accessed from clinicaltrials.gov with search terms

pancreatic neoplasms or pancreatic cancer, interventional studies, recruiting or

ongoing, not recruiting, adult and senior, early Phase I and Phase I accessed 21 July

2017. Only trials specifically recruiting PDAC are shown.

Table 2. Ongoing Phase I clinical trials of IMPs in locally advanced or metastatic BTC. Data accessed from clinicaltrials.gov with search terms biliary

neoplasms, bile duct cancer, cholangiocarcinoma, interventional studies, recruiting

or ongoing, not recruiting, adult and senior, early Phase I and Phase I accessed 21

July 2017. Trials in BTC alone are shown in normal font, those recruiting BTC as one

of a number of specific cancer types are shown in italic.

Figure 1: Future work and new models of working in P-B phase I trials.

This figure depicts a proposed future approach for directing P-B patients to early

phase trials within the clinic. In the advanced setting both genetic biomarker driven

trials such as umbrella trials and non-genetic biomarker driven trials (for example

focusing on the microenvironment) will be considered for patients. In all trials,

additional research should be carried out to interrogate patients who respond and

those who develop resistance to the IMP to explore the molecular basis for these

events. In the early disease setting adjuvant trials will consider the addition of

molecular targeted agents to standard of care treatments for patients with actionable

genomic aberrations. Patients receiving neoadjuvant treatment will be offered

window trials with increased opportunity to acquire tissue specimens for translational

research. Liquid biopsies as opposed to tumour tissue biopsies could be used for

translational research at multiple points within this proposed model, particularly given

the challenges of acquiring tissue in P-B malignancies.

* indicates points at which liquid biopsies could be used for translational research.

20

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34

Table 1

NCT number

Trial Target (s) Eligibility Status

  Chemotherapy      

NCT01730222 Nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine

  Locally advanced or metastatic, no prior chemotherapy

ongoing, not recruiting

NCT02324543 Gemcitabine, docetaxel and capecitabine in combination with cisplatin and irinotecan 

  Metastatic, no prior treatment recruiting

NCT02333188 Genetic analysis-guided dosing of nab-paclitaxel, 5-FU, LV and irinotecan 

  Locally advanced or metastatic, no prior chemo

recruiting

NCT02368860 Oxaliplatin, capecitabine and irinotecan   Locally advanced or metastatic recruiting

NCT02504333 Nab-paclitaxel and gemcitabine followed by modified FOLFOX

  Metastatic, no prior treatment recruiting

NCT02620800 Metronomic 5-FU in combination with nab-paclitaxel, bevacizumab, LV and oxaliplatin

  Metastatic, no prior treatment recruiting

  Novel targeted agent in addition to chemo

     

NCT01485744 LDE225 with FOLFIRINOX Hedgehog pathway Locally advanced or metastatic, no prior chemotherapy

ongoing, not recruiting

NCT01489865 Phase I/II Study of ABT-888 in combination With 5-fluorouracil and oxaliplatin (Modified FOLFOX-6)

PARP inhibitor Locally advanced or metastatic, known BRCA mutation or strong FH suggestive BRCA

recruiting

NCT01506973 Hydroxychloroquine in combination with nab-paclitaxel and gemcitabine

Autophagy Locally advanced or metastatic, no prior chemotherapy

recruiting

35

NCT number

Trial Target (s) Eligibility Status

NCT01660971 Gemcitabine and dasatinib when given together with erlotinib

Dasatinib - Bcr-Abl and Src tyrosine kinase inhibitor, erlotinib EGFR tyrosine kinase inhibitor

Locally advanced or metastatic, no prior gemcitabine

ongoing, not recruiting

NCT01663272 Cabozantinib (XL184) and gemcitabine c-met inhibitor Locally advanced or metastatic, at least 1 prior chemotherapy

ongoing not recruiting

NCT01825603 ADH-1 with gemcitabine hydrochloride and cisplatin

Angiogenesis Locally advanced or metastatic, no prior chemotherapy

recruiting

NCT01835041 CPI-613 in combination With modified FOLFIRINOX

Mitochondrial metabolism Metastatic, no prior treatment ongoing, not recruiting

NCT01924260 MLN8237 and gemcitabine Aurora kinase A Locally advanced or metastatic, failed standard therapies

ongoing, not recruiting

NCT01934634 LCL161 and gemcitabine plus Nab-Paclitaxel Proapoptotic Agonist Metastatic, no prior treatment ongoing not recruiting

NCT01959139 Modified FOLFIRINOX + pegylated recombinant human hyaluronidase (PEGPH20) versus modified FOLFIRINOX alone

Hyaluronic acid (extracellular matrix)

Locally advanced or metastatic, newly diagnosed

ongoing, not recruiting

NCT02050178 OMP-54F28 in combination with nab-paclitaxel and gemcitabine 

Wnt signalling Metastatic, no prior treatment ongoing not recruiting

NCT02037230 Wee1 inhibitor AZD1775, in combination with gemcitabine (+radiation)

Wee 1 inhibitor Locally advanced, no prior treatment recruiting

NCT02101580 ADI-PEG 20 plus nab-paclitaxel and gemcitabine i

Arginine metabolism Locally advanced or metastatic, failed standard therapies (dose expansion: no prior)

ongoing, not recruiting

NCT02138383 Enzalutamide in combination with gemcitabine Anti-androgen Locally advanced or metastatic. For recruiting

36

NCT number

Trial Target (s) Eligibility Status

and nab-paclitaxel dose expansion tumour must express androgen receptor

NCT02154737 Dose escalation study of gemcitabine and pulsed dose erlotinib

EGFR Locally advanced or metastatic, failed first line chemo

recruiting

NCT02155088 BYL719 in combination with gemcitabine and (nab)-paclitaxel 

PI3Kα inhibitor Locally advanced or metastatic, no prior chemo

ongoing, not recruiting

NCT03086369 Nab-paclitaxel and gemcitabine with or without olaratumab

PDGF-R α Metastatic, no prior treatment recruiting

NCT02005315 Vantictumab (OMP-18R5) in combination with nab-paclitaxel and gemcitabine i

Wnt signalling Metastatic, no prior treatment ongoing, not recruiting

NCT02021422 Anakinra in combination with mFOLFIRINOX Interleukin-1 receptor antagonist

Locally advanced or metastatic ongoing, not recruiting

NCT02227940 Ceritinib in combination with gemcitabine or gemcitabine/abraxane

Alk Locally advanced or metastatic recruiting

NCT02231723 BBI608 administered in combination with gemcitabine and nab-paclitaxel, mFOLFIRINOX, FOLFIRI, or MM-398 with 5-FU and leucovorin.

STAT3 and beta-catenin pathways

Metastatic, 1 prior chemotherapy recruiting

NCT02352831 Tosedostat with capecitabine Aminopeptidases Locally advanced or metastatic, progression after gemcitabine based chemotherapy

recruiting

NCT02451553 Afatinib dimaleate with capecitabine EGFR/HER2 Tyrosine Kinase Inhibitor

Locally advanced or metastatic, ≤2 prior chemotherapy

recruiting

NCT02336087 Gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, metformin

Glucose metabolism Locally advanced or metastatic recruiting

37

NCT number

Trial Target (s) Eligibility Status

hydrochloride, and a standardized dietary supplement

NCT02501902 Palbociclib (oral Cdk 4/6 Inhibitor) plus Abraxane (registered) (nab-paclitaxel)

Cdk 4/6 inhibitor Metastatic, no prior nab-paclitaxel recruiting

NCT02514031 ARQ-761 (beta-lapachone) with gemcitabine/nab-paclitaxel

NQO1-mediated programmed cancer cell necrosis.

Locally advanced or metastatic, no prior gemcitabine

recruiting

NCT02562898 Ibrutinib combined with gemcitabine and nab-paclitaxel

Bruton's tyrosine kinase (BTK)

Metastatic, no prior treatment recruiting

NCT02574663 TGR-1202 as a single agent or in combination with nab-paclitaxel + gemcitabine or with FOLFOX

PI3Kδ inhibitor Relapsed or refractory ongoing, not recruiting

NCT02608229 BVD-523 plus nab-paclitaxel and gemcitabine ERK1/ERK2 inhibitor Locally advanced or metastatic, newly diagnosed

recruiting

NCT02671890 Disulfiram and gemcitabine  Muscle degradation Metastatic recruiting

NCT02737228 CG200745 PPA in combination with gemcitabine and erlotinib

Histone deacetylase (HDAC) inhibitor

Locally advanced or metastatic, no prior chemotherapy

recruiting

NCT02896907  Ascorbic acid and FOLFIRINOX   Locally advanced or metastatic, no prior chemotherapy

recruiting

NCT02959164 Decitabine in combination with gemcitabine Nucleic Acid Synthesis Inhibitor.

Metastatic, no prior treatment recruiting

NCT02975141 Afatinib and gemcitabine/nab-paclitaxel EGFR and HER2 Metastatic, no prior treatment recruiting

NCT02672917 Human monoclonal antibody 5B1 (MVT-5873) as monotherapy and with standard of care chemotherapy

Tumour cells expressing Ca19.9

Locally advanced or metastatic recruiting

38

NCT number

Trial Target (s) Eligibility Status

  Novel target      

NCT02146313 DMUC4064A MUC16 Locally advanced or metastatic, MUC16 positive, received standard of care chemo

ongoing, not recruiting

NCT02179970 Continuous IV administration of the CXCR4 antagonist, plerixafor (mozobil)

CXCR4 Locally advanced or metastatic, failed standard therapies

recruiting

NCT02985125 LEE011 plus everolimus CDK4/6 inhibitor everolimus mTOR inhibitor

Metastatic pancreatic cancer refractory to 5-FU and gemcitabine-based chemo

recruiting

NCT02528526 OXY111A  Hypoxia modifier Unresectable recruiting

NCT02657330 SBP-101 Polyamine analogue Locally advanced or metastatic, at least 1 prior

recruiting

NCT02726854 Apatinib VEGFR-2 Locally advanced or metastatic, at least 1 prior

recruiting

NCT02847000 p53/p16-independent epigenetic therapy with oral decitabine/tetrahydrouridine

Nucleic Acid Synthesis Inhibitor and cytidine deaminase inhibitor and multidrug resistance modulator

Locally advanced or metastatic, progression after 1st line chemotherapy

recruiting

Immunotherapy

Immunotherapy only (single agent or combination

NCT00669734 Intratumoral PANVAC-F plus PANVAC-V, PANVAC-F and rH-GM-CSF

  Locally advanced or low volume metastatic

ongoing, not recruiting

NCT01897415 Autologous T cells transfected with chimeric   Metastatic, at least 1 prior ongoing, not

39

NCT number

Trial Target (s) Eligibility Status

anti-mesothelin immunoreceptor SS1 recruiting

NCT02465983 Combination therapy with CART-meso cells and CART19 cells

  Metastatic, at least 1 prior chemotherapy

recruiting

NCT02706782 Vascular interventional therapy mediated Mesothelin-targeted chimeric antigen receptor T cells

  Locally advanced or metastatic, failed standard, mesothelin postiive

recruiting

NCT02744287 PSCA-specific chimeric antigen receptor engineered T cells (BPX-601)

  Locally advanced, failed standard recruiting

NCT03008304 High-activity natural killer cells   Small volume metastatic disease, failed standard

recruiting

NCT02653313 Intravenous and intratumoral administration of ParvOryx

Oncoloytic parvovirus Metastatic with at least one hepatic metastasis, failed 1st line

recruiting

NCT03165591 Therapeutic vaccine, V3-P   Locally advanced, raised Ca19.9 recruiting

NCT03168139 Olaptesed Pegol alone or in combination with pembrolizumab

CXCL12 (olaptesed pegol), PD-1 (pembrolizumab)

Metastatic with liver metastases, failed at least 1 prior chemotherapy

recruiting

NCT03193190 Atezolizumab in combination with cobimetinib, PEGPH20 or BL-8040

  Metastatic recruiting

NCT02908451 AbGn-107 Tumor-associated antigen (TAA) AG7 combined with cytotoxic

Locally advanced or metastatic, failed at least 1 prior chemotherapy

recruiting

With chemotherapy

NCT01342224 Telomerase vaccine with GM-CSF in combination with gemcitabine and radiotherapy

  Locally advanced ongoing, not recruiting

NCT01473940 Ipilimumab in combination with gemcitabine CTLA-4 Locally advanced or metastatic ongoing, not

40

NCT number

Trial Target (s) Eligibility Status

recruiting

NCT01781520 Dendritic cell activated Cytokine induced killer treatment in combination with S-1 (5-FU pro-drug)

  Locally advanced or metastatic recruiting

NCT02045589 Intratumoral injections of VCN-01 in combination with nab-paclitaxel and gemcitabine

  Locally advanced ongoing, not recruiting

NCT02045602 Intravenous Administration of VCN-01 oncolytic adenovirus with or without nab-paclitaxel and gemcitabine

  Locally advanced or metastatic recruiting

NCT02309177 Nivolumab with nab-paclitaxel +/- gemcitabine PD-1 Locally advanced or metastatic recruiting

NCT02529579 iAPA-DC/CTL adoptive cellular immunotherapy in combination with gemcitabine

  Locally advanced or metastatic recruiting

NCT02548169 Antigen-loaded dendritic cell vaccine with either FOLFIRINOX or nab-paclitaxel and gemcitabine

  Two groups: borderline resectable and locally advanced/metastatic

recruiting

NCT02620423 REOLYSIN® and chemotherapy (gemcitabine OR irinotecan OR 5-FU) in combination with pembrolizumab

Reovirus (REOLYSIN®), PD-1 (pembrolizumab)

Metastatic, failed 1st line chemotherapy

ongoing, not recruiting

NCT02705196 LOAd703 oncolytic virus therapy in combination with nab-paclitaxel and gemcitabine

Oncolytic adenovirus Metastatic recruiting

NCT02810418 Mesothelin-targeted immunotoxin LMB-100 alone or in combination with nab-paclitaxel

  Locally advanced or metastatic, mesothelin positive

recruiting

NCT02894944 Replication-competent Adenovirus-mediated double suicide gene therapy in combination with

  Locally advanced recruiting

41

NCT number

Trial Target (s) Eligibility Status

standard of care chemotherapy

NCT01834235  NPC-1C monoclonal antibody alone or in combination with nab-paclitaxel and gemcitabine

  Locally advanced or metastatic, previously treated with FOLFIRINOX

ongoing, not recruiting

NCT02077881 Indoximod in combination with nab-paclitaxel and gemcitabine

Immune "checkpoint" pathway indoleamine 2,3-dioxygenase (IDO)

Metastatic, no prior treatment recruiting

NCT02345408 CCX872-B in combination with FOLFIRIONX CCR2 Locally advanced or metastatic ongoing, not recruiting

NCT02559674 ALT-803 in combination with nab-paclitaxel and gemcitabine

IL-15 superagonist complex, immunostimulatory effect NK and T cells

Locally advanced or metastatic, 1 prior chemotherapy (but not nab-paclitaxel)

recruiting

NCT02583477 MEDI4736 in combination with nab-paclitaxel and gemcitabine or AZD5069

PD-L1 Metastatic, no more than 1 prior chemotherapy

ongoing, not recruiting

With another technique/target

NCT02311361 Tremelimumab and/or MEDI4736 in combination with radiation

CTLA-4 (tremleimumab) and PD-L1 (MEDI4736)

Locally advanced recruiting

NCT02718859 Irreversible electroporation and natural killer cells

  Locally advanced or metastatic recruiting

NCT02777710 Durvalumab in combination with pexidartinib PD-L1 (durvalumab), KIT, CSF1R and FLT3 (pexidartinib)

Locally advanced or metastatic, at least 1 prior line of chemotherapy

recruiting

NCT03118349 177Lu Human monoclonal antibody 5B1 (MVT-1075) in combination with a blocking dose of MVT-5873 as radioimmunotherapy

  Locally advanced or metastatic, at least one prior, elevated Ca19.9

recruiting

42

NCT number

Trial Target (s) Eligibility Status

NCT03180437 γδ T Cell Immunotherapy in combination with cryotherapy

  Locally advanced or metastatic recruiting

NCT02734160 Galunisertib (LY2157299) and durvalumab (MEDI4736)

Transforming Growth Factor-β Receptor (Galunisertib), PD-L1 (durvalumab)

Recurrent or refractory metastatic recruiting

Table 2

NCT number

Trial Target (s) Eligibility Status

Chemotherapy

NCT02351765 Acelarin in combination with cisplatin

Nucleoside analogue of gemcitabine

Locally advanced, recurrent or metastatic BTC, no prior chemotherapy for advanced disease

recruiting

NCT02240238 NC 6004 in combination with gemcitabine.

Nanoparticle cisplatin Locally advanced, recurrent or metastatic BTC, no prior chemotherapy for advanced disease

recruiting

NCT02333188 Genetic analysis-guided dosing of nab-paclitaxel, 5-FU, LV, and irinotecan (FOLFIRABRAX)

  Locally advanced, recurrent or metastatic BTC, no prior chemotherapy for advanced disease

recruiting

Targeted plus chemotherapy

 

NCT03082053 varlitinib in combination with capecitabine

EGFR, HER2 and HER4 Locally advanced, recurrent or metastatic BTC recruiting

NCT02773459 MEK162 in combination with Mek Gemcitabine-pre-treated non-resectable, recurrent or recruiting

43

NCT number

Trial Target (s) Eligibility Status

capecitabine metastatic biliary tract cancer

NCT02451553 Afatinib in combination with capecitabine

EGFR and HER2 Metastatic BTC, refractory to standard therapies recruiting

NCT02992340 Varlitinib in combination with gemcitabine and cisplatin

EGFR, HER2 and HER4  Locally advanced, recurrent or metastatic BTC, no prior chemotherapy

recruiting

NCT01825603 ADH-1 in combination with gemcitabine and cisplatin

Angiogenesis  Adenocarcinoma of the biliary tree locally advanced, but non-resectable, metastatic or residual disease, no prior chemotherapy for advanced disease

recruiting

NCT02375880 DKN-01 in combination with gemcitabine and cisplatin

Dkk-1  (Wnt signalling pathway)

Carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder.

recruiting

NCT02495896 sEphB4-HSA in combination with gemcitabine and cisplatin

Ephrin B4 Locally advanced or metastatic gallbladder cancer or cholangiocarcinoma, no prior chemo

recruiting

NCT02128282 CX-4945 in combination with gemcitabine and cisplatin

CK-2 Locally advanced or metastatic cholangiocarcinoma recruiting

NCT02784795 LY3039478 in combination with cisplatin and gemcitabine

Notch Cholangiocarcinoma and pre-screened Notch pathway alterations

recruiting

NCT03027284 Merestinib in combination with cisplatin and gemcitabine

c-Met Locally advanced or metastatic BTC recruiting

NCT03102320 Anetumab ravtansine in combination with cisplatin

Mesothelin Locally advanced, recurrent or metastatic cholangiocarcinoma, mesothelin-expressing

recruiting

Targeted

NCT01766219 CPI-613 Angiogenesis Locally advanced or metastatic cholangiocarcinoma, refractory standard therapies

recruiting

NCT01438554 Pazopanib and GSK1120212 Pazopanib, a Locally advanced or metastatic cholangiocarcinoma ongoing,

44

NCT number

Trial Target (s) Eligibility Status

VEGFR/PDGFR/Raf Inhibitor, and GSK1120212, a MEK

not recruiting

NCT02073994 AG-120 IDH-1 IDH1 gene-mutated cholangiocarcinoma, progression after gemcitabine

ongoing, not recruiting

NCT03144661 INCB062079 FGFR-4 Locally advanced or metastatic cholangiocarcinoma recruiting

NCT03149549 CX-2009 CD166 Locally advanced or metastatic cholangiocarcinoma recruiting

NCT02675946 CGX1321 Wnt signalling Advanced BTC recruiting

Immunotherapy

NCT02632019 Dendritic cell-precision T cell for neo-antigen combined with gemcitabine treatment

Advanced BTC recruiting

NCT03042182 Oral therapeutic vaccine V3-X locally advanced or metastatic cholangiocarcinoma, elevated Ca19.9

recruiting

NCT02443324 Ramucirumab plus pembrolizumab

VEGFR2 (ramucirumab) and PD-1 (pembrolizumab)

Locally advanced, recurrent or metastatic BTC recruiting

NCT02268825 MK-3475 in combination with mFOLFOX6 and celecoxib

PD-1 (MK-3475) and COX-2 (celecoxib)

Locally advanced, recurrent or metastatic BTC ongoing, not recruiting

NCT03095781 XL888 in combination with pembrolizumab

Hsp90 inhibitor (XL888) and PD-1 (pembrolizumab)

Locally advanced or metastatic cholangiocarcinoma, failed at least 1 prior chemotherapy

recruiting

45

46