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
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
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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
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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
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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
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