Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04289961 |
| Other study ID # |
18_DOG03-436 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
June 12, 2019 |
| Est. completion date |
April 6, 2023 |
Study information
| Verified date |
August 2023 |
| Source |
The Christie NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is a research study in which bio-specimens (whole blood, plasma and serum from
peripheral circulation and portal vein) will be collected from patients with pancreatic
adenocarcinoma for translational research. These samples will be used for (but not limited
to) identification and characterisation of blood-borne biomarkers at the genomic and protein
expression level. Examples of such biomarkers are circulating tumour cells (CTCs), CTC
clusters and circulating DNA (which can be tumour derived, or from unaffected/normal cells).
CTC-enriched blood samples may also be used to generate CTC-derived tumour explant (CDX)
models in immunocompromised mice in order to produce suitable disease models in which to test
novel therapies and identify new molecular targets. In addition, permission will be sought
from study participants for the research team to access clinical information from medical
notes to aid in determining the clinical relevance of biomarkers identified during the course
of this study. Validated biomarkers are anticipated to be used in designing future
biomarker-directed clinical trials in these disease groups.
Description:
Pancreatic Ductal Adenocarcinoma (PDAC) presents an urgent medical need. Approximately 9000
new cases of pancreatic cancer are diagnosed every year in the United Kingdom (UK) and
worldwide it is projected to become the second most common cause of cancer related death by
2030. Currently the diagnostic pathway starts with pancreatic protocol Computed Tomgraphy
(CT) scan which demonstrates sensitivity of 90% and specificity of 99% in diagnosis of
pancreatic cancer. Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET)
can assist with ambiguous masses. Despite the high sensitivity and specificity of imaging
modalities, definitive diagnosis is routinely obtained only by endoscopic ultrasound
(EUS)-guided fine-needle aspiration (FNA). During this procedure four "passes" (biopsies) on
average are required to obtain sufficient tissue for diagnosis.
Patients usually present with locally advanced or metastatic disease and are offered standard
of care chemotherapy, which has only a limited impact on overall survival. Consequently the
5-year overall survival (OS) is only 2% with no significant improvement over the last 40
years. Approximately only 20% of the patients are eligible for surgical resection which is
followed by adjuvant chemotherapy. However, 66% of these patients will experience local or
distant recurrence, leading to a median overall survival in the range of 28 months. Improved
stratification of patients for existing treatments may thus avoid unnecessary overtreatment
and associated side effects to improve quality of life; conversely, it may also enable
selection for a more appropriate treatment.
A significant reason for the lack of progress in tackling metastatic disease is the poor
understanding of the biology and pathophysiology of metastasis. Studying the biology of PDAC
metastasis is hampered by the fact that it is difficult to obtain tissue from the primary and
metastatic sites. Moreover, serial biopsies following progression during treatment is largely
not feasible, further hindering insight into the mechanisms of development of treatment
resistance. The only easily-accessible blood-borne biomarker that is currently used in clinic
is the serum marker carbohydrate antigen (CA) 19-9. However, its clinical use is limited
firstly by the fact that 5-10% of the population are Lewis blood group negative and do not
express CA19-9. Furthermore it is elevated in non-malignant pancreatic and extra-pancreatic
diseases. Finally, CA19-9 cannot provide information about the genetic landscape that drives
PDAC metastasis.
Metastatic spread is primarily haematogenous whereby tumour cells enter the circulation to
metastasize mainly to the liver and lung. Such tumour cells have been shown to travel either
as single circulating tumour cells (CTCs) or as groups of cells termed Circulating Tumour
Microemboli (CTM). Heterogeneous CTM composed of cells expressing either epithellial or
mesenchymal markers were isolated from patients with pancreatic cancer using a
filtration-based method, the Isolation by Size of Epithelial Tumour cells platform (ISET), in
a study performed at the Christie NHS Foundation Trust. As such, isolation and
characterisation of CTCs and CTM will provide new insight into the underlying biological
dependencies of metastasizing tumour cells and may thus provide opportunities to develop
better and more accurate diagnostic and prognostic assays as well as opportunities to treat
metastatic disease.
Detection and isolation of CTCs and CTM is limited by the fact that they represent very rare
events compared to other cellular elements in the circulation. To this end, methods
exploiting characteristics that differentiate CTCs from blood cells have been developed to
overcome this obstacle. These CTC workflows usually start by enriching CTCs from a blood
sample utilizing either surface markers present exclusively on CTCs, or their unique physical
properties such as size, inertia, dielectric charge and density. Following enrichment, CTCs
are isolated and can be simply enumerated or they are used for more advanced downstream
analysis including genomic, transcriptomic and proteomic analysis as well as in vivo
applications in cell culture and mouse models, with the aim of gaining insight into their
function as metastatic seeds and biomarker development.
In the clinical setting, CTCs can be used to aid decision making. Indeed, enumeration of CTCs
detected by the CellSearch platform has been FDA approved for prognosis and monitoring of
metastatic breast, colorectal and prostate cancer. However, isolation and enumeration of CTCs
in pancreatic cancer has given inconsistent results between studies as to whether CTCs can be
used as prognostic biomarkers. These studies analysed CTCs isolated from peripheral blood.
However, as the main venous drainage of the pancreas is through the portal vein to the liver,
it may be hypothesized that CTCs could be filtered and removed as they pass through the liver
capillaries. Hence, in order to define the biological and prognostic role of CTCs in
pancreatic adenocarcinoma, it is critical to initiate studies with blood isolated from the
portal vein to bypass confounding effects. Indeed, detection of CTCs in portal vein (PV)
blood acquired at operation was recently reported by Bissolati et al.. By obtaining
peripheral vein samples at the same time, this study confirmed that CTC number was greater in
portal compared to peripheral samples and also demonstrated significant correlation between
CTC positivity in portal vein samples and frequency on liver metastasis. However, it failed
to show significant correlation with OS or Disease Free Survival (DFS). PV sampling has been
performed safely; in December 2015 Catenacci et al. reported collection of PV blood from 18
patients with pancreatobilliary cancers by EUS-FNA with no complications during the
procedure. PV puncture has also been previously reported for islet cell transplantation in
patients with Type 1 Diabetes Mellitus. This procedure has low morbidity and also, potential
complications, such as portal vein thrombosis, perihepatic or intraparenchymal hepatic
haemorrhage and haemothorax are reported at a low rate.
During EUS-FNA a curvilinear echoendoscope is advanced to the distal stomach or duodenal bulb
to provide a window of access to a branch of the PV. After verifying venous flow by Doppler
signal, a 19-gauge EUS-FNA needle is advanced transhepatically into the portal vein branch.
With the needle in the portal vein, the stylet is removed and negative-pressure suction is
applied to aspirate blood. A transhepatic approach for portal vein branch access is an
absolute requirement of this technique in order to minimize the risk of bleeding. The
puncture site is monitored under EUS for complications. As tumour tissue will be obtained at
the same time, a potential risk is the introduction of cancer cells into the circulation as
the needle is withdrawn from the tumour. This risk however is circumvented as the route of
the needle into the portal vein would avoid the primary mass.
The primary reason for drug failure in PDAC is the failure to identify predictive biomarkers
for treatment response which would allow enrichment of patient sub-groups most likely to
benefit from an individual therapy. This is in contrast to other major cancer types, in which
advances in development of new cancer therapeutics and resulting improvement in survival
outcomes are mainly due to the use of predictive biomarkers to select patients who will
derive differential benefit from a particular therapeutic agent. Trastuzumab in breast
cancers over-expressing HER-2, cetuximab for KRAS wild-type colorectal cancer, and gefitinib
and erlotinib for Epidermal Growth Factor Receptor (EGFR) mutant non-small cell lung cancer
best exemplify this therapeutic paradigm. By providing greater numbers of CTCs and CTM,
analysis of PV sample will enable studies of their biology as well as development of cell
lines and CDX models to allow identification of novel biomarkers and targets for new
treatments.
Considering current gaps in knowledge of tumour biology of PDAC and the lack of progress in
therapeutics, there is an urgent clinical need to develop a research strategy that will allow
the discovery and validation of new biomarkers in this group of patients, and inform on
biomarker-directed clinical trials to ultimately improve survival. To initiate such a
research strategy, there is a need for systematic, prospective collection and analysis of
blood samples acquired from peripheral and portal vein circulation to identify blood-borne
surrogate tumour markers that will enable physicians to obtain relevant information for
making personalised therapeutic decisions, in a minimally-invasive way.
