To analyse the relation between oncogenic signaling and the tumour immune contexture in patients with advanced melanoma and pancreatic cancer with resistance to (immuno)therapy, aiming to identify targets and approaches for future (combination)…
ID
Source
Brief title
Condition
- Other condition
- Skin neoplasms malignant and unspecified
Synonym
Health condition
maligne neoplasmata pancreas
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this study is the number of patients for whom both
tumour WGS and immune profiles could be adequately obtained.
The co-primary endpoint is the frequency of *inflamed* vs *immune
excluded/desert* tumours (based on tumour infiltrating immune cells) in
patients with
o NRAS/KRAS mutant vs wild-type tumours
o High vs low mutational tumour load
Secondary outcome
Secondary endpoints of this study are:
• The percentage of patients with evaluable tumour DNA, RNA and (tissue and
peripheral) immune profiles
• The frequency of (potentially) actionable genomic alterations, including but
not limited to HER2 amplification and mutation, HRD signature, Microsatellite
instability, gene fusions
• The relation between tumour and peripheral immune profiles
• The percentage of patients with melanoma with evaluable (phospho)proteomic
profiles
• A database of all (coded) data and biobank of all (remaining) tissues and
PBMCs obtained in this study.
Background summary
The introduction of immune checkpoint inhibitors (ICI) as anticancer therapy
have marked a therapeutic renaissance for patients with advanced melanoma and
several other types of cancer. Still, not all patients benefit (long term) from
current ICI-based cancer immunotherapy and, sometimes severe, immune related
adverse events (irAE) occur frequently. Acquired and intrinsic resistance to
immune checkpoint blockade is a major problem. Its underlying mechanisms are
complex and incompletely understood. Genetic aberrations inherent to cancer
development may directly or indirectly contribute to ICI resistance.
Tumour profiling based on whole-genome sequencing (WGS) may identify these
aberrations, which sometimes represent molecular targets for which approved
targeted therapies are available. Besides on tumour mutational load, WGS may
potentially inform immunotherapy response or resistance as certain oncogenic
driver mutations, e.g. KRAS, are linked to immune suppressive mechanisms that
shape the tumour immune microenvironment and immune response.
Linking WGS profiles with immune status may thus widen the scope of therapeutic
targets to include specific immunotherapy options besides, or in support of,
immune checkpoint blockade. It is of interest to explore this option and obtain
proof of concept in an immunogenic vs. poorly immunogenic tumour type, more
specifically in melanoma vs pancreatic cancer. In the latter tumour type
(chemo)resistance is probably related to low mutation levels resulting in lack
of tumour lymphocyte infiltration and a tumour microenvironment (TME) with an
abundance of non-cancer cell components.
Study objective
To analyse the relation between oncogenic signaling and the tumour immune
contexture in patients with advanced melanoma and pancreatic cancer with
resistance to (immuno)therapy, aiming to identify targets and approaches for
future (combination) treatment.
Study design
Investigator-initiated observational tumor profiling study with a one-time
invasive procedure (biopsy protocol);
Patients undergo tumor biopsy and venipuncture once.
Study burden and risks
Patients will undergo a extra tumour biopsy once during a tumour biopsy
procedure done performed as part of standard treatment of which in our opinion
the possible benefits - tumour WGS profiling to obtain information on potential
therapeutic targets and potential access to off-label molecular targeted
treatment - outweigh the potential risk for individual patients. The procedure
will encompass biopsy of a safely accessible metastatic lesion and will be
performed according to routine (diagnostic) procedures. Generally, these
biopsies will require CT- or ultrasound (US) guidance. Although frequently
uncomfortable, tumour biopsy is generally safe and well tolerated with standard
precautionary (including local anaesthetics) measures. For US-guided liver
biopsies, there is a very small chance of bleeding. CT-guided lung biopsies
bear the risk of (a small) pneumothorax which generally does not require
intervention. As a whole, this protocol may significantly contribute to
improved understanding of ICI resistance and the relation between the
(oncogenic) signalling and immune context in patients with ICI resistant
tumours.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
1. Diagnosis of locally advanced or metastatic cutaneous/mucosal melanoma or
pancreatic cancer, meeting the following characteristics:
a. Melanoma
i. Patients with histologically proven locally advanced or metastatic melanoma
(stage IV), with intrinsic or acquired resistance to treatment with immune
checkpoint inhibition (anti-PD1 antibody +/- ipilimumab)
ii. Patients with locoregional or distant recurrence either during, or within 3
months after completion or discontinuation of (neo)adjuvant anti-PD1-based
immunotherapy for stage III melanoma.
b. Pancreatic cancer
i. Patients with histologically proven metastatic pancreatic cancer with
progression under or after standard first-line chemotherapy (FOLFIRINOX or
gemcitabine/nab-paclitaxel).
2. Patients must be willing and able to provide written informed consent and be
willing and able to comply with the study protocol.
3. Patients must be >=18 years of age.
4. Metastatic or locoregional lesion of which a tumour needle biopsy can be
safely obtained according to routine clinical practice.
Exclusion criteria
Patients with metastatic or locally advanced lesions which are not considered
to be technically and/or safely biopsied
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL82542.029.22 |