Radio guided lymph node dissection in oligo metastatic prostate cancer patients

Patients diagnosed with prostate cancer do not die from the primary tumour, but
from (extended) metastatic disease. One of the first steps towards extended
metastatic disease is the presence of lymph node metastases, which is an
important factor in determining therapy and prognosis. Although historically
all patients with lymph node metastases are considered incurable, research has
shown that patients with only small (<8mm) nodal metastases have a better
prognosis as compared to patients with more extensive involvement . In patients
with only small nodal metastases, therapy with curative intent might be
pursued, e.g. by surgical resection or loco-regional radiotherapy. With
continuously improving opportunities to very selectively treat small numbers of
metastatic sites it is of utmost importance to accurately diagnose the first
signs of oligo-metastatic disease and to define its extent.
Conventional imaging techniques such as CT and MRI are limited in
detecting small lymph node metastases. Consequently, nodal involvement is
detected only through lymph node dissection and research demonstrated that even
standard pelvic lymph node dissection (PLND) may miss lymph node involvement
outside the standard boundaries of the surgical template. Within the Radboudumc
ferumoxtran-10-enhanced MRI (nano-MRI) as well as68Ga/18F-PSMA PET/CT are
innovative techniques which are promising for presurgical diagnosis of limited
nodal disease, especially when used complementary.
However, the biggest challenge we currently face is the surgical
removal of these (small) lymph nodes, to histopathologically validate the
presurgical imaging findings and to treat oligometastatic disease with curative
intent (resection of all identified lymph node metastases). Small suspicious
lymph nodes, deeply embedded in highly vascularised abdominal lipid tissue, may
be difficult to detect during surgery.
When radiolabelled, PSMA ligands can be used as a tracer to identify
prostate cancer metastases. Therefore, we propose a clinical trial to
investigate the feasibility of radio-guided surgery, using a radiolabelled
tumour-targeting tracer (111In-PSMA-I&T) which can be detected by a gamma-probe
during PLND. This technique could potentially aid the surgeon in detecting
(small) lymph node metastasis intra-operatively.

The primary aim of this study is to evaluate the feasibility and safety of
In-111-PSMA I&T radio guided surgery in patients diagnosed with prostate cancer
who are highly suspected of having pelvic lymph node metastasis based on
pre-operative imaging.

The study is a prospective, single arm open label phase I/II study. Patients
with prostate cancer who have a high risk of lymph node metastases based on
PSMA PET/CT and scheduled for PLND (with or without prostatectomy) will be
recruited. Eligible patients will receive an additional nano-MRI to complement
pre-operative imaging. Twenty-four hours before surgery, patients will receive
111In- labelled PSMA-I&T. According standard of care, PLND*s are performed at
the Canisius Wilhelmina Hospital (CWZ) in Nijmegen, through existing
collaboration of the urology departments. During surgery, the surgeon will be
provided with a gamma-probe to detect PSMA expressing lymph nodes in vivo.
Dissected samples will be systematically assessed on tracer accumulation using
the gamma probe in vivo as well as ex vivo. After surgery, the samples will be
scanned in the small animal SPECT/CT and 7T-MRI. After scanning, samples will
be presented to pathologists for pathological analysis according to standard of
care including staining for PSMA expression. At 3 months after surgery,
patients will undergo a PSMA-PET/CT. Up until one year after surgery patients
will be followed according to standard of care-guidelines by 3-monthly
serum-PSA measurements.

Not applicable.

The main burdens and risks for participating patients are summarized below.

Exposure to contrast agents
Investigational product
Radio guided surgery will be performed using the radiolabelled PSMA agent
111In-PSMA-I&T. This product is a composition of the radio-isotope Indium-111
and the ligand PSMA-I&T. The composed product it is a relatively new,
non-registered pharmaceutical, which was first synthesized in 2015 at the
Technical University München (1). No specific toxicity data on the combination
of PSMA-I&T and Indium-111 is available in literature, however clinical studies
in over 30 patients reported no adverse events or complications related to the
administration of the tracer (2, 3). Furthermore, more extensive safety data on
the PSMA-I&T ligand is available. These studies investigated the toxicity and
safety of this ligand when labelled with Gallium-68 and Lutetium-177 in both
tumour baring mice and humans (4, 5). In those studies no clinically
significant adverse effects were found related to the administration of the
ligand.
Considering this data and the fact that the administered activity of
177Lu-PSMA-I&T is significantly higher than the radiation dosage of Indium in
this study-protocol, we do not expect clinically significant adverse effects of
111In-PSMA-I&T. However, we will assess the safety of the tracer in this study
by closely monitoring adverse events, laboratory and vital parameters. Based on
biodistribution and dosimetry studies, the main potential organs at risk are
the kidneys. Low tracer uptake in normal bone marrow and salivary glands may
also be of particular interest, especially in therapeutic applications (higher
activity dosages)(5). Based on these findings, we will assess the potential
bone-marrow toxicity and nephrotoxicity by laboratory tests before and after
administration. For more detailed information on this subject also refer to the
Investigator Brochure on 111In-PSMA-I&T (D1).
The extra radiation dosage which patients receive from the
administration of 150 MBq of this agent is calculated to be an effective
radiation dosage of 8.1mSv. When considering patient category and age, the
relative radiation dosage however will be 1.62mSv (see also the Radiation
Ethics Form, K6). This falls within the scope of other commonly used imaging
modalities in nuclear medicine practice and is considered to be an acceptable
dose according to the International Commission on Radiological Protection
(ICRP).

Non-investigational products: ferumoxtran-10 enhanced MRI
All study participants will undergo a nano-MRI scan prior to their surgery
(PLND). For this nano-MRI scan, patients will receive ferumoxtran-10 contrast
24 hours prior to scanning. Within the Radboudumc there is much experience with
this agent and scanning method, which is carried out on a daily basis. The
burdens of this imaging modality to participants consist of the intravenous
injection of the contrast agents, which will be administered over the course of
60-75 minutes, and the duration of the MRI-scan, for which the patient has to
lie still for approximately 1.5 hours.
Risks related to the contrast agent ferumoxtran-10 are discussed more
extensively in the Investigators Brochure of ferumoxtran-10 (D1). Safety data
is based on 1663 treated patients or healthy volunteers. Forty-four of those
patients (2.6%) experienced SAE*s, from those patients only 7 were considered
related to the contrast agent (an estimated risk of 0.2-0.9%). Serious
potentially allergic reactions have been uncommonly (0.4%) observed during
clinical studies of Ferumoxtran-10. These types of reactions, which included
anaphylactic shock, may very rarely be life- threatening or fatal. They can
occur irrespectively of the dose of Ferumoxtran-10 administered. In the
unlikely event an allergic reaction occurs, anti-anaphylactic medication will
be present in the room where the infusion takes place. Mild adverse events are
implied to be related to infusion speed. Most reported side effects were back
pain (3%), headache (2.5%) and hypersensitivity symptoms (up to 2.5%). These
symptoms were mild to moderate, short (less than one hour after infusion) and
had a favourable outcome. By lowering the infusion speed the risk of adverse
events is limited.

Non-investigational product: 18F/68Ga-PSMA-PET/CT
In patient follow up after surgery, patients will receive an extra
18F/68Ga-PSMA-PET/CT scan. Extensive experience has been gained in research as
well as clinical use of this product. Risks related to the administration of
this contrast agent are discussed extensively in the Investigators Brochure on
18F-PSMA-1007 (D1.3.) and 68Ga-PSMA-HBED-CC (D1.4.). The main burdens of this
imaging modality are related to the extra exposure to ionizing radiation. This
is discussed in the Radiation Ethics Form (K6). The total effective dose for
this scan is 17mSv (18F-PSMA-PET/CT, 68Ga is lower). When considering patient
category and age, the relative radiation dosage will be 3mSv. This falls within
the scope of other commonly used imaging modalities in nuclear medicine
practice and is considered to be an acceptable dose according to the
International Commission on Radiological Protection (ICRP).

Total ionising radiation exposure
The total effective dose (including 111In-PSMA-I&T and 18F/68Ga-PSMA-PET/CT)
for patients when participating in this study is calculated to be approximately
22mSv. Considering our patient population a detriment factor of 0.2 is used to
correct for this category. The relative radiation dosage will be approximately
5 mSv. According to the ICRP guidelines, the risk coefficient for stochastic
effects (fatal cancer) after exposure to radiation at low dose is 5.5% per 1000
mSv(6).

Increased clinic visits
Compared to standard of care, patients who are included in the study protocol
will be subject to increased clinic visits. Two extra trips to the hospital are
incorporated in this study protocol, comprising the injection of intravenous
nano-contrast, nano-MRI scanning and injection of 111In-labelled PSMA-I&T. To
limit discomfort for patients due to the extra visits, we will combine these
procedures in a minimal amount of two visits. Those visits will take place at
the Radboudumc for all participants, during the two days prior to the planned
surgery. The visits will not cause any delay to surgery planning.
Post-operatively, all study related visits will be combined with standard
visits.

Invasive measurements
For safety analysis, blood clearance analysis and the injection of contrast
agents for imaging, participants will be submitted to several intravenous
injections/drips. To minimize invasiveness, we will use infusion systems were
possible. In total, patients will have 3 infusion systems (for both injection
and blood sampling), 2 intra muscular injection (within scope of nano-MRI), 1
venepuncture and 1 intravenous injection.

Other potential burdens
During surgery, urologists will be provided with a gamma-probe to
detect tumour-positive pelvic lymph nodes. Since this is an extension to normal
PLND (without the use of detection devices, standard of care), the usage of the
device might prolong the duration of the surgery up to maximally 15 extra
minutes. Surgeons and operation room staff will be lectured in handling the
probe to minimise delay.

Potential benefits
Participants do not directly benefit from participation in the study.