A confirmatory, prospective, open-label, single-arm, reader-blinded multi-centre phase 3 study to assess the diagnostic accuracy of Ferumoxtran-10-enhanced Magnetic Resonance Imaging (MRI) and unenhanced MRI in reference to histopathology in newly-diagnosed prostate cancer (PCA) patients, scheduled for radical prostatectomy (RP) with extended pelvic lymph node dissection (ePLND)

The treatment strategy in most cases of cancers is dependent on the staging of
the patient*s cancer according to the TNM (tumour-node-metastases)
classification. A reduction of cancer mortality could be obtained with
appropriate prevention, better and earlier diagnosis and therapeutic progress
induced by a better tool.
Detection of lymph node metastases is very important for correctly assessing
prognosis and planned therapy in patients with pelvic cancers. Computed
tomography (CT) and magnetic resonance imaging (MRI) are used to identify the
lymph nodes but the diagnosis is then based on criteria of size and shape of
the nodes and these are not specific enough to discriminate between metastatic
and non-metastatic lymph nodes. Particularly, normal size lymph nodes with
metastatic involvement are frequently not detected and enlarged inflammatory
lymph nodes cannot be differentiated from metastatic nodes (Ferrucci et al.,
1990). The use of ultrasmall superpara¬magnetic iron oxide (USPIO) such as
Ferumoxtran-10 (Ferrotran®, formerly Sinerem® or Combidex®) as a contrast agent
for MRI could improve this diagnosis.
At present, lymph node metastatic involvement is one of the most important
parameters of the prognosis and one of the indicators in the choice of
different treatments, i.e., surgery, chemotherapy or radiotherapy.
Ferrotran®-enhanced MRI can provide a non-invasive and non-irradiative imaging
tool for accurate N-staging, even in case of normal-sized lymph nodes carrying
micrometastases, in one single MR examination which would complete the
evaluation of primary tumour spread in pelvic cancer patients.
For prostate cancer patients the determination of the extent of the tumour
spread in the lymph nodes is an important information, which cannot be answered
sufficiently with current imaging technology.
The clinical studies performed with Ferumoxtran-10 clearly showed that
Ferumoxtran-10-enhanced MRI offers higher diagnostic performance than
conventional MRI, and is sensitive and specific for the detection of lymph-node
metastases (Wu et al., 2011). Also, the technique shows a better sensitivity
than any other non-surgical technique available. Ferumoxtran-10 enhanced MRI
also provides a very high negative predictive value for the lymph nodes present
in the surgical area of lymphadenectomy as well as outside this area.
Thus Ferumoxtran-10-enhanced MRI is expected to improve prostate cancer
N-staging and to provide high sensitivity and specificity which are not reached
by the conventional MRI (sole measurement of node size of the lymphatic chains
draining the prostate gland).
This pivotal study is designed to achieve marketing authorisation for
Ferumoxtran-10, taking into account the flaws in design and evaluation of MRI
scans of the former phase 3 study (ALS 44-003-A) which was withdrawn from
marketing application by Guerbet in 2007. The previous study failed to
demonstrate a consistent and statistically significant benefit in sensitivity
and failed to confirm non-inferiority with regard to specificity due to
inconsistent results between readers of the MRI scans.
Saving Patients* Lives Medical B.V. has decided to attempt a new marketing
authorisation application based on a new and better-designed phase 3 study,
using up-to-date equipment.
Taking into account previous recommendations of the EMEA scientific advice as
well as the recent BfArM scientific advice on 12-Apr-2018, Saving Patients*
Lives Medical B.V. has carefully designed the planned pivotal Phase III study
SPL-01-001 and believes that with this new fully blinded centralised reading of
the MR images, the study can prove the diagnostic performance of
Ferumoxtran-10, within the context of a new MA submission.

Primary Objectives
1. To confirm superiority of Ferrotran®-enhanced MRI over unenhanced MRI in
sensitivity to detect metastases in normal size pelvic lymph nodes in using
histopathology after lymph node dissection as established reference method
(Gold Standard).
2. To confirm non-inferiority of Ferrotran®-enhanced MRI compared with
unenhanced MRI in specificity with a margin of 15% in using histopathology
after lymph node dissection as established reference method (Gold Standard).

Secondary Objectives

1. To confirm non-inferiority of Ferrotran®-enhanced MRI compared with
unenhanced MRI in sensitivity with a margin of 15% to detect any pelvic lymph
node metastases in using histopathology after lymph node dissection as
established reference method (Gold Standard).
2. To evaluate the number and sites (gross- and sub-regions) of affected lymph
nodes removed and not removed by ePLND comparing the unenhanced MRI at
follow-up and the pre-surgery MRIs (unenhanced and Ferrotran®-enhanced).
3. To assess the clinical safety and tolerability of a single slow drip
Ferrotran® infusion.
4. To assess the impact of Ferrotran®-enhanced MRI on the patient management
plan.

It will be a confirmatory, prospective, open-lable, single-arm, reader-blinded,
multi-centre phase 3 study. For an individual patient, the total duration of
the study, including screening period, will be 9 to 18 weeks. the study as a
whole will take about 1.5 tot 2 years, depending on the recruitment.

Screening
Informed consent is to be obtained before any screening-related assessments
will be conducted.
Patients will be screened for eligibility for the study from Day -28 and up to
one day (Day -1) before treatment with Ferrotran®. Eligibility criteria include
the availability of histologically confirmed diagnosis, tumour staging and PSA
assessment as part of the standard of care.
After signing the informed consent form, patients will undergo the following
screening investigations and procedures:
• Review of inclusion/exclusion criteria (incl. information on histologically
confirmed diagnosis, tumour staging and PSA level as taken from standard of
care investigations, completed Briganti nomogram)
• Demographics & medical history (incl. concurrent conditions and concomitant
medication)
• Physical examination
• Vital signs
• 12-lead ECG
• Safety laboratory (haematology, biochemistry and urinalysis)
• Concomitant medication (up to 4 weeks prior to Day 0)
• Baseline findings
• Unenhanced/native MRI of the pelvic lymph nodes will serve as Baseline MRI
scan, unless available from previous work-up (in any case, not conducted any
longer than 28 days before treatment and in compliance with parameters set out
in the imaging manual).
• Definition of a clinical patient management or treatment plan by completion
of a pre-defined questionnaire based on all available clinical information
(except Ferrotran®-enhanced MRI).

Treatment (Day 0)
On Day 0, the eligibility will be confirmed as per the screening results.

Pre-dose:
Assessments performed on Day 0 at pre-dose will include:
• Physical examination
• Vital signs
• Concomitant medication
• Baseline findings
• Weight for the calculation of Ferrotran® dose
Baseline results are findings from physical examination and vital signs
recorded on Day 0 pre-dose. Baseline results for 12-lead ECG and safety
laboratory parameters will be taken from screening investigations.

Administration of Study Drug (Time-point 0):
A weight-adjusted dose of Ferrotran® will be slowly infused IV over
approximately 30 minutes at an infusion rate of max. 4 mL/min.
The solution must be administered within 24 hours after dilution.
Patients must be closely monitored by study personnel for 60 minutes from the
start of the infusion for any allergic or infusion-related reactions as well as
other AEs.
In case of any AE the infusion must be stopped immediately and appropriate
action must be taken. If there are only mild AEs (e.g. back pain, flush) the
infusion can be continued at a lower rate after resolution of the symptoms.

Time-point 4 Hours (±15 Minutes) after End of Infusion:
At 4 hours (*15 minutes) after the end of the Ferrotran® infusion, but before
discharge, the following will be assessed:
• Vital signs
• Safety laboratory (haematology, biochemistry and urinalysis)
• 12-lead ECG
• Concomitant medication
• Adverse events

Imaging on Day 1 (24 to 36 Hours after End of Infusion):
• Ferrotran®-enhanced pelvic MRI (searching sequence only, no characterisation
of lymph nodes)
• Adverse events
• Concomitant medication

Safety Follow-up (Day 7 and/or One Day before or on Day of Surgery)
The safety follow-up assessments will be performed on Day 7 for all patients.
For patients with a scheduled surgery after Day 7 until Day 42, the following
assessments will be repeated either one day before or directly on the day of
surgery:
• Physical examination
• Vital signs
• 12-lead ECG
• Safety laboratory (haematology, biochemistry and urinalysis)
• Concomitant medication
• Adverse events
In the time period after the Ferrotran®-enhanced MRI evaluation by local
readers, but before RP/ePLND, the clinical management or treatment plan will be
revised by completing a pre-defined questionnaire based on all available
clinical information including Ferrotran®-enhanced MRI.

Surgery (Day 7 to Day 42)
Before surgery, MRI scans will be read by local readers who are trained to
harmonise their reading performance in a standardised manner. Results from the
reads of the local readers have to be available before surgery and will be
communicated in time to the urology surgeons so that they can schedule the
surgery thereafter. Results from MRI scans in multiple views (axial, sagittal,
coronal), including a MR-angiography sequence will serve as a diagnostic tool
to guide the lymph node dissection.
All medications and therapies that were given as part of routine procedure for
the surgery will be reported within the frame of this clinical study in
cumulative rather than individual doses per generic drug.
The dissected tissue containing the lymph nodes will be collected per defined
region in at least 8 vials with a fixating agent. After fixation, the tissue
will be transferred to the histopathologist.
The blinded off-site reading will be done independently of surgery.
The pre-scheduled radical prostatectomy with the ePLND will be performed as per
standard of care.

EoS Visit (8±1 weeks after Surgery)
At 8 (±1) weeks after the prostatectomy with ePLND, a PSA measurement and a
native, unenhanced MRI of the pelvic region will be performed for evaluation of
secondary efficacy endpoints, i.e. identification of metastatic lymph nodes
that have been overlooked and thus were not removed during the ePLND.
In addition, blood and urine samples will be collected to assess long-term
safety of Ferrotran®.
Any treatment (radiation, chemo-, immuno- or hormonal therapy) which might be
scheduled as standard of care after the surgery shall be omitted until the FUP
MRI was performed. Thus, if the investigator deems such excluded treatment
necessary, s/he should aim to commence the treatment AFTER the unenhanced FUP
MR imaging. In these special cases, the unenhanced FUP MRI and the long-term
safety lab can be brought forward (if necessary) and will not have to be
scheduled 8 (±1) weeks after the surgery.
Any AEs that will be recorded during the FUP-MRI are considered (MRI or blood
sampling)-procedure-related, unless an abnormal safety lab value constitutes an
AE.
The purpose of the FUP MRI is to reveal any lymph nodes that have possibly been
overlooked during surgery.

Not applicable

Benefit-Risk-Assessment
More than 1660 patients or healthy volunteers have received Ferumoxtran-10 in
clinical studies. The safety profile of Ferumoxtran-10 is well known and the
product can be considered safe with a good tolerability. The safety data pooled
over all 37 clinical studies that were conducted with Ferumoxtran-10 so far,
confirm that whatever the rates compared (number of AEs, or patients with at
least one AE), tolerance in the Ferumoxtran-10 group was similar to that of the
placebo group. 386 (23.2%) of the 1663 study participants who received
Ferumoxtran-10 reported at least one AE, versus 19 (25.3%) of the 75 patients
who received placebo.
The indication for Ferumoxtran-10-enhanced MRI in the diagnosis of lymph node
metastases in MRI, is justified in view of the major therapeutic consequences
associated with better staging of prostate cancer patients, because this
technique provides a non-invasive and non-irradiative imaging tool which helps
in the N staging of prostate cancer patients, and which performs better than
current imaging modalities in prostate cancer.
Indeed, in the case of pelvic cancers, such as prostate, bladder and uterus
cancers, surgery is currently considered the only method capable of excluding
metastatic spread to the lymph nodes that is not without complications, or even
mortality.
Thus, Ferumoxtran-10-enhanced MRI would help to decrease the number of patients
unnecessarily undergoing a radical surgery (prostatectomy) and would provide a
non-invasive and non-irradiative imaging tool to enhance detection of malignant
lymph nodes (the technique shows a better sensitivity than any other
non-surgical technique available). Ferumoxtran-10-enhanced MRI also provides a
very high negative predictive value for the lymph node present in the surgical
area of lymphadenectomy as well as outside this area.
This would allow the patient to benefit for the best treatment according to
his/her status, and to avoid an invasive surgery and a long surgical procedure.
Furthermore, it is fair to say that Ferumoxtran-10-enhanced MR generates many
fewer false negative patients than other imaging modalities with respect to
lymph node metastases detection, and as many or more false positive patients,
and that both the false negatives and the false positives produced by this
technique will decrease in the future in parallel with advances in MR
technology. Such advances are currently under way with optimization of the
sequences that improves spatial resolution in the pelvic wall area as well as
in the para-aortic and para-metrial tissues for instance; also with high field
MRI (3T). It should also benefit from the expertise that needs to be acquired
(detection of lymph nodes and recognition of these structures as such, and
signal assessment on Ferumoxtran-10-enhanced images to differentiate benign
from malignant nodes). This may be done by providing radiologists with
appropriate training in terms of MR sequence parameters and planes, lymph node
anatomy, appearance of benign and malignant lymph node using
Ferumoxtran-10-enhanced images. An appropriate educative tool could be a
learning set of images illustrating the most representative cases.
According to Barentsz et al. [Barentsz, 2005; Barentsz et al., 2007]
Ferumoxtran-10 has an important clinical impact, as the diagnosis will be more
precise and less invasive to obtain. Subsequently, this will reduce morbidity
and health care costs.

General Safety
From the ample safety data on Ferrotran® gained so far from more than 1660
study subjects (healthy volunteer or patient), it can be concluded that the AEs
most frequently occur within a short period of time after the infusion.
Most hypersensitivity reactions, especially after first administration of
Ferrotran®, occurred immediately or within an hour after administration,
although the possibility of delayed reactions up to several days after the
infusion cannot be completely ruled out.
The most frequently reported AE after Ferrotran® infusion was back pain. In 50%
of the events, back pain began within the first 5 minutes after administration
and resolved before the end of the infusion. The occurrence of back pain can be
reduced by infusing Ferrotran® at higher dilutions and lower infusion rates.
The great majority of the first observed symptoms consisted of hypersensitivity
reactions (merging pruritus, urticaria, rash and erythema), resembling type I
allergic reactions as regards their clinical characteristics. These symptoms
usually occurred very rapidly, during infusion, and led to temporary or
definitive discontinuation of the infusion in a number of cases. Other symptoms
(*flushing* and *feeling hot*), when reported with no associated allergic-like
events, could correspond to reactions such as those classified as *infusion-
related reactions*, not being specifically linked to an underlying allergic
physio-pathological mechanism.
The incidence of *chest pain* was very similar between the Ferrotran® group
(1.4%) and the placebo group (1.3%), and the available data do not provide
sufficient information for discussing their physiopathology.
The incidence of *hypotension* or *blood pressure decrease* was very low: 12
AEs (0.7%), of which 3 were reported to be serious and considered to be related
to Ferrotran®.
Medical supervision for 60 minutes from the start of the infusion is required
particularly because of the potential for severe allergic or infusion-like
reactions. Resuscitation material (oxygen equipment, adrenaline, antihistamines
and corticosteroids) must be available during administration of the product to
treat such reactions. Most of these reactions occur immediately or within an
hour after the start of the infusion and cannot be predicted. Their mechanism
is not dose-dependent. If such reactions occur, the infusion must be stopped
immediately and appropriate treatment must be administered.
A risk of hypersensitivity reactions may exist even when Ferrotran® is
administered for the first time. Most hypersensitivity reactions occur
immediately or within an hour after Ferrotran® infusion. However, the
possibility of delayed reactions, occurring up to several days after the
infusion, cannot be excluded. Hypersensitivity reactions can be more severe in
patients treated with beta-blockers, particularly in patients with bronchial
asthma. These patients may be refractory to standard treatment of
hypersensitivity reactions with beta-agonists. Patients with a history of
hypersensitivity, including allergy to an iodinated contrast agent, should be
carefully monitored, as the risk of adverse reactions, particularly allergic
reactions, is increased in these patients.
In case of back pain, the infusion must be stopped and the patient must be kept
under medical surveillance until the symptoms resolve. The administration of
Ferrotran® can then be continued under medical supervision by reducing the
infusion rate.
In case of extravasation, the severity of the lesions should be assessed and
adapted treatment implemented.
Another aspect that should be considered is that between Day 7 and Day 42 of
the planned study, the pre-planned radical prostatectomy with ePLND will be
performed. It cannot be ruled out that this major surgery is associated with
several AEs. This might lead to a bias with regard to further results of safety
assessments and AE monitoring performed after the surgery and render any
assessment of relationship of the AE to the Ferrotran® infusion not verifiable.
During a surgery like RP with ePLND considered here for the prostate cancer
patients, the blood loss or transfusion amounts are in the range of 0.5 L to >1
L; i.e. approx. 10% to >20% of the entire blood volume of 4-6 L, will be
exchanged. The iron content in blood is around 1 g/L and hence 0.5 to >1 g will
be lost/exchanged during a surgery. This is about 3-5-fold the total amount of
Ferrotran® administered.
Since the bleeding will cause major changes in the entire iron metabolism and
also all iron related blood parameters, it seems impossible to measure the
impact of Ferrotran® infusion on iron and other parameters in the blood during
and after the surgery. Additionally, all other parameters such as the
inflammation markers will of course also change considerably after the surgery.

Iron Overload
It is well known that the magnetic resonance signal in the lymph nodes returns
to baseline about 7 days after Ferrotran® infusion because the iron contained
in Ferrotran® is incorporated into the body*s iron store and is progressively
found in the red blood cells (haemoglobin). Like endogenous iron, it is
eliminated very slowly since only 16% to 21% of the iron injected is eliminated
after 84 days via the faeces (urinary excretion negligible < 1%). It is
noteworthy that a single dose of Ferrotran® contains less iron than a single
unit (200 mL) of whole blood.
The plasma elimination half-life in humans is 21 to 30 hours (mean: 26.6 hours)
in humans and is not dose-dependent. The volume of distribution is between 2.6
and 3.71 (mean: 2.8 L), which is equivalent to the plasma compartment. The
total clearance is between 0.018 and 0.027 L/day/kg (mean: 0.0022 L/day/kg).
Moreover, the magnetic resonance signal in Ferrotran®-enhanced MRI scans
returns to baseline about 7 days (lymph nodes) and 1-2 months (liver) after the
administration of Ferrotran®, indicating the uptake of the iron nanoparticles
into the mononuclear phagocytic system and their progressive biodegradation
(loss of magnetic properties of the nanoparticles) and incorporation into the
whole body iron system.
Intravenous iron has been used for more than 10 years to treat iron deficiency
anaemia in patients unable to absorb oral iron preparations. The preparation
Ferinject 50 mg (iron carboxymaltose) is also an iron-sugar complex, and
received EU marketing authorisation in 2007. According to the SmPC, patients
with iron deficiency anaemia usually receive intravenous doses of up to 1000 mg
iron per week over longer periods of time.
As iron is expected to be incorporated into the metabolism, and is an essential
trace element, the iron itself at physiological doses is not linked to any
safety concerns, but the intravenous administration was shown to be accompanied
by immediate hypersensitivity reactions in some cases.
Therefore, the EMA Committee for Medicinal Products for Human Use (CHMP) issued
a review of intravenous iron-containing medicines used to treat iron deficiency
and anaemia in 2013, and concluded that the benefits of these medicines are
greater than their risks, provided that adequate measures are taken to minimise
the risk of allergic reactions (EMA recommendations EMA/579491/2013).
Oral iron preparations such as ferro sanol® duodenal are given in doses of 100
mg per day for the prevention and treatment of iron deficiency, and are
available over-the counter. These preparations are taken daily over months or
years, without any safety concerns. Intravenous iron is given at doses of 1000
mg per week over long periods of time without any safety concerns except the
immediate risk of hypersensitivity reactions.
None of the total 1663 study subjects who have received Ferrotran® infusion
experienced any AEs or other safety problems related to the iron load after
Ferrotran® infusion. Patients with disorders associated with iron overload or
disturbances in the utilisation of iron (e.g., haemochromatosis,
haemosiderosis, chronic haemolytic anaemia with frequent blood transfusions)
will be excluded from participation in the study.
Despite the fact, that during surgery the patient might suffer a significant
blood loss, SPL has decided to assess long-term safety at 8 weeks after surgery
taking further blood and urine samples.

Conclusions
The dose of 203 mg Fe for a 78 kg person in a single infusion of Ferrotran® is
about twice the long-term daily dose of OTC oral iron supplements, about one
fifth of the regular 1000 mg weekly infusions of intravenous iron for the
treatment of iron deficiency anaemia, and between 0.0058% and 0.0041% of the
total body iron. The amount of iron administered within the study is even below
or in the range of normal iron uptake by food.
Therefore, this dose is considered to be well within the range of physiological
iron supplementation, and a safety follow-up of one week is considered to be
more than adequate.