MagSNOLL: Magnetic Sentinel Node and Occult Lesion Localisation: A feasibility study using magnetic nano particles for sentinel node biopsy and localization of occult breast cancers.

The MagSNOLL Multicentre Trial is a continuation of two earlier conducted
studies (SentiMAG and MelaMAG Trial). The initial clinical pilot study was
conducted by Chief Investigator, Mr. Michael Douek, at University College
Hospital. Ten patients with newly diagnosed breast cancer scheduled for
sentinel node biopsy were recruited prior to surgery. These patients received a
radioisotope injection and underwent lymphoscintigraphy a day prior to surgery.
On the morning of surgery, they received a subcutaneous injection and underwent
lymphoscintigraphy a day prior to surgery. On the morning of surgery, they
received a subcutaneous injection of a SPIO tracer (Endorem, Guerbet, Paris) in
the MRI Department. Dynamic axillary MRI before and after injection of the SPIO
identified lymphatic tracts and sentinel nodes in 5/6 patients (1 scan failed
for technical reasons).
Under general anesthetic, patients routinely received an intradermal injection
of patent blue dye (Guerbet, Paris). The sentinel nodes were localized using
both a gamma-probe and magnetometer prototype 1. Skin localization with
magnetometer prototype 1 ands the gamma probe were identical. A total of 19
sentinel nodes were resected from 9 patients. Intra-operative localization
using the combined technique was successful in detecting 19/19 (100%) nodes and
using magnetometer prototype 1 alone in 19/19 (100%). Once found by the
surgeon, most sentinel nodes were easily identified as black from SPIO
deposition.

Following the initial pilot study, several challenges were identified,
including interference from large metal objects, the shape of the probe and the
stability of the magnetic field. These were rectified and a second prototype
was developed (prototype II). The Chief Investigator relocated to Guy's
Hospital and a further 43 patients were recruited into an extended phase I/II
trial. The overall ex-vivo SentiMAG Multicentre trial SLN detection rate was
86% (37/43 patients) and was higher in patients who received SPIO more than one
hour prior to surgery (93%, 14/15 patients). Data on the laboratory performance
of the CE-marked SentiMAG was performed successfully on the 6th Decembre 2010.

The principal objective of the study is to determine if the performance of the
new technique (magnetic tracer and magnetometer) is equivalent to the
performance of the standard technique (patent blue dye and radioisotope, wire
localization).

The primary objective of the MRI is to localize the SLN, the secondary
objective of the MRI subprotocol is to determine if MRI can be used as an
non-invasive method for identification of metastasis in lymph nodes.

The MagSNOLL Multicentre Trial is a phase II paired equivalence trial. The
study will be coordinated from Kings's College Londen (Guy's Hospital) by the
Chief Investigator Mr. Michael Douek. The trial aimed to recruit 160 patients.
Patients will receive a radioisotope injection and a intra tumoral Sienna+
injection. In cetres that also participate in the MRI sub protocol, patients
will undergo a pre-operative MRI after the injection of Sienna+. At the Medisch
Spectrum Twente pre-operative MRI scans will be performed depending on the
availability of the MRI scanning slots.

Intra-operatively, patients will receive an intradermal injection of patent
blue (Guerbet, Paris). The occult lesion and all sentinel nodes detected intra
operatively using the the SentiMAG will be excised and sent separately to the
pathology department. Then the standard technique, the gamma probe, is used to
see whether there is activity remained behind. This tissue will be removed and
sent to the pathology department separately. The removed breast tissue will be
checked for the presence of the hydrophilic clip marker, at the radiology
department.

All lymph nodes will be assessed histologically and the nodal status will be
related back to the SLNB detection rate with each technique.
Patients will be followed post-operatively (7-14 days after surgery) to assess
if staining occurs or for any other adverse event. If staining is present,
photographs will be taken. Further follow-up is at 3 months and at 1 year.
Patients will be followed up for a total of 5 years, in accordance with current
local policies.

The Medisch Spectrum Twente and the ZGT will participate the standard protocol
and the MRI sub protocol. As part of the MRI subprotocol, patients will undergo
an MRI scan prior tho the scheduled operation. The scan will take roughly 30
minutes and involves lying down in a tubular scanner. After the intra-tumoral
injection of 0,5ml Sienna+ several scans are performed. The scan may need to be
repeated if the contrast is not yet visible at 2 or 24 hours after the initial
scan, but further injections will not be required.

The operation will be performed as already planned by the surgeon. In addition
to the normal patent blue and radioactive injection, an additional injection of
Sienna+ and placing an hydrophilic clip marker is administered. During surgery,
the sentinel nodes and occult lesion will be detected with the SentiMAG
magnetometer. All excised nodes will be sent seperately to the pathology
department.

As already mentioned in Section E9 of this form, there is a chance of
developing skin discoloration (tattoo) after injection of Sienna+. However,
this is a prevalent problem with the use of blue dye and not with the use of a
magnetic tracer. In previous SentiMAG studies, we used a magnetic dye that is
similar to Sienna+, called Endorem. Injection of Endorem resulted in minimal
skin discoloration in only 6 of 51 patients.

Another potential risk might be the chance of developing adverse reactions to
Sienna+. However, when similar materials to Sienna+ have been injected
intravenously in significantly higher doses, less than 1% of the patients
exhibited adverse reactions, subcutaneous injection and the majority of the
dose is intended to be surgically removed (with the cancer tissue and nodes)
leaving only a small interstitial residue.

Sienna+ has been reviewed and tested as specified in EN 10993-1-2009 based on
specified site of injection and showed no serious reaction after injection.

The great advantage of this method is the detection of the lymph nodes and the
tumor without the use of radio-active substances. This is not only a benefit
for the patients regarding the radiation, but has also logistical and
administrative benefits for the hospital.