Detection of Lymph Node Metastases in Papillary Thyroid Cancer using EMI-137 enhanced Molecular Fluorescent Guided Imaging: a multicentre feasibility and safety study

Almost 50 % of papillary thyroid cancer (PTC) patients have central lymph node
metastases (CLNM), which are associated with a high risk of persistent or
recurrent disease. Approximately 5-20% of patients eventually develop
loco-regional recurrent disease. However, the practice of performing a
prophylactic central lymph node dissection (PCLND) routinely remains
controversial. The proponents argue that without a PCLND, PTC patients with
positive lymph nodes have an increased risk of local recurrence, and postponed
node dissection leads to with 5-6 fold higher risk of morbidity. If performed,
PCLND in clinical node negative patients increases staging to pN1 in more than
50% of the cases without increasing survival. To prevent one reoperation, 20
PCLNDs are needed. The complication rate (permanent hypo-parathyroidism and
recurrent nerve damage) in PCLND is lower when compared to a technically
challenging re-exploration in recurrent disease, with reported incidences of
0.6% and 7.3-20%, respectively. Opponents of routine PCLND point out the lack
of randomized clinical trials and object to treatment-induced
hypo-parathyroidism and recurrent nerve damage for the N0 patients. The
national protocol in the Netherlands advises based on a very low grade of
evidence to perform a CLND in case of males aged over 45 yrs, large or
multifocal tumours, or extra capsular growth. Currently, no diagnostic tool is
available which reliably identifies these patient categories. Therefore, there
is a clear need for novel diagnostic imaging modalities that overcome this
issue. Molecular Fluorescence Guided Imaging (MFGI) is potentially such a
diagnostic tool. The administration of NIR fluorescent tracers can increase
detection accuracy of cancer and nodal metastatic tissue using macroscopic
MFGI. Therefore, we aimed to identify a GMP-produced near infrared (NIR) tracer
that potentially has a high target-to-background ratio in PTC compared to
normal thyroid tissue. Tyrosine-protein kinase Met (c-Met) is significantly
upregulated at the protein level in PTC compared to normal thyroid tissue. We
therefore hypothesize that the GMP-produced NIR-fluorescent tracer EMI-137
(targeting c-Met, peak emission at 675 nm range) might be useful for imaging
of PTC and nodal metastases. Our aim is to investigate if the administration of
EMI-137 is a feasible approach to enable detection of PTC and nodal metastases.
Eventually, we might also be able to visualize multifocality, more selective
lateral neck dissections and asses residual tissue after thyroidectomy.
Ultimately, all of these strategies may reduce overtreatment, morbidity, and
costs while maintaining the same or better effectiveness with a lower
recurrence rate and improved quality of life.

2.1 Primary Objective
- To determine the optimal dose of the c-Met targeting NIRF tracer EMI-137 for
an adequate tumor-to-background ratio (TBR) in PTC lymph node metastases.

2.2 Secondary Objectives
- To obtain information on safety aspects of administration by registration of
conjugate integrity, side effects, adverse events (AE), serious adverse events
(SAE) and suspected unexpected serious adverse reactions (SUSAR).
- To determine the feasibility of ex-vivo spectroscopy measurements of PTC and
lymph nodes for quantification of the fluorescence signal of EMI-137.
- To correlate and validate ex-vivo fluorescence signals with histopathology
and immunohistochemistry.
- To evaluate the distribution of EMI-137 on a microscopic level.
- To quantify sensitivity and specificity of EMI-137 for PTC and nodal
metastasis in order to make a power size calculation for a possible subsequent
diagnostic accuracy study.
- To correlate the combined results of histopathology and ex-vivo fluorescence
imaging with preoperative imaging results.

The study is designed as a Phase I study for patients with confirmed PTC, for
which we will determine a safety profile of the c-Met targeted tracer according
to Common Terminology Criteria for Adverse Events (CTC) 5.0 criteria by
implementing a dose-finding method. Additionally, we will perform ex vivo
fluorescence imaging (white-light (WL), fluorescence (FL), overlay) and
spectroscopy of the thyroid gland, lymph node metastases and normal tissue at
predefined time-points. The aim is to identify the dosage group with the best
tumor-to-background ratio (TBR) in lymph node metastasis. Based on an earlier
NIR fluorescence endoscopy study using the same tracer EMI-137 (targeting
c-Met), we will start the Phase I study with a classical 4x3 scheme. 0.045
mg/kg (n=3), 0.09 mg/kg (n=3), 0.13 mg/kg (n=3), and 0.18 mg/kg (n=3). We will
start with the dosing 0.09 mg/kg, increase to 0.13 mg/kg and finish with a
dosage of 0.18 mg/kg. Following completion of all dosage groups an interim
analysis will be performed to assess safety and the dosage that provides the
optimal TBR in nodal metastasis. A maximum concentration level of 0.18 mg/kg is
accepted as the upper limit, as patients with PTC have an excellent long-term
prognosis. A dose limiting toxicity (DLT) of one per group is accepted. After
obtaining the safety profile of all three dosing groups, we will then analyze
the TBR for each dosing group. The TBR will be calculated as follows: TBR =
(tumor fluorescence)/(surrounding tissue fluorescence). Should the 0.09 mg/kg
group have an excellent TBR we will deescalate back to a 0.045 mg/kg group
(n=3) to evaluate TBR and reduce possible tracer toxicity. If the TBR
difference between dosage groups is not sufficient, the dosage groups can be
extended with 3 additional patients per group followed by an interim analysis.
Finally, for the dosing cohort with the most optimal TBR we will expand this
group to a total of 10 patients to have a minimal significant data set which
will serve for a subsequent diagnostic accuracy study. If two dosing groups
have a similar TBR as calculated from the second interim analysis, both dosage
groups can be extended to a total of 10 patients. Should the safety profile or
dosage in terms of optimal TBR not be sufficient, we abandon the tested tracer.

Tracer administration: EMI-137 will be administered 2 hours prior to incision
by infusion and patients will be monitored for potential side effects. Dosages
administered throughout the study will be either 0.045, 0.09, 0.13 or 0.18
mg/kg.

Specimen related study protocol: The excised specimens will undergo
histopathological assessment according to the current standard used in clinical
cancer care. Diagnosis, tumor size, multi-focality, margins and selected
histological features necessary for clinical decision making will be provided
by the pathologist. Next to this, ex vivo imaging and spectroscopy will be
performed on the excised specimen. Ex vivo fluorescence images and spectroscopy
data will be related to histopathological data (H&E and additional
immunohistochemical stainings such as c-Met) and the location of the
fluorescent lesions.

Burden-extra procedures: 1) Intravenous administration of EMI-137

Risks: None of the preclinical toxicology and safety pharmacology studies
performed with EMI-137 identified any specific adverse safety signals relevant
to the injection of EMI-137 in humans. A possible SAE for injection of EMI-137
could be an allergic and/or anaphylactic reaction, therefore a crash cart with
medication to convert an anaphylactic reaction will be present at the site of
the injection.

Benefit: Patients will have no direct benefit from this study. Surgery will be
planned as usual. During surgery, no decisions will be made based on the
fluorescence imaging. The benefit of this study will be the assessment of
safety and the establishment of usefulness of EMI-137 during surgery to
identify PTC and central lymph node metastases. Clinical experience will be
obtained with fluorescent labeled tracers during surgery PTC. The results of
these types of study will be at least beneficial for other patients with cancer
in the future.