Precision Thyroid Cancer Surgery With Molecular Fluorescent Guided Imaging (TARGET)

University Medical Center Groningen (UMCG)

Status and phase: Completed; Phase 1

Conditions: Lymph Node Metastases; Papillary Thyroid Cancer

Treatments: Drug: IV adminstration of EMI-137; Device: Spectroscopy; Device: Multispectral Fluorescence Reflectance Imaging

Study type: Interventional

Funder types: Other

Identifiers

NCT03470259

NL62817.042.17

Details and patient eligibility

About

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. 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. The complication rate 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. 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 Surgery (MFGS) is potentially such a diagnostic tool. The administration of NIR fluorescent tracers can increase detection accuracy of cancer and nodal metastatic tissue using macroscopic MFGS. 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. The investigators therefore hypothesize that the GMP-produced NIR-fluorescent tracer EMI-137 (targeting c-Met, peak emission at 675 nm range) might be useful for intraoperative imaging of PTC and nodal metastases. The investigators' aim is to investigate if the administration of EMI-137 is a feasible approach to detect PTC nodal metastases. Ultimately, this method might be useful to improve patient selection for CLND. 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.

Full description

See brief summary

Enrollment: 19 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age ≥ 18 years, eligible for surgery

2. Bethesda VI fine needle aspiration (FNA) thyroid or FNA proven PTC metastasis (primary or recurrence).

3. Scheduled to undergo central and/or lateral lymph node dissection with or without thyroidectomy as discussed in the Multi-Disciplinary Thyroid Board.

4. WHO performance score of 0-2.

5. Written informed consent.

6. Mentally competent person who is able and willing to comply with study procedures.

7. For female subjects who are of childbearing potential are premenopausal with intact reproductive organs or are less than two years post-menopausal:

   • A negative serum pregnancy test prior to receiving the tracer
   • Willing to ensure that she or her partner uses effective contraception during the trial and for 3 months thereafter.

Exclusion criteria

1. Pregnancy or breast feeding
2. Advanced stage thyroid cancer not suitable for surgical resection
3. Medical or psychiatric conditions that compromise the patient's ability to give informed consent
4. Concurrent anticancer therapy (chemotherapy, radiotherapy, vaccines, immunotherapy) delivered within the last three months prior to the start of the treatment
5. The subject has been included previously in this study or has been injected with another investigational medicinal product within the past six months
6. History of myocardial infarction (MI), TIA, CVA, pulmonary embolism, uncontrolled congestive heart failure (CHF), significant liver disease, unstable angina within 6 months prior to enrollment
7. Any significant change in their regular prescription or non-prescription medication between 14 days and 1 day prior to IMP administration.

Trial design

Primary purpose: Diagnostic

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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19 participants in 4 patient groups

EMI-137 0.09mg/kg administration

Experimental group

Description:

Three patients will be once administered with EMI-137 0.09 mg/kg. Thereafter the patient will be observed for an hour. Two hours after injection surgery will be performed and only ex-vivo imaging and spectroscopy will be performed of thyroid glands and lymph nodes with a multispectral Near Infrared Fluorescence (NIRF) camera system and spectroscopy system. After interim analysis will be decided if this dosage group has an adequate tumor-to-background ratio and dose extension will be performed.

Treatment:

Device: Multispectral Fluorescence Reflectance Imaging

Device: Spectroscopy

Drug: IV adminstration of EMI-137

EMI-137 0.13mg/kg administration

Experimental group

Description:

Three patients will be once administered with EMI-137 0.13 mg/kg. Thereafter the patient will be observed for an hour. Two hours after injection surgery will be performed and only ex-vivo imaging and spectroscopy will be performed of thyroid glands and lymph nodes with a multispectral Near Infrared Fluorescence (NIRF) camera system and spectroscopy system. After interim analysis will be decided if this dosage group has an adequate tumor-to-background ratio and dose extension will be performed.

Treatment:

Device: Multispectral Fluorescence Reflectance Imaging

Device: Spectroscopy

Drug: IV adminstration of EMI-137

EMI-137 0.18mg/kg administration

Experimental group

Description:

Three patients will be once administered with EMI-137 0.18 mg/kg. Thereafter the patient will be observed for an hour. Two hours after injection surgery will be performed and only ex-vivo imaging and spectroscopy will be performed of thyroid glands and lymph nodes with a multispectral Near Infrared Fluorescence (NIRF) camera system and spectroscopy system. After interim analysis will be decided if this dosage group has an adequate tumor-to-background ratio and dose extension will be performed.

Treatment:

Device: Multispectral Fluorescence Reflectance Imaging

Device: Spectroscopy

Drug: IV adminstration of EMI-137

EMI-137 0.045mg/kg administration

Experimental group

Description:

If we have a excellent tumor to background ratio ((tumor fluorescence)/(surrounding tissue fluorescence)) in the 0.09 mg/kg group, we will de-escalate back to a 0.045 mg/kg group to evaluate TBR and reduce possible tracer toxicity in a thyroid cancer population with 90% 20 year survival. Three patients will be once administered with EMI-137 0.045 mg/kg. Thereafter the patient will be observed for an hour. Two hours after injection surgery will be performed and only ex-vivo imaging and spectroscopy will be performed of thyroid glands and lymph nodes with a multispectral Near Infrared Fluorescence (NIRF) camera system and spectroscopy system. After interim analysis will be decided if this dosage group has an adequate tumor-to-background ratio and dose extension will be performed.

Treatment:

Device: Multispectral Fluorescence Reflectance Imaging

Device: Spectroscopy

Drug: IV adminstration of EMI-137