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

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ClinicalTrials.gov Identifier: NCT03470259
Recruitment Status : Recruiting
First Posted : March 19, 2018
Last Update Posted : June 25, 2018
Sponsor:
Collaborator:
UMC Utrecht
Information provided by (Responsible Party):
Schelto Kruijff, MD PhD, University Medical Center Groningen

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Papillary Thyroid Cancer Lymph Node Metastases Drug: IV adminstration of EMI-137 Device: Multispectral Fluorescence Reflectance Imaging Device: Spectroscopy Phase 1

Detailed Description:
See brief summary

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Detection of Thyroid Cancer and Central Lymph Node Metastases Using EMI-137 Enhanced Molecular Fluorescent Guided Imaging: a Multicentre Feasibility and
Actual Study Start Date : June 20, 2018
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : April 2020


Arm Intervention/treatment
Experimental: EMI-137 0.09mg/kg administration

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.

Drug: IV adminstration of EMI-137
Intravenous administration of the fluorescent tracer EMI-137 approximately two hours before incision. Thereafter will be an observational period of an hour.
Other Name: IMP administration

Device: Multispectral Fluorescence Reflectance Imaging
A multispectral Near Infrared Fluorescence (NIRF) camera system sensitive for EMI-137 fluorescence will be used for only ex-vivo Multispectral Fluorescence Reflectance Imaging (MFRI) of the thyroid gland and/or lymph node compartment.
Other Name: MFRI

Device: Spectroscopy
A spectroscopy system sensitive for EMI-137 fluorescence will be used for only ex-vivo spectroscopy of the thyroid gland and/or lymph node compartment.

Experimental: EMI-137 0.13mg/kg administration

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.

Drug: IV adminstration of EMI-137
Intravenous administration of the fluorescent tracer EMI-137 approximately two hours before incision. Thereafter will be an observational period of an hour.
Other Name: IMP administration

Device: Multispectral Fluorescence Reflectance Imaging
A multispectral Near Infrared Fluorescence (NIRF) camera system sensitive for EMI-137 fluorescence will be used for only ex-vivo Multispectral Fluorescence Reflectance Imaging (MFRI) of the thyroid gland and/or lymph node compartment.
Other Name: MFRI

Device: Spectroscopy
A spectroscopy system sensitive for EMI-137 fluorescence will be used for only ex-vivo spectroscopy of the thyroid gland and/or lymph node compartment.

Experimental: EMI-137 0.18mg/kg administration

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.

Drug: IV adminstration of EMI-137
Intravenous administration of the fluorescent tracer EMI-137 approximately two hours before incision. Thereafter will be an observational period of an hour.
Other Name: IMP administration

Device: Multispectral Fluorescence Reflectance Imaging
A multispectral Near Infrared Fluorescence (NIRF) camera system sensitive for EMI-137 fluorescence will be used for only ex-vivo Multispectral Fluorescence Reflectance Imaging (MFRI) of the thyroid gland and/or lymph node compartment.
Other Name: MFRI

Device: Spectroscopy
A spectroscopy system sensitive for EMI-137 fluorescence will be used for only ex-vivo spectroscopy of the thyroid gland and/or lymph node compartment.

Experimental: EMI-137 0.045mg/kg administration

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.

Drug: IV adminstration of EMI-137
Intravenous administration of the fluorescent tracer EMI-137 approximately two hours before incision. Thereafter will be an observational period of an hour.
Other Name: IMP administration

Device: Multispectral Fluorescence Reflectance Imaging
A multispectral Near Infrared Fluorescence (NIRF) camera system sensitive for EMI-137 fluorescence will be used for only ex-vivo Multispectral Fluorescence Reflectance Imaging (MFRI) of the thyroid gland and/or lymph node compartment.
Other Name: MFRI

Device: Spectroscopy
A spectroscopy system sensitive for EMI-137 fluorescence will be used for only ex-vivo spectroscopy of the thyroid gland and/or lymph node compartment.




Primary Outcome Measures :
  1. The feasibility of Molecular Fluorescence Guided Surgery using EMI-137 [ Time Frame: From tracer administration until after data analyses which will take up to 1.5year ]
    To determine the optimal dose of the c-Met targeting NIRF tracer EMI-137 for an adequate TBR in PTC lymph nodes metastases using 3, and possibly 4, different dosages op EMI-137.


Secondary Outcome Measures :
  1. Safety of using EMI-137 through monitoring vital signs [ Time Frame: 1 day ]
    To evaluate the safety of EMI-137 through monitoring vital signs for evaluating possible (severe) adverse events.

  2. Safety of using EMI-137 through monitoring injection site [ Time Frame: 1 day ]
    To evaluate the safety of EMI-137 through monitoring the injection site for evaluating possible (severe) adverse events.

  3. Feasibility of MFGS for detecting nodal metastasis [ Time Frame: Up to one year ]
    To evaluate the feasibility of MFGS for the assessment of PTC and nodal metastasis by calculating target-to-background ratio.

  4. Feasibility of spectroscopy for detecting fluorescence of PTC and lymph nodes [ Time Frame: Up to one year ]
    To determine the feasibility of ex vivo spectroscopy measurements of PTC and lymph nodes for quantification of the fluorescence signal of EMI-137

  5. Validation of flourescence [ Time Frame: Up to one year ]
    To correlate and validate fluorescence signals detected ex vivo with histopathology and immunohistochemistry by determining if high flourescence areas show tumorcells in pathological examination.

  6. Distribution of EMI-137 [ Time Frame: Up to 1.5 year ]
    To evaluate the distribution of EMI-137 on a microscopic level using fluorescence microscopy.

  7. Sensitivity and specificity of EMI-137 [ Time Frame: Up to 1.5 year ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03470259


Contacts
Contact: Schelto Kruijfff, MD, PhD 0031503612317 s.kruijff@umcg.nl
Contact: Valerie A van der Ploeg, MD 0031503619995 v.a.van.der.ploeg@umcg.nl

Locations
Netherlands
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713GZ
Contact: Schelto Kruijff, MD, PhD    0031503612317    s.kruijff@umcg.nl   
Contact: Valerie A van der Ploeg, MD    0031503619995    v.a.van.der.ploeg@umcg.nl   
Principal Investigator: Schelto Kruijff, MD, PhD         
Principal Investigator: Gooitzen M van Dam, MD, PhD         
University Medical Center Utrecht Not yet recruiting
Utrecht, Netherlands
Contact: Menno Vriens, MD/PhD         
Sponsors and Collaborators
University Medical Center Groningen
UMC Utrecht
Investigators
Principal Investigator: Schelto Kruijfff, MD, PhD University Medical Center Groningen
Principal Investigator: Gooitzen M van Dam, MD, PhD University Medical Center Groningen

Responsible Party: Schelto Kruijff, MD PhD, MD, PhD, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT03470259     History of Changes
Other Study ID Numbers: NL62817.042.17
First Posted: March 19, 2018    Key Record Dates
Last Update Posted: June 25, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Neoplasm Metastasis
Thyroid Diseases
Thyroid Neoplasms
Carcinoma
Neoplastic Processes
Neoplasms
Pathologic Processes
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type