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

• ClinicalTrials.gov Identifier: NCT03470259
• Recruitment Status: Completed
• First Posted: March 19, 2018
• Last Update Posted: January 18, 2020
• Sponsor: University Medical Center Groningen
• Collaborator: Erasmus Medical Center
• Information provided by (Responsible Party): Schelto Kruijff, MD PhD, University Medical Center Groningen

Tracking Information

• First Submitted Date: February 21, 2018
• First Posted Date: March 19, 2018
• Last Update Posted Date: January 18, 2020
• Actual Study Start Date: June 20, 2018
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 12, 2018)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 6, 2018)

• 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.
• 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.
• 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.
• 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
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: March 12, 2018)

• 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.
• 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.
• 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.
• Feasibility of spectroscopy for detecting fluorescence of PTC and lymph nodes [ Time Frame: Up to one year ]
  To determine the feasibility of in vivo and/or ex vivo spectroscopy measurements of PTC and lymph nodes for quantification of the fluorescence signal of EMI-137
• Validation of flourescence [ Time Frame: Up to one year ]
  To correlate and validate fluorescence signals detected in vivo with ex vivo histopathology and immunohistochemistry by determining if high flourescence areas show tumorcells in pathological examination.
• 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.
• 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.
• Correlation of in and ex vivo fluorescence imaging with preoperative imaging results. [ Time Frame: Up to 1.5 year ]
  To correlate the combined results of histopathology and in and ex vivo fluorescence imaging with preoperative imaging results.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Precision Thyroid Cancer Surgery With Molecular Fluorescent Guided Imaging
• Official Title: Detection of Thyroid Cancer and Central Lymph Node Metastases Using EMI-137 Enhanced Molecular Fluorescent Guided Imaging: a Multicentre Feasibility and
• 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.
• Detailed Description: See brief summary
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic

Condition

• Papillary Thyroid Cancer
• Lymph Node Metastases

Intervention

• 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.

Study Arms

• 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.

  Interventions:

  • Drug: IV adminstration of EMI-137
  • Device: Multispectral Fluorescence Reflectance Imaging
  • Device: Spectroscopy
• 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.

  Interventions:

  • Drug: IV adminstration of EMI-137
  • Device: Multispectral Fluorescence Reflectance Imaging
  • Device: Spectroscopy
• 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.

  Interventions:

  • Drug: IV adminstration of EMI-137
  • Device: Multispectral Fluorescence Reflectance Imaging
  • Device: Spectroscopy
• 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.

  Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 16, 2020): 19
• Original Estimated Enrollment (submitted: March 12, 2018): 32
• Actual Study Completion Date: December 31, 2019
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT03470259
• Other Study ID Numbers: NL62817.042.17
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Schelto Kruijff, MD PhD, University Medical Center Groningen
• Study Sponsor: University Medical Center Groningen
• Collaborators: Erasmus Medical Center

Investigators

• Principal Investigator: Schelto Kruijfff, MD, PhD; University Medical Center Groningen
• Principal Investigator: Gooitzen M van Dam, MD, PhD; University Medical Center Groningen

• PRS Account: University Medical Center Groningen
• Verification Date: January 2020