Cetuximab-IRDye 800CW and Intraoperative Imaging in Finding Pancreatic Cancer in Patients Undergoing Surgery

Study Overview
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Brief Summary
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This phase 1-2 trial studies the side effects and best dose of cetuximab-IRDye 800CW when used with intraoperative imaging, to determine the utility of cetuximab-IRDye 800CW to identify and assess pancreatic cancer in patients undergoing surgery to remove the tumor. Cetuximab-IRDye 800CW may help doctors better identify cancer in the operating room by making the cancer visible when viewed through a fluorescent imaging system.

Detailed Description
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This is a dose-escalation study of 50 mg or 100 mg cetuximab-IRDye800. Clearance of the tumor margin during surgical resection of pancreatic cancer is clinical importance, as margin-positive resections are suspected to be associated with rapid emergence of distant metastases shortly after surgery. However, pancreatic cancer is known to be difficult to visualize intraoperatively. Nonetheless, better detection of tumor tissue might improve the rate of complete tumor clearance, thereby improving outcomes. However, in order to be actionable, the data from such enhanced tumor detection must be available during the resection procedure. This study evaluates the use of a dye, Cetuximab-IRDye 800CW, that is administered pre-surgery, and is detectable during the surgical procedure. Florescent Imaging Cetuximab is a chimeric (mouse/human) monoclonal antibody that targets the epidermal growth factor (EGF) receptor (EGFR). EGFR is highly-expressed in pancreatic ductal adenocarcinoma (PDAC) and is a good target for antibody-mediated imaging, due to its transmembrane position. Cetuximab-IRDye 800CW is cetuximab labeled with IRDye800, an N-hydroxysuccinimide (NHS) ester infrared dye. IRDye800 has very similar properties compared to indocyanine green, and indocyanine green is readily detectable with a number of imaging systems. This study evaluates the Cetuximab-IRDye 800CW as a intraoperative labeling agent. Patients receive Cetuximab-IRDye 800CW intravenously (IV) at 50 mg or 100 mg over 30 minutes to 1 hour on day 0. Within 2 to 5 days, patients undergo surgery with intraoperative imaging. Cetuximab-IRDye 800CW is used as part of a tumor-targeted molecular imaging procedure operating on the principles of differential accumulation of the antibody-dye conjugate in pancreatic tumor tissue vs normal pancreatic tissue vs pancreatitis tissue. Excised tissues are prepared as formalin-fixed paraffin-embedded (FFPE) blocks for assessment of fluorescent intensity. Photoacoustic imaging (PAI) For purposes of non-quantitative comparison, photoacoustic imaging (PAI) of the tumor lesions is also conducted. PAI refers to a non-invasive evaluation by ultrasound of the area of the resected tumor and surrounding tissue. PAI may have special utility for detecting tumors within 5 to 7 mm of depth, with a high degree of spatial resolution, which might be useful to enhance generation of tumor-free surgical margins. PAI does not utilize ionizing radiation, and should complement and conform to the findings from the fluorescent imaging. PRIMARY OBJECTIVE: Determine the efficacy of cetuximab-IRDye800 in intraoperatively identifying pancreatic cancer compared to surrounding normal pancreatic and extrapancreatic tissue, as measured by tumor-to-background ratio. SECONDARY OBJECTIVE: Determine the tolerability of the cetuximab IRDye800 as an imaging agent in patients undergoing resection of pancreatic cancer.

Official Title
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Intraoperative Pancreatic Cancer Detection Using Multimodality Molecular Imaging

Conditions
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Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Cetuximab-IRDye800
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Clinically suspected or biopsy confirmed diagnosis of pancreatic adenocarcinoma Planned standard of care surgery with curative intent for pancreatic adenocarcinoma ≥ 19 years of age Life expectancy of more than 12 weeks EITHER Karnofsky performance status of at least 70%, OR Eastern Cooperative Oncology Group (ECOG)/Zubrod level 1 Hemoglobin ≥ 9 gm/dL Platelet count ≥ 100,000/mm^3 Magnesium > the lower limit of normal (LLN) per institution normal lab values Potassium > LLN Calcium > LLN Thyroid-stimulating hormone (TSH) < 13 micro International units/mL EXCLUSION CRITERIA Received an investigational drug within 30 days prior to first dose of cetuximab IRDye800 Myocardial infarction (MI); cerebrovascular accident (CVA); uncontrolled congestive heart failure (CHF); or unstable angina within 6 months prior to enrollment History of infusion reactions to cetuximab or other monoclonal antibody therapies Pregnant or breastfeeding Evidence of QT prolongation on pretreatment electrocardiography (ECG) (greater than 440 ms in males or greater than 450 ms in females) Lab values that in the opinion of the primary surgeon would prevent surgical resection Patients receiving class IA (quinidine, procainamide) or class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cetuximab IRDye800, 50 mg<br>On day 0, participants receive a 100 mg cetuximab loading dose by intravenous infusion (IV), followed 1 hour later by cetuximab-IRDye 800CW IV at 50 mg, followed by surgery with intraoperative imaging within 2 to 5 days. | Drug: Cetuximab-IRDye800<br>* Administered intravenously (IV) at 50 or 100 mg<br>* Other names: Cetuximab-IRDye 800CW;Drug: Cetuximab<br>* Administered as a 100 mg IV loading dose<br>* Other names: C225;|
| Experimental: Cetuximab IRDye800, 100 mg<br>On day 0, participants receive a 100 mg cetuximab loading dose by intravenous infusion (IV), followed 1 hour later by cetuximab-IRDye 800CW IV at 100 mg, followed by surgery with intraoperative imaging within 2 to 5 days. | Drug: Cetuximab-IRDye800<br>* Administered intravenously (IV) at 50 or 100 mg<br>* Other names: Cetuximab-IRDye 800CW;Drug: Cetuximab<br>* Administered as a 100 mg IV loading dose<br>* Other names: C225;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peri-operative Cetuximab-IRDye800 Fluorescent Imaging, Both Doses | Cetuximab-IRDye800 (50 mg or 100 mg) was administered pre-operatively, and the uptake of the dye was assessed by observed fluorescence intra-operatively (ie, in vivo) and post-operatively (ex vivo, or back table), in tumorous (tumor or tumor-bearing lymph nodes) or normal (non-tumorous) tissues. Collectively, intra-operative and immediately post-operative are considered peri-operative. The outcome tumor-to-background ratio (TBR) is measured as the mean of the ratios observed between tumor and normal tissue for the participants, and the outcome is expressed as the mean with standard deviation. | up to 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cetuximab-IRDye800 Labeling Intensity in Tumor and Non-Tumor Tissues (Ex Vivo) | Cetuximab-IRDye800 (50 mg or 100 mg) florescence intensity was assessed in normal pancreatic tissue; pancreatitis tissue; and pancreatic tumor tissue prepared as formalin-fixed paraffin-embedded (FFPE) blocks. Fluorescent intensity was measured in the image for each tissue, and expressed as counts per pixel. The outcome is expressed for each tissue as the dose-independent mean counts/pixel for the cohort. The outcome is expressed as the mean counts/pixel with standard deviation. | up to 14 days | 
| Effect of Cetuximab-IRDye800 Dose on Fluorescence Intensity | Cetuximab-IRDye800 (50 mg or 100 mg) florescence intensity was assessed in normal pancreatic tissue; pancreatitis tissue; and pancreatic tumor tissue prepared as formalin-fixed paraffin-embedded (FFPE) blocks. Fluorescent intensity was measured in the image for each tissue, and expressed as counts per pixel. The outcome is expressed for each tissue as the dose-independent mean fluorescent intensity (MFI) for the cohort. The outcome is expressed as a mean with standard deviation, by dose. | up to 14 days | 
| Sensitivity and Specificity of Ex Vivo Fluorescent Imaging | Sensitivity is the ability of a test to correctly identify patients with the condition, ie, how well Cetuximab-IRDye800 fluorescent imaging detects true-positive patients. Sensitivity is defined as [TP/(TP+FN)], where TP=true-positive, and FN=false-negative. The outcome is a % without dispersion. A higher % means a greater probability that an imaging target identified as cancerous is confirmed by histology to be cancerous, and a lower % means reduced confidence in that result. Specificity is the ability of a test to correctly identify patients who do not have the condition, ie, how well Cetuximab-IRDye800 fluorescent imaging detects true-negative patients. Specificity is defined as [TN/(TN+FP)], where TN=true-negative, and FP=false-positive. The outcome is a % without dispersion. A higher % means a greater probability that an imaging target identified as non-cancerous is confirmed by histology to be non-cancerous, and a lower % means reduced confidence in that result. | up to 14 days | 
| Cetuximab-IRDye800 Tumor Detection in Lymph Nodes | Cetuximab-IRDye800 (50 mg or 100 mg) florescence intensity was assessed in excised lymph nodes (ie, ex vivo) that were histologically-determined to be normal or tumor-bearing. Fluorescent intensity was measured in the image for each lymph using close-field fluorescence imaging and expressed as counts per pixel. The outcome is expressed for each tissue as the dose-independent mean fluorescent intensity (MFI) for the cohort. The outcome is expressed as the mean MFI with standard deviation. | up to 14 days | 
| Signal-to-Noise Ratio (SNR) by Ex Vivo Photoacoustic Imaging (PAI) | Photoacoustics were assessed as the signal-to-noise ratio (SNR), a unit-less number, as observed for tumor vs surrounding tissue using an ultrasound device. The value observed for tumor tissue is considered signal, and the value for normal tissue is considered noise. The more the ratio is greater than 1 reflects the more that the tumor tissue reflects an ultrasound signal compared to normal tissue. The outcome is expressed as the ratio of mean SNR signal for tumor tissue to normal tissue, without dispersion. | up to 5 days | 
| Signal-to-Noise Ratio (SNR) by In Vivo Photoacoustic Imaging (PAI) | Photoacoustic imaging (PAI) was to be used to evaluate tumor and normal margin tissues (waste tissue) immediately peri-operatively (in vivo) and prior to pathological evaluation. The signal-to-noise ratio (SNR) as measured in dB of the tumor was to be calculated in the tumor specimens for comparison to surrounding normal tissue. The outcome would be expressed as the mean of the ratios, with standard deviation, and data used to qualitatively confirm the findings with Cetuximab-IRDye 800CW fluorescent imaging. | up to 5 days | 
| Toxicity (≥ Grade 2) | Toxicity was assessed as the number of grade 2 or greater adverse events [Common Terminology Criteria for Adverse Events (CTCAE) version 4.03] determined to be clinically-significant and definitely-, probably-, or possibly-related to cetuximab-IRDye 800CW. The outcome is reported as the number of treatment-related adverse events ≥ grade 2 without dispersion, by dose level. | Up to 30 days |