Vandetanib-eluting Radiopaque Embolic Beads in Patients With Resectable Liver Malignancies

Study Overview
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Brief Summary
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This is a pilot, open label single arm phase 0 window of opportunity study of vandetanib-eluting radiopaque beads in patients with resectable liver malignancies.

Detailed Description
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A pilot open-label single arm multicenter phase 0 window of opportunity study of BTG-002814 given up to 3 weeks prior to surgery in up to 12 patients with resectable Hepatocellular carcinoma (HCC) or Colorectal cancer (CRC) with liver metastases.

Official Title
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VEROnA: A Window of Opportunity Study of Vandetanib-eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies

Conditions
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Carcinoma, Hepatocellular, Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: BTG-002814


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adults (≥ 18 years old) Patient with resectable HCC (Child Pugh A, International Normalized Ratio (INR) ≤1.5) or resectable liver metastases from CRC and a candidate for liver surgery Patients with low risk for surgical morbidity and mortality from liver surgery according to the investigators judgement World Health Organization (WHO) performance status 0, 1 or 2 Adequate haematological function with Hb >90 g/L, absolute neutrophil count >1.5 x 10^9/L, Plt >100 x 10^9/L Adequate liver function with serum bilirubin <1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) (or aspartate aminotransferase (AST) if ALT not available) ≤5 x ULN, alkaline phosphatase (ALP) <5 x ULN Adequate renal function with serum creatinine ≤1.5 x ULN and calculated creatinine clearance (GFR) ≥50 mL/min estimated using a validated creatinine clearance calculation (e.g., Cockcroft-Gault or Wright formula). Patient is willing to provide blood samples, and tissue samples at surgical resection, for research purposes Patient is willing and able to provide written informed consent Exclusion Criteria: Any systemic chemotherapy within 3 months of the screening visit or any plan to administer systemic chemotherapy prior to surgery Previous treatment with transarterial embolisation (with or without chemotherapy) of the liver, prior radiotherapy or ablation therapy to the liver or prior yttrium-90 microsphere therapy Any contraindication to vandetanib according to its local label including: Hypersensitivity to the active substance Congenital long corrected QT interval (QTc) syndrome Patients known to have a QTc interval over 480 milliseconds Concomitant use of medicinal products known to also prolong the QTc interval and/or induce Torsades de pointes Any contraindication to hepatic artery catheterisation or hepatic embolisation procedures (e.g. portal venous thrombosis, severely reduced portal venous flow or hepatofugal blood flow, untreated varices at high risk of bleeding) Women of childbearing potential not using effective contraception or women who are breast feeding Confirmed allergy to iodine-based intravenous contrast media Patients who cannot have CT, MRI or dynamic contrast-enhanced (DCE) MRI Imaging (according to site policy) Active uncontrolled cardiovascular disease Any co-morbid disease or condition or event that, in the investigator's judgment, would place the patient at undue risk and would preclude the safe use of BTG-002814 Levels of potassium, calcium, magnesium or thyroid stimulating hormone (TSH) outside the normal ranges, and that in the investigator's judgement are clinically significant, or other laboratory findings that in the view of the investigator makes it undesirable for the patient to participate in the study Patients who have participated in another clinical trial with an investigational product within 4 weeks prior to the screening visit

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 1 mL BTG-002814 containing 100 mg vandetanib
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BTG-002814<br>Single arm: BTG-002814 (vandetanib-eluting radiopaque beads) | Drug: BTG-002814<br>* BTG-002814 containing 100 mg vandetanib<br>* Other names: vandetanib-eluting radiopaque beads;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Assess the Safety and Tolerability of Treatment With BTG-002814 | Adverse events (AEs) related to treatment with BTG-002814 using the National Cancer Institute- Common Terminology Criteria for Adverse Events- Version 4.0 (NCI-CTCAE v4.0) | Continuously throughout the study totalling 9 weeks | 
| Maximum Concentration (Cmax) of Vandetanib and N-desmethyl Vandetanib in Plasma Following Treatment With BTG-002814 | Pharmacokinetic (PK) analysis of participants plasma samples by liquid chromatography with tandem mass spectrometry at the following timepoints: pre-treatment, post treatment (2 hours, 4 hours, 24 hours), prior to surgery, and end of study to derive Cmax. | pre-treatment, 2 hours post-treatment, 4 hours post treatment, 24 hours post treatment, prior to surgery, and end of study (28-32 days post-surgery) | 
| Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | PK analysis of participants resected liver tissue samples by liquid chromatography with tandem mass spectrometry to determine vandetanib concentrations at the centre, middle, and edge of the tumour, as well as in the normal tissue surrounding the tumour (1cm away). | Following surgical resection of tumour | 
| Time Taken to Reach the Maximum Concentration (Tmax) of Vandetanib and N-desmethyl Vandetanib in Plasma Following Treatment With BTG-002814 | PK analysis of participants plasma samples by liquid chromatography with tandem mass spectrometry at the following timepoints: pre-treatment, post treatment (2 hours, 4 hours, 24 hours), prior to surgery, and end of study to derive Tmax | pre-treatment, 2 hours post-treatment, 4 hours post treatment, 24 hours post treatment, prior to surgery, and end of study (28-32 days post-surgery) | 
| Concentration of Vandetanib and N-desmethyl Vandetanib in Plasma Over Time Until End of Study Following Treatment With BTG-002814 | PK analysis of participants plasma samples by liquid chromatography with tandem mass spectrometry at the following timepoints: pre-treatment, post treatment (2 hours, 4 hours, 24 hours), prior to surgery, and end of study to derive AUCEoS (area under the curve at end of study). | pre-treatment, 2 hours post-treatment, 4 hours post treatment, 24 hours post treatment, prior to surgery, and end of study (28-32 days post-surgery) | 
| Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | PK analysis of participants resected liver tissue samples by liquid chromatography with tandem mass spectrometry to determine N-desmethyl vandetanib concentrations at the centre, middle, and edge of the tumour, as well as in the normal tissue surrounding the tumour (1cm away). | Following surgical resection of tumour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | An automated thresholding and filtering algorithm was designed to allow the volume of delivered beads to be quantitatively determined for regions of interest (liver, registered sample, tumour, tumour dilated 1cm, tumour dilated 2cm) from the pre-surgical non-contrast CT scan and the PET/CT of the explanted liver samples following surgery. | 1 day after treatment | 
| Evaluation of Histopathological Features in the Surgical Specimen (Malignant and Non-malignant Liver Tissue) by Analysing Percentage of Tumour Necrosis and Viability | An evaluation of histopathological features in both malignant and non-malignant liver tissue from the surgical specimen was performed by microscopic examination. Sections of resected liver tissue was paraffin-embedded and Hematoxylin and Eosin (H&E) slides were produced. The H&E slides were scanned to produce 3D pathology models of tumour volume and compared to the 3D models generated from clinical imaging. This allowed the extent of tumour necrosis and viable tumour to be determined. | Post-surgery (tumour resection) | 
| Evaluation of Histopathological Features in the Surgical Specimen (Malignant and Non-malignant Liver Tissue) by Assessing Number of Participants With Any Vascular Changes. | An evaluation of histopathological features in both malignant and non-malignant liver tissue from the surgical specimen was performed by microscopic examination. Sections of resected liver tissue was paraffin-embedded and Hematoxylin and Eosin (H&E) slides were produced. The H&E slides were scanned to produce 3D pathology models of tumour volume and compared to the 3D models generated from clinical imaging. This allowed any vascular changes to be determined. | Post-surgery (tumour resection) | 
| Assessment of Changes in Blood Flow on Dynamic Contrast-Enhanced (DCE) MRI Following Treatment With BTG-002814. The Following Parameters Will be Derived From DCE-MRI Images: Ktrans, Kep and Ve. | After acquisition of DCE-MRI liver sequences, tumour signal intensity curves were used to calculate tissue parameters describing tumour perfusion, blood flow and vascularity, before and following treatment with BTG 002814. Bland Altman analysis showed the variability between baseline and pre-treatment readings to be too high, so an interpretation of the changes in blood flow prior to surgery is unreliable. | Baseline, pre-treatment, up to 3 days prior to surgical resection of tumour | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mCRC, HCC, radiopaque beads, vandetanib