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

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ClinicalTrials.gov Identifier: NCT03291379
Recruitment Status : Completed
First Posted : September 25, 2017
Results First Posted : February 3, 2021
Last Update Posted : February 3, 2021
Sponsor:
Information provided by (Responsible Party):
Biocompatibles UK Ltd

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Metastatic Colorectal Cancer Drug: BTG-002814 Early Phase 1

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 1 mL BTG-002814 containing 100 mg vandetanib
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: VEROnA: A Window of Opportunity Study of Vandetanib-eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies
Actual Study Start Date : May 17, 2017
Actual Primary Completion Date : August 3, 2019
Actual Study Completion Date : August 3, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Vandetanib

Arm Intervention/treatment
Experimental: BTG-002814
Single arm: BTG-002814 (vandetanib-eluting radiopaque beads)
Drug: BTG-002814
BTG-002814 containing 100 mg vandetanib
Other Name: vandetanib-eluting radiopaque beads




Primary Outcome Measures :
  1. To Assess the Safety and Tolerability of Treatment With BTG-002814 [ Time Frame: Continuously throughout the study totalling 9 weeks ]
    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)

  2. Maximum Concentration (Cmax) of Vandetanib and N-desmethyl Vandetanib in Plasma Following Treatment With BTG-002814 [ Time Frame: 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) ]
    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.

  3. Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 [ Time Frame: Following surgical resection of tumour ]
    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).

  4. Time Taken to Reach the Maximum Concentration (Tmax) of Vandetanib and N-desmethyl Vandetanib in Plasma Following Treatment With BTG-002814 [ Time Frame: 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) ]
    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

  5. Concentration of Vandetanib and N-desmethyl Vandetanib in Plasma Over Time Until End of Study Following Treatment With BTG-002814 [ Time Frame: 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) ]
    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).

  6. Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 [ Time Frame: Following surgical resection of tumour ]
    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).


Secondary Outcome Measures :
  1. Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT [ Time Frame: 1 day after treatment ]
    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.

  2. Evaluation of Histopathological Features in the Surgical Specimen (Malignant and Non-malignant Liver Tissue) by Analysing Percentage of Tumour Necrosis and Viability [ Time Frame: Post-surgery (tumour resection) ]
    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.

  3. Evaluation of Histopathological Features in the Surgical Specimen (Malignant and Non-malignant Liver Tissue) by Assessing Number of Participants With Any Vascular Changes. [ Time Frame: Post-surgery (tumour resection) ]
    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.

  4. 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. [ Time Frame: Baseline, pre-treatment, up to 3 days prior to surgical resection of tumour ]

    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.



Other Outcome Measures:
  1. Study Blood Biomarkers With the Potential to Identify Patients Likely to Respond to Treatment With BTG-002814 [ Time Frame: Baseline, pre-treatment, 1 day after treatment, Up to 3 days prior to surgical resection, end of study (28-32 days post-surgery). ]
    The following serum biomarkers were measured at Baseline, pre-treatment, 1 day after treatment, Up to 3 days prior to surgical resection, end of study ; cytokines, chemokines and growth factors relevant to cancer and inflammation.

  2. Study Tissue Biomarkers to Explore Key Immune, Inflammatory and Drug Related Mechanisms [ Time Frame: Baseline, pre-treatment, Up to 3 days prior to surgical resection. ]
    The following tissue biomarkers were measured at Baseline, pre-treatment, Up to 3 days prior to surgical resection; Levels of serum alpha-fetoprotein (AFP) in patients with HCC. Levels of serum Carcinoembryonic Antigen (CEA), Cancer Antigen (CA)19-9 and CA-125 in patients with metastatic colorectal cancer (mCRC).



Information from the National Library of Medicine

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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. Male or female adults (≥ 18 years old)
  2. 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
  3. Patients with low risk for surgical morbidity and mortality from liver surgery according to the investigators judgement
  4. World Health Organization (WHO) performance status 0, 1 or 2
  5. Adequate haematological function with Hb >90 g/L, absolute neutrophil count >1.5 x 10^9/L, Plt >100 x 10^9/L
  6. 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
  7. 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).
  8. Patient is willing to provide blood samples, and tissue samples at surgical resection, for research purposes
  9. Patient is willing and able to provide written informed consent

Exclusion Criteria:

  1. Any systemic chemotherapy within 3 months of the screening visit or any plan to administer systemic chemotherapy prior to surgery
  2. 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
  3. 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
  4. 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)
  5. Women of childbearing potential not using effective contraception or women who are breast feeding
  6. Confirmed allergy to iodine-based intravenous contrast media
  7. Patients who cannot have CT, MRI or dynamic contrast-enhanced (DCE) MRI Imaging (according to site policy)
  8. Active uncontrolled cardiovascular disease
  9. 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
  10. 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
  11. Patients who have participated in another clinical trial with an investigational product within 4 weeks prior to the screening visit

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): NCT03291379


Locations
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United Kingdom
University College London Hospital
Bloomsbury, London, United Kingdom, NW1 2BU
Sponsors and Collaborators
Biocompatibles UK Ltd
Investigators
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Principal Investigator: Professor Ricky Sharma University College, London
  Study Documents (Full-Text)

Documents provided by Biocompatibles UK Ltd:
Statistical Analysis Plan  [PDF] May 16, 2019
Study Protocol  [PDF] December 3, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Biocompatibles UK Ltd
ClinicalTrials.gov Identifier: NCT03291379    
Other Study ID Numbers: BTG-002814-01
First Posted: September 25, 2017    Key Record Dates
Results First Posted: February 3, 2021
Last Update Posted: February 3, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Biocompatibles UK Ltd:
mCRC, HCC, radiopaque beads, vandetanib
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Liver Diseases