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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

Tracking Information
First Submitted Date  ICMJE May 17, 2017
First Posted Date  ICMJE September 25, 2017
Results First Submitted Date  ICMJE October 5, 2020
Results First Posted Date  ICMJE February 3, 2021
Last Update Posted Date February 3, 2021
Actual Study Start Date  ICMJE May 17, 2017
Actual Primary Completion Date August 3, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 14, 2021)
  • 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)
  • 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.
  • 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).
  • 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
  • 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).
  • 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).
Original Primary Outcome Measures  ICMJE
 (submitted: September 21, 2017)
  • 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) [ Time Frame: Continuously throughout the study totalling 9 weeks ]
    To assess the safety and tolerability of treatment with BTG-002814
  • Concentration of vandetanib and N-desmethyl vandetanib in plasma following treatment with BTG-002814 [ Time Frame: 0, 2, 4, 24, 36 hours post treatment and, 1 day prior to and 30-32 days after liver resection surgery ]
    Measure the plasma concentrations of vandetanib and the N-desmethyl metabolite following treatment with BTG-002814
  • Concentration of vandetanib and N-desmethyl vandetanib in resected liver tissue following treatment with BTG-002814 [ Time Frame: 7-21 days following treatment ]
    Measure the concentrations of vandetanib and the N-desmethyl metabolite in the resected liver tissue samples following treatment with BTG-002814
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2021)
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2017)
  • BTG-002814 distribution [ Time Frame: 1 day after treatment ]
    Distribution of BTG-002814 on non-contrast enhanced imaging of tumor vasculature and regions of interest using 4D CT
  • Evaluation of histopathological features [ Time Frame: 7 to 21 days after treatment ]
    Evaluation of histopathological features in the surgical specimen (malignant and non-malignant liver tissue): tumor necrosis, viable tumor, vascular changes
  • Assessment of changes in blood flow [ Time Frame: Baseline, day 1, 6 to 20 days after treatment] ]
    Assessment of changes in blood flow on DCE-MRI following treatment. The following parameters will be derived from DCE-MRI images: Ktrans, Kep and Ve
Current Other Pre-specified Outcome Measures
 (submitted: January 14, 2021)
  • 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.
  • 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).
Original Other Pre-specified Outcome Measures
 (submitted: September 21, 2017)
  • Blood biomarkers [ Time Frame: Throughout study involvement totaling 9 weeks ]
    Study blood biomarkers with the potential to identify patients likely to respond to treatment with BTG-002814
  • Distribution of BTG-002814 [ Time Frame: 7 to 21 days after treatment ]
    Correlate the distribution of BTG-002814 on imaging with pathology by 3D modeling
 
Descriptive Information
Brief Title  ICMJE Vandetanib-eluting Radiopaque Embolic Beads in Patients With Resectable Liver Malignancies
Official Title  ICMJE VEROnA: A Window of Opportunity Study of Vandetanib-eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE 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
Condition  ICMJE
  • Carcinoma, Hepatocellular
  • Metastatic Colorectal Cancer
Intervention  ICMJE Drug: BTG-002814
BTG-002814 containing 100 mg vandetanib
Other Name: vandetanib-eluting radiopaque beads
Study Arms  ICMJE Experimental: BTG-002814
Single arm: BTG-002814 (vandetanib-eluting radiopaque beads)
Intervention: Drug: BTG-002814
Publications * Beaton L, Tregidgo HFJ, Znati SA, Forsyth S, Clarkson MJ, Bandula S, Chouhan M, Lowe HL, Zaw Thin M, Hague J, Sharma D, Pollok JM, Davidson BR, Raja J, Munneke G, Stuckey DJ, Bascal ZA, Wilde PE, Cooper S, Ryan S, Czuczman P, Boucher E, Hartley JA, Lewis AL, Jansen M, Meyer T, Sharma RA. VEROnA Protocol: A Pilot, Open-Label, Single-Arm, Phase 0, Window-of-Opportunity Study of Vandetanib-Eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies. JMIR Res Protoc. 2019 Oct 2;8(10):e13696. doi: 10.2196/13696.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 8, 2019)
8
Original Estimated Enrollment  ICMJE
 (submitted: September 21, 2017)
12
Actual Study Completion Date  ICMJE August 3, 2019
Actual Primary Completion Date August 3, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03291379
Other Study ID Numbers  ICMJE BTG-002814-01
Has Data Monitoring Committee No
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  ICMJE
Plan to Share IPD: Undecided
Responsible Party Biocompatibles UK Ltd
Study Sponsor  ICMJE Biocompatibles UK Ltd
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Professor Ricky Sharma University College, London
PRS Account Biocompatibles UK Ltd
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP