Carcinoma, Hepatocellular, Metastatic Colorectal Cancer
Conditions
Keywords
mCRC, HCC, radiopaque beads, vandetanib
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.
Interventions
DRUGBTG-002814
BTG-002814 containing 100 mg vandetanib
Sponsors
Biocompatibles UK Ltd
Boston Scientific Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
1 mL BTG-002814 containing 100 mg vandetanib
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | 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). |
| To Assess the Safety and Tolerability of Treatment With BTG-002814 | 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 | 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 | 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 | 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 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | 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 | 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. | 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. | 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
| Measure | Time frame | Description |
|---|---|---|
| Study Blood Biomarkers With the Potential to Identify Patients Likely to Respond to Treatment With BTG-002814 | 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 | 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). |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BTG-002814 Single arm: BTG-002814 (vandetanib-eluting radiopaque beads)
BTG-002814 (vandetanib-eluting radiopaque beads): BTG-002814 containing 100 mg vandetanib | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | BTG-002814 |
|---|---|
| Age, Continuous | 62.5 years |
| Number of liver lesions | 1.6 Count STANDARD_DEVIATION 1.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United Kingdom | 8 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 7 Participants |
| Tumour type Hepatocellular carcinoma (HCC) | 2 Participants |
| Tumour type Metastatic colorectal cancer (mCRC) | 6 Participants |
| World Health Organisation (WHO) Performance Status Grade 0 (asymptomatic) | 8 Participants |
| World Health Organisation (WHO) Performance Status Grade 1 (Symptomatic, but ambulatory) | 0 Participants |
| World Health Organisation (WHO) Performance Status Grade 2 (Symptomatic, <50% in bed) | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 8 |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 4 / 8 |
Outcome results
Primary
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).
Time frame: Following surgical resection of tumour
Population: Results were not available for 2 patients where sample was incorrectly prepared, or no sample was received. For patients with multiple tumours, only the treated tumours were sampled and analysed. The results for this outcome measure are reported by individual subject (where data was available), by each sample location (centre, middle, edge of the tumour, 1cm away from tumour) per row.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 07: N-desmethyl Vandetanib concentration edge of tumour | 28.7 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 07: N-desmethyl Vandetanib concentration 1cm away from tumour | 84 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08: N-desmethyl concentration centre of tumour | 39.3 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (1 cm lesion): N-desmethyl Vandetanib concentration 1cm away from tumour | 342 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (inferior lesion): N-desmethyl Vandetanib concentration 1cm away from tumour | 405 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 01: N-desmethyl Vandetanib concentration centre of tumour | 4620 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 01: N-desmethyl Vandetanib concentration middle of tumour | 4740 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 01: N-desmethyl Vandetanib concentration edge of tumour | 3680 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 01: N-desmethyl Vandetanib concentration 1cm away from tumour | 280 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 03: N-desmethyl concentration centre of tumour | 69.6 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 03: N-desmethyl Vandetanib concentration middle of tumour | 59.8 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 03: N-desmethyl Vandetanib concentration edge of tumour | 69.2 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 03: N-desmethyl Vandetanib concentration 1cm away from tumour | 831 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 05: N-desmethyl concentration centre of tumour | 421 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 05: N-desmethyl Vandetanib concentration middle of tumour | 418 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 05: N-desmethyl Vandetanib concentration edge of tumour | 469 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 05: N-desmethyl Vandetanib concentration 1cm away from tumour | 544 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 06: N-desmethyl concentration centre of tumour | 113 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 06: N-desmethyl Vandetanib concentration middle of tumour | 93.9 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 06: N-desmethyl Vandetanib concentration edge of tumour | 11.4 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 06: N-desmethyl Vandetanib concentration 1cm away from tumour | 55.6 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 07: N-desmethyl concentration centre of tumour | 21 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 07: N-desmethyl Vandetanib concentration middle of tumour | 15.7 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (1cm lesion): whole tumour N-desmethyl concentration | 208 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (inferior lesion): N-desmethyl concentration centre of tumour | 80.2 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08: N-desmethyl Vandetanib concentration middle of tumour | 57.1 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (inferior lesion): N-desmethyl Vandetanib concentration middle of tumour | 101 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08: N-desmethyl Vandetanib concentration edge of tumour | 145 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (inferior lesion): N-desmethyl Vandetanib concentration edge of tumour | 171 ng/mL |
| BTG-002814 | Concentration of N-desmethyl Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08: N-desmethyl Vandetanib concentration 1cm away from tumour | 389 ng/mL |
Primary
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).
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)
Population: all participants treated with BTG-002814
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BTG-002814 | Concentration of Vandetanib and N-desmethyl Vandetanib in Plasma Over Time Until End of Study Following Treatment With BTG-002814 | Vandetanib Plasma AUCEoS | 6979.3 ng*h/mL | Standard Deviation 3188.21 |
| BTG-002814 | Concentration of Vandetanib and N-desmethyl Vandetanib in Plasma Over Time Until End of Study Following Treatment With BTG-002814 | N-desmethyl Plasma AUCEoS | 81.1 ng*h/mL | Standard Deviation 169.4 |
Primary
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).
Time frame: Following surgical resection of tumour
Population: Results were not available for 2 patients where sample was incorrectly prepared, or no sample was received. For patients with multiple tumours, only the treated tumours were sampled and analysed. The results for this outcome measure are reported by individual subject (where data was available) by each sample location (centre, middle, edge of the tumour or 1cm away from tumour) per row.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 01: Vandetanib concentration centre of tumour | 404000 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 01: Vandetanib concentration middle of tumour | 394000 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 01: Vandetanib concentration edge of tumour | 327000 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 01: Vandetanib concentration 1cm away from tumour | 10800 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 03: Vandetanib concentration centre of tumour | 8510 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 03: Vandetanib concentration middle of tumour | 11000 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 03: Vandetanib concentration edge of tumour | 18800 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 03: Vandetanib concentration 1cm away from tumour | 9120 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 05: Vandetanib concentration centre of tumour | 7340 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 05: Vandetanib concentration middle of tumour | 7550 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 05: Vandetanib concentration edge of tumour | 12500 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 05: Vandetanib concentration 1cm away from tumour | 7090 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 06: Vandetanib concentration centre of tumour | 160000 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 06: Vandetanib concentration middle of tumour | 151000 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 06: Vandetanib concentration edge of tumour | 11100 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 06: Vandetanib concentration 1cm away from tumour | 1480 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 07: Vandetanib concentration centre of tumour | 4570 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 07: Vandetanib concentration middle of tumour | 531 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 07: Vandetanib concentration edge of tumour | 441 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 07: Vandetanib concentration 1cm away from tumour | 2760 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08: Vandetanib concentration centre of tumour | 1140 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (1cm lesion): whole tumour Vandetanib concentration | 93500 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (inferior lesion): Vandetanib concentration centre of tumour | 6180 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08: Vandetanib concentration middle of tumour | 1240 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (inferior lesion): Vandetanib concentration middle of tumour | 1440 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08: Vandetanib concentration edge of tumour | 2840 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (inferior lesion): Vandetanib concentration edge of tumour | 2710 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08: Vandetanib concentration 1cm away from tumour | 29100 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (1 cm lesion): Vandetanib concentration 1cm away from tumour | 5350 ng/mL |
| BTG-002814 | Concentration of Vandetanib in Resected Liver Tissue Following Treatment With BTG-002814 | Subject 08 (inferior lesion): Vandetanib concentration 1cm away from tumour | 6010 ng/mL |
Primary
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.
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)
Population: all participants treated with BTG-002814
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BTG-002814 | Maximum Concentration (Cmax) of Vandetanib and N-desmethyl Vandetanib in Plasma Following Treatment With BTG-002814 | Vandetanib Plasma Cmax | 24.3 ng/mL | Standard Deviation 13.94 |
| BTG-002814 | Maximum Concentration (Cmax) of Vandetanib and N-desmethyl Vandetanib in Plasma Following Treatment With BTG-002814 | N-desmethyl Plasma Cmax | 0.6 ng/mL | Standard Deviation 0.82 |
Primary
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
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)
Population: all participants treated with BTG-002814
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BTG-002814 | Time Taken to Reach the Maximum Concentration (Tmax) of Vandetanib and N-desmethyl Vandetanib in Plasma Following Treatment With BTG-002814 | Vandetanib Plasma Tmax | 26.0 hours | Standard Deviation 67.08 |
| BTG-002814 | Time Taken to Reach the Maximum Concentration (Tmax) of Vandetanib and N-desmethyl Vandetanib in Plasma Following Treatment With BTG-002814 | N-desmethyl Plasma Tmax | 0.8 hours | Standard Deviation 1.04 |
Primary
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)
Time frame: Continuously throughout the study totalling 9 weeks
Population: Safety population - all participants treated with BTG-002814
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BTG-002814 | To Assess the Safety and Tolerability of Treatment With BTG-002814 | participants with treatment emergent Adverse Events (AEs) | 8 Participants |
| BTG-002814 | To Assess the Safety and Tolerability of Treatment With BTG-002814 | participants with treatment emergent Serious Adverse Events (SAEs) | 4 Participants |
Secondary
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.
Time frame: Baseline, pre-treatment, up to 3 days prior to surgical resection of tumour
Secondary
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.
Time frame: 1 day after treatment
Population: All 8 subjects treated with BTG-002814 were analysed, however, not all subjects have sampling of all regions (liver, registered sample, tumour, tumour dilated 1cm, tumour dilated 2cm) due to some samples not being able to be accurately processed and registered. The data for this outcome measure is reported by individual subject, for each sample region (where data is available) per row.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 04: Liver | 852.03 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 05: Liver | 849.29 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 05: Registered sample | 751.62 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 05: Tumour | 0 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 5: Tumour dilated 1cm | 15.26 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 05: Tumour dilated 2cm | 86.28 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 01: Liver | 928.83 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 01: Registered sample | 399.27 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 01: Tumour | 361.14 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 01: tumour dilated 1cm | 393.79 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 01: Tumour dilated 2cm | 479.28 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 02: Liver | 764.69 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 02: Tumour | 596.78 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 02: Tumour dilated 1cm | 617.72 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 02: Tumour dilated 2cm | 649.97 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 03: Liver | 594.79 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 03: Registered sample | 116.54 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 03: Tumour | 0.32 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 03: Tumour dilated 1cm | 36.26 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 03: Tumour dilated 2cm | 108.85 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 06: Liver | 202.56 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 06: Registered sample | 148.09 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 06: Tumour | 51.14 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | ubject 06: Tumour dilated 1cm | 115.39 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 06: Tumour dilated 2cm | 166.80 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 07: Liver | 720.78 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 07: Registered sample | 103.82 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 07: Tumour | 4.32 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 07: Tumour dilated 1cm | 75.43 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 07: Tumour dilated 2cm | 133.26 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 08: Liver | 693.73 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 08: Registered sample | 422.37 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 08: Tumour | 21.87 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 08: Tumour dilated 1cm | 264.90 µL |
| BTG-002814 | Evaluate the Anatomical Distribution of BTG-002814 on Non-contrast Enhanced Imaging Using 4D CT | Subject 08: Tumour dilated 2cm | 378.15 µL |
Secondary
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.
Time frame: Post-surgery (tumour resection)
Population: all participants treated with BTG-002814
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BTG-002814 | Evaluation of Histopathological Features in the Surgical Specimen (Malignant and Non-malignant Liver Tissue) by Analysing Percentage of Tumour Necrosis and Viability | Tumour necrosis | 92.5 percentage of surgical specimen |
| BTG-002814 | Evaluation of Histopathological Features in the Surgical Specimen (Malignant and Non-malignant Liver Tissue) by Analysing Percentage of Tumour Necrosis and Viability | Viable tumour | 7.5 percentage of surgical specimen |
Secondary
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.
Time frame: Post-surgery (tumour resection)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BTG-002814 | Evaluation of Histopathological Features in the Surgical Specimen (Malignant and Non-malignant Liver Tissue) by Assessing Number of Participants With Any Vascular Changes. | Vascular changes absent | 8 Count of Participants |
| BTG-002814 | Evaluation of Histopathological Features in the Surgical Specimen (Malignant and Non-malignant Liver Tissue) by Assessing Number of Participants With Any Vascular Changes. | Vascular changes present | 0 Count of Participants |
Other Pre-specified
Study Blood Biomarkers With the Potential to Identify Patients Likely to Respond to Treatment With BTG-002814
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.
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).
Other Pre-specified
Study Tissue Biomarkers to Explore Key Immune, Inflammatory and Drug Related Mechanisms
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).
Time frame: Baseline, pre-treatment, Up to 3 days prior to surgical resection.