Clinical Trial Results:
Title: A confirmatory, prospective, open-label, multi-centre phase 3 study to evaluate diagnostic performance of 89Zirconium-labelled girentuximab (89Zr-TLX250) to non-invasively detect clear cell renal cell carcinoma (ccRCC) by positron-emission tomography/CT(PET/CT) imaging in patients with indeterminate renal masses (ZIRCON study).
Trial design: This was a confirmatory, prospective, open-label, multi-centre phase 3 study (ZIRCON) designed to confirm the sensitivity and specificity of PET/ computed tomography (CT) imaging with 89Zr-TLX250 to non-invasively detect ccRCC in patients with a pre-study diagnosed indeterminate renal mass (IRM) of up to 7 cm (stage cT1) who were scheduled for partial or total nephrectomy. Histological confirmation served as standard of truth, to assess sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), as well as accuracy of 89Zr-TLX250 PET/CT imaging. The qualitative 89Zr-TLX250 PET/CT imaging assessment of 3 trained independent readers blinded to patient medical history was compared to their confirmed histology data for the primary analysis.
Approximately 250 adult patients were planned to be recruited in Europe, Australia, Canada, and the USA, who had access to PET/CT imaging. The number of enrolled patients was increased to 332 to ensure adequate power to calculate both sensitivity and specificity of 89Zr-TLX250 PET/CT imaging; 300 patients were dosed.
Following informed consent, a screening visit was performed during which baseline examinations were performed. The study schedule was planned considering a delivery timeline for 89Zr-TLX250 of 7-10 days from the central study radiopharmacy, an imaging interval of 5 ± 2 days post administration (p.a.), and planned nephrectomy any time after the PET/CT imaging visit, but no later than 90 days p.a. of 89Zr-TLX250 and after image acquisition.
Treatment consisted of a single administration of the diagnostic agent for each patient.
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Summary
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EudraCT number |
2018-002773-21 |
Trial protocol |
NL GB BE ES |
Global end of trial date |
07 Nov 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Dec 2023
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First version publication date |
28 Dec 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
89Zr-TLX250-003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03849118 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
TELIX International Pty Ltd
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Sponsor organisation address |
Main Office, Suite 401, 55 Flemington Road, North Melbourne, Australia, VIC 3051
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Public contact |
clinical trials information, ABX-CRO advanced pharmaceutical services , 0049 351214440, info@abx-cro.com
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Scientific contact |
clinical trials information, ABX-CRO advanced pharmaceutical services , 0049 351214440, info@abx-cro.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Oct 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Oct 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Nov 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to evaluate the sensitivity and specificity of qualitative assessment of PET/CT imaging with 89Zr-TLX250 to non-invasively detect ccRCC in patients with indeterminate renal masses, using histology as standard of truth.
The qualitative 89Zr-TLX250 PET/CT imaging assessment of 3 independent readers was the primary imaging result.
Sensitivity was defined as the proportion of patients with a true positive (TP) 89Zr-TLX250 PET/CT scan (detection of clear cell carcinoma), relative to those with positive histopathological diagnosis for ccRCC.
Specificity was the proportion of patients with a true negative (TN) 89Zr-TLX250 PET/CT imaging result (no ccRCC), relative to those with a negative histopathological diagnosis of non-ccRCC.
The positive/negative predictive values (PPV/NPV) were the probabilities that, respectively, a positive/negative histopathology diagnosis was obtained given that the result of the 89Zr-TLX PET/CT scan was positive/negative (for ccRCC).
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Protection of trial subjects |
Patient accrual and histological results were centrally evaluated and monitored by an Independent Data Monitoring Committee (IDMC) blinded to 89Zr-TLX250 PET/CT images as well as to PET/CT results from the independent image reviewers.
The study protocol, amendments, the informed consent/assent form(s), and information sheets were approved by the appropriate and applicable Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs).
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP).
An informed consent form explaining the procedures of the study, including potential hazards, was reviewed and approved by the corresponding IEC/IRB before the study was allowed to start at each site. Each patient was asked to read the informed consent form and it was also verbally explained to all patients by the study staff. Each patient was given the opportunity to ask questions and the time to discuss the study and its implications with their family and surrogates. Patients were assured of their right to withdraw from the study at any time without suffering any disadvantages and without having to provide a reason for their decision.
The patient was only allowed to undergo any study specific procedures after signing the informed consent form.
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Background therapy |
Prior and concomitant medication were recorded in the eCRF beginning at screening and throughout the study from Day 0, until the end of study (EOS) visit. Anaesthetics, analgesics, sedatives and laxatives given in routinely used regimen and dosage in connection with nephrectomy were not to be recorded in the eCRF. Prior medications (within 30 days from planned dosing visit at Day 0) and all medications (including herbal medications) taken from Day 0 until EOS had to be recorded in the patient’s eCRF, including concomitant medication or physical therapy for AEs. Vitamins, herbal preparations and other nutritional supplements were permitted during this study but had to be recorded. Patients were allowed to be vaccinated against COVID-19; the recommendation was for the patient to be asymptomatic and having recovered from any side effects due to immunisation prior to study drug administration. The vaccine had to be listed as a concomitant medication. Planned antineoplastic therapies were not allowed for the study period between administration of study drug and imaging. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Aug 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 35
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
France: 45
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Country: Number of subjects enrolled |
Netherlands: 38
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Country: Number of subjects enrolled |
Belgium: 29
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
Turkey: 29
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Country: Number of subjects enrolled |
United States: 113
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Country: Number of subjects enrolled |
Canada: 6
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Worldwide total number of subjects |
300
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EEA total number of subjects |
116
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
176
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From 65 to 84 years |
121
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85 years and over |
3
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Recruitment
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Recruitment details |
Patients were recruited at 32 centres in 9 countries with access to PET/CT imaging. Recruitment into the study continued until the number of patients required to conduct a powered statistical analysis was recruited. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Following informed consent, a screening visit was performed during which baseline examinations were performed. These included medical history, physical exam, vital signs, haematology and serum chemistry, urinalysis, pregnancy test, and 12 lead ECG. | ||||||||||||||||||
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Period 1
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Period 1 title |
Baseline (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Blinding implementation details |
Not applicable.
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Arms
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Arm title
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Safety analysis set (SAF) 89Zr-TLX250 PET/CT imaging | ||||||||||||||||||
Arm description |
The safety analysis set (SAF) consisted of all patients who received 89Zr-TLX250. The qualitative 89Zr-TLX250 PET/CT imaging assessment was performed by 3 trained independent readers blinded to patient medical history and histology results. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
89Zr-TLX250
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
The dose was a single administration of 37 MBq (±10%) 89Zr-TLX250, containing a mass dose of 10 mg of girentuximab.
Each patient received a single slow intravenous (IV) administration over a minimum of 3 minutes on Day 0 (after pre-dose assessments), at the nuclear medicine centre of the respective study site.
No dietary restrictions prior to dosing were necessary.
Imaging results for this arm were compared against confirmed histopathology diagnoses.
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Baseline characteristics reporting groups
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Reporting group title |
Safety analysis set (SAF) 89Zr-TLX250 PET/CT imaging
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Reporting group description |
The safety analysis set (SAF) consisted of all patients who received 89Zr-TLX250. The qualitative 89Zr-TLX250 PET/CT imaging assessment was performed by 3 trained independent readers blinded to patient medical history and histology results. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Safety analysis set (SAF) 89Zr-TLX250 PET/CT imaging
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Reporting group description |
The safety analysis set (SAF) consisted of all patients who received 89Zr-TLX250. The qualitative 89Zr-TLX250 PET/CT imaging assessment was performed by 3 trained independent readers blinded to patient medical history and histology results. | ||
Subject analysis set title |
Full analysis set (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Full Analysis Set (FAS) consisted of all enrolled patients who had evaluable PET/CT imaging and a confirmed histopathology diagnosis.
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End point title |
89Zr-TLX250 PET/CT imaging - Reader 01 [1] | ||||||||||||||
End point description |
The primary study objective was to evaluate the diagnostic efficacy in all patients by comparing the sensitivity and specificity of 89Zr-TLX250 PET/CT imaging to thresholds of 0.70 (sensitivity) and 0.68 (specificity) for the lower 95% CI, using histology as standard of truth.
The co-primary variables as part of the primary objective were sensitivity and specificity of 89Zr-TLX250 PET/CT imaging to detect clear cell renal cell cancer (ccRCC).
The sensitivity and specificity values were determined by 3 independent readers. This endpoint included all 284 patients from the FAS.
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End point type |
Primary
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End point timeframe |
From baseline up to Day 90
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analyses of the primary endpoint are not yet ready for publication. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
89Zr-TLX250 PET/CT imaging - Reader 02 [2] | ||||||||||||||
End point description |
The primary study objective was to evaluate the diagnostic efficacy in all patients by comparing the sensitivity and specificity of 89Zr-TLX250 PET/CT imaging to thresholds of 0.70 (sensitivity) and 0.68 (specificity) for the lower 95% CI, using histology as standard of truth.
The co-primary variables as part of the primary objective were sensitivity and specificity of 89Zr-TLX250 PET/CT imaging to detect clear cell renal cell cancer (ccRCC).
The sensitivity and specificity values were determined by 3 independent readers. This endpoint included all 284 patients from the FAS.
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End point type |
Primary
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End point timeframe |
From baseline to Day 90
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analyses of the primary endpoint are not yet ready for publication. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
89Zr-TLX250 PET/CT imaging - Reader 03 [3] | ||||||||||||||
End point description |
The primary study objective was to evaluate the diagnostic efficacy in all patients by comparing the sensitivity and specificity of 89Zr-TLX250 PET/CT imaging to thresholds of 0.70 (sensitivity) and 0.68 (specificity) for the lower 95% CI, using histology as standard of truth.
The co-primary variables as part of the primary objective were sensitivity and specificity of 89Zr-TLX250 PET/CT imaging to detect clear cell renal cell cancer (ccRCC).
The sensitivity and specificity values were determined by 3 independent readers. This endpoint included all 284 patients from the FAS.
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End point type |
Primary
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End point timeframe |
From baseline to Day 90
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The analyses of the primary endpoint are not yet ready for publication. |
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From baseline to Day 90
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Safety analysis set (SAF)
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Reporting group description |
The safety analysis set (SAF) consisted of all patients who received 89Zr-TLX250. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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07 Nov 2018 |
Main changes were:
o The section on benefit risk assessment was updated
o Additional morphological CT imaging was removed from the study schedule to reduce the radioactivity burden.
o patient identification was adapted to a five-digit number composed of two parts to reflect the situation on site
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13 Dec 2018 |
Main changes were:
o Dosimetry data from previous studies were added as justification
o The need for a repeat anatomical CT scan during the study was omitted
o The CT scan was changed to a low-dose CT for the purpose of attenuation correction of the PET data only.
o As an administrative change, the contact details of the two central labs (for histology and for safety lab assessments) were added.
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22 Mar 2019 |
Main changes were:
o A calibrated ionization chamber for the individual measurement of the dose of 37 MBq of 89Zr-TLX250 was added to the protocol.
o Total radiation exposure was changed to reflect the whole-body exposure as a result of the imaging modalities used during the study.
o A cautionary note was inserted about the risks associated with this moderate exposure and the conditions of radiological protection for caregivers.
o According to new stability data for 89Zr-girentuximab, shipping and storage conditions were changed.
o In response to an investigator, ultrasound imaging was explicitly excluded from the standard of care imaging collected pre-baseline.
o Preliminary safety data from the bridging dosimetry study ZIRDOSE were added to the protocol to confirm the good safety profile of 89Zr-girentuximab. |
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15 Jun 2021 |
Main changes were:
o The first secondary objective/endpoint was also defined as primary objective/endpoint, to give two co-primary objectives/endpoints.
o The ranking order of the remaining objectives and endpoints was also changed, and some details were added to the objectives and endpoints for clarity.
o The statistical power was adjusted to accommodate for a higher percentage of non-ccRCC patients.
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01 Apr 2022 |
Main changes were:
o The secondary objectives were divided and reorganised into key secondary objectives and other secondary objectives to improve clarity and prioritise statistical evaluations.
o Due to the actual numbers of patients observed during trial enrolment with cT1a tumours that were ccRCC positive and ccRCC negative, the total sample size was increased to ensure a minimum of negative patients to meet the aims of the study. Therefore, the statistical sample size calculation as well as the definition of statistical power were slightly changed to adapt for patient recruitment.
o Due to the higher number of patients required to be enrolled to achieve a sufficient per-protocol population, the planned duration of the study had to be extended.
o In addition, some explanatory statements were added to account for FDA comments. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
