89Zr-TLX250 for PET/CT Imaging of ccRCC- ZIRCON Study

Study Overview
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Brief Summary
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89Zr-TLX250 is under clinical development as a diagnostic agent targeting clear cell renal cell carcinoma.

Detailed Description
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This is a confirmatory, prospective, open-label, multi-centre phase 3 study to evaluate sensitivity and specificity of 89Zr-TLX250 Positron Emission Tomography/Computed Tomography (PET/CT) imaging to non-invasively detect clear cell renal cell cancer (ccRCC) in adult patients with indeterminate renal masses (IRM), scheduled for partial or total nephrectomy. Patients, will be recruited in 12-15 renal cancer care specialist centres, who have access to state-of-the-art PET/CT imaging equipment. The study involves a single administration of 89Zr-TLX250. Imaging will then be conducted 5 +/-2 days post administration. The partial/total nephrectomy will then be performed at institutional discretion any time following the PET/CT imaging visit, but no later than 90 days post administration of 89Zr-TLX250. Histological tumour samples will be prepared and used for histological diagnosis of the renal mass (ccRCC or non-ccRCC) read by a central laboratory. On Day 5 +/-2 post study drug administration, an abdominal PET/CT imaging will be obtained. In patients, in which unexpected evidence for disseminated disease is observed, PET/CT imaging may be extended to complete whole body imaging(vertex of skull to toe) at the discretion of the investigator. Image data analyses will be performed by a central image core lab. Qualitative visual analysis (presence or absence of localised 89Zr-TLX250 uptake inside or in vicinity of renal lesion, as seen on contrast-enhanced CT or MRI), will be used to assess test performance or 89Zr-TLX-250 PET/CT imaging to non-invasively detect ccRCC, using histological results from the central histological reference laboratory as standard of truth.

Official Title
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A Confirmatory, Prospective, Open-label, Multi-centre Phase 3 Study to Evaluate Diagnostic Performance of Zirconium-labelled Girentuximab to Non-invasively Detect ccRCC by PET/CT Imaging in Patients With Indeterminate Renal Masses

Conditions
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Clear Cell Renal Cell Carcinoma

Intervention / Treatment
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* Diagnostic Test: 89Zr-girentuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written and voluntarily given Informed Consent Male or female ≥18 years of age Imaging evidence of a single indeterminate renal mass of ≤7cm in largest diameter (tumour stage cT1) , on CT or MRI with and without contrast agent, suspicious for ccRCC Scheduled for lesion resection as part of regular diagnostic work-up within 90 days from planned 89Zr-TLX250 administration Negative serum pregnancy tests in female patients of childbearing potential (at Screening and within 24 hours prior to receiving investigational product) for patients included in France only, verification and confirmation of their affiliation with a social security Sufficient life expectancy to justify nephrectomy Consent to practice double-barrier contraception until a minimum of 42 days after 89Zr-TLX250 administration Exclusion Criteria: Bioptic procedure (rather than a partial or total nephrectomy) planned for histological species delineation of IRM Renal mass known to be a metastasis of another primary tumour Active non-renal malignancy requiring therapy during the time frame of the study participation Chemotherapy, radiotherapy or immunotherapy within 4 weeks prior to the planned administration of 89Zr-TLX250 or continuing adverse effects (> grade 1) from such therapy (Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0) Planned antineoplastic therapies (for the period between administration of 89 Zr-TLX250 and imaging) Exposure to murine or chimeric antibodies within the last 5 years Previous administration of any radionuclide within 10 half-lives of the same Serious non-malignant disease (e.g. psychiatric, infectious, autoimmune or metabolic) that may interfere with the objectives of the study or within the safety of compliance of the subjects as judged by the Investigator Mental impairment that may compromise the ability to give Informed Consent and comply with the requirements of the study Exposure to any experimental diagnostic or therapeutic drug within 30 days from the date of planned administration of 89Zr-TLX250 Women who are pregnant or breastfeeding Known hypersensitivity to Girentuximab or DFO (Desferrioxamine) Renal insufficiency with glomerular filtration rate (GFR) ≤ 60 millilitres/min/1.73m2 Vulnerable patients (e.g being in detention)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: diagnostic, confirmatory, prospective, multi-centre
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 89Zr-girentuximab<br>A single administration of 37 Megabecquerel (MBq) (±10%) 89Zr-girentuximab, containing a mass dose of 10 mg of girentuximab, followed by a diagnostic scan on Day 5 ± 2 days after administration. | Diagnostic Test: 89Zr-girentuximab<br>* Single IV administration on Day 0, followed by diagnostic scan on Day 5 +/- 2 days.<br>* Other names: 89Zr-DFO-TFP-girentuximab (GTX);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate sensitivity and specificity of qualitative assessment of PET/CT imaging with 89Zr-TLX250 to noninvasively detect ccRCC in patients with indeterminate renal masses, using histology as standard of truth. | This outcome will be evaluated on all patients by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This will be compared against the histological determination of the lesion type following resection of the lesion | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Histological confirmation from nephrectomy material will serve as standard of truth. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine sensitivity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in the subgroup of patients with indeterminate renal masses of ≤ 4 cm in largest diameter (cT1a) | This outcome will be evaluated on all patients with a lesion ≤ 4cm in largest diameter by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To determine specificity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in the subgroup of patients with indeterminate renal masses of ≤ 4 cm in largest diameter (cT1a) | This outcome will be evaluated on all patients with a lesion ≤ 4cm in largest diameter by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To evaluate positive predictive value (PPV), and accuracy of 89Zr-girentuximab PET/CT imaging to detect ccRCC in patients with indeterminate solid renal masses, and in patients with indeterminate renal masses of ≤ 4 cm (cT1a). | This outcome will be determining the proportion (as a percent) of the whole study population in which the PET/CT imaging could correctly predict if an individual patient had clear cell renal cell carcinoma or can correctly predict if the patient did not have clear cell renal cell carcinoma | This analysis will be conducted after all patients have completed study involvement | 
| To define a standardized uptake value (SUV) cut-off for 89Zr-girentuximab, suitable to discriminate ccRCC from non-ccRCC | This outcome will be conducted on the whole study population and will use the counts derived from the PET/CT imaging of the 89Zr in the target tissue in order to see if there is a mathematical way to derive the tumour type information from the imaging alone. The tumour type will be determined by the histological sample obtained following resection. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab | 
| To evaluate the correlation between 89Zr- girentuximab SUVs and degree of histological carbonic anhydrase IX (CAIX) expression | This outcome will be assessed on all patients. The counts derived from the PET/CT imaging of the renal lesion will be compared with the amount of CAIX expressed in the histologically extracted sample | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab | 
| To evaluate inter-reader variability of diagnostic assessments of 89Zr- girentuximab PET/CT images, when performed by multiple readers | This outcome will be conducted on all patients. Three blinded readers operating independently will be used to read each patient PET/CT image and determine if the target lesion is positive for Zr89. A comparison of findings will then be made between the readers for each patient individually. | This analysis will be conducted through study completion, on average of 5 months | 
| To evaluate intra-reader variability of diagnostic assessments of 89Zr- girentuximab PET/CT images | This outcome will be conducted on a randomly determined subset of 10% of the patients. Three readers blinded to the histological outcome will be asked to read each patient PET/CT image on two occasions and determine if the target lesion is positive for Zr89. The results will be evaluated as a percent figure to consistently report the same finding with each patient. | This analysis will be conducted through study completion, on average of 5 months | 
| To evaluate safety parameter of Heart rate in patients administered with 89Zr-girentuximab. | This outcome will be measured as beats per minute on all patients with treatment-related adverse events based on criteria as determined by the NCI CTCAE v 5.0 criteria | Patients will be evaluated for the 90 day period following administration of 89Zr-girentuximab | 
| To evaluate safety parameter of blood pressure in patients administered with 89Zr-girentuximab. | This outcome will be measured as mmHg on all patients with treatment-related adverse events based on criteria as determined by the NCI CTCAE v 5.0 criteria | Patients will be evaluated for the 90 day period following administration of 89Zr-girentuximab | 
| To evaluate negative predictive value (NPV) and accuracy of 89Zr-girentuximab PET/CT imaging to detect ccRCC in patients with indeterminate solid renal masses | This outcome will be determining the proportion (as a percent) of the whole study population in which the PET/CT imaging could correctly predict if an individual patient had clear cell renal cell carcinoma or can correctly predict if the patient did not have clear cell renal cell carcinoma | This analysis will be conducted through study completion, on average 5 months | 
| To evaluate safety parameter related to Liver function in patients administered with 89Zr-girentuximab | This outcome will be measured on all patients with treatment-related adverse events based on criteria as determined by the NCI CTCAE v 5.0 criteria. Results will be assessed by number of participants with abnormal laboratory values. | Patients will be evaluated for the 90 day period following administration of 89Zr-girentuximab | 
| To evaluate safety parameter related to Renal function in patients administered with 89Zr-girentuximab | This outcome will be measured on all patients with treatment-related adverse events based on criteria as determined by the NCI CTCAE v 5.0 criteria. Results will be assessed by number of participants with abnormal laboratory values. | Patients will be evaluated for the 90 day period following administration of 89Zr-girentuximab | 
| To evaluate safety parameter related to Full Blood Count in patients administered with 89Zr-girentuximab | This outcome will be measured on all patients with treatment-related adverse events based on criteria as determined by the NCI CTCAE v 5.0 criteria. Results will be assessed by number of participants with abnormal laboratory values. | Patients will be evaluated for the 90 day period following administration of 89Zr-girentuximab | 
| To evaluate sensitivity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in patients with IRMs ≤ 3 cm lesions | This outcome will be evaluated on all patients with a lesion ≤ 3 cm in largest diameter by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To evaluate sensitivity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in patients with IRMs ≤ 2 cm. | This outcome will be evaluated on all patients with a lesion ≤ 2 cm in largest diameter by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To evaluate sensitivity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in patients with Bosniak 3 lesions. | This outcome will be evaluated on all patients with a Bosniak 3 lesion by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To evaluate sensitivity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in patients with Bosniak 4 lesions. | This outcome will be evaluated on all patients with a Bosniak 4 lesion by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To evaluate specificity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in patients with IRMs ≤ 3 cm lesions | This outcome will be evaluated on all patients with a lesion ≤ 3 cm in largest diameter by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To evaluate specificity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in patients with IRMs ≤ 2 cm. | This outcome will be evaluated on all patients with a lesion ≤ 2 cm in largest diameter by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To evaluate specificity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in patients with Bosniak 3 lesions. | This outcome will be evaluated on all patients with a Bosniak 3 by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 
| To evaluate specificity of 89Zr-TLX250 PET/CT imaging to detect ccRCC in patients with Bosniak 4 lesions. | This outcome will be evaluated on all patients with a Bosniak 4 by using a PET/CT machine to determine the uptake of the Zr89 radiotracer within the renal lesion. This amount of uptake in the lesion will be compared with the histologically determined cancer type following resection of the lesion. | Single diagnostic administration, followed by a diagnostic scan on Day 5 ± 2 days. Resection to be conducted within 90 days of administration of 89Zr-girentuximab. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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clear cell renal cell carcinoma, PET/CT imaging, 89Zr-girentuximab