Clinical trial NCT04726033: 64Cu-TLX592 Phase I Safety, PK, Biodistribution and Dosimetry Study (CUPID Study)
Official title: A Phase I, Single Centre, Open-label Study of TLX592 to Assess the Safety and Tolerability, Pharmacokinetics, Biodistribution and Radiation Dosimetry in Patients Diagnosed With Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Metastatic Prostate Cancer
Keywords: prostate cancer
biodistribution
64Cu-TLX592
pharmacokinetics
dosimetery
safety
Lead sponsor: Telix Pharmaceuticals (Innovations) Pty Limited
Sponsor class: INDUSTRY
First posted: 2021-01-27
Enrollment: 14
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will consist of four groups with the initial three groups undergoing dose escalation and the fourth group will be to confirm the optimal dose and imaging conditions.
Primary purpose: TREATMENT

Brief summary: This is a Phase 1 trial of TLX592, a humanised, engineered monoclonal antibody HuX592r conjugated with a DOTA chelator and radiolabelled with 64Cu (64Cu-TLX592). TLX592 is being developed as a PSMA-targeting antibody to be radiolabelled with a therapeutic radiosotope for the treatment of PSMA-expressing tumours, therefore this study has been designed to assess the safety and tolerability, pharmacokinetics, whole body biodistribution and radiation dosimetry of 64Cu-TLX592.

Detailed description: The optimisation dose and imaging conditions will be conducted in prostate cancer patients with with oligometastatic disease ( (defined as 5 sites or less outside of the prostate bed). On determining the optimal dose and imaging conditions, an additional cohort of patients with a higher tumour burden such as multiple metastatic sites across ≥10 regions will be assessed.

Study conduct:

Nine, prostate cancer patients with oligometastatic disease as detected using 68Ga-PSMA-11 or 18F-DCFPyl PSMA PET/CT scanning (defined as 5 sites or less outside of the prostate bed) will be randomised to one of three treatment groups to receive a single injection of:

* Group 1: 2mg of TLX592, labelled with 300 MBq (± 10%) 64Cu.
* Group 2: 2mg of TLX592, labelled with 300 MBq (± 10%) 64Cu combined with 8mg of unlabelled TLX592 (mass dose of 10mg).
* Group 3: 2mg of TLX592, labelled with 300 MBq (± 10%) 64Cu combined with 18mg of unlabelled TLX592 (mass dose of 20mg). If one of the three patients in a specific group experiences a dose-limiting toxicity, three more patients will be treated at the same dose level.

Patients with a higher tumour burden such as multiple metastatic sites across ≥10 regions \[regions: prostate bed, pelvic lumph nodes, skeleton, distant sites (including viscera)\] as detected on 68Ga-PSMA or 18F-DCFPyl PMSA imaging agent will be allocated to a fourth group.

• Group 4: based on the result of Groups 1-3, the optimal dose and imaging timepoints will be selected to treat 3 patients with higher tumour burden (≥10 metastatic sites and/or visceral disease as detected on a 68Ga-PSMA-11 or 18F-DCFPyl PSMA PET/CTscan).

For dosimetry analysis, biodistribution whole body PET/CT imaging will be performed at 1, 4 ± 0.5h, 20 ± 4h, with the option for a an additional two scans to be performed between the 36-120 hours post administration of the investigational product. The additional scans after the 20h timepoint will be at the discretion of the investigator. Patients will be imaged on a Siemens Biographe scanner, offering the possibility of TOF (time-of-flight) and non-TOF reconstruction.

Comparative tumour PET/CT imaging:

On Days 0, 1 and potentially at 36-120h the biodistribution and tumour imaging will be performed using gated or list mode acquisition, for generation of sub-partitioned data.Such data will allow the mathematical generation of statistically independent images for various dose levels, based on the actual dose administered in the trial.

An end of study visit will be conducted on Day 28 ± 2 days. 64Cu-TLX592 images will be centrally analysed for absorbed organ and whole body doses in a standardised fashion. In addition, tumour absorbed doses will be determined for scientific purposes (estimation of achievable tumour doses of therapeutic nuclides labelled to TLX592). All image data analyses will be performed / confirmed centrally.

Pharmacokinetic analysis:

Blood samples will be taken at the following times and counted in a gamma counter:

* Pre-dose
* 1, 4 ± 0.5h, 20 ± 4h and 48 ± 4h after the administration of 64Cu-TLX592.

Eligibility criteria: Inclusion Criteria:

* Written informed consent.
* Biochemically recurrent metastatic adenocarcinoma of the prostate, or metastatic primary adenocarcinoma of the prostate.
* Histologically or cytologically confirmed diagnosis of adenocarcinoma of prostate.
* PSMA-expressing prostate adenocarcinoma as seen on 68Ga-PSMA-11 or 18F- DCFPyl PSMA PET/CT scanning within the last 1 month showing PSMA-avid disease.
* ECOG performance status of 0 - 1.
* Normal organ function and marrow reserve:
* White blood cell (WBC) count ≥ 2.5 x 109/L or absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
* Platelets ≥ 100 x 109/L.
* Haemoglobin ≥ 90g/L.
* Bilirubin \< 1.5 x upper limit of normal (ULN) (or if bilirubin is between 1.5 - 2x ULN, must have a normal conjugated bilirubin).
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.0 x ULN (or

  * 5.0 x ULN in the presence of liver metastases).
* Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min.

Exclusion Criteria:

A patient is excluded from participation in the trial if one or more of the following criteria are met:

* Known active brain metastases.
* Serious active infection (as assessed by investigator).
* Other serious illness(es) involving the cardiac, respiratory, CNS, renal, hepatic or haematological organ systems which might preclude completion of this study or interfere with determination of causality of any adverse effects experienced in this study.
* Known or suspected allergies, hypersensitivity, or intolerance to the IMP or its excipients.
* Other investigational agents within 4 weeks of randomization.
* Radiotherapy or immunotherapy within 4 weeks prior to the planned administration of 64Cu-TLX592 or continuing adverse effects (\> grade 1) from such therapy \[Common Terminology Criteria for Adverse Events (CTCAE) version 5\].
* Previous administration of any radionucleotide within 10 half-lives of 64Cu.
* Inability to understand, or unwilling to sign, a written informed consent document or to follow investigational procedures in the opinion of the investigator.
* Patients who are unable to maintain self-care.

Primary outcomes:
measure: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0
timeFrame: Day 1 to 28
measure: Pharmacokinetics of 64Cu-TLX592
timeFrame: Day 1-4 after a single administration of 64Cu-TLX592
measure: Biodistribution of 64Cu-TLX592
timeFrame: Up to 24h after a single administration of 64Cu-TLX592
measure: Dosimetry of 64Cu-TLX592
timeFrame: Up to 5 days after a single administration of 64Cu-TLX592
Secondary outcomes:
measure: Optimal antibody dose of TLX592
timeFrame: Single diagnostic administration 1 day, followed by a diagnostic scan on Day 1
measure: Comparison of PSMA-targeting of different PMSA-imaging agents
timeFrame: Single diagnostic administration 1 day, followed by a diagnostic scan on Day 1.
Other outcomes:
Locations:
city: Perth
country: Australia
facility: Envision Medical Imaging
state: Western Australia
city: Perth
country: Australia
facility: GenesisCare Wembly
state: Western Australia
Study officials:
References: