Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000959673
Ethics application status
Approved
Date submitted
28/07/2023
Date registered
4/09/2023
Date last updated
21/04/2025
Date data sharing statement initially provided
4/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Lutetium-177-anti-Programmed Cell Death-Ligand 1 single domain antibodies (177Lu-anti-PD-L1 sdAb) in metastatic solid tumours.
Scientific title
Phase 0/1 Study of the Safety and Tolerability of 177Lu-RAD204, a Lutetium-177 Radiolabelled Single Domain Antibody Against Programmed Cell Death-Ligand 1 in Patients with Metastatic Solid Tumours.
Secondary ID [1] 309695 0
177Lu-RAD204.2023.0001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumours. 330762 0
Condition category
Condition code
Cancer 327599 327599 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study involves the use of investigational compound, 177Lu-RAD204 in patients with PD-L1 positive solid tumours. Among the tumour types to be included in this study are non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), triple negative breast cancer (TNBC), cutaneous melanoma, head and neck squamous cell carcinoma (HNSCC) and endometrial cancer. There will be 2 different phases in this study whereby Phase 0 (Imaging period) using 10 mCi of 177Lu-RAD204 and Phase I (treatment period) where 2 different dose levels (30 mCi and 40mCi) of 177Lu-RAD204 will be explored.

The investigational product/IP (177Lu-RAD204) given during Phase 0 will be indicated as 177Lu-RAD204im while the IP given during Phase 1 (treatment period) will be indicated as 177Lu-RAD204tr.

For Phase 0, after undergo screening, if patient is deemed eligible, they will be taking 1 dose of 10mCi of 177Lu-RAD204im and if they tolerate the study drug after 2 weeks, they can roll-over to Phase 1 where patient will receive either 30mCi (dose level 1) or 40mCi (dose level 2) of 177Lu-RAD204tr every 6 weeks with a maximum of 3 doses given. Further treatment cycle will be considered if investigator deems that patient is receiving benefit from study drug, with sponsor approval.

177Lu-RAD204 will be administered as intravenous (IV) bolus injection under the supervision of the study Investigator or appropriately qualified delegate. Patient medical record will be used to monitor adherence to the intervention.

The continuous safety evaluation will be performed by sponsor, medical monitor, the investigators. A DSMB (Data Safety Monitoring Board) or equivalent committee will be established for the determination of dose escalation and monitoring of dose-limiting toxicity (DLT) for all patients who received 177Lu-RAD204.
Intervention code [1] 326571 0
Diagnosis / Prognosis
Intervention code [2] 326572 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335456 0
Phase 0 To assess the biodistribution, pharmacokinetics and radiation dosimetry of 177Lu-RAD204im in selected organs and tumour lesions
Timepoint [1] 335456 0
• Time Activity Curves (TACs), describing % of the injected activity vs time will be derived for selected organs and tumours. - Investigational Product (IP) uptake (in % injected activity) over time will be assessed from the multi-timepoint Single Photon Emission Computed Tomography (SPECT CT) images acquired. The images will be analysed using MIM software. • Absorbed radiation doses of 177Lu-RAD204im in critical organs (kidneys, bone marrow, liver, lungs and bladder) - ICRP phantom-based dosimetry method will be used to calculate internal absorbed radiation doses in the critical organs. • Terminal Elimination Half-life of 177Lu-RAD204im in blood at baseline, 1 hr (Day 1), 3 hr (Day 1), 24 hr (Day 2), 48 hr (Day 3), 168 hr (Day 8) • Time-integrated activity coefficients of 177Lu-RAD204im in organs and tumour lesions - will be derived from the TACs determined per method above using SPECT/CT images.
Primary outcome [2] 335457 0
Phase 1 • To assess the safety and tolerability of 177Lu-RAD204tr • To determine the recommended dose(s) for 177Lu-RAD204tr for future explorations
Timepoint [2] 335457 0
• Safety is evaluated with the properties, incidence, nature and severity of adverse events (AEs) and serious adverse events (SAEs), abnormal laboratory parameters, vital signs, and electrocardiogram (ECG) results per Common Terminology Criteria for Adverse Event (CTCAE) v5.0- abnormal laboratory parameters & DLTs assessed using blood samples; Vital signs assessed using finger pulse oximeter and digital thermometer; • Incidence of dose-limiting toxicities (DLTs) during the first 6 weeks following 177Lu-RAD204tr injection cycle of treatment
Secondary outcome [1] 424725 0
Phase 0 • To assess the safety and tolerability of a single dose of 177Lu-RAD204im. • To confirm the recommended dose(s) of 177Lu-RAD204im for future exploration.
Timepoint [1] 424725 0
• Safety is evaluated with the properties, incidence, nature and severity of AEs and SAEs, abnormal laboratory parameters, vital signs, and electrocardiogram (ECG) results per Common Terminology Criteria for Adverse Events (CTCAE) v5.0- abnormal laboratory parameters assessed using blood samples; Vital signs assessed using finger pulse oximeter and digital thermometer.
Secondary outcome [2] 424726 0
Phase 1 • To assess the preliminary antitumour activity of 177Lu-RAD204tr.
Timepoint [2] 424726 0
Objective response rates (ORR), Duration of response (DOR) asssessed by RECIST v1.1 • Progression-free survival- Progression free survival is defined as the interval from date of enrolment to the date of first evidence of disease progression or death from any cause, whichever occurs first. Overall survival (OS) - to measure the length of time from start of 177Lu-RAD204tr until the death of patient from any cause.
Secondary outcome [3] 424727 0
Phase 1 • To assess the biodistribution, pharmacokinetic and radiation dosimetry of 177Lu-RAD204tr
Timepoint [3] 424727 0
• Time Activity Curves (TACs), describing % of the injected activity vs time will be derived for selected organs and tumours. - Investigational Product (IP) uptake (in % injected activity) over time will be assessed from the multi-timepoint Single Photon Emission Computed Tomography (SPECT CT) images acquired. The images will be analysed using MIM software. • Absorbed radiation doses of 177Lu-RAD204tr in critical organs (kidneys, bone marrow, liver, lungs and bladder) - ICRP phantom-based dosimetry method will be used to calculate internal absorbed radiation doses in the critical organs. • Terminal Elimination Half-life of 177Lu-RAD204tr in blood at baseline, 1 hr (Day 1), 3 hr (Day 1), 24 hr (Day 2), 48 hr (Day 3), 168 hr (Day 8) • Time-integrated activity coefficients of 177Lu-RAD204tr in organs and tumour lesions - will be derived from the TACs determined per method above using SPECT/CT images. .

Eligibility
Key inclusion criteria
Inclusion criteria
To be eligible for study, a participant must meet all of the following inclusion criteria:

1. Willing and able to provide informed consent prior to start of any study procedures and assessments and must be willing to comply with all study procedures.
2. Adult participants = 18 years of age.
3. Participants with a documented history of histopathologically confirmed metastatic NSCLC, SCLC, TNBC, cutaneous melanoma, HNSCC, and endometrial cancer with documented disease progression during or after their most recent line of anticancer therapy. Participants must be refractory to or have refused standard of care therapy (including PD-1/PD-L1 inhibitors), or have no standard of care therapy available that is likely to provide clinical benefit.
4. Participants with PD-L1 positive NSCLC, SCLC, TNBC, cutaneous melanoma, HNSCC, and endometrial cancer:
- If the participant tumour’s PD-L1 expression status is unknown, PD-L1 positivity may be determined in a pre-screening step whereby the participant may be approached to provide written informed consent to have their tumour tissue undergo IHC testing as determined by a validated test (tumour tissue may be obtained from archived samples or from a freshly obtained biopsy).
- Any number of prior treatment lines are allowed.
5. Must have at least 1 measurable target lesion according to RECIST version 1.1.
6. Eastern Cooperative Oncology Group (ECOG) performance status = 2.
7. Participants must have a life expectancy of = 4 months in the opinion of the Investigator.
8. Women of childbearing potential (WOCBP) must have a negative beta-human chorionic gonadotropin (ß-hCG) test and must not be breastfeeding. WOCBP are defined as those who are not surgically sterile or post-menopausal. Female participants will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. Female participants < 50 years old who meet the criteria for post-menopausal status without previous surgical sterilisation should be considered for further investigation with luteinising hormone (LH) and follicle stimulating hormone (FSH) levels to confirm serological post-menopausal status.
9. WOCBP must agree to use a highly effective method of contraception during the study and for 14 days after the last injection of 177Lu-RAD204im and/or 6 months after the last dose of 177Lu-RAD204tr, whichever occurs later. Acceptable methods of contraception are described in Section 13.3 of the Protocol.
10. Male participants who are able to father a child must agree to avoid impregnating a partner and to adhere to a highly effective method of contraception during the study and for 14 days after the last injection of 177Lu-RAD204im and/or 6 months after the last dose of 177Lu-RAD204tr, whichever occurs later. All male participants must agree to not donate sperm during the study and for 14 days after the last injection of 177Lu-RAD204im and/or 6 months after the last dose of Lu-RAD204tr, whichever occurs later. Acceptable methods of contraception are described in Section 13.3 of the Protocol.
11. Participants with previously treated brain metastases are eligible to participate if:
- they are neurologically and radiologically stable (no evidence of progression by imaging; same imaging modality [magnetic resonance imaging (MRI) or computed tomography (CT) scan] must be used for each assessment) for at least 28 days prior to the first dose of 177Lu-RAD204,
- do not require steroids to treat associated neurological symptoms, and
- have no history of leptomeningeal disease or spinal cord compression.
12. For Phase I:
- Participants must have positive lesion(s) by 177Lu-RAD204im SPECT/CT per central review as described in Image Review Charter, and
- Participants without any positive lesion by 177Lu-RAD204im SPECT/CT, e.g. due to poor image quality, may be allowed to enrol on a case-by-case basis at the discretion of the Principal Investigator and in discussion with study Sponsor, provided the participant’s tumour is known to express PD-L1.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria
A participant who meets any of the following exclusion criteria must be excluded from study:
1. History of prior organ transplant.
2. Any other known, active malignancy, except for treated cervical intraepithelial neoplasia or non-melanoma skin cancer. Patients with a history of malignancies of low recurrence potential who have received curative-intent therapy may be approved on a case-by-case basis in discussion with study Sponsor, if it is determined not to put the patient at an increased risk of adverse drug effects and/or interfere with the integrity of study outcome.
3. Have any medical condition that would, in the Investigator’s judgment, prevent the participant’s full participation in the clinical study due to safety concerns or compliance with clinical study procedures such as participants with severe claustrophobia who are unresponsive to oral anxiolytics, participants with low back pain who cannot lie comfortably on an imaging table, participants who are hyperactive or hyperkinetic such that they cannot tolerate lying still for multiple time point imaging procedures, etc.
4. Residual toxicity = Grade 2 from prior anti-cancer therapy (except alopecia).
5. History of uncontrolled allergic reactions and/or known or expected hypersensitivity to protein therapeutics, 177Lu-RAD204 or any of its excipients.
6. Inadequate organ functions as reflected in laboratory parameters:
- Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 60 mL/min
- Platelet count of < 100 × 10^9/L
- Absolute neutrophil count (ANC) < 1.5 × 10^9/L
- Haemoglobin < 9 g/dL
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN, or > 5 × ULN for patients with known liver metastases
-Total bilirubin > 1.5 × ULN, except for patients with documented Gilbert’s syndrome who are eligible if total bilirubin = 3 × ULN
- For participants not taking warfarin or other anticoagulants: international normalised ratio (INR) = 1.5 or prothrombin time (PT) = 1.5 × ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) = 1.5 × ULN. Participants taking warfarin must be on a stable dose that results in a stable INR < 3.5. Among participants receiving other anticoagulant therapy, PT or aPTT must be within the intended therapeutic range of the anticoagulant.
7. Patients requiring blood product transfusion within 4 weeks of first dose of 177Lu-RAD204tr are not eligible to participate.
8. Clinically significant cardiovascular disease including but not limited to:
- Unstable angina
- Acute myocardial infarction within 6 months prior to screening
- New York Heart Association (NYHA) Class II or greater congestive heart failure (see Section 20.6)
- Clinically significant abnormalities in rhythm, conduction or morphology on resting ECG (e.g. complete left bundle branch block, third degree heart block)
- Uncontrolled hypertension
- Known LVEF < 50%
- QTcF > 470 msec for females and QTcF > 450 msec for males on screening electrocardiogram (ECG) or congenital long QT syndrome.
9. Participation in any other investigational trial at the time of informed consent signature.
10. Pregnant or lactating women.

The following exclusion criteria applies to participants in Phase I:
11. Major surgery within 4 weeks prior to first dose of 177Lu-RAD204tr.
12. Received anti-cancer therapy, including chemotherapy, immunotherapy, radiation therapy, biologic, herbal therapy, or any investigational therapy or investigational device, within 28 days (or 5 half-lives for biologic/non-cytotoxic agents, whichever is shorter), prior to the first dose of 177Lu-RAD204tr.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher immune-mediated AE.
NOTE: endocrine immune-mediated AEs that are controlled with replacement therapy are allowed.
14. Has had or is scheduled to have major surgery < 28 days prior to the first dose of 177Lu-RAD204tr.
15. Positive status for human immunodeficiency virus (HIV).
16. Active or chronic hepatitis B or C. Chronic hepatitis B or hepatitis C with undetectable viral loads on stable suppression therapy may be allowed on a case-by-case basis in discussion with study Sponsor.
17. Any medical condition which, in the opinion of the Investigator, places the participant at an unacceptably high risk for toxicities.
18. Any uncontrolled intercurrent illness or clinically significant uncontrolled condition(s), including but not limited to active bacterial, fungal, or viral infections requiring systemic therapy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Eligible patient will receive single dose of 177Lu-RAD204im in Phase 0 and if no safety concern, patient will roll-over to Phase 1 to receive 177Lu-RAD204tr (one of the 2 treatment dose levels).
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/04/2024
Actual
9/07/2024
Date of last participant enrolment
Anticipated
30/06/2025
Actual
Date of last data collection
Anticipated
10/10/2025
Actual
Sample size
Target
23
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA
Recruitment hospital [1] 26184 0
Wollongong Hospital - Wollongong
Recruitment hospital [2] 27062 0
Cancer Research SA - Adelaide
Recruitment hospital [3] 27063 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 27798 0
GenesisCare - Murdoch - Murdoch
Recruitment postcode(s) [1] 42056 0
2500 - Wollongong
Recruitment postcode(s) [2] 43129 0
5000 - Adelaide
Recruitment postcode(s) [3] 43130 0
2747 - Kingswood
Recruitment postcode(s) [4] 43990 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 313889 0
Commercial sector/Industry
Name [1] 313889 0
Radiopharm Theranostics Ltd
Country [1] 313889 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Radiopharm Theranostics Ltd
Address
Suite 1, Level 3, 62 Lygon Street
Carlton South, VIC 3053
Country
Australia
Secondary sponsor category [1] 315736 0
Commercial sector/Industry
Name [1] 315736 0
GenesisCare Clinical CRO Pty Ltd
Address [1] 315736 0
Buildings 7C & D, Level 1. The Mill, 41-43 Bourke Road Alexandria NSW 2015
Country [1] 315736 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314699 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 314699 0
Ethics committee country [1] 314699 0
Australia
Date submitted for ethics approval [1] 314699 0
06/11/2023
Approval date [1] 314699 0
22/12/2023
Ethics approval number [1] 314699 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126762 0
A/Prof Daniel Brungs
Address 126762 0
Wollongong Hospital Loftus St, Wollongong NSW 2500
Country 126762 0
Australia
Phone 126762 0
+61 02 42225200
Fax 126762 0
Email 126762 0
[email protected]
Contact person for public queries
Name 126763 0
Dr Sherin Al-Safadi
Address 126763 0
Radiopharm Theranostics Pty. Suite 1, Level 3, 62 Lygon StreetCarlton South, VIC 3053
Country 126763 0
Australia
Phone 126763 0
+61 03 98245254
Fax 126763 0
Email 126763 0
[email protected]
Contact person for scientific queries
Name 126764 0
Sherin Al-Safadi
Address 126764 0
Radiopharm Theranostics Pty.Suite 1, Level 3, 62 Lygon StreetCarlton South, VIC 3053
Country 126764 0
Australia
Phone 126764 0
+61 03 98245254
Fax 126764 0
Email 126764 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: No individual participant data will be publicly available. Data will be anonymised and analysed as a cohort.



What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.