177Lu-anti-PD-L1 sdAb in Metastatic Non-small Cell Lung Cancer

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 Non-small Cell Lung Cancer

This is a first-in-human, open-label study consisting of a Screening Period, an Imaging Period, and a Treatment Period in eligible non-small lung cancer patients who are positive for the biomarker PDL-1. The Screening period lasts up to 4 weeks. The Phase 0 (Imaging Period) is used to determine if patient's tumor(s) are still positive for the biomarker, as well as radiation dosimetry with low dose 177Lu-RAD204im (for a period of up to 2 weeks following the first injection of 177Lu-RAD204im), to assess the safety of the drug. Following the 2 week safety assessment, the subject is eligible to enter Phase I (Treatment Period) with gradual dose increases of 177Lu-RAD204tr. The Treatment Period lasts up to 3 cycles every 6 weeks, with additional extension to a maximum study dose interval of 12 weeks to be approved on a case-by-case basis in discussion with study Sponsor. During the Treatment Period, subjects will be assessed for both safety and treatment response using conventional images and clinical laboratory tests.

Study Overview

• Status: Recruiting
• Conditions: Non Small Cell Lung Cancer; PDL1 Gene Mutation
• Intervention / Treatment: Drug: 177Lu-RAD204

• Study Type: Interventional
• Enrollment (Estimated): 23
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Kenneth O'Byrne, MD; Phone Number: +610449091958; Email: kenneth.obyrne@health.qld.gov.au

Study Locations

• Australia
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
      • Contact: Kenneth O'Byrne, MD; Phone Number: +610449091958; Email: kenneth.obyrne@health.qld.gov.au
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Recruiting
      • Hollywood Private Hospital
      • Contact: Joe Cardaci, MD; Phone Number: 0893862844; Email: jcardaci@dni.com.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 histopathological confirmed metastatic NSCLC that is unresectable, progressive and for which standard treatment measures are no longer effective.
4. Participants with a documented history of PD-L1 positive NSCLC. Any number of prior treatment lines are allowed in this study, however at least one of the treatment line(s) must include an anti-PD(L)-1 antibody. Participants with any documented PD-L1 positivity by immunohistochemistry (IHC) without prior treatment with anti-PD(L)-1 antibody may be allowed on a case-by-case basis in discussion with study Sponsor, if it is determined not to put the participant at an increased risk of adverse drug effects and/or interfere with the integrity of study outcome.
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
6. Participants must have a life expectancy of >4 months in the opinion of the Investigator.
7. Women of childbearing potential (WOCBP) must have a negative beta-human chorionic gonadotropin (β-hCG) test and must not be breastfeeding. WOCBP are defined as those who are not surgically sterile or post-menopausal. Female subjects will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. Female subjects < 50 years old who meet the criteria for post-menopausal status without previous surgical sterilization should be considered for further investigation with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels to confirm serological post-menopausal status.
8. 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 the Protocol.
9. Male subjects 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 subjects must agree to not donate sperm during the study and for 14 days after the last injection of 177Lu-RAD204im and/or 4 months after the last dose of Lu-RAD204tr, whichever occurs later. Acceptable methods of contraception are described in the Protocol.
10. Subjects with previously treated brain metastases are eligible to participate if: they are clinically 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; and any neurologic symptoms returned to baseline. Note: Subjects with a history of leptomeningeal disease may not participate even if stable clinically.
11. For Phase I: Participants must have positive lesion(s) by 177Lu-RAD204im SPECT/CT as described in Image Review Manual. Estimated total radiation dose to healthy organs derived from phase 0 dosimetry must not exceed dose constraints according to the American Association of Physicists in Medicine Quantitative Analysis of Normal Tissue Effect in the Clinic (QUANTEC) and International Commission on Radiological Protection (ICRP), in discussion with study Sponsor.

Exclusion Criteria:

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 1 from prior anti-cancer therapy (except alopecia). Participants with > Grade 1 toxicity from prior anti-cancer 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.
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 or serum creatinine >1.5 x upper limit of normal (ULN)
   • Platelet count of < 75 x 109/L
   • Absolute neutrophil count (ANC) < 1.0 x 109/L
   • Haemoglobin < 9 g/dL
   • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x ULN, or > 5 x ULN for patients with known liver metastases
   • Total bilirubin > 1.5 x ULN, except for patients with documented Gilbert's syndrome who are eligible if total bilirubin ≤ 3 x ULN
   • For participants not taking warfarin or other anticoagulants: international normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 x ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤1.5 x 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 or acute myocardial infarction within 6 months prior to screening
   • Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (New York Heart Association (NYHA) grade ≥ 2)
   • Uncontrolled arterial hypertension or unstable clinically significant arrhythmia
   • 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 apply to participants in Phase I:

11. Major surgery within 4 weeks prior to first dose of 177Lu-RAD204tr. Exceptions may be approved on a case-by-case basis in discussion with study Sponsor, if it is determined not to put the participant at an increased risk of adverse drug effects and/or interfere with the integrity of study outcome.
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/noncytotoxic agents, whichever is shorter), prior to the first dose of 177Lu-RAD204tr. Focal palliative radiotherapy given within 28 days prior to the first dose of 177Lu-RAD204tr may be approved on a case-by-case basis in discussion with the Sponsor, if it is determined not to put the participant at an increased risk of adverse drug effects and/or interfere with the integrity of study outcome. For participants who received radiotherapy more than 28 days prior to the first dose of 177Lu-RAD204tr, efforts should be made to calculate the prior radiation absorbed dose to each critical organ such as the kidneys, liver, lungs, and bone marrow. The absorbed dose limits for critical organs should not exceed the cumulative absorbed dose from the prior radiopharmaceutical and/or external beam radiation therapy (EBRT) treatment(s) and the planned course of treatment in this study. Participants who would have cumulative absorbed dose to critical organs exceeded will not be enrolled in the study.
13. Has had or is scheduled to have major surgery < 28 days prior to the first dose of 177Lu-RAD204tr. Elective surgical procedures not considered to put participants at higher risk of AEs may be allowed on a case-by-case basis in discussion with the Sponsor.
14. Positive status for human immunodeficiency virus (HIV).
15. 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.
16. Any medical condition which, in the opinion of the Investigator, places the participant at an unacceptably high risk for toxicities.
17. 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time Activity Curves (TACs)	Percent of the injected activity vs time for selected organs and tumors	72 hours
Radiation dosimetry of Lu177-RAD204im	Absorbed radiation doses of 177Lu-RAD204im in critical organs (e.g., kidneys, bone marrow)	72 hours
Pharmacokinetics of 177Lu-RAD204im	Half-life of 177Lu-RAD204im in blood	72 hours
Biokinetics of 177Lu-RAD204im	Time-integrated activity coefficients of 177Lu-RAD204im in organs and tumor lesions	72 hours
Safety and tolerability of 177Lu-RAD204tr	The properties, incidence, nature and severity of AEs and SAEs per Common Terminology Criteria for Adverse Events (CTCAE) v5.0	6 weeks
Recommended dose(s) of 177Lu-RAD204tr for future exploration	Incidence of dose-limiting toxicities (DLTs) during the first 6 weeks following 177Lu-RAD204tr injection cycle of treatment	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of a single dose of 177Lu-RAD204im	The properties, incidence, nature and severity of AEs and SAEs per Common Terminology Criteria for Adverse Events (CTCAE) v5.0	6 weeks
Recommended dose(s) of 177Lu-RAD204im for future exploration	Incidence of dose-limiting toxicities (DLTs) in the first 2 weeks following 177Lu-RAD204im injection	2 weeks
Preliminary antitumor activity of 177Lu-RAD204tr	Objective response rates (ORR) as assessed by RECIST v1.1	Up to 30 weeks
Radiation dosimetry of 177Lu-RAD204tr	Absorbed radiation doses of 177Lu-RAD204tr in critical organs (e.g., kidneys, bone marrow)	72 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of agreement between 177Lu-RAD204im and standard of care imaging	Standard of care imaging may include but is not limited to 18F-FDG-PET, CT-scan and/or 99mTc-MDP-bone	Up to 30 weeks
Effect of 177Lu-RAD204im and 177Lu-RAD204tr on tumor markers	Circulating tumor DNA	Up to 30 weeks

Collaborators and Investigators

• Sponsor: Radiopharm Theranostics, Ltd

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: February 22, 2024
• First Submitted That Met QC Criteria: March 7, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 23, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Non Small Cell Lung Cancer; PDL1 Positive
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: 177Lu-RAD204.2023.0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes