First-in-human Diagnostic Imaging Profile of the Theranostic Pair [68Ga]Ga-DOTA-STR-17126 and Low Dose [177Lu] Lu-DOTA-STR-17126 in Patients With Advanced or Metastatic Cancer

This study is an open-label, first-in-human, exploratory Phase 0 clinical trial conducted at a single centre in Australia to characterise the safety profile, imaging performance, biodistribution, pharmacokinetics, and radiation dosimetry of the DOTA-STR-17126 theranostic pair in patients with advanced malignancy. The investigational approach uses a stepwise theranostic design in which all enrolled participants receive a single intravenous bolus administration of the GRPR-targeted PET radiopharmaceutical [68Ga]Ga-DOTA-STR-17126, followed by serial whole-body PET/CT imaging to evaluate tumour uptake and normal organ distribution. Participants demonstrating sufficient GRPR-positive tumour uptake on PET imaging may subsequently receive a single low-dose, slow intravenous infusion of [177Lu]Lu-DOTA-STR-17126, with serial planar and SPECT/CT imaging performed over several days to assess biodistribution and enable organ and tumour dosimetry calculations. Blood and urine samples are collected at predefined time points to support pharmacokinetic and radiation dosimetry analyses, alongside intensive clinical and laboratory safety monitoring. The study is exploratory in nature and is designed to optimise imaging protocols, generate human dosimetry data, and establish an initial safety and tolerability profile for this novel GRPR antagonist-based theranostic platform, thereby informing the design and dose selection for subsequent phase I/II clinical development.

Inclusion criteria

Inclusion criteria

refer to the enrolment of participants for the PET/CT and SPECT/CT imaging with the radioligands; PET imaging tracer [68Ga]Ga-DOTA-STR-17126 and with the SPECT imaging tracer [177Lu]Lu-DOTA-STR-17126. Participants must meet all of the following inclusion criteria to be eligible for enrolment.

• Ability to understand and willingness to provide informed consent
• Adults ≥ 18 years of age
• Must have the following histologically or cytologically confirmed diagnosis of advanced or metastatic i. breast cancer ii. prostate cancer
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Participant must have clinical or radiological documented tumour progression as established by the Investigator within 30 days of signing consent for the study
• Participants who have exhausted standard-of-care systemic therapies in their metastatic setting. At least one detectable by conventional imaging tumour lesion with any diameter of ≥ 1 cm in size
• Participants must have adequate organ and bone marrow function, defined as follows:

i. Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 ii. Platelet count ≥ 100,000/mm3 iii. Haemoglobin ≥ 9.0 g/dL iv. AST, ALT, alkaline phosphatase ≤ 3 times upper limit of normal (ULN) if there is no evidence of liver metastases or ≤5 ULN in the presence of liver metastases v. Total bilirubin ≤ 2 times upper limit of normal (ULN) vi. Creatinine ≤ 2 times ULN and creatinine clearance (CrCL) ≥ 60mL/min using the Cockcroft Gault equation (Appendix 2)

• Able to remain still for up to 60 minutes per scan
• Any other condition which, in the opinion of the Investigator, would preclude participation in this study Optional: Participants that have available archival tissue (at least 15 consecutive, unstained, formalin-fixed, paraffin embedded (FFPE) slides or 1 FFPE block), or a fresh tumour biopsy sample that opt to provide samples will be used for GRPR analysis (histology staining or RNA measurements). Participants without any archival tissue or fresh biopsy sample, or who refuse to provide archival tissue are still eligible for the study.

Exclusion criteria

Participants must not be enrolled into the trial if one or more of the following criteria are met. Participants must NOT meet any of the following Exclusion criteria to be eligible for enrolment:

• Known hypersensitivity to the investigational medicinal products (DOTA-STR-17126) or any of the excipients.
• Participants with Class 3 or 4 New York Heart Association (NYHA) Congestive Heart Failure.
• Average QTc (using the Fridericia correction calculation) > 470 msec for females and QTcF >450 msec for males on screening ECG or history of congenital long QT syndrome.
• Clinically significant bleeding within two weeks prior to trial entry (i.e., gastrointestinal bleeding, intracranial bleeding).
• Pregnant or lactating women. i. For female participants of childbearing potential or male participants with female partner of childbearing potential, who are not willing to practice highly effective contraception during the trial and for at least 6 months after [177Lu] Lu-DOTA-STR-17126 administration ii. Sexually active males must use a condom during intercourse while taking the drug and for 4 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Female partners of childbearing potential should use highly effective contraceptive methods during and up to 6 months after stopping treatment.
• Have any medical condition that impairs complete bladder emptying. Participants with permanent urinary indwelling catheter (IDC) or nephrostomy may be allowed to enrol on a case-by-case basis in discussion with Principal Investigator, 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.
• Major surgery, defined as any surgical procedure that involves general anaesthesia and a significant incision (i.e., larger than what is required for placement of a central venous access, percutaneous feeding tube, or biopsy) within 30 days before study day 1 or anticipated surgery within the subsequent 43 days (6 weeks).
• Has an additional active malignancy requiring therapy within the past 2 years.
• History of another malignancy within 3 years before study enrolment. A subject with the following malignancies is allowed if considered cured or unlikely to recur within 3 years:

i. Carcinoma of the skin without melanomatous features ii. Curatively treated cervical carcinoma in situ iii. Bladder tumours considered superficial such as non-invasive (T1a) and carcinoma in situ (T1s), thyroid papillary cancer with prior treatment

• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy within 30 days prior to trial enrolment.
• Psychiatric illness/social situations that would interfere with compliance with study requirements.
• Cannot undergo PET/CT scanning because of weight limits (350 lbs or 160 kg).
• Prior exposure to any other GRPR-targeting therapeutic agents.
• Prior treatment with any systemic anti-cancer therapy including chemotherapy, immunotherapy, biological therapy, radiation therapy, biologic, hormonal or herbal therapy, or any investigational therapy or investigational device, unless:

i. Standard of care or maintenance therapy such as, luteinizing hormone-releasing hormone (LHRH) or gonadotropin releasing hormone (GnRH) for patients with prostate cancer; selective estrogen receptor modulators or aromatase inhibitors or GnRH inhibitors for breast cancer, ii. Within more than 30 days of chemotherapy, herbal therapies and monoclonal antibodies, iii. Within more than 5 half-lives for biologic/non-cytotoxic targeted agents, iv. Within more than 8 weeks prior radiation therapies External Beam Radiotherapy (EBRT) and/or Radioligand Therapy (RLT). Focal palliative radiotherapy given within 8 weeks prior to the low dose of [177Lu] Lu-DOTA-STR-17126 may be approved on a case-by-case basis, 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, v. For participants who received radiotherapy (EBRT and/or RLT) more than 8 weeks prior to the low dose of 177Lu-DOTA-STR-17126, efforts should be made to calculate the prior radiation absorbed dose to each critical organ such as the kidneys, liver, lungs, and bone marrow.

• Patients with a history of inflammatory disease which according to the investigator may interfere with correct evaluation of radioactive uptake, especially those affecting the thoraco-abdominal cavities (i.e., autoimmune, granulomatous disease).
• Any clinically significant toxicity (with the exception of alopecia) related to prior anti-tumour therapy not resolved to Grade 1 or baseline.