Phase II Trial of Lu-177 FAP-2286 in Patients With Carcinoma of Unknown Primary

The aim of the Lu-FAP-CUP trial is to assess preliminary efficacy signal of 177Lu-FAP-2286 in CUP patients with 68Ga-FAPI-46 positive disease.

This is a prospective, open label, single site, phase II clinical trial designed to evaluate the safety and efficacy of 177Lu-FAP-2286 monotherapy in CUP patients.

Patients who meet all eligibility criteria will be registered into the trial and receive up to 6 cycles of 177Lu-FAP-2286 monotherapy every 28 days.

Inclusion criteria

Patients must meet all the following criteria for trial entry:

• Patient has provided written informed consent
• Patients aged 18 years or over at Screening
• Diagnosed with CUP based on a diagnostic work-up, including, but not limited to; a detailed clinical assessment; a CT CAP; pathological review of tumour tissue; and other appropriate tests as per the Cancer Council Optimal Care Pathway guidelines.
• Progressed on 1st line platinum doublet chemotherapy +/- immunotherapy +/- antibody therapy
• 68Ga-FAPI-46 positive disease on 68Ga-FAPI-46-PET/CT defined as 68Ga-FAPI-46 uptake at PET/CT with SUVmax of ≥ 8 in at least 50% of target lesions and above surrounding background in the remaining target lesions
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix 1).
• Life expectancy greater than 3 months
• Adequate bone marrow, hepatic and renal function defined by the following laboratory results:

• Haemoglobin ≥ 90 g/L independent of transfusion (no red blood cell transfusion within 4 weeks before the haematology Screening assessment)
• Absolute neutrophil count ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Creatinine clearance (CrCl) ≥ 60 mL/min calculated using the Cockcroft-Gault equation (Appendix 2)
• Serum bilirubin ≤ 1.5 x upper limit of normal (ULN); Patients with known Gilbert's disease may have a bilirubin ≥ 3.0 x ULN
• Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2 x ULN (or ≤ 5 x ULN in the presence of liver metastases)
• Have measurable disease per RECIST1.1 (Appendix 3)
• Sexually active Patients are willing to use medically acceptable forms of barrier contraception as outlined in Section 8.1.5.1, during treatment and for 6 months following the last dose of treatment
• Women of childbearing potential (WCBP) must have a negative serum pregnancy test result
• Willing to undergo biopsies if disease is considered accessible and biopsy is feasible
• Willing and able to comply with all trial requirements, including all treatment and required assessments and follow-up procedures, in the Investigator's judgment

Exclusion criteria

• Patients who meet any of the following criteria will be excluded from trial entry:

• Uncontrolled medical or psychological conditions that may prevent commencement of systemic treatment
• Symptomatic and/or untreated central nervous system metastases or leptomeningeal disease. Patients must be clinically stable for at least 4 weeks without steroid treatment
• Surgical procedure (minor surgery ≤ 5 days, or major surgery ≤ 21 days) prior to registration or active infection requiring systemic treatment Note: Placement of vascular access devices, laparoscopy and prophylactic procedures to stabilise bone lesions are not considered major surgical procedures
• Received anticancer treatment ≤ 14 days prior to registration (≤ 28 days prior in case of checkpoint inhibitor or other antibody therapies)
• Severe impaired cardiac function (left ventricular ejection fraction < 35%) or clinically significant uncontrolled cardiac disease
• Severe urinary incontinence, voiding dysfunction, or unrelieved urinary obstruction
• Ongoing AEs from anticancer treatment > Grade 1 as per CTCAE v5.0, with the exception of alopecia
• Received prior radiopharmaceutical therapy or radioembolisation, or prior extensive external beam radiation therapy (EBRT) to bone marrow or any prior EBRT directly to kidney or received any EBRT within 2 weeks prior to registration
• Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo procedures outlined in this protocol with reasonable safety
• Prior cancer diagnosis with the exception of:

• Malignancy treated with curative intent and with no known active disease ≥ 3 years and of low potential risk of recurrence
• Adequately treated basal cell or squamous cell skin carcinoma or non-invasive melanoma
• Adequately treated non-muscle invasive bladder cancer (Tis, Ta and low grade T1 tumours)
• Adequately treated carcinoma in situ without evidence of disease
• Cancer patients with incidental histologic findings of prostate cancer that, in the opinion of the Investigator, is not deemed to require active therapy (e.g., incidental prostate cancer identified following cystoprostatectomy that is tumour/node/metastasis stage ≤ pT2N0)
• Greater than one prior line of systemic treatment
• Known allergy or reaction to 18F, 68Ga or 177Lu radiopharmaceuticals
• Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in the protocol with reasonable safety