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

The aim of the study is to test if a new radionuclide therapy, called 177-Lu-FAP-2286, works to treat cancer in patients with Cancer of Unknown Primary (CUP).

Study Overview

• Status: Not yet recruiting
• Conditions: Cancer of Unknown Primary
• Intervention / Treatment: Drug: 177Lu-FAP-2286

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Linda Mileshkin; Phone Number: +61 3 8559 5000; Email: Contact.Bact@petermac.org
• Study Contact Backup: Name: Tharani Sivakumaran; Phone Number: +61 3 8559 5000; Email: Contact.Bact@petermac.org

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
      • Contact: Linda Mileshkin; Phone Number: +61 3 8559 5000; Email: Contact.Bact@petermac.org
      • Contact: Tharani Sivakumaran; Phone Number: +61 3 8559 5000; Email: Contact.Bact@petermac.org

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

Patients must meet all the following criteria for trial entry:

1. Patient has provided written informed consent
2. Patients aged 18 years or over at Screening
3. 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.
4. Progressed on 1st line platinum doublet chemotherapy +/- immunotherapy +/- antibody therapy
5. 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
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix 1).
7. Life expectancy greater than 3 months

8. 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)
9. Have measurable disease per RECIST1.1 (Appendix 3)
10. 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
11. Women of childbearing potential (WCBP) must have a negative serum pregnancy test result
12. Willing to undergo biopsies if disease is considered accessible and biopsy is feasible
13. 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:

  1. Uncontrolled medical or psychological conditions that may prevent commencement of systemic treatment
  2. Symptomatic and/or untreated central nervous system metastases or leptomeningeal disease. Patients must be clinically stable for at least 4 weeks without steroid treatment
  3. 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
  4. Received anticancer treatment ≤ 14 days prior to registration (≤ 28 days prior in case of checkpoint inhibitor or other antibody therapies)
  5. Severe impaired cardiac function (left ventricular ejection fraction < 35%) or clinically significant uncontrolled cardiac disease
  6. Severe urinary incontinence, voiding dysfunction, or unrelieved urinary obstruction
  7. Ongoing AEs from anticancer treatment > Grade 1 as per CTCAE v5.0, with the exception of alopecia
  8. 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
  9. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo procedures outlined in this protocol with reasonable safety

  10. 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
  11. 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)
  12. Greater than one prior line of systemic treatment
  13. Known allergy or reaction to 18F, 68Ga or 177Lu radiopharmaceuticals
  14. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in the protocol with reasonable safety

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 177Lu-FAP-2286; In this single arm study, patients with CUP will receive up to 6 cycles of 177Lu-FAP-2286 monotherapy every 28 days.	Drug: 177Lu-FAP-2286; 177Lu-FAP-2286 is a novel radioligand therapy. FAP-2286 is a small molecular ligand that binds to the fibroblast activated protein on cancer associated fibroblasts. Lutetium-177 (177Lu) is a nuclear reactor-produced radiometal with a half-life of 6.7 days. 250 mCi of 177Lu-FAP-2286 will be given once every 28 days for a maximum duration of 6 cycles of treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR is defined as complete response (CR) or partial response (PR) as per RECIST1.1 at any time after commencement of treatment.	From start of treatment until end of follow-up (study completion- 2 years after the last patient has commenced treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS will be measured from the date of treatment commencement to the first evidence of disease progression per RECIST1.1 oir death due to any cause	start of treatment until end of follow-up period (study completion- 2 years after the last patient has commenced treatment) or death/withdrawal of patient consent
Evaluation of Safety	Safety will be evaluated by determining the type, grade and relationship to treatment of Adverse Events (AE's), assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0	From the start of treatment until the 6-week post treatment safety follow-up visit
PERCIST response	18F-FDG-PET/CT response 12 weeks after commencement of FAP-directed radioligand therapy as per PERCIST	From screening till 12 weeks after commencing treatment

Collaborators and Investigators

• Sponsor: Peter MacCallum Cancer Centre, Australia
• Collaborators: National Health and Medical Research Council, Australia; Novartis; University of Melbourne; SOFIE
• Investigators: Principal Investigator: Linda Mileshkin, Peter MacCallum Cancer Centre, Australia

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: August 28, 2025
• First Submitted That Met QC Criteria: February 22, 2026
• First Posted (Actual): February 25, 2026

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 22, 2026
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: radiopharmaceutical; theranostic; cancer of unknown primary; Peptide Receptor Radionuclide Therapy (PRRT); 177Lu-FAP-2286; FAP-2286; Fibroblast Activation Protein (FAP); cancer-associated fibroblasts (CAF); Peptide-Targeted Radioligand Therapy (PTRT); Targeted radioligand therapy (TRT); Targeted radionuclide therapy; Ga-FAPI-46
• Other Study ID Numbers: 25/113

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: No
• Studies a U.S. FDA-regulated device product: No