ANZCTR - Registration

Registration number

ACTRN12626000505303

Ethics application status

Approved

Date submitted

20/03/2026

Date registered

23/04/2026

Date last updated

23/04/2026

Date data sharing statement initially provided

23/04/2026

Type of registration

Prospectively registered

Titles & IDs

Public title

A Phase 1a/1b Dose-Escalation and Expansion Study of [¹77Lu]Lu-FAP-2286 Radioligand Therapy in Combination with Dual Immune Checkpoint Blockade (Nivolumab and Ipilimumab) in Patients with Unresectable or Advanced Malignant Pleural Mesothelioma (MPM)

Scientific title

A Phase 1a/1b Dose-Escalation and Expansion Study of [¹77Lu]Lu-FAP-2286 Radioligand Therapy in Combination with Dual Immune Checkpoint Blockade (Nivolumab and Ipilimumab) in Patients with Unresectable or Advanced Malignant Pleural Mesothelioma (MPM)

Additional trial identifiers [1]

RGS8039

Universal Trial Number (UTN)

Trial acronym

Related trial records

Health condition

Health condition(s) studied:

Malignant Pleural Mesothelioma

Condition category

Condition code

Cancer

Lung - Mesothelioma

Intervention/exposure

Study type

Interventional

Description of the intervention or exposure

Patients may be treatment-naïve or have received prior therapy, as detailed in inclusion criteria, but must be candidates for nivolumab + ipilimumab immunotherapy (either as first-line or early-line treatment).

Fibroblast activation protein-alpha (FAP) is a cell-surface marker expressed by cancerous cells, including those in patients with mesothelioma. [¹77Lu]Lu-FAP-2286 is a novel small-molecule radioconjugate consisting of a high-affinity FAP inhibitor (FAP-2286) linked to the beta-emitting radionuclide Lutetium-177. Lutetium-177 emits medium-energy beta particles with a short path length (~1–2 mm in tissue), suitable for delivering lethal radiation to targeted cells and their immediate microenvironment.

This is an open-label, single-arm Phase 1 trial with a dose-escalation phase (1a) followed by an expansion phase (1b). In Phase 1a, a 3+3 cohort design will be used to escalate the dose of [¹77Lu]Lu-FAP-2286 (radioligand) while patients receive fixed-dose nivolumab and ipilimumab therapy (dual checkpoint blockade). Three dose levels of [¹77Lu]Lu-FAP-2286 are planned: Cohort 1: 1.85 GBq; Cohort 2: 3.7 GBq; Cohort 3: 5.55 GBq. Each dose is administered every 6 weeks (one cycle = 42 days) in combination with immunotherapy. Dose escalation will proceed sequentially if dose limiting toxicities (DLT) criteria are not met. The maximum tolerated dose (MTD) is defined as the highest dose at which 1 of 6 patients experiences a DLT in the first cycle. Once the MTD/recommended phase 2 dose (RP2D) is determined, the Phase 1b expansion may enrol additional patients (approximately 6–12) at that dose to further characterise safety and gather preliminary efficacy and biomarker data.

A traditional 3+3 schema will guide escalation. The first cohort begins at 1.85 GBq; if DLTs are within acceptable limits, the next cohort receives 3.7 GBq, etc. Dose escalation stops when the MTD is reached or the highest dose (5.55 GBq) is deemed safe. Up to 6 patients may be evaluated at each level. Intra-patient dose escalation is not permitted. Decisions to escalate are confirmed by the Safety Review Committee (investigators and sponsor representatives) after all Cycle 1 safety data for a cohort are reviewed.

All patients receive concurrent radioligand therapy and immune checkpoint blockade in 42-day cycles:

1. [¹77Lu]Lu-FAP-2286 Radioligand: Administered intravenously once every 6 weeks (Day –5 to Day 1 of each cycle, timed 3–5 days prior to immunotherapy start). The administered activity depends on cohort (1.85, 3.7, or 5.55 GBq in dose-escalation; RP2D dose in expansion). Patients may receive up to 4 cycles of [¹77Lu]Lu-FAP-2286 (total of 6 months therapy) if benefiting and if safety parameters (e.g. hematologic recovery, cumulative dose limits) allow.

2. Nivolumab + Ipilimumab (Dual Checkpoint Inhibition): Standard approved dosing for Malignant Pleural Mesothelioma (MPM) will be used. Nivolumab 360 mg intravenously and ipilimumab 1 mg/kg intravenously are administered on Day 1 of each 42-day cycle, followed by an additional nivolumab 360 mg intravenously on Day 22 (mid-cycle). This regimen (nivolumab every 3 weeks + ipilimumab every 6 weeks) is continued until disease progression, unacceptable toxicity, or up to 17 cycles (approximately 2 years), in line with standard immunotherapy practice.

3. [68Ga]Ga-FAP-2286 (Imaging agent)
Description: This is the Ga-68 labeled version of the same FAP-2286 peptide (with DOTA chelator binding Ga-68). Ga-68 (t1/2 ~68 min, positron emitter) for PET imaging. Provided as a cold kit to be radiolabeled using a Ga-68 generator eluent.
• Use in Study: To identify FAP-expressing lesions, response monitoring and as an exploratory imaging biomarker. Administered intravenously at a dose of ~100–300 MBq (microgram peptide mass ~40 µg).
• Safety: Prior studies with FAPI PET in humans (including >40 MPM patients) exposed up to 296 MBq, no treatment-related adverse events were observed. Allergic reactions are extremely rare. We will monitor for 1 hour post injection for any issues (none expected).
• Radiation Dosimetry: Estimated human effective dose ~0.011–0.017 mSv/MBq (kidneys highest organ dose: ~0.12 mGy/MBq). This is comparable or lower than Ga-DOTATATE.
• Storage: Ga generator and cold kit per manufacturer. Post labeling used promptly due to short half-life.

Intervention code [1]

Treatment: Drugs

Description of the comparator or control

The study has a single treatment arm - all participants receive the combination therapy; there is no placebo or control arm.

Control group

Uncontrolled

Outcomes

Primary outcome [1]

1. Maximum Tolerated Dose (MTD) of [¹77Lu]Lu-FAP-2286: MTD is defined as the highest radioactivity dose level at which no more than 1 out of 6 patients experiences a DLT in the first cycle.

Timepoint [1]

The MTD/RP2D determination will be made by the investigators in consultation with the Sponsor after review of all Cycle 1 safety data across cohorts including vitals signs and adverse events.

Primary outcome [2]

2. Safety Profile: This encompasses the incidence, severity, and timing of all adverse events (AEs) and serious adverse events (SAEs) attributed to the combination. Particular focus on hematologic toxicity (rates of neutropenia, thrombocytopenia, etc.), organ-specific toxicities (renal function changes, liver enzyme elevations), and immune-related AEs (frequency of pneumonitis, colitis, dermatitis, endocrinopathies from nivolumab/ipilimumab).

Timepoint [2]

Narrative summaries: Due to the small sample size, safety results will primarily be descriptive and narrative. For example: “X% of patients experienced Grade 3 AE; the most common were ___.” Patients are assessed frequently for toxicity through Day 42. Particularly after each treatment, patients will be observed in the nuclear medicine clinic for at least 1–2 hours.

Secondary outcome [1]

Objective Response Rate (ORR): The proportion of patients with a confirmed radiographic response, defined as either Complete Response (CR) or Partial Response (PR) per modified RECIST (mRECIST) for mesothelioma (which accounts for pleural thickness measurements). Because we have both pleural disease and possibly nodules, we will use modified RECIST criteria for mesothelioma (which typically measure tumour thickness at fixed points) or RECIST1.1 if applicable (e.g. for nodal or metastatic lesions). A confirmed response means the finding is verified by a follow-up scan at least 4–6 weeks later.

Timepoint [1]

We expect ORR evaluation ~12 weeks after start for each patient and updated with best overall response during treatment at the following 12 weekly scans.

Secondary outcome [2]

Utilise [68Ga]Ga-FAP-2286 PET scans to confirm tumour FAP expression at baseline for patient selection, and measure changes in radiotracer uptake after 1–2 cycles (to assess treatment effect on tumour/stromal FAP expression).

Timepoint [2]

An endpoint of interest: the percentage change in SUVmax of index lesions after 2 cycles of treatment.

Eligibility

Key inclusion criteria

Patients must meet all of the following criteria to be included:
1. Diagnosis: Histologically or cytologically confirmed malignant pleural mesothelioma (MPM) of any subtype (epithelioid, sarcomatoid, or biphasic).
2. Disease Status: Unresectable or advanced disease (equivalent to IMIG Stage III or IV) not amenable to curative surgical resection. This includes patients with locally advanced disease, metastatic or recurrent mesothelioma.
3. Prior Treatment: Patients should be eligible to receive standard immune checkpoint inhibitor (ICI) therapy. This typically means either (a) no prior systemic therapy for mesothelioma (first-line setting), or (b) prior receipt of 1 line of systemic therapy (e.g. prior chemotherapy) is allowed if the patient has not yet had immunotherapy and now immunotherapy is indicated as next line. Prior palliative radiotherapy is permitted provided it was completed within 4 weeks before Cycle 1 Day 1 and the patient has recovered from related toxicities.
4. Tumour FAP Expression: Demonstrated uptake on baseline 68Ga-FAP-2286 PET scan, consistent with significant FAP expression in tumour lesions. At least one measurable tumour site should show uptake above background (as per central nuclear medicine physician assessment). Rather than a specific SUV threshold (e.g. SUVmax higher than certain value or tumour-to-background ratio), for this Phase 1 we will use a qualitative criterion: any clear FAPI-PET uptake in tumour above blood pool qualifies as FAP positive. (All PET images will be centrally reviewed for eligibility.)
5. Measurable Disease: At least one measurable lesion by imaging per modified RECIST (mRECIST) for mesothelioma (this may include pleural thickness measurements) or standard RECIST 1.1 if applicable. This lesion should be FDG-PET avid or CT-visible and FAPI-PET avid, to allow multi-modality assessment.
6. Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status 0–1. Patients must be ambulatory and capable of self-care; those who are bedridden or need extensive assistance (ECOG 2–4) are not eligible due to the intensive nature of the trial.
7. Organ Function: Adequate baseline organ and marrow function to receive both radioligand and immunotherapy:
• Bone marrow: Absolute neutrophil count (ANC) greater than or equal to 1.5 ×10^9/L; Platelets greater than or equal to 100 ×10^9/L; Hemoglobin greater than or equal to 9 g/dL (transfusion allowed to meet threshold).
• Renal: Creatinine clearance greater than or equal to 60 mL/min (by Cockcroft-Gault or measured).
• Hepatic: AST/ALT less than or equal to 2.5× upper limit of normal (ULN) (if no liver metastases) or less than or equal to 5× ULN (if liver involvement); total bilirubin less than or equal to1.5× ULN (or less than or equal to 3× ULN for Gilbert’s syndrome); albumin less than or equal to 30 g/L (for proper dosimetry and immune function).
• Coagulation: prothrombin time (PT) or INR less than or equal to 1.5× ULN (if not on anticoagulation).
• Thyroid function: TSH within normal range (or adequately controlled on hormone replacement), given potential immune thyroiditis risk with checkpoint inhibitors.
8. Life Expectancy: Estimated life expectancy at least 12 weeks (3 months) in the opinion of investigators.
9. Age: Adults age at least 18 years. There is no upper age cutoff aside from fitness, because many mesothelioma patients are older; however, patients must meet fitness criteria above.
10. Consent: Ability to understand and willing to sign a written informed consent. Patients must be able to comply with trial requirements (e.g. attend regular visits, complete QoL questionnaires). Consent must be obtained prior to any study-specific procedures.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Healthy volunteers

No

Key exclusion criteria

Patients who meet any of the following criteria will be excluded:
1. Insufficient FAP Expression: Patients whose baseline 68Ga-FAP-2286 PET scan shows low or no FAP uptake in tumour lesions (below the protocol-defined threshold).
2. Prior FAP-targeted RLT: Any history of prior treatment with FAP-targeted radiopharmaceuticals (e.g. 177Lu-FAP-2286 or similar investigational agents). Prior diagnostic FAP PET imaging is allowed, but no prior therapeutic intent FAP-therapy.
3. Prior Immunotherapy Toxicity: History of severe immune-related adverse events from any prior checkpoint inhibitor therapy. Specifically, if a patient previously received an anti-PD-1/PD-L1 or anti-CTLA-4 agent and experienced Grade 3 immune-mediated toxicity that was steroid-refractory or led to treatment discontinuation, they are excluded. Examples: life-threatening pneumonitis, colitis, neurotoxicity, or any unresolved moderate/severe immune toxicity.
4. Uncontrolled Pleural Effusion or Ascites: Patients with symptomatic or clinically significant third-space fluid accumulation that is not controlled by drainage or other measures. For example, a large pleural effusion requiring frequent (more than monthly) taps, or an effusion causing dyspnoea at rest. Such effusions can complicate dosimetry (diluting radiotracer) and may be a sign of very advanced disease that could preclude completing protocol therapy. Patients can become eligible if the effusion is managed (e.g. indwelling pleural catheter or pleurodesis) and symptoms resolve to acceptable level.
5. Rapidly Progressive Disease: Clinical or radiological evidence of very rapid disease progression that, in the investigator’s judgment, would make it unsafe for the patient to wait through the trial procedures or complete at least one cycle.
6. CNS Metastases: Presence of untreated or symptomatic central nervous system (CNS) metastases. Mesothelioma rarely metastasises to brain, but if present, it must be treated (surgically or with radiation) and the patient must be neurologically stable off steroids for at least 4 weeks to be eligible.
7. Second Active Malignancy: Concurrent active malignancy requiring therapy, or history of other malignancy within the last 2 years, except non-melanoma skin cancer or in-situ carcinoma of cervix/bladder that has been definitively treated, or other malignancies treated with curative intent and with no evidence of active disease on recent imaging.
8. Significant Co-morbidities: Any uncontrolled intercurrent illness or serious medical condition that would increase risk of trial therapy. This includes but is not limited to:
• Cardiac: Recent myocardial infarction (within 6 months), unstable angina, uncontrolled congestive heart failure (NYHA class III-IV), clinically significant arrhythmias not controlled by meds.
• Respiratory: Interstitial lung disease or pulmonary fibrosis that could be worsened by radiotherapy or immunotherapy; baseline oxygen-dependent status due to non-mesothelioma causes.
• Autoimmune Disorders: Active autoimmune disease requiring systemic treatment in past 2 years (e.g. lupus, rheumatoid arthritis, multiple sclerosis) – because checkpoint inhibitors can exacerbate autoimmunity. Exceptions: vitiligo, type I diabetes, hypothyroidism on hormone replacement, or mild psoriasis not requiring systemic therapy are allowed.
• Infections: Active infection requiring IV antibiotics; HIV infection with uncontrolled viral load or AIDS (unless on effective ART with undetectable HIV, which is allowed); chronic HBV or HCV with significant liver damage (patients with HBV/HCV well-controlled on treatment might be allowed with close monitoring).
9. Organ Dysfunction: Any hepatic, renal, or bone marrow insufficiency that fails inclusion thresholds, or any condition that, per investigator, poses prohibitively high risk for study therapy (e.g. baseline lymphocyte count extremely low, raising concerns for severe hematologic toxicity).
10. Allergies: Known severe hypersensitivity to any components of [¹77Lu]Lu-FAP-2286, 68Ga-FAP-2286, nivolumab, or ipilimumab (or their excipients). Patients with minor infusion reactions to mAbs in the past could be premedicated and are not automatically excluded, but a history of anaphylaxis to a monoclonal antibody would exclude.
11. Pregnancy or Breastfeeding: Women who are pregnant or breastfeeding are excluded due to potential harm to fetus/infant from radiation and drugs. Women of childbearing potential must have a negative pregnancy test within 7 days prior to treatment start. Both female and male participants of reproductive potential must agree to use highly effective contraceptive methods during treatment and for a defined period, as follows:
• Female patients of childbearing potential: use highly effective contraception during treatment and for 5 × biologically effective half-life of [¹77Lu]Lu-FAP-2286 plus 6 months after end of treatment.
• Male patients with reproductive potential: must use condoms during treatment and for 5 × biologically effective half-life + 90 days after end of treatment; female partners of male patients must use highly effective contraception over the same period.
If a participant or their partner becomes pregnant, they must notify the study team immediately.

Study design

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

6/07/2026

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

50

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

WA

Recruitment hospital [1]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [2]

Sir Charles Gairdner Hospital - Nedlands

Recruitment postcode(s) [1]

6150 - Murdoch

Recruitment postcode(s) [2]

6009 - Nedlands

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

South Metropolitan Health Service

Country [1]

Australia

Primary sponsor type

Government body

Name

South Metropolitan Health Service

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

WA Health Central HREC

Ethics committee address [1]

https://www.health.wa.gov.au/Articles/U_Z/WA-Health-Central-HREC

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

03/10/2025

Approval date [1]

17/12/2025

Ethics approval number [1]

Summary

Brief summary

Brief description of the study purpose
This Phase 1 study is testing the safety of a new targeted radioactive treatment, [¹77Lu]Lu FAP 2286, given together with standard immunotherapy (nivolumab and ipilimumab), to find the safest dose and understand how the combination behaves in patients with malignant pleural mesothelioma.

Who is it for?
You may be eligible for this study if you are male or female aged 18 or over with advanced or unresectable malignant pleural mesothelioma whose cancer shows uptake on a specialised FAP PET scan and who are eligible to receive immunotherapy.

Study details
All participants will receive an intravenous dose of the investigational radioligand [¹77Lu]Lu FAP 2286 every 6 weeks for up to 4 cycles, alongside standard nivolumab and ipilimumab immunotherapy.
The early part of the study tests increasing dose levels of the radioligand to identify the safest dose, followed by an expansion group treated at the selected dose.
Participants will undergo regular blood tests, imaging (including specialised FAP PET scans), and clinical assessments to monitor safety and response.
The results from this study will help determine whether combining targeted radiotherapy with immunotherapy is safe and feasible, and may inform future studies aiming to improve outcomes for people with mesothelioma.

Trial website

Public notes

Contacts

Principal investigator

Name

Dr Zeyad Al-Ogaili

Address

Fiona Stanley Hospital, 11 Robin Warren Drive, MURDOCH WA 6150

Country

Australia

Phone

+61 8 6152 1876

Email

[email protected]

Contact person for public queries

Name

Dr Zeyad Al-Ogaili

Address

Fiona Stanley Hospital, 11 Robin Warren Drive, MURDOCH WA 6150

Country

Australia

Phone

+61 8 6152 1876

Email

[email protected]

Contact person for scientific queries

Name

Dr Zeyad Al-Ogaili

Address

Fiona Stanley Hospital, 11 Robin Warren Drive, MURDOCH WA 6150

Country

Australia

Phone

+61 8 6152 1876

Email

[email protected]

Trial Review

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Documents added automatically