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)

Exclusion Criteria19

• Patients who meet any of the following criteria will be excluded:
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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).
• 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.
• 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.