Overview

This is a first-in-human, multicenter, open-label Phase 1/2 study designed to evaluate the safety, efficacy, and tolerability of \[225Ac\]Ac-FL-261, a targeted radioligand therapy directed at c-MET, in participants with advanced or metastatic solid tumors. Phase 1 will identify the recommended dose through dose escalation, followed by a randomized comparison of two candidate dosing regimens (dose optimization). In Phase 2, the selected dose will be tested in independent cohorts by tumor type.

Eligibility

Inclusion Criteria:

• They have signed the consent form before any study-related tests or procedures are done and are willing to follow all study requirements.
• They are 18 years of age or older.
• They have a confirmed diagnosis of an advanced or metastatic cancer that cannot be cured with surgery, radiation, or other treatments.
• Phase 1: Non-squamous non-small cell lung cancer (ns-NSCLC).
• Phase 2: Non-squamous non-small cell lung cancer (ns-NSCLC), colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), or cholangiocarcinoma (bile duct cancer).
• Their cancer has worsened after previous treatments, or they cannot receive further standard treatments because of reasons such as side effects or medical conditions.
• For lung cancer (ns-NSCLC): Previously treated with chemotherapy, immunotherapy, and targeted therapies if applicable.
• For colorectal cancer (CRC): Previously treated with standard chemotherapy and other suitable targeted or immune therapies if specific genetic changes were present.
• For head and neck cancer (HNSCC): Previously treated with platinum-based chemotherapy and immunotherapy.
• For cholangiocarcinoma: Previously treated with at least one chemotherapy regimen.
• The cancer must be c-MET positive, meaning laboratory testing of the tumor shows a moderate to high level of c-MET protein in at least half of the cancer cells.
• At least one tumor can be measured on scans according to standard cancer assessment criteria.
• The participant is generally well enough for daily activities, with an ECOG Performance Status of 0 or 1 (fully active or only restricted in strenuous activities).
• Important organs are functioning adequately, based on blood and laboratory test results, including:
• Normal heart rhythm measurement (QTc interval).
• Women who can become pregnant must have a negative pregnancy test during screening and again shortly before starting study treatment.
• Women who can become pregnant must use an effective birth control method from the first dose of study treatment until 6 months after the last dose.
• Sexually active men must use a barrier method of contraception (such as condoms) during the study and for about 3 months after the last dose. They must also not donate sperm during this period.

Exclusion Criteria:

• Cancer has spread to the brain or spinal cord and has not been treated.
• People with previously treated brain metastases may still be eligible if they are stable, have no symptoms, and are not taking steroids for neurological problems.
• They have a serious medical or mental health condition that could make participation unsafe or affect the study results.
• They have previously received radioactive cancer treatments, such as radioembolization (for example, Y-90 treatment).
• They received anti-cancer treatment within the last 4 weeks before starting the study drug.

They received an experimental (investigational) anti-cancer treatment within the last 4 weeks or within 5 half-lives of that treatment (whichever period is longer).

• They received radiation therapy too recently, including:
  • Radiation to a large area of bone marrow within 6 weeks before study treatment, or
  • Radiation to a specific area within 2 weeks before study treatment.
• They had major surgery within the last 6 weeks or have not completely recovered from the surgery and its side effects.
• They are allergic to the study drug or any of its ingredients.
• They are currently participating in another clinical trial that involves treatment or intervention.
• They still have significant side effects from previous cancer treatments.
  • People may still be eligible if they have:
  • Hair loss of any severity,
  • Mild to moderate nerve damage (Grade 2),
  • Moderate fatigue (Grade 2),
  • Stable diabetes,
  • Well-controlled underactive or overactive thyroid disease.
• They have a history of interstitial lung disease (a serious lung condition that causes scarring and inflammation of the lungs).
• They have serious heart disease, including:
  • Heart attack within the last 6 months,
  • Unstable chest pain (angina),
  • Moderate to severe heart failure,
  • Uncontrolled high blood pressure,
  • Uncontrolled abnormal heart rhythms,
  • Severe narrowing of the aortic heart valve.
• They have an active infection that requires treatment, including:
  • HIV,
  • Hepatitis B,
  • Hepatitis C,
  • COVID-19 (SARS-CoV-2).

However, some people with chronic HIV, hepatitis B, or hepatitis C may be allowed to participate if their infection is well controlled and approved by the study doctor.

• They have had another type of active cancer within the last 3 years, apart from the cancer being studied.
  • Some exceptions may be allowed if the other cancer is well controlled and does not require treatment during the study.
• They are pregnant or breastfeeding, or plan to become pregnant or donate eggs during the study or within 6 months after the last dose of the study drug.