The goal of this clinical trial is to learn about the safety of drug [Ac225]RTX-2358 and the diagnostic imaging agent [Cu64]LNTH-1363S. Additionally Ratio Therapeutics will learn if [Ac225]RTX-2358 drug is effective in treating advanced sarcoma.

The main questions the study aims to answer in Phase/Part 1 of the trial are:

• Is [Ac225]RTX-2358 tolerable or does it cause toxicities (medical problems) in patients.
• What is the most tolerable dose of [Ac225]RTX-2358
• Does the treatment show effectiveness on advanced sarcoma

Participants will:

• Take drug [Ac225]RTX-2358 once every 8 weeks (4 cycle target; 6 cycle maximum) over a period of 12 months
• Visit the clinic three times for the first week of cycle one, then once a week for the remaining 7 weeks of cycle 1 for check-ups and tests.
• For cycles 2-6: patient will visit the clinic once every 2 weeks for checkups and tests
• Remain in long term follow-up for a period of four additional years

RTX-2358-101 is an open-label, seamless, Phase 1/2 clinical study to evaluate safety, tolerability, dosimetry, biodistribution, pharmacokinetic (PK), and anti-tumor activity of [Ac225]RTX-2358. [Ac 225]-RTX-2358 is for patients with relapsed or treatment-resistant soft tissue sarcoma.

The study consists of two phases, an ascending administered activity phase (Phase1) and an expansion phase (Phase 2). In the Phase 1 portion of the trial patients will be divided into three groups, each group receiving a higher dose than the last. A modified "3 + 3" dose escalation with Phase 1 queue (IQ) design approach will be used, with potential backfill in administered activity cohorts.

Patients must be 18 or older, have soft tissue sarcoma that can be measured by imaging, and meet specific health requirements, including good organ function and a positive PET scan. Each treatment cycle in the phase 1 portion of the study involves a single injection on Day 1, followed by eight weeks of monitoring. Patients have a target of four cycles of treatment, with the possibility of two more (six maximum), if their side effects are mild and their disease hasn't worsened.

A Safety Review Committee (SRC) will review the data from each group in the Phase 1 portion to decide when it's safe to move to the next dose level. The SRC will also provide recommendations on timing and administered activity for backfill cohorts to gather additional safety and preliminary data on effectiveness. Patients that receive at least one treatment in the Phase 1 portion of the study, will be followed will be followed in Active (AFUP) or Long-term follow-up (LTFU). The AFUP will follow patients until confirmation of disease progression or start of subsequent anti-cancer therapy. After AFUP, the patient will enter LTFUP. Patients who discontinue with confirmed progressive disease will be monitored for LTFU via remote or onsite visits every 6 months until 5 years after the start of treatment to track long-term safety, disease progression, and overall survival.

The Phase 2 portion of the study will evaluate the efficacy and safety of [Ac225]RTX-2358 of up to 50 patients.

Inclusion Criteria:

• 18 years of age or older.

• History of relapse and refractory soft tissue sarcoma.

  1. Histological confirmation of sarcoma at any point since diagnosis
  2. At least 1 prior treatment regimen

• Measurable disease as per RECIST (v1.1) for soft tissue sarcoma that is also positive on FAPi PET/CT or PET/MRI scan.

• ECOG performance status of 0 or 1.

• Adequate Organ reserve and renal function as evidenced by:

  1. Neutrophil count ≥ 1200 µL without granulocyte colony stimulating factor

  2. Platelet count ≥ 100,000 µL

  3. Hemoglobin ≥ 8 g/dL

  4. Total bilirubin level ≤ 1.5 × upper limit of normal (ULN).

  5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN.

  6. Calculated creatinine clearance ≥ 60 mL/min. 6. Coagulation parameters (prothrombin time, international normalized ratio and activated partial thromboplastin time) ≤ 1.5 × ULN 7. All patients (males and females of childbearing potential) must agree to practice 2 forms of highly effective contraceptive precautions to prevent pregnancy from the time consent is signed and throughout the trial.

     8. The patient or the patient's legal representative must be willing and able to provide written informed consent.

     Exclusion Criteria:

• History of whole pelvic irradiation.

• History of radioligand therapy.

• Treatment within 14 days prior to first administration with:

  1. Palliative surgery or external beam radiation.
  2. Approved anticancer therapy including chemotherapy or immunotherapy.
  3. Any investigational therapy.
  4. Any major surgery (e.g., requiring general anesthesia).

• Patients who are scheduled for external beam radiation therapy or radioligand therapy during the study period.

• Congestive heart failure > Class II New York Heart Association Functional Classification, current pericarditis, myocardial infarction within 6 months, or symptomatic coronary artery disease.

• Patients with uncontrollable incontinence.

• Unstable or clinically significant concurrent medical condition that would, in the opinion of the Investigator, jeopardize the safety of a patient and/or their compliance with the protocol.

• Active infection requiring systemic antibacterial/antibiotic, antifungal, or antiviral therapy. Chronic antiviral therapy for stable viral disease can be included.

• History of active fibrotic condition.

• Any active malignancy other than sarcoma that requires treatment.

• Stable brain metastasis is allowed but documented untreated metastases to brain or meninges are excluded.

• Currently pregnant or lactating.

• Known allergy to any of the study drugs or their excipients.

• Inability or unwillingness to comply with any of the required imaging studies or study assessments.