Actinium Therapy for Late-stage Aggressive Sarcomas

Not Applicable

Not yet recruiting

• Conditions: Advanced Soft Tissue Sarcoma
• Interventions: Drug: [Ac 225]RTX-2358; Diagnostic Test: [Cu64]LNTH-1363S

• Registration Number: NCT07156565
• Lead Sponsor: Ratio Therapeutics, Inc.

Brief Summary

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

Detailed Description

RTX-2358-101 is an open-label, seamless, Phase1/2 clinical study to evaluate safety, tolerability, dosimetry, biodistribution, pharmacokinetic (PK), and anti-tumor activity of \[Ac225\]RTX-2358. \[Ac 225\]-RTX-2358 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 standard "3 + 3" dose escalation approach will be used, meaning three patients will start in each group, and more may be added if needed, to confirm safety.

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. Once dose escalation of all cohorts is approved, patients can be added to two higher-dose groups 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 for an initial period of 48 weeks for safety. After the first year, patients will have telephone check-ins every six months for up to four more years 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 on up to 50 patients.

Study Timeline

• Study First Submitted: 2025-01-17
• Status Verified: 2025-08
• Study First Submitted QC: 2025-08-27
• Last Update Submitted: 2025-08-27
• Study First Posted: 2025-09-05
• Last Update Posted: 2025-09-05
• Study Start: 2025-10-01
• Primary Completion: 2028-01
• Study Completion: 2032-01-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 26

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 in which at least 1 tumor lesions has an SUV mean of greater than or equal to 2.

• 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 (.

• 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Treatment with [Ac 225]RTX-2358	[Ac 225]RTX-2358	The study design is a 3+3 escalating group design.
Treatment with [Ac 225]RTX-2358	[Cu64]LNTH-1363S	The study design is a 3+3 escalating group design.

Primary Outcome Measures

Name	Time	Method
Evaluate the safety (Frequency and severity of treatment emergent adverse events (TEAEs), Dose Limiting Toxicities (DLTs), serious adverse events (SAEs) and adverse events of special interest) of [Ac225-]RTX-2358.	48 weeks	Frequency and severity of treatment emergent adverse events (TEAEs), Dose Limiting Toxicities (DLTs), serious adverse events (SAEs) and adverse events of special interest (AESIs).; Preliminary efficacy response across all cycles in Phase 1.

Secondary Outcome Measures

Name	Time	Method
Determination the normal tissue radiation dosimetry of [Ac225]RTX-2358	Day 1, 3, 8	Radiation absorbed dose estimates for selected normal tissues.; Analysis of radioactive blood samples for select timepoints.
Evaluate the preliminary anti-tumor activity of [Ac225]RTX-2358 in patients with relapsed or refractory soft tissue sarcoma	48 weeks	Duration of Response (DOR), defined as the duration of time from first date of observed response (CR or PR), to first date of disease progression of death from any cause.
Determine the pharmacokinetics (PK) of [Ac224]RTX-2358	Day 1, 3 and 8	Half life for \[Ac 225\]RTX 2358.
Evaluate the safety and tolerability of [Cu-64]LNTH-1363S	Up to 2 weeks after the [Cu64]LNTH-1363S injections	Frequency and severity of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE)s
Assess impact of treatment to quality of life (QoL) - European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLC-C30 Version 3)	48 Weeks	Change from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLC-C30 Version 3)