(P 530) FIH PHASE I STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND ANTITUMOR ACTIVITY OF THE001 COMBINED WITH REGIONAL HYPERTHERMIA IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOFT TISSUE SARCOMA

Objective: Doxorubicin (DOX) is the most relevant chemotherapeutic agent for the treatment of soft tissue sarcomas (STS). Because DOX is known to induce immunogenic cell death, combination therapies of DOX with immune checkpoint inhibitors have gained interest. Regional hyperthermia (RHT) has been shown to improve survival in locally advanced high-risk STS when combined with DOX-based chemotherapy, and stimulates the tumor microinvironment to enhance antitumour immune activity. THE001 is a thermosensitive liposomal formulation of DOX based on phosphatidyldiglycerol as the key membrane component. After intravenous administration, THE001 releases DOX in the bloodstream once the temperature in the target area is above 40°C. The application of THE001 plus RHT resulted in preclinical models in up to 15-fold higher DOX concentrations in the tumor and is expected to improve clinical treatment efficacy.

Methods: THE001 in combination with RHT is being evaluated in an open-label, non-randomized, dose-escalation study in patients with locally advanced or metastatic STS (NCT ID: NCT05858710). The study explores ascending doses of intravenous THE001 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD). From cycle 2, RHT is performed simultaneously. THE001 study began enrolling patients in April 2023 and is conducted at the LMU Klinikum and the Helios Klinikum Berlin Buch. Adverse events are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 and Choi criteria and safety findings reviewed by an independent Data Safety Monitoring Board, which will determine the MTD. Key Phase 1 eligibility criteria include 1) locally advanced (unresectable) or metastatic STS for which treatment with DOX monotherapy is appropriate, and 2) pretreatment with DOX combination chemotherapy (DOX/ifosfamide or DOX/dacarbazine) achieved at least stable disease; for patients who received DOX in an adjuvant setting, local recurrence free interval of >6 months is required, 3) progressive disease not suitable for surgery after 3a) only one further line of chemotherapy (including tyrosine-kinase inhibitor) if the RHT field targets the clinically relevant tumor manifestation/s (e.g., locally advanced or multifocal intraabdominal STS; diffuse metastatic STS in which RHT of a tumor manifestation [e.g., liver] is considered relevant although other systemic metastases are present that do not endanger the patient), or 3b) two or more further lines of chemotherapies (including TKI) for patients with metastatic STS and a tumor manifestation suitable for RHT. Further clinical evaluations of THE001 plus RHT are planned in follow-on studies, e.g. in patients with unresectable localized STS as monotherapy and in combination with ifosfamide (undifferentiated pleomorphic sarcoma) or dacarbazine (leiomyosarcoma) in neoadjuvant therapy of patients with locally-advanced high-risk STS.

Results: Not applicable

Conclusion: Not applicable