(P 437) CLINICAL DATA CONFIRM GALENIC PRINCIPLE AND DEMONSTRATE THERAPEUTIC POTENTIAL OF THE001 (DPPG2-TSL-DOX) PLUS REGIONAL HYPERTHERMIA IN SOFT TISSUE SARCOMA

Objective: Doxorubicin (DOX) remains standard therapy for soft tissue sarcoma (STS). However, clinical benefits are limited by systemic toxicity and low intratumoral drug levels. THE001 (DPPG2-TSL-DOX) is a thermosensitive liposomal DOX formulation designed for heat-triggered, intravascular release, enabling high local drug concentrations with systemic exposure comparable to conventional DOX. In preclinical models, THE001 + regional hyperthermia (RHT) achieved up to 15-fold higher intratumoral DOX. Complementary, in a neoadjuvant study in feline sarcoma, 3 of 4 animals treated with THE001 + RHT had < 10% vital tumor cells (pCR), compared to 0 of 4 with standard DOX + RHT.

Methods: Phase 1 dose-escalation trial [NCT05858710] in heavily (including DOX-) pretreated participants (pts) with advanced unresectable/metastatic STS. THE001 IV was administered q3w for up to 12 cycles. From cycle 2 onwards, RHT is applied. Primary objectives are safety and definition of Highest Tolerated Dose (HTD); responses are assessed per RECIST v1.1 and Choi. Pharmacokinetics (PK) evaluate heat-induced DOX release and systemic exposure of DOX and liposomal components.

Results: Seven pts were treated in DL1 (20mg/m²; n=4) and DL2 (40mg/m²; n=3). No dose-limiting toxicities occurred with low rate of grade ≥3 TRAEs for THE001 + RHT (3.4% of all AE), leading to determination of 40mg/m² as HTD for THE001 + RHT in this setting. In DL1, 3 pts achieved local tumor control in RHT-region with one stable disease (SD) per RECIST 1.1. In DL2, all pts achieved SD, with 2 of 3 meeting Choi response criteria. Two pts completed 12 cycles with one (epithelioid sarcoma) becoming eligible for resection with no vital tumor cells in resected target lesion. PK profiles showed near-complete DOX release upon heating. Systemic AUCinf was comparable to conventional DOX, while Cmax was substantially lower, suggesting reduced cardiotoxicity.

Conclusion: THE001 + RHT demonstrates clinical activity, proof of galenic principle, and a favorable safety profile in STS. Exploration in the neoadjuvant setting aims to enhance pathological responses (e.g., pCR rate) and immune induction. Orphan Drug Designation by EMA and FDA were granted for THE001 + RHT, validating the potential in STS.