SPEDOX-6: First-in-human Phase IB/IIA trial on soft tissue sarcomas

Purpose: Soft tissue sarcomas (STSs) are extremely aggressive & deadly rare tumors with multiple subtypes. Early diagnosis is very difficult & STSs are frequently diagnosed only at advanced stages. DOX has remained the only standard of care in past 45 years with low efficacy and high dose-dependent cardiotoxicity. Better agents are urgently needed. Methods: Our patented single protein encapsulation (SPE) platform allows encapsulation of small-molecule drugs by a single protein (albumins or globulins) to make new generation nanodrugs that have no artificial nanoparticles, no chemical modifications to drugs and proteins. SPEDOX-6 was successfully prepared by encapsulated 9 doxorubicin (DOX) molecules into the binding pockets of each native HSA molecule, which was confirmed and characterized by UV, fluorescence, membrane dialysis, size-exclusion HPLC and size distribution. SPEDOX-6 provides a novel approach for improving DOX's efficacy and reducing its side effects by targeting cancer cells with low neonatal Fc receptor (FcRn) levels. Results: In mouse model, heart tissues' DOX was 4 to 8 times lower from SPEDOX-6 than from DOX, indicative of lower cardiotoxicity of SPEDOX-6. PK profiles of same dose for SPEDOX-6 and DOX shown that SPEDOX-6 has shown 48X increase of SPEDOX-6 total exposure upon its encapsulation. In rat model, the total exposure for SPEDOX-6 increases 7-17 times compared to DOX. SPEDOX-6's cardiotoxicity at 50 mg/kg was undetectable, in contrast to observable DOX's cardiotoxicity at 5-10 mg/kg. In mouse model efficacy study on HT-1080 (STS), SPEDOX-6 remarkably suppresses HT-1080 (the lowest FcRn) with 3 out of 10 mice tumor free. SPEDOX-6 at 30 mg/kg is significantly better than Doxil at 4 mg/kg (MTD) and DOX at 3.5 mg/kg (MTD) in inhibiting SK-ES-1 (Ewing sarcoma, with the highest FcRn) tumor growth, but SPEDOX-6 has less efficacy against SK-ES-1, relative to HT-1080. For MB-MDA-231 (TNBC, medium FcRn) model, SPEDOX-6 has shown superior anticancer efficacy in comparison to DOX. Combined with 3 mouse model studies, SPEDOX-6's antitumor efficacy displays an inverse relationship with the FcRn expression level, thereby providing a potential mechanism for SPEDOX-6 to effectively target tumors with low FcRn. IND (IND #: 152154) applications with 8 dosing escalation levels were approved by FDA and first-in-human phase IB was initiated at UCI and Cedar Sinai in June 2025 (NCT07064018). At present, initial dose (20 mg/m 2 ) with 3 patients (lung/pancreatic/cervical cancer) was completed and dose level 2 (40 mg/m 2 ) is underway with enrollment of 3 patients (2 STSs/ uterine cancer). Conclusions: With Orphan Drug Designation of SPEDOX-6, only phase 2A trial is needed for full approval, granted by FDA. Superior clinical antitumor efficacy of SPEDOX-6 on STSs is expected to be achieved because a possible high dose at 310 mg/m 2 (> 4-folds DOX) can be used for treating patients without cardiotoxicity, which will save lots of lives.