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Pegylated liposomal doxorubicin (PLD) in combination with ifosfamide demonstrated manageable toxicity and encouraging clinical activity in patients with advanced soft tissue sarcoma, according to results from a phase 1, single-center, dose-escalation trial (ChiCTR1900028270).
Twenty-three patients were enrolled and treated using a 3+3 dose-escalation design, with PLD initiated at 30 mg/m² and increased in 5 mg/m² increments. Two patients experienced dose-limiting toxicities at 55 mg/m², and the maximum tolerated dose (MTD) was determined to be 50 mg/m² in combination with IFO at 3 g/m² per day on days 1 to 3. The most common grade 3/4 treatment-emergent adverse events included leukopenia (86.96%), neutropenia (82.61%), and lymphopenia (56.52%). Twelve patients elected to continue treatment beyond the dose-finding phase
Across all dose levels, the overall response rate (ORR) was 33.33% (95% CI, 9.92%-65.11%), and the disease control rate (DCR) was 83.33% (95% CI, 51.59%-97.91%).
“This regimen demonstrated a tolerable safety profile and promising efficacy, indicating potential benefits for patients with advanced soft tissue sarcoma,” lead study author Ting Ye, MD, of Union Hospital, Tongji Medical College, Huazhong University, and colleagues wrote in the publication. “These preliminary findings necessitate further research to validate the efficacy and safety of this treatment over multiple cycles and to explore the full therapeutic potential of the regimen in this patient population.”
Phase 1 Study Design
This single-center, dose-escalation study was conducted at Huazhong University of Science and Technology enrolled patients 18 to 70 years of age who had an ECOG performance status of 0 or 1, along with normal bone marrow hematopoietic and cardiac function. Enrollment required a diagnosis of advanced soft tissue sarcoma confirmed by two senior pathology experts. Patients with soft tissue sarcoma subtypes not amenable to PLD plus ifosfamide, including gastrointestinal stromal tumor, embryonal/acinar rhabdomyosarcoma, and Ewing’s sarcoma, were excluded.
The treatment regimen consisted of PLD in combination with ifosfamide at 3 g/m²/day on days 1 through 3. PLD was initiated at 30 mg/m² and escalated in 5 mg/m² increments to a maximum of 70 mg/m² using a standard 3+3 design. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered 48 hours after chemotherapy completion.
The primary objective was to determine the MTD, defined as the highest dose level at which no more than 33% of patients experienced a DLT within the first 21 days of treatment. The secondary objective was to evaluate the safety profile of the regimen, characterized by the incidence and severity of AEs.
Baseline Patient Demographics
From January 2020 to September 2022, 23 patients were enrolled, including 12 males (52.17%) and 11 females (47.83%). The median age was 49 years (range, 30-68). Most patients (69.57%) had an ECOG performance status of 0, while 30.43% had a performance status of 1.
Disease stage at enrollment was advanced in the majority of cases, with 22 patients (95.65%) presenting with AJCC stage IV disease and 1 patient (4.35%) with stage III disease. The number of involved organs at baseline was 0 in 1 patient (4.35%), 1 organ in 16 patients (69.57%), and more than 1 organ in 6 patients (26.09%).
Tumor locations varied, with the most common being the legs (34.78%), followed by visceral sites (17.39%). Other locations included the arms (8.70%), back (8.70%), abdominal cavity (8.70%), hip (8.70%), neck or jaw (8.70%), and thorax (4.35%).
Histologic subtypes were diverse. Fibrosarcoma was the most frequent (17.39%), followed by synovial sarcoma (13.04%) and leiomyosarcoma (13.04%). Other subtypes included malignant peripheral nerve sheath tumor (8.70%), undifferentiated sarcoma (8.70%), liposarcoma (4.35%), myxoid liposarcoma (4.35%), dedifferentiated liposarcoma (4.35%), epithelioid sarcoma (4.35%), unclassifiable STS with rhabdomyocyte differentiation (4.35%), pleomorphic rhabdomyosarcoma (4.35%), epithelioid hemangioendothelioma (4.35%), angiosarcoma (4.35%), and malignant granular cell tumor (4.35%).
Reference
Ye T, Fan L, Cao R, Peng L, Chen J. Phase I trial of pegylated liposomal doxorubicin combined with ifosfamide for advanced soft tissue sarcoma. Drug Des Devel Ther. 2025;19:6817-6827.doi:10.2147/DDDT.S529231