THE001 Plus Regional Hyperthermia Shows Early Efficacy, Safety in Pretreated Soft Tissue Sarcoma

Soft Tissue Sarcoma |
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THE001 (DPPG2-TSL-DOX) in combination with regional hyperthermia therapy displayed encouraging clinical activity with a favorable safety profile in heavily pretreated patients with soft tissue sarcoma, according to data from an ongoing phase 1 trial (NCT05858710).1

Patients who received THE001, which is a thermosensitive liposomal formulation of doxorubicin, at a dose of 20 mg/m² (dose level 1) or 40 mg/m² (dose level 2) achieved a median progression-free survival (PFS) of 4.5 months. Patients treated at dose level 2 (n = 3) experienced a mean PFS of 7.1 months, with 2 patients achieving a partial response and completing the maximum extended treatment phase of 12 cycles.

The safety profile of THE001 was favorable across both dose levels, with no dose-limiting toxicities (DLTs) or high-grade treatment-related adverse effects that led to discontinuation being reported.

“These findings not only provide consistent proof of the galenic concept of heat-triggered, largely complete [doxorubicin] release from THE001, but also demonstrate clinical benefit in a highly challenging patient population,” Frank Hermann, MD, chief medical officer of Thermosome, stated in a news release. “We are particularly encouraged by the results of one participant who underwent resection after 12 full treatment cycles with THE001 and regional hyperthermia with no vital tumor cells found in the resected target lesion. These results clearly support future exploration in the neoadjuvant setting.”

In May 2025, the FDA granted orphan drug designation to THE001 for the treatment of patients with soft tissue sarcoma.2 The regulatory decision was supported by prior data from the phase 1 study.

The open-label phase 1 study is examining THE001 as monotherapy or in combination with regional hyperthermia in adult patients with pretreated locally advanced unresectable or metastatic soft tissue sarcoma.3,4 In order to be eligible for the trial, patients need to have experienced disease progression and be not amenable to surgery, measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 to 2, and adequate hematologic, organ, and coagulation function within 14 days prior to enrollment.3 Patients were also required to be pretreated with an anthracycline; anthracycline therapy in the adjuvant setting was permitted.

Patients received THE001 at dose level 1, dose level 2, or 50 mg/m2 (dose level 3) in six 21-day cycles.4 After cycle 2, patients were treated with regional hyperthermia every 3 weeks.3,4 Dexrazoxane was also administered for cardioprotection.

The study’s primary end point is determination of the maximum tolerated dose of THE001.3 Secondary end points include safety, laboratory values, electrocardiogram and echocardiogram abnormalities, renal toxicities, and pharmacokinetic measures. Other outcomes consisted of radiographic response rate, radiographic local response rate, and tumor temperatures.

Additional safety data from the phase 1 trial revealed that, at a data cutoff of October 30, 2024, 2 serious adverse effects (SAEs) occurred; both were deemed unrelated to study treatment.4 No suspected unrelated SAEs or DLTs were reported at this time.

“It is exciting to see the promising results of THE001 combined with regional hyperthermia, demonstrating strong potential to address the high unmet need for better treatments for soft tissue sarcoma,” Shreyaskumar R. Patel, MD, medical director of the Sarcoma Center, Robert R. Herring Distinguished Professor of Cancer Research, and a professor in the Department of Sarcoma Medical Oncology, Division of Cancer Medicine, at the University of Texas MD Anderson Cancer Center in Houston, added in the news release.1 “Expansion into phase 2, also including the US, would offer a much-needed validation of this new therapeutic strategy for patients with soft tissue sarcomas. I look forward to supporting the advancement of this innovative treatment option to improve outcomes for patients here in the United States and globally on the back of the orphan drug designation granted by the FDA.”

References

1. Thermosome reports encouraging clinical data of THE001 in advanced soft tissue sarcomas. News release. Thermosome. June 24, 2025. Accessed June 24, 2025. https://www.thermosome.com/news/
2. Thermosome receives U.S. orphan drug designation for lead compound THE001, expands patent estate. News release. Thermosome. May 12, 2025. Accessed June 24, 2025. https://www.thermosome.com/news/
3. Study of DPPG2-TSL-DOX combined with hyperthermia in soft tissue sarcoma. ClinicalTrials.gov. Updated February 21, 2025. Accessed June 24, 2025. https://clinicaltrials.gov/study/NCT05858710
4. Di Gioia D, Reichardt P, Güler SE, et al. Phase I study of THE001 (DPPG²-TSL-DOX) combined with regional hyperthermia in patients with locally advanced or metastatic soft tissue sarcoma. Presented at: 2024 CTOS Annual Meeting. November 13-16, 2024; San Diego, CA. Abstract P 410.