SBRT Combined With Reduced-Dose Anthracycline Chemotherapy and Toripalimab as Neoadjuvant Therapy for Localized High-Risk Undifferentiated Pleomorphic Sarcoma (SPARK)

September 8, 2026 updated by: Tianjin Medical University Cancer Institute and Hospital

A Single-Arm Phase II Exploratory Study of Neoadjuvant Immunotherapy Plus Chemotherapy Plus SBRT Triplet Therapy and Postoperative Stratified Maintenance Therapy for Undifferentiated Pleomorphic Sarcoma

This is a prospective, single-center, single-arm, open-label phase II exploratory study to evaluate the efficacy, safety, and immune remodeling effects of stereotactic body radiotherapy (SBRT) combined with reduced-dose anthracycline chemotherapy and the PD-1 inhibitor toripalimab as neoadjuvant therapy, followed by postoperative stratified maintenance therapy, in patients with localized high-risk undifferentiated pleomorphic sarcoma (UPS). A Simon two-stage design will be used, with 39 patients planned (stage 1: 13 patients; 35 patients in total, including a 10% dropout rate). Treatment consists of SBRT (8-10 Gy in 5 fractions) followed by toripalimab (240 mg intravenously every 3 weeks, 3 cycles in the neoadjuvant phase) combined with liposomal doxorubicin (30-40 mg/m² intravenously every 3 weeks, 2 cycles in the neoadjuvant phase). After response evaluation, radical surgery is performed. Postoperative stratified maintenance therapy is delivered according to pathological response: patients achieving major pathologic response (MPR) or hyalinized pathologic response (HPR) receive toripalimab monotherapy (240 mg every 3 weeks, up to 14 cycles), while those not achieving MPR/HPR receive toripalimab combined with liposomal doxorubicin (2-4 cycles). The primary endpoint is the rate of major pathologic response (MPR). Secondary endpoints include the rate of hyalinized pathologic response (HPR), radiologic objective response rate (ORR), R0 resection rate, limb salvage rate, and safety.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Undifferentiated pleomorphic sarcoma (UPS) accounts for 5-10% of soft tissue sarcomas. For localized high-risk UPS of the extremities, the standard of care is preoperative radiotherapy plus radical surgery; however, even with R0 resection, the risk of distant metastasis is 30-40% and 2-year disease-free survival is approximately 50%. The SARC028 study showed an objective response rate of 23% in UPS with pembrolizumab, and SU2C-SARC032 demonstrated that adding perioperative pembrolizumab to preoperative radiotherapy improved 2-year DFS (67% vs 52%, HR 0.61). Preclinical and clinical data suggest that stereotactic body radiotherapy (SBRT) with high dose per fraction better synergizes with immune checkpoint blockade than conventional fractionation; sparing the tumor-draining lymph nodes is critical for preserving immune priming.

This phase II study evaluates the triplet neoadjuvant regimen of SBRT, reduced-dose anthracycline chemotherapy, and toripalimab followed by postoperative stratified maintenance in patients with localized high-risk UPS. The fixed treatment schedule is: weeks 1-3 SBRT (8-10 Gy in 5 fractions, on alternate days or consecutively) plus first dose of toripalimab; week 4 first chemotherapy cycle plus second dose of toripalimab; weeks 5-6 recovery; week 7 second chemotherapy cycle plus third dose of toripalimab; weeks 8-9 recovery and response assessment; weeks 10-12 radical surgery. Postoperative maintenance begins within 4-8 weeks after surgery. Patients achieving MPR or HPR receive toripalimab monotherapy 240 mg every 3 weeks for up to 14 cycles; patients not achieving MPR/HPR receive toripalimab for 14 cycles combined with liposomal doxorubicin (2-4 cycles; 2 cycles for HPR >30%).

The sample size uses Simon's two-stage Minimax design with one-sided alpha of 0.05 and 80% power, assuming P0 = 60% and P1 = 80%. The first stage enrolls 13 patients (stop if <=8 responders); the second stage expands to 35 patients total (declare regimen ineffective if <=25 responders overall). Allowing for a 10% dropout rate, the planned total enrollment is 39 patients.

Efficacy assessment: pathologic response (MPR defined as <=10% residual viable tumor cells; HPR defined as >30% hyalinization) is evaluated using a standardized pathology SOP, with confirmation by an independent central pathology laboratory. Radiologic response is evaluated by RECIST v1.1 every 12 weeks. Safety: adverse events are graded per NCI CTCAE v5.0; all adverse events are recorded up to at least 100 days after the last dose. Major wound complications are monitored within 90 days after surgery. Follow-up: visits at 30 days and 84 days after surgery, then every 3 months for survival; imaging every 12 weeks in the first year, every 24 weeks in the second year, and every 6-12 months in years 3-5; ctDNA and peripheral blood immune monitoring every 3 months for at least 2 years.

Study Type

Interventional

Enrollment (Estimated)

39

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
      • Tianjin, China
        • Tianjin Medical University Cancer Institute & Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Inclusion Criteria:

  1. Male or female, aged 18 to 75 years.
  2. Histologically confirmed UPS, screened locally and confirmed by central pathology before enrollment. Adequate IHC (at least CK, S100, SOX10, SMA, desmin, MDM2, CDK4) and NGS when feasible (MDM2/CDK4 amplification mandatory) to exclude dedifferentiated liposarcoma and other differentiated tumors.
  3. UPS of extremities or trunk. Max diameter >5 cm, or <=5 cm with any of: encasement of major neurovascular bundle >180 degrees; expected limb functional loss >50% after resection; MDT deems R0 difficult. SBRT-feasible anatomy with >3 mm margin to critical neurovascular structures or joint.
  4. Regional nodes evaluated by imaging (US/CT/MRI/PET-CT). Suspicious nodes (short axis >=10 mm, abnormal morphology, or high FDG) require pathology. Uninvolved nodes must not be irradiated; involved nodes included with radical dose or resected.
  5. Treatment-naive: no prior chemotherapy, targeted therapy, immunotherapy, or local radiotherapy.
  6. At least one measurable lesion per RECIST v1.1.
  7. ECOG 0-1.
  8. Adequate organ function.
  9. Signed ICF, good compliance, willing to provide fresh tumor and blood for translational research.

Exclusion Criteria:

  1. Other malignancy, except completed treatment with no recurrence/metastasis within 2 years.
  2. Major surgery within 4 weeks, or systemic steroids (>10 mg/day prednisone equivalent) or immunosuppressants within 2 weeks.
  3. Active infection requiring systemic therapy; active HBV (DNA >=2000 IU/mL), HCV, syphilis, or HIV positive.
  4. Active or relapsing autoimmune disease.
  5. Severe comorbidity: NYHA >=III, ischemic heart disease, uncontrolled hypertension/diabetes; interstitial lung disease or severe pulmonary impairment.
  6. Known active brain metastases.
  7. Pregnancy/breastfeeding, or refusal of effective contraception.
  8. Any investigator-judged risk to safety or completion.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental Arm
Single-arm. All enrolled patients receive triplet neoadjuvant therapy: SBRT (8-10 Gy in 5 fractions, alternate days or consecutively) first, with concurrent toripalimab (240 mg IV q3w, 3 neoadjuvant cycles) plus liposomal doxorubicin (30-40 mg/m2 IV q3w, 2 neoadjuvant cycles). Radical surgery at weeks 10-12. Postoperative stratified maintenance within 4-8 weeks: MPR/HPR -> toripalimab 240 mg q3w up to 14 cycles; non-MPR/HPR -> toripalimab q3w 14 cycles plus liposomal doxorubicin 2-4 cycles (2 cycles if HPR >30%).
Drug: Toripalimab
Toripalimab 240 mg IV q3w; 3 neoadjuvant doses from SBRT start; maintenance up to 14 cycles until progression, death, or unacceptable toxicity.
Drug: Liposomal doxorubicin
Liposomal doxorubicin 30-40 mg/m2 IV q3w; 2 neoadjuvant cycles. Non-MPR/HPR: 2-4 adjuvant cycles (2 cycles if HPR >30%).
Radiation: Stereotactic body radiotherapy (SBRT)
SBRT 8-10 Gy x 5 (median 8 Gy x 5), over 5-10 days in weeks 1-3, IGRT required.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Rate of Major Pathologic Response (MPR)
Time Frame: At surgery
At surgery

Secondary Outcome Measures

Outcome Measure
Time Frame
Rate of Hyalinized Pathologic Response (HPR)
Time Frame: At surgery
At surgery
Objective Response Rate (ORR)
Time Frame: After completion of neoadjuvant therapy, before surgery (approximately weeks 8-9 after enrollment)
After completion of neoadjuvant therapy, before surgery (approximately weeks 8-9 after enrollment)
R0 Resection Rate
Time Frame: At surgery
At surgery
Limb Salvage Rate
Time Frame: At surgery
At surgery
Adverse Events
Time Frame: From the first dose of study treatment until at least 100 days after the last dose
From the first dose of study treatment until at least 100 days after the last dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tianjin Medical University Cancer Institute and Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2026

Primary Completion (Estimated)

January 1, 2029

Study Completion (Estimated)

September 1, 2030

Study Registration Dates

First Submitted

September 8, 2026

First Submitted That Met QC Criteria

September 8, 2026

First Posted (Actual)

September 14, 2026

Study Record Updates

Last Update Posted (Actual)

September 14, 2026

Last Update Submitted That Met QC Criteria

September 8, 2026

Last Verified

September 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SPARK-UPS-01
  • E20261130 (Other Identifier: Tianjin Medical University Cancer Institute & Hospital Medical Ethics Committee)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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