The Combination of Radiotherapy，Surufatinib and Sintilimab in High-Risk Localized Soft Tissue Sarcoma

A Prospective Phase Ib/II Trial of Radiotherapy Combined With Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in High-Risk Localized Soft Tissue Sarcoma (IRIS)

This is a prospective, single-center, single-arm, phase Ib/II clinical trial. The study aims to evaluate the safety and efficacy of the treatment which combines radiotherapy, Sintilimab (Anti-PD1 Antibody) and Surufatinib (small-molecule Tyrosine Kinase inhibitor) in patients with high-risk localized soft tissue sarcoma.

There will be 52 patients with high-risk localized extremity and trunck soft tissue sarcoma recruited. The trail is designed as a two-stage study. In safety lead-in phase (phase Ib), using 3+3 design, 6 cycles of Surufatinib (250mg, 200mg, qd) and Sintilimab (200mg, q3w) will be applied. And radiotherapy (BED=50-60Gy (α/β=10)) will begin in week 4 of the therapy. In extended phase (phase II), Surufatinib will be applied in the recommended phase 2 dose (RP2D) according to phase Ib. And 200mg Sintilimab and radiotherapy will be applied as before. The dose-limiting toxicity (DLT) in phase Ib and objective response rate (ORR) in phase Ib+Phase II will be mainly analyzed.

Inclusion Criteria:

• Aged from 18 to 70, with life expectancy more than 2 years
• Histologically confirmed STS, G2 or G3
• Has imaging-confirmed localized lesions on the limbs or trunk without distant metastases
• Has>5 cm lesions, or the lesions are determined to be borderline resectable or unresectable by a multidisciplinary consultation.
• Experience local recurrence after surgery (disease-free survival more than 2 months after surgery) or primary tumor
• ECOG performance status 0-1
• Demonstrate adequate organ function (bone marrow, liver, kidney and clotting function) within 7 days before the first administration without using blood products or hematopoietic stimulating factors.
• Fully informed and willing to provide written informed consent for the trial

Exclusion Criteria:

• The presence of regional or distant metastases detected by imaging evaluation

• The following histological types: osteosarcoma, chordoma, classic chondrosarcoma, Kaposi's sarcoma, malignant mesothelioma, radiation-induced sarcomas

• History of another primary malignant tumor within the past three years or at the same time (excluding localized basal cell carcinoma, cutaneous squamous cell carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, adenocarcinoma in situ of cervix, or other previous malignant tumor with a disease-free survival of more than 10 years)

• Receiving any other chemotherapy or targeted therapy within 4 weeks before enrollment

• Prior treatment using anti-PD1 immunotherapy

• Prior radiotherapy towards the target lesion or has other contraindications to radiotherapy or surgery

• Baseline laboratory indicators do not meet the following criteria: neutrophils

  ≥1.5×10^9/L, Hb≥90g/L, PLT≥100×10^9/L , ALT ≤2.5 ULN, AST ≤2.5 ULN, Cr≤ 1.5 ULN or creatinine clearance rate <50ml/min, TBIL ≤1.5 ULN, APTT≤1.5 ULN, PT ≤1.5 ULN

• Urinary protein ≥ 2+, or 24-hour urine protein ≥1.0g/24h

• Uncontrolled hypertension: SBP >140mmHg or DBP > 90mmHg

• Uncontrolled hyperglycemia or coagulation disorder

• Active infection requiring systemic anti-infective therapy

• Uncontrolled mental diseases

• Previous surgery within 2 weeks of before enrollment (excluding diagnostic biopsy or peripherally inserted central catheter implantation)

• History of immunodeficiency diseases or active autoimmune disease requiring systemic treatment

• Pregnant or lactating women

• Allergic to any component of the therapy