Neoadjuvant Chemotherapy Combined With Targeted Treatment in High-risk Retroperitoneal Sarcoma (NATARS)

Neoadjuvant Chemotherapy Combined With Targeted Treatment in High-risk Retroperitoneal Sarcoma-- A Nationwide Multicentered Prospective Controlled Study

The goal of this clinical trial is to explore the potential survival benefits of neoadjuvant chemotherapy combined with target treatments followed by radical surgery in patients with primary high-risk/grade retroperitoneal sarcoma.

The main questions it aims to answer are:

• Whether the 1,3-year progression-free survival time(PFS) is prolonged in the neoadjuvant therapy group, compared with the surgery-only group.
• The Overall survival time in the two groups.
• The safety and tolerance in the neoadjuvant therapy group.

Participants will be allocated into two groups once they meet the inclusion criteria.

• Surgery-only Group: Patients will directly undergo surgeries after the confirmation of diagnosis through pre-operative biopsy.
• Neoadjuvant therapy group: Patients will receive the neoadjuvant chemotherapy combined with target treatment for three circles before the following sarcoma resectional surgeries.

Study Overview

• Status: Enrolling by invitation
• Conditions: Retroperitoneal Sarcoma
• Intervention / Treatment: Procedure: Radical Surgery; Drug: Doxorubicin+Ifosfamide+Anlotinib(AI+A)

• Study Type: Interventional
• Enrollment (Anticipated): 102
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Peking University First Hospital
    • Beijing, Beijing, China
      • Beijing Friendship Hospital
  • Shandong
    • Qingdao, Shandong, China
      • The Affiliated Hospital of Qingdao University
  • Shanghai
    • Shanghai, Shanghai, China
      • Shanghai Zhongshan Hospital
    • Shanghai, Shanghai, China
      • Shanghai Cancer Hospital, Minhang Branch
  • Shanxi
    • Xi'an, Shanxi, China
      • First Affiliated Hospital Xi'an Jiaotong University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically proven primary high-risk Retroperitoneal sarcoma(RPS) (Including Dedifferentiated liposarcoma (DDLPS), leiomyosarcoma(LMS), Undifferentiated pleomorphic sarcoma(UPS), Solitary fibrous tumor(SFT)).
• Primary localized RPS without histories of surgical resection, chemo- or radio-therapy, targeted therapy. Patients who underwent laparotomy with biopsy only will also be considered as primary cases.
• Without histories of second malignant tumors.

• In DDLPS

  • Diagnosis should be confirmed based on MDM2(Mouse double minute 2 homolog) and CDK4(Cyclin-dependent kinase 4) expression on IHC (immunohistochemistry), while MDM2 amplification in the Fish test is highly recommended.
  • All grade 2-3 DDLPS can be included.

• In LMS

  • All grades of LMS can be included.
  • Tumor size ≥10cm

• In UPS or SFT

  • All grades of UPS can be included.
  • High-risk SFT with a score ≥6 in 'Risk stratification of SFT for development of metastasis' introduced in The 5th edition of the WHO(World Health Organization) Soft tissue sarcoma classification.
• Sarcoma without protruding across the diaphragm
• Possibility of R0/R1 resection evaluated through preoperative MDT(multi-disciplinary team) discussion
• No multi-organ or system dysfunction/failure or patients with slight dysfunction of organ/system could be easily recovered
• Tolerable of chemotherapy and surgery through MDT evaluation and tests.
• American Society of Anesthesiologist (ASA) ≤3
• Fully understand the informs and consent to participate in the study.

Exclusion Criteria:

• Sarcoma confirmed originating from the GI tract, uterus, or urinal tract.
• Patients included in the study through preoperative biopsy or MDT discussion, with WDLPS, grade 1 LPS, or other types of tumors not mentioned in the Inclusion criteria evaluating through final pathological findings.
• Sarcoma protruded into the chest cavity evaluated through preoperative imaging or surgical reports.
• Metastasis confirmed pathologically or highly suspicious metastatic lesions through radiological findings, PET-CT(Positron emission tomography) is highly recommended, MDT discussion and evaluation are needed.
• Histories of administration of Anthracyclines, Ifosfamide, and targeted agents.
• Severe contradiction to surgery and chemotherapies, including persistent myelosuppression, myocardial/cerebral/pulmonary infarction, uncontrolled cardiac arrhythmia, etc within the last 6 months
• Indication of severe infection or undergoing surgeries with high-risk hemorrhages in one month.
• Persistent one or more organ or system dysfunctions, could not be recovered prior to the study.
• Female patients who are pregnant or breastfeeding or female and male patients of reproductive potential who are not willing to employ effective birth control methods.
• Patients with psychological conditions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: The Surgery only Group; Procedure: Radical resectional surgery	Procedure: Radical Surgery; Radical sarcoma resectional surgery
Experimental: The Neoadjuvant Therapy Group; Neoadjuvant chemotherapy + Target therapy+ Radical resectional Surgery Drugs: Doxorubicin（PLD） 40mg/㎡ d1, Ifosfamide 1g/㎡ d1-5, Anlotinib10mg d1-14 Q3weeks * 3 Circles, Watch-Wait 4-6 weeks	Procedure: Radical Surgery; Radical sarcoma resectional surgery; Drug: Doxorubicin+Ifosfamide+Anlotinib(AI+A); Doxorubicin（PLD） 40mg/㎡ d1, Ifosfamide（I） 1g/㎡ d1-5, Anlotinib（A）10mg d1-14 Q3weeks * 3 Circles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year Progression Free Survival(PFS)	Progression free survival will be measured from the date of surgery to the date of progression or death, whichever occurs first.	3 years after first patient enrolled in

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-year PFS	Progression free survival will be measured from the date of surgery to the date of progression or death, whichever occurs first.	1year after first patient enrolled in.
1 year Overall survival(OS)	OS will be measured from the date of surgery to the date of death, whatever the causes of death.	1year after first patient enrolled in
3-year OS	OS will be measured from the date of surgery to the date of death, whatever the causes of death.	3 years after first patient enrolled in
5-year PFS	Progression free survival will be measured from the date of surgery to the date of progression or death, whichever occurs first.	5 years after first patient enrolled in.
5-year OS	OS will be measured from the date of surgery to the date of death, whatever the causes of death.	5 years after first patient enrolled in
Safety and toxicity of neoadjuvant therapy	Safety and toxicity will be evaluated through blood tests, echocardiography, ECG, etc.	1-d, 7-d after the first date of each neoadjuvant therapy session.
Postoperative morbidities	Operative outcomes including morbidities will be collected and compared in two groups.	30-d, 90-d, 1-year separately after the date of surgery.

Collaborators and Investigators

• Sponsor: Peking University International Hospital
• Collaborators: Peking University First Hospital; Beijing Friendship Hospital; Shanghai Zhongshan Hospital; First Affiliated Hospital Xi'an Jiaotong University; The Affiliated Hospital of Qingdao University; Shanghai Cancer Hospital, China
• Investigators: Study Chair: Chenghua Luo, MD, PhD, Peking University International Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Anticipated): November 1, 2025
• Study Completion (Anticipated): November 1, 2027

Study Registration Dates

• First Submitted: April 16, 2023
• First Submitted That Met QC Criteria: April 25, 2023
• First Posted (Actual): May 6, 2023

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Survival; Neoadjuvant therapy; Target therapy; Retroperitoneal Sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Ifosfamide; Doxorubicin
• Other Study ID Numbers: PKUIH-RPS01; Z221100007422042 (Other Grant/Funding Number: Beijing Municipal Science & Technology Commission, Administrative Commission of Zhongguancun Science Park)

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
• product manufactured in and exported from the U.S.: No