Phase II Study of Irinotecan Liposome (II) Combined With Temozolomide and Fluzoparib in Recurrent or Metastatic Ewing Sarcoma

Single-center, Single-arm, Phase II Study of Irinotecan Liposome (II) Combined With Temozolomide and Fluzoparib in the Treatment of Recurrent or Metastatic Ewing Sarcoma

The current study is an investigator-initiated, single-arm phase 2 study that enrolled patients with recurrent and/or metastatic Ewing sarcoma for the treatment of Irinotecan Liposome (II) Combined with Temozolomide and Fluzoparib as the second-line treatment.

Study Overview

• Status: Recruiting
• Conditions: Ewing Sarcoma
• Intervention / Treatment: Drug: irinotecan liposome (II) + temozolomide + fluzoparib

Detailed Description

This study is a single-center, single-arm, phase II study evaluating the efficacy and safety of irinotecan liposome (II) combined with temozolomide and fluzoparib in the treatment of recurrent or metastatic ewing sarcoma which progressed on 1st line chemotherapy. Eligible patients will be included in this study and treated according to the protocol. Study treatment will be continued until disease progression, unacceptable toxicity, or patient's decision/consent withdrawal. Local investigators will determine disease progression, radiologic or clinical deterioration. A Simon Two-Stage design will enroll approximately 13 patients into Stage 1, and if criteria are met to move to Stage 2, an additional 16 patients will be enrolled.

PRIMARY OBJECTIVE:

I. To assess the antineoplastic efficacy of irinotecan liposome (II) combined with temozolomide and fluzoparib in the treatment of recurrent or metastatic Ewing sarcoma, as measured by the objective response rate (ORR).

SECONDARY EFFICACY OBJECTIVES:

I. To determine the disease control rate (DCR) for irinotecan liposome (II) combined with temozolomide and fluzoparib in the treatment of recurrent or metastatic Ewing sarcoma.

II. To calculate the duration of response (DOR) for irinotecan liposome (II) combined with temozolomide and fluzoparib in the treatment of recurrent or metastatic Ewing sarcoma.

III. To measure median progression-free survival (PFS) in recurrent or metastatic Ewing sarcoma patients who have received irinotecan liposome (II) combined with temozolomide and fluzoparib.

VI. To measure median overall survival (OS) in recurrent or metastatic Ewing sarcoma patients who have received irinotecan liposome (II) combined with temozolomide and fluzoparib.

SECONDARY SAFETY OBJECTIVE:

I. To assess the toxicity profile of irinotecan liposome (II) combined with temozolomide and fluzoparib in the treatment of recurrent or metastatic Ewing sarcoma according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

Exploratory OBJECTIVE:

I. To explore the relationship between mutations and expression of DNA Homologous Recombination Repair (HRR) related genes (such as BRCA1/2, PALB2, etc.) and clinical efficacy (such as ORR, DoR, etc.), as well as resistance mechanisms.

• Study Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jin Wang, MD; Phone Number: 86+020-87343190; Email: wangjinr@sysucc.org.cn
• Study Contact Backup: Name: Chuanghzong Deng, MD; Phone Number: 86+020-87340519; Email: dengchzh@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun Yat-sen University Cancer Center
      • Contact: Email: dengchzh@sysucc.org.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

-1. Patients aged 18 to 75 years (calculated as of the date of signing the informed consent), regardless of gender.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 3. Histologically confirmed advanced or metastatic Ewing sarcoma, with at least one measurable lesion that has not been treated locally (according to RECIST v1.1, this measurable lesion must have a maximum diameter of ≥ 10 mm on spiral CT scans or a short diameter of ≥ 15 mm for enlarged lymph nodes).

4. The primary tumor or locally recurrent tumor cannot be completely resected through surgery or other local treatments (e.g., stereotactic radiosurgery, argon-helium knife, ultrasound-guided focused ultrasound, etc.); first-line chemotherapy (VAC/IE) has failed, leading to distant metastasis, and the metastatic tumors cannot be completely resected through surgery or other local treatments; or the patient refuses surgery or other local treatments.

5. Expected survival of ≥ 12 weeks. 6. Basic normal function of major organs, with severe abnormalities in blood, heart, lung, liver, kidney, bone marrow functions, or immune deficiency diseases meeting protocol requirements:

1. Complete Blood Count (CBC): (No blood transfusion, use of Granulocyte-Colony Stimulating Factor [G-CSF], or corrective therapy within 14 days prior to screening)

   - Hemoglobin ≥ 90 g/L;

   • Neutrophil count ≥ 1.5 × 10^9/L;
   • Platelet count ≥ 75 × 10^9/L;

2. Biochemical Tests: (No albumin infusion within 14 days)

   • Albumin ≥ 29 g/L;
   • Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal (ULN);
   • Total bilirubin (TBIL) ≤ 1.5 times ULN;
   • Creatinine (Cr) ≤ 1.5 times ULN or Cr clearance > 50 mL/min (Cockcroft-Gault formula):
   • Male: Cr clearance = ((140 - age) × weight) / (72 × blood Cr)
   • Female: Cr clearance = ((140 - age) × weight) / (72 × blood Cr) × 0.85
   • Weight in kg; blood Cr in mg/mL;
   • Urinary protein < 2+ (if urinary protein ≥ 2+, a 24-hour urine protein quantification can be performed, with < 1.0 g in 24 hours allowing for inclusion);
3. Coagulation Function: Activated partial thromboplastin time (APTT) and International Normalized Ratio (INR) ≤ 1.5 × ULN (patients on stable doses of anticoagulants like low molecular weight heparin or warfarin, with INR within the expected therapeutic range, can be screened);
4. Thyroid Function: Thyroid-Stimulating Hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be evaluated, with normal levels allowing for inclusion;

5. Echocardiogram: Left ventricular ejection fraction (LVEF) ≥ 60%. 7. Non-surgically sterile or premenopausal female patients must use a medically approved contraceptive method (such as an intrauterine device, contraceptive pills, or condoms) during the study treatment period and for 6 months after the end of study treatment; non-surgically sterile premenopausal females must have a negative serum or urine HCG test within 7 days prior to study enrollment and must not be breastfeeding; male patients with female partners of childbearing potential should use effective contraception during the study and for 6 months after the last dose of fluzoparib, liposomal irinotecan, or temozolomide.

   8. Understanding the study procedures and methods, voluntarily participating in this trial, and signing the informed consent form in writing, with a full understanding of the trial content, process, and potential adverse reactions.

   Exclusion Criteria:

   • 1. Plans to receive any other anti-tumor treatments during this trial. 2. Received radiotherapy for Ewing sarcoma within 4 weeks prior to the first administration of the study drug, or received other investigational drugs or cell therapies.

     3. Presence of intracranial tumor lesions diagnosed by imaging. 4. History of other active malignancies within the past 5 years, or currently having other active malignancies aside from Ewing sarcoma. Curatively treated localized tumors, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, prostate in situ carcinoma, cervical in situ carcinoma, and breast in situ carcinoma, are allowed.

     5. Presence of clinically symptomatic ascites requiring paracentesis or drainage, or having undergone paracentesis within the last 3 months; only those with small amounts of ascites detected by imaging but without clinical symptoms are excluded; uncontrolled or moderate to severe pleural effusion or pericardial effusion; evidence of intraperitoneal free air that cannot be explained by paracentesis or recent surgical procedures.

     6. History of epilepsy, or having experienced diseases that can induce seizures (including transient ischemic attacks, strokes-not just isolated imaging findings of cerebral ischemia without clinical history, or head trauma with loss of consciousness requiring hospitalization) within 12 months prior to the first administration of the study drug.

     7. Previous treatment with PARP inhibitors, irinotecan, temozolomide, including but not limited to fluzoparib.

     8. History of allergic reactions, including severe drug allergies or drug hypersensitivity; known allergies or intolerances to fluzoparib, liposomal irinotecan, temozolomide, or their excipients.

     9. Severe infections (CTCAE grade > 2) occurring within 4 weeks prior to the first administration of the study drug, such as severe pneumonia requiring hospitalization, bacteremia, or infections with complications; baseline chest imaging indicating active pulmonary inflammation, presence of infection symptoms and signs within 2 weeks before the first administration of the study drug, or requiring oral or intravenous antibiotic treatment (excluding prophylactic use of antibiotics).

     10. Cannot discontinue the use of medications that may affect P-glycoprotein (P-gp) during the study period.

     11. Use of strong or moderate inhibitors or inducers of hepatic drug-metabolizing enzyme CYP3A4 within 14 days prior to the first administration of the study drug.

     12. Presence of factors that impair swallowing, chronic diarrhea, bowel obstruction, or other factors affecting drug intake and absorption.

     13. History of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), or having had other malignancies within 5 years prior to the first administration of this study (with the exception of completely resolved in situ cancers and malignancies determined by the investigator to have slow progression).

     14. Co-infection with other viral infections (anti-HCV positive, anti-HIV positive, HBsAg positive) or syphilis infection.

     15. History of immune deficiency (including positive human immunodeficiency virus [HIV] test, other acquired or congenital immune deficiencies) or history of organ transplantation.

     16. Known history of abuse of psychotropic substances, alcoholism, or drug abuse.

     17. Any condition judged by the investigator to pose a significant risk to patient safety or to affect the patient's ability to complete the study (such as poorly controlled hypertension, severe diabetes, thyroid disease, and psychiatric disorders) or any other situation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: irinotecan liposome (II) + temozolomide + fluzoparib; irinotecan liposome (II) combined with temozolomide and fluzoparib

Drug: irinotecan liposome (II) + temozolomide + fluzoparib; Drug Irinotecan Hydrochloride Liposome Injection（II）56.5mg/m2, IV infusion administered on day 1 of every 28-day cycle until disease progression, unacceptable toxicity or death. Other names: HR070803. Drug Fluzoparib 50mg PO bid, administered continuously until disease progression, unacceptable toxicity or death. 28 days as a treatment cycle. Other names: SHR-3162. Drug Temozolomide 30mg/m2 PO qd, administered on day 1 to day 5 of every 28-day cycle until disease progression, unacceptable toxicity or death.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate(ORR)	Objective Response Rate(CR+PR), defined as best overall response (complete or partial response) across all assessment time points, determined using RECIST v1.1 criteria.	From Cycle 1 Day 1 (C1D1) to treatment discontinuation for any reason, average of 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate （DCR）	Percentage of patients whose BOR is assessed as CR, PR, or Stable Disease (SD)	From Cycle 1 Day 1 (C1D1) to treatment discontinuation for any reason, average of 4 months
Duration of Response （DoR）	The time between the date of the radiological evaluation that first confirmed CR or PR and the date of the radiation evaluation that first confirmed Progressive Disease (PD)	From first confirmed CR or PR to confirmed PD, average of 4 months
Progression Free Survival (PFS)	Time from C1D1 until the date of objective PD (as assessed by RECIST v1.1) or the date of death (by any cause in the absence of disease progression)	From Cycle 1 Day 1 (C1D1) to first documented objective PD or death if PD does not occur, average of 4 months
Overall Survival (OS)	Time from C1D1 until the date of death by any cause. Patients who are still alive at the time of the analysis, or who have become lost to follow-up or withdrawn consent will be censored at their last date known to be alive	From Cycle 1 Day 1 (C1D1) to death from any cause, average of 12 months
Incidence of Adverse Events [safety and tolerability]	Adverse events defined according to Common Terminology for Adverse Events (CTCAE) v5.0	From Cycle 1 Day 1 (C1D1) to 30 days after the last dose of study treatment

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: Jiangsu Hengrui Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Jin Wang, MD, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): February 1, 2028

Study Registration Dates

• First Submitted: February 10, 2025
• First Submitted That Met QC Criteria: February 13, 2025
• First Posted (Actual): February 14, 2025

Study Record Updates

• Last Update Posted (Actual): May 31, 2025
• Last Update Submitted That Met QC Criteria: May 27, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Ewing sarcoma; PARP; temozolomide; fluzoparib; irinotecan liposome
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma, Ewing; Sarcoma; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Irinotecan; Fluzoparib
• Other Study ID Numbers: B2024-859-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

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