Pegylated Liposomal Doxorubicin Versus Pirarubicin Plus Ifosfamide, Dacarbazine in Locally Advanced, Unresectable or Metastatic Soft-tissue Sarcoma

Study Overview
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Brief Summary
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Advanced soft tissue sarcoma patients who have previously recieved anthracyclines might still benefit from doxorubicin, ifosfamide and dacarbazine. However doxorubicin might be stopped using because of chronic cumulative heart toxicity. Several efforts have been made to improve the toxicity profile of conventional anthracyclines, including the use of liposomal encapsulation technology and the development of novel anthracycline analogs,such as pegylated liposomal doxorubicin and pirarubicin. However their actual effectiveness and toxicity have not been studied in prospective trial. The purpose of the study is to investigate whether they are available for this group of patients.

Detailed Description
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We design this multicentre, open-label, randomised, phase 2 trial at 5 academic hospitals in China. Eligible patients need to be aged 16 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy will be available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Participants will be randomly assigned (1:1) to receive pegylated liposomal doxorubicin (60 mg/m² via continuous intravenous infusion for 4-6 h on day 1 of every 21-day cycle for up to six cycles) or pirarubicin (30 mg/m2/d continuous intravenous infusion for 3h on day 1 and 2 of every 21-day cycle for up to six cycles) plus ifosfamide ( 2 g/m²/d intravenously for 2h on day 2,3 and 4 of every 21-day cycle for up to six cycles), dacarbazine (300 mg/m²/d intravenously for 2h on day 2,3 and 4 of every 21-day cycle for up to six cycles ).After six cycles of treatment, patients will be followed up expectantly whereas patients with stable or responsive disease are allowed to continue with ifosfamide and dacarbzine until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, drug administration method, and previous systemic therapy. Patients and investigators will not be masked to treatment assignment. The primary endpoint is progression survival, analysed in the intention-to-treat population. Safety analyses will be done in all patients who receive any amount of study drug.

Official Title
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Comparing the Effectiveness and Toxicity for Locally Advanced, Unresectable or Metastatic Soft-tissue Sarcoma Patients Who Had Received Total Dose of Anthracycline Antibiotics More Than 300mg/m2 With Pegylated Liposomal Doxorubicin Versus Pirarubicin Plus Ifosfamide, Dacarbazine, a Multicentre, Open-label, Randomised Phase 2 Trial

Conditions
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Progression-free Survival, Overall Survival, Toxicity

Intervention / Treatment
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* Drug: pegylated liposomal doxorubicin
* Drug: pirarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 16 years or older; diagnosis of an advanced unresectable or metastatic soft tissue sarcoma, of intermediate or high grade, for which no standard curative therapy is available; cumulative dose of anthracycline antibiotic ≥ 300mg/m2; stable or responsive to doxorubicin, potential beneficiary; an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, a life expectancy of at least 3 months; measurable disease according to RECIST 1.1; adequate end-organ and haemopoietic function. Exclusion Criteria: progress over doxorubicin; previous mediastinal or cardiac radiotherapy; a low-grade tumour according to standard grading systems (eg, American Joint Committee on Cancer grade 1 and 2 or Fédération Nationale des Centres de Lutte Contre le Cancer grade 1); significant cardiac dysfunction; severe chronic obstructive pulmonary disease; a known infection with HIV or active infection with hepatitis B or hepatitis C; known brain metastases unless previously treated and well controlled for a period of 3 months or longer; combination with other anti-tumor therapy; pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomly assigned (1:1) to receive pegylated liposomal doxorubicin (50 mg/m² on day 1 of every 21-day cycle for up to six cycles) or pirarubicin (60 mg/m² on day 1 of every 21-day cycle for up to six cycles) plus ifosfamide (2 g/m²/d d2-4 of every 21-day cycle for up to six cycles) and dacarbazine (300 mg/m²/d d2-4 of every 21-day cycle for up to six cycles).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>participants will recieve pegylated liposomal doxorubicin (50 mg/m²d1) plus ifosfamide (2 g/m²/d d2-3), dacarbazine (300 mg/m²/d d2-3). | Drug: pegylated liposomal doxorubicin<br>* Several efforts have been made to improve the toxicity profile of conventional anthracyclines, including the use of liposomal encapsulation technology,such as pegylated liposomal doxorubicin.<br>|
| Placebo Comparator: Arm B<br>participants will recieve pirarubicin (60 mg/m²d1) plus ifosfamide (2 g/m²/d d2-3), dacarbazine (300 mg/m²/d d2-3). | Drug: pirarubicin<br>* Another effort has been made to improve the toxicity profile of conventional anthracyclines is the development of novel anthracycline analogs,such as pirarubicin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival | Progression-free survival is defined as time from randomisation to the first occurrence of progression of disease or death from any cause within 63 days of last response assessment or randomisation. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival | overall survival is defined as the duration from date of randomisation to the date of death from any cause. | 12 months | 
| objective response rate, ORR | objective response rate includes complete and partial responses as defined by RECIST version 1.1. | 12 weeks | 
| left ventricular ejection fraction function | We use ultrasound to routinely estimate the left ventricular ejection fraction function. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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soft tissue sarcoma, pegylated liposomal doxorubicin, pirarubicin, toxicity for heart, cumulative dose