Feasibility Study of Interval Compressed Regimen Using Four-drugs for Osteosarcoma

Study Overview
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Brief Summary
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The aim of the study is to test the feasibility of four-drug, interval-compressed regimen in osteosarcoma. Primary objective is to explore the toxicity and mortality related to treatment. Secondary objectives are to examine tumor necrosis rates after neoadjuvant chemotherapy, and to evaluate the usefulness of circulating cell-free DNA, survivin, or transforming growth factor-beta1 levels as well as programmed cell death ligand 1 expression in tumor specimen as a predictive or prognostic biomarker in osteosarcoma patients.

Detailed Description
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In this study, the investigators will investigate the feasibility of interval compressed regimen using four-drugs in newly-diagnosed osteosarcoma patients. Four drugs will be adriamycin, high-dose methotrexate, cisplatin, ifosfamide. All these drugs will be given preoperatively in an interval-compressed schedule, but postoperatively at a regular interval. Neoadjuvant therapy will be composed of two courses, and adjuvant therapy of two or three courses depending on necrosis rates following neoadjuvant therapy.

Official Title
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Feasibility Study of Interval Compressed Regimen Using Four-drugs for Osteosarcoma

Conditions
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Osteosarcoma, Feasibility, Treatment Response, Biomarker

Intervention / Treatment
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* Drug: Poor responder group adjuvant chemotherapy
* Drug: Good responder group adjuvant chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed osteosarcoma patients under age 40 years. Exclusion Criteria: Patients who don't meet the organ function criteria as follows; renal function : CCr or GFR or eGFR ≥ 70 mL/min/1.73 m2 liver function : AST/ALT ≤ 5 x upper limit, total bilirubin ≤ 1.5 x upper limit of normal for age cardiac function : shortening fraction ≥ 24% or ejection fraction ≥ 50% (Echo) lung function : No dyspnea on rest, If dyspnea exists, SpO2 95% or more in room air by pulse oximetry, hematologic : ANC ≥ 750/uL and platelet ≥ 75,000/uL

Ages Eligible for Study
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Maximum Age: 40 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: four-drug interval-compressed regimen<br>Interventions for 'four-drug interval-compressed regimen': Drug: methotrexate, cisplatin, doxorubicin, ifosfamide. Newly diagnosed oseteosarcoma patients under 40 years are eligible. Neoadjuvant chemotherapy with four drugs in an interval-compressed schedule will be done as a single arm. Duration of neoadjuvant chemotherapy will be 10 weeks like that of conventional three-drug regimen, although four-drugs are employed in the current protocol. After tumor resection operation, participants will be divided to poor responder group and good responder group based on 90% necrosis rate of a tumor specimen. Poor responder group and will be assigned to 'Poor responder group adjuvant chemotherapy' and good responder will be assigned to 'Good responder group adjuvant chemotherapy'. | Drug: Poor responder group adjuvant chemotherapy<br>* Poor responder group (necrosis ≤ 90%) : week 0, 7 and 14, doxorubicin; week 2, 9 and 16, ifosfamde, week 4, 11, 18 and 19, methotrexate; wk 5, 12 and 20 B. Resection of tumor C. Adjuvant chemotherapy Poor responder group (necrosis ≤ 90%) week 0, 7 and 14, doxorubicin; week 2, 9 and 16, ifosfamde, week 4, 11, 18 and 19, methotrexate; wk 5, 12 and 20 Good responder group (necrosis > 90%) week 0 and 8, doxorubicin; week 2 and 10, ifosfamide; week 4, 5, 12 and 13, methotrexate; week 6 and 14, cisplatin<br>* Other names: PR adjuvant four-drug interval-compressed regimen;Drug: Good responder group adjuvant chemotherapy<br>* Good responder group (necrosis > 90%) : week 0 and 8, doxorubicin; week 2 and 10, ifosfamide; week 4, 5, 12 and 13, methotrexate; week 6 and 14, cisplatin<br>* Other names: GR adjuvant four-drug interval-compressed regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity determined according to CTCAE | treatment-related toxicity (organ dysfunction, neutropenic fever, infection, mortality, et al.) | Until study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tumor necrosis rate | necrosis rate of the excised tumor after neoadjuvant chemotherapy | Until study completion, an average of 3years | 
| Predictive or prognostic biomarker | Usefulness of circulating cell-free DNA, survivin, transforming growth factor-beta1 levels and programmed cell death 1 expression in tumor specimen as a biomarker | Until study completion, an average of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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four-drugs, interval-compression