Apatinib for Advanced Osteosarcoma After Failure of Standard Multimodal Therapy

Study Overview
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Brief Summary
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After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades.Thus, the investigators explored apatinib activity in patients with relapsed and unresectable osteosarcoma after the failure of first-line or second-line chemotherapy. Patients >16 years, progressing after standard treatment, were eligible to receive 500 mg or 750 mg of apatinib once daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months and objective response rate (ORR). Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety.

Detailed Description
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Patients Eligible patients should have the following characteristics: age >16 years; diagnosis of high-grade osteosarcoma confirmed histologically and reviewed centrally; prior treatment (completed >4 weeks before trial entry) consisted of standard high-grade osteosarcoma chemotherapy agents including doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide; metastatic relapsed and unresectable progressive disease (PD); Eastern Cooperative Oncology Group performance status 0-1 with a life expectancy >3 months; adequate renal, hepatic, and hemopoietic function. Additionally, the investigators require normal or controlled blood pressure, as well as surgery and/or radiotherapy completion at least 1 month before enrollment. All enrolled patients showed radiological evidence of disease progression and the lesion could be evaluated according to RECIST 1.1 before treatment start. Treatment Patients are planned to be treated with a dose of apatinib 500 mg(BSA ≤1.5) or 750mg(BSA>1.5) once daily. The dose was reduced or temporarily suspended according to predefined rules and after considering any observed toxicity, which was assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Following adverse event resolution, apatinib can be restarted at the maximally tolerated dose and continued until progression, unacceptable toxicity or patient refusal. The study was approved by participating hospital review boards, and conducted according to the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice guidelines. Each patient provided written informed consent. Efficacy Assessment Before starting treatment, patients should be staged with chest and abdomen computed tomography (CT) and magnetic resonance imaging (MRI) (whenever indicated by the clinical situation). And all those patients should be tested by Immunohistochemistry of the VEGFR-2 over-expression of the paraffin embedded samples of the lesion or mRNA testing VEGFR-2 over-expression of the fresh specimen. Baseline assessment included also full blood count, serum chemistry, electrocardiogram and physical examination. In light of its potential role in osteosarcoma response assessment, [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) is suggested but not mandated for patient enrollment, and its impact on tumor response assessment was purely exploratory. All tests were repeated after 2 months and, thereafter, at 2-month intervals unless there were toxic effects or disease progression suspicion. Response was assessed by CT/MRI scan according to RECIST 1.1. Thus, both complete and partial remission needed confirmation within 4 weeks of when a response was first demonstrated. Stable disease (SD) was confirmed after a minimum of 8 weeks. The investigators thoroughly probe for and record any sign(s) of treatment-induced improvement, be it minor response (MR) as tumor shrinkage <30%, and/or nondimensional tumor responses including Hounsfield unit measured tissue density changes or osteoid matrix calcification. The primary end point progression-free survival (PFS) at 4 months is calculated from the date of treatment start until the time of disease progression or death, whichever came first. Patients alive and free from progression would be censored. Secondary end points included the following: PFS; OS; overall response rate, defined as complete responses (CRs) + partial responses (PRs) + MRs; disease control rate (overall response rate + SDs); patterns of nondimensional response; clinical benefit rate (CBR) (PFS rate at 4 months) and duration of response. Duration of response is calculated from the day of first response assessment until either progression/death (event) or last day of follow-up (censored). Last, the investigators evaluate any clinical improvement by means of the Pain Analgesic Score via the Brief Pain Inventory (BPI) score form that was filled in by patients themselves. Analgesic medication use was recorded according to the analgesic score: 0 = none; 1 = minor analgesics; 2 = tranquillizers, antidepressants, muscle relaxants and steroids; 3 = mild narcotics; 4 = strong narcotics.

Official Title
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A Phase II Trial of Apatinib in Relapsed and Unresectable High-grade Osteosarcoma After Failure of Standard Multimodal Therapy

Conditions
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Osteosarcoma, Metastasis

Intervention / Treatment
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* Drug: apatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age >16 years; diagnosis confirmed histologically and reviewed centrally; prior treatment (completed >4 weeks before trial entry) consisted of standard high-grade osteosarcoma chemotherapy agents including doxorubicin, cisplatin, high- dose methotrexate, and ifosfamide; metastatic relapsed and unresectable progressive disease (PD); Eastern Cooperative Oncology Group performance status 0-1 with a life expectancy >3 months; adequate renal, hepatic, and hemopoietic function; normal or controlled blood pressure; surgery and/or radiotherapy completion at least 1 month before enrollment. Exclusion Criteria: no pulmonary artery or venous tumor embolus; previously exposed to other TKIs; central nervous system metastasis; have had other kinds of malignant tumors at the same time; cardiac insufficiency or arrhythmia; uncontrolled complications, such as diabetes mellitus and so on; coagulation disorders; urine protein≥ ++; pleural or peritoneal effusion that needs to be handled by surgical treatment; combined with other infections or wounds.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: apatinib<br>apatinib 750mg tablet or 500mg tablet by mouth, Qd half an hour after dinner | Drug: apatinib<br>* Apatinib is a small-molecule VEGFR tyrosine kinase inhibitor, similar to vatalanib (PTK787), but with a binding affinity 10 times that of vatalanib or sorafenib.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival, PFS | calculated from the date of treatment start until the time of disease progression or death, whichever comes first. | 4 months | 
| Objective response rate, ORR | CR+PR at 3 months | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival, OS | calculated from the date of treatment start until last follow-up or death, whichever comes first. | 12 months | 
| Clinical benefit rate, CBR | CR+PR+SD at 6 months | 6 months | 
| Duration of response, DOR | Duration of response is calculated from the day of first response assessment until either progression/death (event) or last day of follow-up (censored). | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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osteosarcoma, metastasis, advanced, apatinib