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The aim of this study is to evaluate the efficacy and safety of Second-line chemotherapy combined with Apatinib for the patients with resectable pulmonary metastasis of osteosarcoma.
After standard chemotherapy and surgery for the localized disease, pulmonary metastases of osteosarcoma occurs in up to 40% of cases and still remain challenging without satisfactory regimen. Apatinib is a oral kinase inhibitor of receptor tyrosine targeting VEGFR2. A pilot study indicated that Apatinib improved the PFS after multi-line chemotherapy failure, and might partly reversed chemo-refractory status for advanced osteosarcoma. Thus, the investigators explored the efficacy of combining Apatinib with current available second-line chemotherapy compared to chemotherapy alone for treating first resectable pulmonary metastases of osteosarcoma following the failure of first-line chemotherapy and wide/radical-margin surgery. Participants will receive 250 mg of apatinib twice daily combined with gemcitabine-docetaxel (GD) regimen before and after the surgical resection of the pulmonary metastases. Osteosarcoma patients with pulmonary recurrence only at baseline will be recruited in the study. The primary end point is progression-free survival rate (PFR) compared with historical control. A12 month PFR of 30% or less is considered inactive, while a 12 month PFR of 50% or greater is regarded as of interest for additional development. With a type I error rate of 5% and a power of 83%, the number of patients needed for this design is 43.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Apatinib + GD group | Experimental | Apatinib + GD regimen. For unilateral metastases,3 cycles before metastasectomy, and 4 cycles after. For bilateral metastases, 3 cycles before first metastasectomy, 1 cycle inbetween, and then second metastasectomy followed by 4 cycles. Apatinib monotherapy is then maintained until 1 year following complete resection. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Apatinib | Drug | Apatinib 250mg tablet by mouth, bid. 48 hrs break before and 96 hrs after the surgical resection of the pulmonary metastases. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 12 months Progression-free survival rate(12mPFR) | The proportion of patients with progression-free survival at 12 months according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). A 12mPFR of 30% or less is considered inactive, while a 12mPFR of 50% or greater is regarded as of interest for additional development | 12 months from the recruitment of the study |
| Measure | Description | Time Frame |
|---|---|---|
| Overall survival (OS) | calculated from the date of treatment start until last follow-up or death, whichever comes first. | Baseline until death, followed through study completion, an average of 2 years |
| Total resectability |
| Measure | Description | Time Frame |
|---|---|---|
| Exploratory outcome: Subgroup analysis of progression-free survival(PFS) | The PFS for each subgroups in terms of clinicopathological characteristics (age, gender, histological type, solitary or multiple metastases, unilateral or bilateral metastases, early or late metastases, calcifying or non-calcifying lesions, with or without lesion cavitation, with or without AEs [especially pneumothorax, hand-foot skin reactions, hair depigmentation], etc) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Weibin Zhang, PhD, MD | Ruijin Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ruijin Hospital Shanghai Jiao Tong University School of Medicine | Shanghai | Shanghai Municipality | 200025 | China |
The data of IPD is available to researcher's upon reasonable request, in accordance to the local legislator's policy ( such as genetic sequencing data)
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| ID | Term |
|---|---|
| D012516 | Osteosarcoma |
| ID | Term |
|---|---|
| D018213 | Neoplasms, Bone Tissue |
| D009372 | Neoplasms, Connective Tissue |
| D018204 | Neoplasms, Connective and Soft Tissue |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| C553458 | apatinib |
| D004358 | Drug Therapy |
| ID | Term |
|---|---|
| D013812 | Therapeutics |
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An Independent radiologic reviewing committee assess the radiological tumor response in a blinded manner. Data Safety and Monitoring Board (DSMB) access the outcome in the interim analysis and final analysis
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| GD regimen | Drug | One cycle: gemcitabine 900 mg/m^2 over 90 min on Day 1, and gemcitabine 900 mg/m^2 and docetaxel 75 mg/m^2 on Day 8. Every 21 days were eligible. 1~2 -week break before and 2-week break after the surgical resection of the pulmonary metastases is taken. |
|
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The number of patients undergoing pre-planned metastasectomy divided by the number of patients considered resectable at baseline
| after neoadjuvant systemic therapy, an average of 8~9 weeks |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | The occurrence of each adverse events(AEs), severe AEs(SAEs) and death according the CTCAE_5.0 | through study completion, an average of 1 years |
| Objective response rate (ORR) | Complete Response(CR)+Partial Response(PR) after neoadjuvant systemic therapy | after neoadjuvant systemic therapy, an average of 8~9 weeks |
| Clinical benefit rate (CBR) | CR+PR+stable disease (SD) after neoadjuvant systemic therapy | after neoadjuvant systemic therapy, an average of 8~9 weeks |
| Progression free survival (PFS) | Progression free survival according to RECIST 1.1 | Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) |
| OS rate | the proportion of OS at 12, 24 months | 12 and 24 months from baseline |
| Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) |
| Exploratory outcome: The correlation of potential pathological biomarker with PFS | The correlation between the expression of VEGFR2, CD34, Ki-67 and immune cell infiltration by immunohistochemistry and PFS | Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) |
| Exploratory outcome: Tumor response pre-metastasectomy as a predictor of PFS | to compare the PFS of the three group according to tumor response pre-metastasectomy (group1: CR/PR, group2: SD, group3 PD) | Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) |
| Exploratory outcome: Tumor cavitation as a prognostic factor for oncological outcome | to compare the predictive value of the Crabb's modified RECIST criteria with the original RECIST 1.1 criteria in terms of PFS and OS | Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) |
| Exploratory outcome: AEs of the targeted therapy as prognostic factors for oncological outcome, especially pulmonary lesion cavitation/pneumothorax and hair depigmentation | to correlate the incidence of targeted therapy related AEs （especially pneumothorax, hand foot skin reactions, skin and hair depigmentation and fatigue）with the PFS/OS for the treatment arm. | Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) |
| Correlation of KDR 604 polymorphism with pulmonary lesion cavitation/pneumothorax and with PFS | According to our previous retrospective analysis, we aim the validate the correlation of KDR 604 AA，AG，GG genotype with the incidence of pulmonary lesion cavitation/pneumothorax and PFS among all patients. | Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) |
| Exploratory outcome: 1.0-mm CT scan for the early identification small lung nodule as pulmonary recurrence | to compare the diagnostic value of the 1.0 mm versus 5.0 mm CT scan for the radiological evaluation of small lung nodule as tumor recurrence | Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) |
| D009369 | Neoplasms |
| D012509 | Sarcoma |