Pulmonary Resectable Metastases of Osteosarcoma With Anti-angiogenics and CHemotherapy

Osteosarcoma Clinical Trial

— PROACH  

Official title:

A Phase II Study of Gemcitabine-docetaxel Chemotherapy With Anti-angiogenic Therapy for Pulmonary Resectable Metastases of Osteosarcoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03742193
• Other study ID #: 2018LLS-NO.84-3
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 11, 2019
• Est. completion date: December 30, 2023

Study information

• Verified date: October 2023
• Source: Ruijin Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 43
• Est. completion date: December 30, 2023
• Est. primary completion date: November 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years to 50 Years

Eligibility

Inclusion Criteria:

• age between 10 and 50 years;
• diagnosis of histologically confirmed high grade osteosarcoma;
• identification of pulmonary metastases without the existence of local recurrence(previous re-resection of local recurrence with wide margin is allowed).
• resectable pulmonary nodule(s), defined as nodule(s) that are removable by wedge resection/ segmentectomy/lobectomy without necessitating a pneumonectomy (e.g., nodules immediately adjacent to the main stem bronchus or main pulmonary vessels)
• prior treatment consisted of standard National Comprehensive Cancer Network (NCCN) guideline recommended first-line chemotherapy
• wide/radical-margin surgical resection of the primary tumor completed at least 4 weeks before enrollment.
• Eastern Cooperative Oncology Group(ECOG) performance status 0-2 with a life expectancy >3 months;
• adequate renal, hepatic, and hemopoietic function;
• normal or controlled blood pressure;
• no thoracic comorbidities with adequate pulmonary function eligible for thoracic surgery

Exclusion Criteria:

• previously exposed to GD chemotherapy or VEGFR2 Tyrosine-kinase inhibitors (TKIs);
• existence of local recurrence;
• 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 or Hemorrhagic diseases ;
• metastases considered unresectable or borderline resectable at baseline
• intolerable of thoracis surgery
• pleural or peritoneal effusion that needs to be handled by surgical treatment;
• combined with other infections or wounds
• wound dystrophy, poor soft-tissue around implantation or other wound complications risky of non-healing given angiogenesis inhibitor assessed by the investigators

Related Conditions & MeSH terms

• Apatinib
• Neoplasm Metastasis
• Osteosarcoma
• Pulmonary Metastases

Intervention

Drug:
• Apatinib
Apatinib 250mg tablet by mouth, bid. 48 hrs break before and 96 hrs after the surgical resection of the pulmonary metastases.
• GD regimen
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.

Locations

Country	Name	City	State
China	Ruijin Hospital Shanghai Jiao Tong University School of Medicine	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Ruijin Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)	Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)
Other	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)
Other	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)
Other	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)
Other	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)
Other	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)
Other	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)
Primary	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
Secondary	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
Secondary	Total resectability	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
Secondary	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
Secondary	Objective response rate (ORR)	Complete Response(CR)+Partial Response(PR) after neoadjuvant systemic therapy	after neoadjuvant systemic therapy, an average of 8~9 weeks
Secondary	Clinical benefit rate (CBR)	CR+PR+stable disease (SD) after neoadjuvant systemic therapy	after neoadjuvant systemic therapy, an average of 8~9 weeks
Secondary	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)
Secondary	OS rate	the proportion of OS at 12, 24 months	12 and 24 months from baseline