Pulmonary Resectable Metastases of Osteosarcoma With Anti-angiogenics and CHemotherapy (PROACH)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Pulmonary Metastases; Osteosarcoma; Apatinib
• Intervention / Treatment: Drug: Apatinib; Drug: GD regimen

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Ruijin Hospital Shanghai Jiao Tong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Apatinib + GD group; 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.

Drug: Apatinib; Apatinib 250mg tablet by mouth, bid. 48 hrs break before and 96 hrs after the surgical resection of the pulmonary metastases.; Other Names: VEGFR Inhibitor; Drug: 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.; Other Names: Chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

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.	Baseline until death, followed through study completion, an average of 2 years
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
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
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
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

Other Outcome Measures

Outcome Measure	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)	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)

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Investigators: Principal Investigator: Weibin Zhang, PhD, MD, Ruijin Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2019
• Primary Completion (Estimated): November 15, 2023
• Study Completion (Estimated): December 30, 2023

Study Registration Dates

• First Submitted: September 25, 2018
• First Submitted That Met QC Criteria: November 14, 2018
• First Posted (Actual): November 15, 2018

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 29, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Processes; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Neoplasm Metastasis; Osteosarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Apatinib
• Other Study ID Numbers: 2018LLS-NO.84-3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No