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Pulmonary Resectable Metastases of Osteosarcoma With Apatinib and CHemotherapy (PROACH)

Primary Purpose

Osteosarcoma, Pulmonary Metastases, Apatinib

Status
Active
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Apatinib
GD regimen
Sponsored by
Ruijin Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Osteosarcoma

Eligibility Criteria

10 Years - 50 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Ruijin Hospital Shanghai Jiao Tong University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Apatinib + GD group

Arm Description

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.

Outcomes

Primary Outcome Measures

12 months Progression-free survival rate(12mPFR)
The proportion of paitents 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

Secondary Outcome Measures

Overall survival (OS)
calculated from the date of treatment start until last follow-up or death, whichever comes first.
Total resectability
The number of patients undergoing pre-planned metastasectomy divided by the number of patients considered resectable at baseline
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
Objective response rate (ORR)
Complete Response(CR)+Partial Response(PR) after neoadjuvent systemic therapy
Clinical benefit rate (CBR)
CR+PR+stable disease (SD) after neoadjuvent systemic therapy
Progression free survival (PFS)
Progression free survival according to RECIST 1.1
OS rate
the proportion of OS at 12, 24 months

Full Information

First Posted
September 25, 2018
Last Updated
February 12, 2023
Sponsor
Ruijin Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03742193
Brief Title
Pulmonary Resectable Metastases of Osteosarcoma With Apatinib and CHemotherapy
Acronym
PROACH
Official Title
A Phase II Study of Gemcitabine-docetaxel Chemotherapy With VEGFR Inhibitor (Apatinib) for Pulmonary Resectable Metastases of Osteosarcoma
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 11, 2019 (Actual)
Primary Completion Date
July 1, 2023 (Anticipated)
Study Completion Date
December 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ruijin Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Osteosarcoma, Pulmonary Metastases, Apatinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Masking Description
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
Allocation
N/A
Enrollment
43 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Apatinib + GD group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Apatinib
Other Intervention Name(s)
VEGFR Inhibitor
Intervention Description
Apatinib 250mg tablet by mouth, bid. 48 hrs break before and 96 hrs after the surgical resection of the pulmonary metastases.
Intervention Type
Drug
Intervention Name(s)
GD regimen
Other Intervention Name(s)
Chemotherapy
Intervention Description
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.
Primary Outcome Measure Information:
Title
12 months Progression-free survival rate(12mPFR)
Description
The proportion of paitents 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
Time Frame
12 months from the recruitment of the study
Secondary Outcome Measure Information:
Title
Overall survival (OS)
Description
calculated from the date of treatment start until last follow-up or death, whichever comes first.
Time Frame
Baseline until death, followed through study completion, an average of 2 years
Title
Total resectability
Description
The number of patients undergoing pre-planned metastasectomy divided by the number of patients considered resectable at baseline
Time Frame
after neoadjuvent systemic therapy, an average of 8~9 weeks
Title
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Description
The occurrence of each adverse events(AEs), severe AEs(SAEs) and death according the CTCAE_5.0
Time Frame
through study completion, an average of 1 years
Title
Objective response rate (ORR)
Description
Complete Response(CR)+Partial Response(PR) after neoadjuvent systemic therapy
Time Frame
after neoadjuvent systemic therapy, an average of 8~9 weeks
Title
Clinical benefit rate (CBR)
Description
CR+PR+stable disease (SD) after neoadjuvent systemic therapy
Time Frame
after neoadjuvent systemic therapy, an average of 8~9 weeks
Title
Progression free survival (PFS)
Description
Progression free survival according to RECIST 1.1
Time Frame
Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)
Title
OS rate
Description
the proportion of OS at 12, 24 months
Time Frame
12 and 24 months from baseline
Other Pre-specified Outcome Measures:
Title
Exploratory outcome: Subgroup analysis of progression-free survival(PFS)
Description
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)
Time Frame
Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)
Title
Exploratory outcome: The correlation of potential pathological biomarker with PFS
Description
The correlation between the expression of VEGFR2, CD34, Ki-67 and immune cell infiltration by immunohistochemistry and PFS
Time Frame
Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)
Title
Exploratory outcome: Tumor response pre-metastasectomy as a predictor of PFS
Description
to compare the PFS of the three group according to tumor response pre-metastasectomy (group1: CR/PR, group2: SD, group3 PD)
Time Frame
Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)
Title
Exploratory outcome: Tumor cavitation as a prognostic factor for oncological outcome
Description
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
Time Frame
Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)
Title
Exploratory outcome: AEs of the targeted therapy as prognostic factors for oncological outcome, especially pulmonary lesion cavitation/pneumothorax and hair depigmentation
Description
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.
Time Frame
Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)
Title
Correlation of KDR 604 polymorphism with pulmonary lesion cavitation/pneumothorax and with PFS
Description
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.
Time Frame
Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)
Title
Exploratory outcome: 1.0-mm CT scan for the early identification small lung nodule as pulmonary recurrence
Description
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
Time Frame
Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
10 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Weibin Zhang, PhD, MD
Organizational Affiliation
Ruijin Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ruijin Hospital Shanghai Jiao Tong University School of Medicine
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200025
Country
China

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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)

Learn more about this trial

Pulmonary Resectable Metastases of Osteosarcoma With Apatinib and CHemotherapy

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