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

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ClinicalTrials.gov Identifier: NCT03742193
Recruitment Status : Recruiting
First Posted : November 15, 2018
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Weibin Zhang, MD, PhD., Ruijin Hospital

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 first resectable pulmonary metastasis of osteosarcoma.

Condition or disease Intervention/treatment Phase
Osteosarcoma Pulmonary Metastases Apatinib Drug: Apatinib Drug: GD regimen Phase 2

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 were randomized to an active control arm and an intervention arm in a 1:1 ratio. The experiment group 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 (PFS) .

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 188 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
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
Primary Purpose: Treatment
Official Title: A Multi-center Randomized Controlled Phase II Study of Gemcitabine-docetaxel Chemotherapy With or Without VEGFR Inhibitor (Apatinib) for First Pulmonary Resectable Metastases of Osteosarcoma
Actual Study Start Date : March 11, 2019
Estimated Primary Completion Date : April 1, 2022
Estimated Study Completion Date : September 1, 2022

Resource links provided by the National Library of Medicine


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 Name: 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.

Backbone GD chemotherapy is allowed to be shortened or omitted for both arms for late metastasis(disease-free interval no less than 18 months) with solitary lesion, according each center's practice, but has to remain constant throughout the trial.

Other Name: Chemotherapy

Active Comparator: GD group
GD regimen For unilateral metastases,3 cycles before metastasectomy, and 4 cycles after. For bilateral metastases, 3 cycles before first metastasectomy, 1 cycle in between, and then second metastasectomy followed by 4 cycles
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.

Backbone GD chemotherapy is allowed to be shortened or omitted for both arms for late metastasis(disease-free interval no less than 18 months) with solitary lesion, according each center's practice, but has to remain constant throughout the trial.

Other Name: Chemotherapy




Primary Outcome Measures :
  1. Progression-free survival(PFS) [ Time Frame: Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) ]
    Progression-free survival according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Baseline until death, followed through study completion, an average of 2 years ]
    calculated from the date of treatment start until last follow-up or death, whichever comes first.

  2. Total resectability [ Time Frame: after neoadjuvent systemic therapy, an average of 8~9 weeks ]
    The number of patients undergoing pre-planned metastasectomy divided by the number of patients considered resectable at baseline

  3. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: through study completion, an average of 2 years ]
    The occurrence of each adverse events(AEs), severe AEs(SAEs) and death according the CTCAE_5.0

  4. Objective response rate (ORR) [ Time Frame: after neoadjuvent systemic therapy, an average of 8~9 weeks ]
    Complete Response(CR)+Partial Response(PR) after neoadjuvent systemic therapy

  5. Clinical benefit rate (CBR) [ Time Frame: after neoadjuvent systemic therapy, an average of 8~9 weeks ]
    CR+PR+stable disease (SD) after neoadjuvent systemic therapy

  6. PFS rate [ Time Frame: 3 and 6 months from baseline ]
    the proportion of PFS at 3, 6 months according to RECIST 1.1

  7. OS rate [ Time Frame: 12 and 24 months from baseline ]
    the proportion of OS at 12, 24 months


Other Outcome Measures:
  1. Exploratory outcome: Subgroup analysis of progression-free survival(PFS) [ Time Frame: Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) ]
    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)

  2. Exploratory outcome: The correlation of potential pathological biomarker with PFS [ Time Frame: Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) ]
    The correlation between the expression of VEGFR2, CD34, Ki-67 and immune cell infiltration by immunohistochemistry and PFS for the experimental arm

  3. Exploratory outcome: Tumor response pre-metastasectomy as a predictor of PFS [ Time Frame: Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) ]
    to compare the PFS of the three group according to tumor response pre-metastasectomy (group1: CR/PR, group2: SD, group3 PD)

  4. Exploratory outcome: Tumor cavitation as a prognostic factor for oncological outcome [ Time Frame: Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) ]
    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

  5. Exploratory outcome: AEs of the targeted therapy as prognostic factors for oncological outcome [ Time Frame: Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) ]
    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.

  6. Exploratory outcome: the pattern of disease progression between the two arms [ Time Frame: Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) ]
    to compare the distribution of pulmonary versus extrapulmonary disease progression as well as the growth pattern of tumor (proportion) between the two arms

  7. Exploratory outcome: 1.0-mm CT scan for the early identification small lung nodule as pulmonary recurrence [ Time Frame: Baseline until disease progression or death, whichever occurs first (followed through study completion, an average of 1.5 years) ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   10 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03742193


Contacts
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Contact: Weibin Zhang, PhD, MD +8613501824630 zhangweibin10368@163.com
Contact: Yuhui Shen, PhD, MD +8613918209875 yuhuiss@163.com

Locations
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China, Shanghai
Ruijin Hospital Shanghai Jiao Tong University School of Medicine Recruiting
Shanghai, Shanghai, China, 200025
Contact: Weibin Zhang, Ph.D., M.D.    +8613501824630    zhangweibin10368@163.com   
Contact: Yuhui Shen, Ph.D., M.D.    +8613918209875    yuhuiss@163.com   
Principal Investigator: Weibin Zhang, Ph.D., M.D.         
Principal Investigator: Yuhui Shen, Ph.D., M.D.         
Sub-Investigator: Qin He, Ph.D., M.D.         
Sub-Investigator: Shizhao Zang, Ph.D., M.D.         
Sub-Investigator: Qiyuan Bao, Ph.D., M.D.         
Sub-Investigator: Junxiang Wen, Ph.D., M.D.         
Sub-Investigator: Yuehao Hu, Ph.D., M.D.         
Sponsors and Collaborators
Ruijin Hospital
Investigators
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Principal Investigator: Weibin Zhang, PhD, MD Ruijin Hospital

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Responsible Party: Weibin Zhang, MD, PhD., Professor, Ruijin Hospital
ClinicalTrials.gov Identifier: NCT03742193     History of Changes
Other Study ID Numbers: RJ2018AT1
First Posted: November 15, 2018    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Neoplasm Metastasis
Sarcoma
Osteosarcoma
Neoplastic Processes
Neoplasms
Pathologic Processes
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Gemcitabine
Apatinib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors