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Apatinib Plus Anti-PD1 Therapy for Advanced Osteosarcoma (APFAO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03359018
Recruitment Status : Completed
First Posted : December 2, 2017
Last Update Posted : May 19, 2020
Sponsor:
Collaborator:
Jiangsu HengRui Medicine Co., Ltd.
Information provided by (Responsible Party):
Peking University People's Hospital

Brief Summary:

After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. We have already finished a prospective trial about apatinib for advanced osteosarcoma(NCT02711007) and find it has a objective response rate of aproximately 45% with median progression-free survival around 5 months. Thus, the investigators explored apatinib activity together with anti-PD1 therapy in order to induce durable response in patients with relapsed and unresectable osteosarcoma after the failure of first-line or second-line chemotherapy.

Apatinib is a small-molecule vascular endothelial growth factors receptor (VEGFR) tyrosine kinase inhibitor, similar to pazopanib, but with a binding affinity 10 times to VEGFR-2 comparing with pazopanib or sorafenib.

SHR-1210 is a humanized anti-PD-1 monoclonal antibody.


Condition or disease Intervention/treatment Phase
Progression-free Survival Overall Survival Clinical Benefit Rate Toxicity Drug: Apatinib Drug: SHR-1210 Phase 2

Detailed Description:
Patients more than 11 years with body surface area more than 1.2m2, progressing after standard treatment, will be eligible to receive 250 or 500 mg of apatinib once daily together with SHR-1210 3mg/kg (no more than 200mg) iv every 2 weeks until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months and overall survival(OS). Secondary objectives were clinical benefit rate (CBR), defined as no progression at 6 months and safety.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 43 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Every patients will received apatinib 500mg or 250mg orally daily and SHR-1210 3mg/kg (no more than 200mg) iv every 2 weeks until disease progression or intolerance to side effects
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Apatinib Mesylate Plus Anti-PD1 Therapy (SHR-1210) in Locally Advanced, Unresectable or Metastatic Osteosarcoma(APFAO)Refractory to Chemotherapy : a Single Institution, Open-label, Phase 2 Trial
Actual Study Start Date : January 1, 2018
Actual Primary Completion Date : October 22, 2019
Actual Study Completion Date : January 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: apatinib plus anti-PD1 therapy arm
Every patients will received apatinib 250mg or 500mg orally daily and SHR-1210 3mg/kg (no more than 200mg) iv every 2 weeks until disease progression or intolerance to side effects.
Drug: Apatinib
Every patients will received apatinib 250mg or 500mg orally daily according to their body surface area (BSA) until disease progression or intolerance to side effects.

Drug: SHR-1210
Every patients will received SHR-1210 3mg/kg (no more than 200mg) iv every 2 weeks until disease progression or intolerance to side effects.




Primary Outcome Measures :
  1. progression-free survival [ Time Frame: up to approximately 24months ]
    Progression-free survival is defined as time from enrollment to the first occurrence of progression of disease or death from any cause within 63 days of last response assessment.

  2. clinical benefit rate [ Time Frame: up to approximately 24months ]
    clinical benefit rate is defined as the proportion of patients who achieve disease control (objective response and stable disease according to RECIST 1.1).


Secondary Outcome Measures :
  1. overall survival [ Time Frame: up to approximately 5 years ]
    overall survival is defined as the duration from date of enrollment to the date of death from any cause.



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Ages Eligible for Study:   11 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age more than or equal to 11 years;
  • diagnosis confirmed histologically and reviewed centrally;
  • prior treatment (completed >4 weeks before trial entry) consisted of standard high-grade osteosarcoma chemotherapy agents including doxorubicin, cisplatin, high- dose methotrexate, and ifosfamide; metastatic relapsed and unresectable progressive disease (PD);
  • having measurable lesion according to RECIST 1.1;
  • Eastern Cooperative Oncology Group performance status 0-1 with a life expectancy >3 months;
  • Patients must have adequate organ function (without blood transfusion, without growth factor or blood components support within 14 days before enrollment)as determined by: Hemoglobin ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥1.5×109/L; Platelet count ≥ 75×109/L (for patients with advanced hepatocellular carcinoma), Platelet count ≥ 100×109/L (for patients with advanced gastric cancer); serum albumin ≥2.8 g/dL; serum total bilirubin (TBIL)≤1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×upper limit of normal(ULN), for subjects with liver metastases, ALT and AST≤5×ULN; Calculated creatinine clearance (CrCl) > 50 mL/min (Cockcroft-Gault formula will be used to calculate CrCl).
  • normal or controlled blood pressure;
  • Females of childbearing potential (FOCBP), who are not surgically sterile or postmenopausal, must conduct pregnancy test (serum or urine) within 7 days before enrollment, and must not be pregnant or breast-feeding women.
  • surgery and/or radiotherapy completion at least 1 month before enrollment.
  • Joining the study voluntarily with good compliance.

Exclusion Criteria:

  • Patients must not have had prior treatment with camrelizumab or any other PD-L1 or PD-1 antagonists.
  • Patients with any active autoimmune disease or history of autoimmune disease, including but not limited to the following: hepatitis, pneumonitis, uveitis, colitis (inflammatory bowel disease), hypophysitis, vasculitis, nephritis, hyperthyroidism, and hypothyroidism, except for subjects with vitiligo or resolved childhood asthma/atopy. Asthma that requires intermittent use of bronchodilators or other medical intervention should also be excluded.
  • Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids. Doses > 10 mg/day prednisone or equivalent are prohibited within 2 weeks before study drug administration. Note: corticosteroids used for the purpose of IV contrast allergy prophylaxis are allowed.
  • Known history of hypersensitivity to any components of the camrelizumab formulation, or other antibody formulation.
  • Active central nervous system (CNS) metastases with clinical symptoms (including cerebral edema, steroid requirement, or progressive disease). Subjects with brain or meningeal metastases that were previously treated must be clinically stable (magnetic resonance imaging [MRI] at least 4 weeks apart do not show evidence of new or enlarging metastases) and have discontinued immunosuppressive doses of systemic steroids (> 10 mg/day prednisone or equivalent) for at least 2 weeks before study drug administration.
  • Patients with other malignant tumor (except cured skin basal cell carcinoma and cervical carcinoma).
  • Clinically significant cardiovascular and cerebrovascular diseases, including but not limited to severe acute myocardial infarction within 6 months before enrollment, unstable or severe angina, or coronary artery bypass surgery, Congestive heart failure (New York heart association (NYHA) class > 2), ventricular arrhythmia which need medical intervention, left ventricular ejection fraction(LVEF) < 50%.
  • Hypertension and unable to be controlled within normal level following treatment of anti-hypertension agents(within 3 months): systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg.
  • Coagulation abnormalities (PT>16s、APTT>43s、TT>21s、Fbg<2g/L), with bleeding tendency or are receiving thrombolytic or anticoagulant therapy.
  • Active infection or an unexplained fever > 38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, subjects with tumor fever may be enrolled).
  • Previous experience abdomen fistula, gastrointestinal perforation, or abdominal abscess within 4weeks.
  • Objective evidence of previous or current pulmonary fibrosis history, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, pulmonary function damaged seriously etc.
  • History of immunodeficiency including seropositivity for human immunodeficiency virus (HIV), or other acquired or congenital immune-deficient disease, or active hepatitis (transaminase does not meet the inclusion, hepatitis B virus (HBV) DNA ≥10⁴ /ml or hepatitis C virus (HCV) RNA≥103 /ml or higher); Chronic hepatitis B virus carriers who HBV DNA<2000 IU/ml(<104/ml), must receive anti-viral treatment throughout the study.
  • Any other medical, psychiatric, or social condition deemed by the investigator to be likely to interfere with a subject's rights, safety, welfare, or ability to sign informed consent, cooperate, and participate in the study or would interfere with the interpretation of the results.

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): NCT03359018


Locations
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China
Musculoskeletal Tumor Center of Peking University People's Hospital
Beijing, China, 100044
Peking University Shougang Hospital
Beijing, China, 100144
Sponsors and Collaborators
Peking University People's Hospital
Jiangsu HengRui Medicine Co., Ltd.
Investigators
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Principal Investigator: Wei Guo, M.D.and Ph.D. Musculoskeletal Tumor Center of Peking University People's Hospital
  Study Documents (Full-Text)

Documents provided by Peking University People's Hospital:
Study Protocol  [PDF] December 2, 2017

Publications of Results:
Other Publications:
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Responsible Party: Peking University People's Hospital
ClinicalTrials.gov Identifier: NCT03359018    
Other Study ID Numbers: PKUPH-sarcoma 02
First Posted: December 2, 2017    Key Record Dates
Last Update Posted: May 19, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: all collected IPD, all IPD that underlie results in a publication
Supporting Materials: Study Protocol
Time Frame: from completion of the study to study publication

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Peking University People's Hospital:
osteosarcoma
advanced
apatinib
PD-1
Additional relevant MeSH terms:
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Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Apatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action