A Phase III Trial of Recombinant Human Apo-2 Ligand for Injection

Study Overview
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Brief Summary
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The trial is to evaluate the efficacy and safety of recombinant human Apo-2 ligand in treating patients with advanced retreated non-small cell lung cancer

Official Title
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A Randomized, Double-blind, Placebo-controlled in Parallel, Multicenter Phase III Trial of Recombinant Human Apo-2 Ligand for Injection（Dulanermin for Injection）in the Treatment of Advanced Non-small Cell Lung Cancer

Conditions
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Non-small-cell Lung Cancer (NSCLC) Stage IV

Intervention / Treatment
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* Biological: Recombinant human Apo-2 ligand for Injection
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18 to 75 years old Pathologically diagnosed advanced non-small cell lung cancer (stage Ⅳ) with measurable lesions (diameter of tumor lesions displayed on CT scan ≥ 10 mm; short diameter of lymph node lesions on CT scan ≥ 15 mm; and no radiotherapy, radiofrequency ablation or other local treatment has been given to such measurable lesions) Patients with negative EGFR or ALK gene-sensitive mutations or unknown status and with treatment failure or recurrence after previously undergoing the treatment with two chemotherapy regimens (at least one platinum-containing two-drug regimen included) Patients with positive EGFR-TKI or ALK-TKI gene-sensitive mutations and with treatment failure or recurrence after previously undergoing one platinum-containing chemotherapy regimen may be included. Note that treatment given in neo-adjuvant therapy phase is not considered a part of the treatment regimen; however, if recurrence occurred within 6 months after the end of adjuvant therapy, the adjuvant therapy is considered a part of the treatment regimen, and if not within such 6 months, the adjuvant therapy is not considered a part of the treatment regimen. The term treatment failure is defined as: (1) progression presents in the course of treatment or after the last treatment with evidence of definitive imaging or clinical progression; (2) patients withdrawn from standard treatment due to inability to tolerate adverse events of grade IV and above hematological toxicity, of grade II and above non-hematological toxicity or of grade II and above major organ damage, such as heart, liver and kidney according to NCI-CTCAE Version 4.0. ECOG status 0-1 Expected survival ≥ 3 months Patients recovered from damages caused by other treatment given to them (≤ grade 1 according to NCI-CTCAE version 4.0); the interval of nitrosourea or mitomycin given was ≥ 6 weeks; the interval of other cytotoxic drugs, Avastin, radiotherapy or surgery was ≥ 4 weeks; and the interval of EGFR TKI molecular targeted drugs was ≥ 2 weeks Major organs function normally, e.g. the following criteria are met (1) Blood routine tests shall comply with the criteria as follows (no transfusion of blood or blood products within 14 days, no correction with G-CSF and other hematopoietic stimulating factors): Hemoglobin（HB） ≥ 90 g/L Absolute neutrophil count（ANC） ≥ 1.5 × 10（9）/L Platelets（PLT ）≥ 80 × 10（9）/L (2) Biochemical test shall comply with the criteria as follows: Total bilirubin（TBIL） < 1.5 × upper limit of normal（ULN） Alanine aminotransferase （ALT） and aspartate aminotransferase（AST） <2.5 × ULN; and < 5 × ULN for patients with liver metastases Serum Cr ≤ 1.25 × ULN or endogenous creatinine clearance > 45 ml / min (Cockcroft-Gault formula) Female patients at a childbearing age must have taken reliable contraceptive measures or received pregnancy test (either by serum or urine) showing a negative result within 7 days before inclusion and are willing to take appropriate contraceptive measures during the trial and in the following 8 weeks after the last administration of the test drug. Male patients shall agree to take appropriate contraceptive measures or have undergone surgical sterilization during the trial and in the following 8 weeks after the last administration of the test drug Subjects shall participate in the study out of their own will, sign the informed consent, have good compliance, and cooperate with follow-up - Exclusion Criteria: Small cell lung cancer (including small cell carcinoma and mixed non-small cell lung cancer) Patients who have a definitive history of severe allergy to biological products Patients with active (without medical control) brain metastases, cancer meningitis, spinal cord compression, or with brain or leptomeninges disorders identified in CT or MRI examination in the inclusion process (however, patients with brain metastases who have completed treatment 21 days prior to the randomization and maintained symptomatic stability may be included) Patients with Grade II and above myocardial ischemia or myocardial infarction and poorly controlled arrhythmia (including male patients with QTc interval ≥ 450 ms and female patients with QTc interval ≥ 470 ms) Patients with Grade III to IV heart dysfunction according to NYHA or left ventricular ejection fraction (LVEF) <50% identified in cardiac ultrasound examination Patients with persistent bradycardia and positive results in the atropine test Patients with diseases concerning hemorrhagic tendency Dropsy of serous cavity (including pleural effusion, ascites, and pericardial effusion) presenting clinical symptoms and requiring medical treatment Patients with active hepatitis B or hepatitis C Patients with active infection requiring anti-microbial treatment (such as antibiotics, antiviral drugs, and antifungal drugs) Patients with a history of psychotropic drug abuse and failure to get rid of those drugs or who have mental disorders Patients who have participated in other clinical trials regarding anti-tumor drugs within 4 weeks prior to randomization Long-term users of adrenal cortex hormones or immunosuppressive agents Patients with a history of or suffering from other non-cured malignancies, except for cured skin basal cell carcinoma, cervical carcinoma in situ and superficial bladder cancer Pregnant or breastfeeding women; fertile patients who are unwilling or unable to take effective contraceptive measures Patients with positive skin test results for injection of recombinant human Apo-2 ligand Other conditions as the researcher consider that may have impacts on the performance of the clinical trial and interpretation of results -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant human Apo-2 ligand<br>Recombinant human Apo-2 ligand for Injection | Biological: Recombinant human Apo-2 ligand for Injection<br>* 150μg/kg/d IV (in the vein), on day 1 to 7 of each 21 day cycle<br>* Other names: Dulanermin for injection;|
| Placebo Comparator: Placebo<br>Mimetic agent for recombinant human Apo-2 ligand for injection | Biological: Placebo<br>* 150μg/kg/d IV (in the vein), on day 1 to 7 of each 21 day cycle<br>* Other names: Mimetic for recombinant human Apo-2 ligand for injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival（OS） | Survival information may be obtained via telephone contact with the patient, patients family or by checking the patients notes, hospital records, contacting the patients general practitioner or public death registry, where it is possible to do so under applicable local laws. | From the date of randomization until the date of death from any cause, Assessed up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression - free survival（PFS） | Progression Free Survival (PFS) : the time from start of study treatment to the first documentation of objective disease progression (PD) or death from any cause. | From date of randomization until the date of first documented progression or the date of death from any cause, whichever came first, evaluate once every six weeks (± 7 days) and assessed up to 36 months | 
| Objective Response Rate (ORR) | Objective response rate: the percentage of subjects who have at least one visit response of CR or PR prior to any evidence of progression | Every 6 weeks (± 7 days) up to 36 months | 
| Disease Control Rate (DCR) | Disease control rate: the percentage of subjects who have at least one visit response of CR or PR or SD prior to any evidence of progression. | Every 6 weeks (± 7 days) up to 36 months | 
| Quality of Life (QoL) |  | An evaluation is made every 3 weeks and until 30 days after the last medication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, Non-Small-Cell Lung, Carcinoma, Bronchogenic, Bronchial Neoplasms, Lung Neoplasms, Thoracic Neoplasms, Neoplasms, Lung Diseases, Antineoplastic Agents, Cytokines, Antineoplastic Agents, Biological activity factor, Genetic Engineering, Molecular Mechanisms of Pharmacological Action, Physiological Effects of Drugs